Toxoplasmosis

Infectious Disease MONDO:0005989 Pathograph 27 Show in embeddings browser Protozoal infection Zoonosis Opportunistic infection

Toxoplasmosis is a zoonotic protozoal infection caused by the obligate intracellular apicomplexan parasite Toxoplasma gondii, which can invade any nucleated cell of any warm-blooded animal. Felids are the only definitive hosts, shedding environmentally resistant oocysts; humans acquire infection by ingesting oocysts from contaminated soil, water or produce, or tissue cysts in undercooked meat. Acute infection is asymptomatic or self-limiting in immunocompetent hosts, but tachyzoites convert to slow-growing bradyzoites inside tissue cysts that persist for life in brain, retina and muscle. Loss of T-cell and interferon-gamma-dependent control permits cyst recrudescence, producing necrotizing toxoplasmic encephalitis in immunocompromised people and recurrent retinochoroiditis even in the immunocompetent. Primary maternal infection in pregnancy can be transmitted transplacentally, causing congenital toxoplasmosis with retinochoroiditis, cerebral calcification and hydrocephalus.

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Classifications

Harrison's Part

◆

Subtypes

Acute acquired toxoplasmosis in the immunocompetent host

Postnatally acquired infection in an immunocompetent host. Usually asymptomatic; when symptomatic, the dominant manifestation is benign, self-limited lymphadenopathy of the head and neck. No subtype_term is bound: MONDO carries dedicated terms for the congenital, ocular and cerebral forms but none for postnatally acquired immunocompetent toxoplasmosis, which is covered by the parent term MONDO:0005989 already on this entry.

Show evidence (1 reference)

PMID:3326123 SUPPORT Human Clinical

"Lymphadenopathy is the most frequent clinical manifestation of acute acquired infection with Toxoplasma in the immunocompetent individual."

Defines the dominant clinical presentation of the acquired immunocompetent form.

Congenital toxoplasmosis MONDO:0005715

Fetal infection following primary maternal infection in pregnancy. Most infected newborns are asymptomatic at birth but remain at risk of late sequelae; overt disease comprises retinochoroiditis, cerebral calcification, hydrocephalus and neurocognitive impairment.

Show evidence (1 reference)

PMID:35874584 SUPPORT Other

"When congenital infection is evident, disease include retinochoroiditis, cerebral calcifications, hydrocephalus, neurocognitive impairment."

Enumerates the defining manifestations of the congenital subtype.

Ocular toxoplasmosis (Toxoplasma retinochoroiditis) MONDO:0005879

Focal necrotizing retinochoroiditis arising from congenital or acquired infection, characteristically recurrent and the leading cause of posterior uveitis worldwide. Ocular toxoplasmosis is also curated as an infectious subtype of the Choroiditis entry, which carries the posterior-uveitis differential and the infectious-versus-autoimmune management fork; this entry models it as a manifestation of systemic T. gondii infection, and the two are complementary views of the same clinical entity.

Show evidence (1 reference)

PMID:36095008 SUPPORT Other

"Ocular toxoplasmosis is the leading cause of posterior uveitis worldwide"

Establishes ocular toxoplasmosis as a distinct and globally dominant clinical subtype.

Toxoplasmic encephalitis (reactivation disease in the immunocompromised) MONDO:0005697

Necrotizing encephalitis arising from recrudescence of latent cerebral tissue cysts when T-cell-dependent control is lost, most commonly in advanced HIV infection.

Show evidence (1 reference)

PMID:35694771 SUPPORT Other

"cerebral toxoplasmosis occurs solely due to the reactivation of a latent infection rather than a new infection."

Defines the reactivation subtype as recrudescence of latent infection rather than new acquisition.

Discussions and Knowledge Gaps

In ocular toxoplasmosis, how much of the retinal tissue destruction is caused by direct parasite cytolysis versus the host inflammatory response to recrudescing cysts, and what determines which patients suffer recurrent sight-threatening flares?

KNOWLEDGE GAP OPEN ocular_pathogenesis_uncertainty

Attached to

pathophysiology#Recurrent Necrotizing Retinochoroiditis

The balance between parasite-driven and immune-driven damage determines whether adjunctive corticosteroids help or harm, yet contemporary reviews state that the mechanisms of ocular involvement remain elusive and that treatment of active and recurrent disease is still unresolved. This entry therefore does not assert a dominant damage mechanism for the ocular node.

Proposed experiments

Paired intraocular parasite load and cytokine profiling across the flare cycle

exp_toxo_ocular_load_vs_cytokine

Measure aqueous and vitreous parasite load by quantitative PCR alongside intraocular cytokine profiling in the same eyes during active flares and in quiescence, to establish whether tissue destruction tracks parasite burden or inflammatory intensity.

Randomised adjunctive corticosteroid trial stratified by parasite load

exp_toxo_ocular_steroid_rct

Randomise patients with active retinochoroiditis to antiparasitic therapy with or without adjunctive corticosteroid, stratified by baseline intraocular parasite load, with lesion size and visual acuity as endpoints.

Show evidence (2 references)

PMID:39452769 SUPPORT Other

"Despite extensive research, the specific mechanisms underlying ocular involvement in T. gondii infection remain elusive, and current diagnostic options have limitations."

Directly documents the mechanistic gap this discussion records.

PMID:39452769 SUPPORT Other

"While existing therapies, such as antimicrobial agents and immunosuppressants, can control active infections, they do not offer a definitive cure or completely prevent recurrence."

Documents that neither antiparasitic nor immunosuppressive therapy resolves the recurrence problem.

No available drug eradicates bradyzoite tissue cysts, so chronic toxoplasmosis cannot be cured and reactivation risk persists for life. What would a cyst-active agent have to do, and does the BFD1 differentiation switch offer a tractable target?

KNOWLEDGE GAP OPEN no_cyst_active_therapy

Attached to

pathophysiology#Lifelong Latent Tissue Cyst Persistence pathophysiology#Bradyzoite Differentiation and Tissue Cyst Formation

Every current regimen acts on the replicating tachyzoite, which is why treatment of encephalitis must be followed by secondary prophylaxis until immune reconstitution. Identification of BFD1 as a master regulator of differentiation provides a genetic handle on the stage conversion that creates the untreatable reservoir.

Proposed experiments

Chemical screen against BFD1-driven differentiation

exp_toxo_bfd1_chemical_screen

Screen compound libraries for agents that block BFD1-driven bradyzoite differentiation, or that force bradyzoite-to-tachyzoite reversion into a drug-susceptible state, using the BFD1 genetic switch as the readout.

Cyst burden reduction and reactivation incidence in vivo

exp_toxo_cyst_burden_reactivation

Test whether pharmacological reduction of brain cyst burden in chronically infected animals lowers the incidence of encephalitis after subsequent immunosuppression.

Show evidence (2 references)

PMID:31955846 SUPPORT In Vitro

"Acute-stage tachyzoites differentiate into chronic-stage bradyzoites, which form intracellular cysts resistant to immune clearance and existing therapies."

Documents that existing therapies do not clear the cyst stage.

PMID:31955846 SUPPORT In Vitro

"BFD1 provides a genetic switch to study and control Toxoplasma differentiation and will inform prevention and treatment of chronic infections."

Supports BFD1 as the tractable handle proposed by this discussion.

Toxoplasma is treated with the same sequential DHFR/DHPS antifolate blockade that the bacterial_folate_synthesis_inhibition module models, but that module is explicitly scoped to bacteria. Should the module be generalised to eukaryotic-parasite antifolate targets, or should a separate protozoal module be created?

CURATION TODO OPEN antifolate_module_scope

Attached to

pathophysiology#Tachyzoite Replication and Haematogenous Dissemination

Pyrimethamine (DHFR) plus sulfadiazine (DHPS) is mechanistically the same sequential-blockade pattern the existing module encodes, and the same drug class treats malaria and Pneumocystis pneumonia. Declaring conformance from this entry would be a category error while the module's stated scope, node names and evidence are bacterial, so no conforms_to has been asserted here. Recording the parallel is more useful than either forcing conformance or silently dropping it.

Show evidence (1 reference)

PMID:26394212 SUPPORT Human Clinical

"such as spiramycin, azithromycin, traditional Chinese medicine (TCM), pyrimethamine- sulfadiazine (P-S), trimethoprim-sulfamethoxazole (TMP-SMX), and pyrimethamine-clindamycin (P-C)"

Confirms that the antifolate combinations named in this discussion are the conventional anti-Toxoplasma regimens, which is what makes the parallel to the bacterial antifolate module worth recording.

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Pathophysiology

Oral Ingestion of Oocysts or Tissue Cysts

Human infection begins with ingestion of environmentally resistant oocysts shed by felids (in soil, water or on crops) or of bradyzoite-containing tissue cysts in undercooked meat.

symbiont entry into host GO:0044409 ↑ INCREASED

Downstream

Intestinal Epithelial Invasion and Conversion to Tachyzoites Ingested parasite stages excyst and invade the gut wall.

Show evidence (1 reference)

PMID:33347832 SUPPORT Other

"being transmitted by ingestion of oocysts that are shed in the faeces of definitive feline hosts and contaminate water, soil and crops, or by consumption of intracellular cysts in undercooked meat from intermediate hosts."

Establishes both oral routes of entry as the initiating event.

Intestinal Epithelial Invasion and Conversion to Tachyzoites

Sporozoites and bradyzoites released in the gut lumen traverse the intestinal epithelium and convert to tachyzoites, the rapidly replicating stage that drives acute infection.

intestinal epithelial cell CL:0002563

symbiont entry into host cell GO:0046718 ↑ INCREASED

Downstream

Active Host Cell Invasion and Parasitophorous Vacuole Formation Tachyzoites propagate by repeated cycles of active host-cell invasion.

Show evidence (1 reference)

PMID:31827072 SUPPORT Other

"Oocysts or bradyzoites contained in the ingested cysts invade the host intestinal epithelium via the digestive tract wall and transform into tachyzoites."

Directly supports epithelial invasion and stage conversion.

Active Host Cell Invasion and Parasitophorous Vacuole Formation

Rather than being passively phagocytosed, the tachyzoite actively penetrates the host cell using microneme and rhoptry-neck adhesins (MIC, AMA and RON proteins) and establishes a parasitophorous vacuole, a replication-permissive compartment that the parasite remodels to control host cell function.

macrophage CL:0000235 dendritic cell CL:0000451

symbiont entry into host cell GO:0046718 ↑ INCREASED

symbiont-containing vacuole membrane GO:0020005

Downstream

Rhoptry and Dense Granule Effector-Mediated Immune Subversion Invasion co-delivers rhoptry and dense granule effectors that reprogram the infected cell.

Tachyzoite Replication and Haematogenous Dissemination Successful intracellular replication seeds systemic spread.

Show evidence (2 references)

PMID:36839525 SUPPORT Other

"During the parasitic invasion, T. gondii creates a parasitophorous vacuole, which enables the modulation of cell functions, allowing its replication and host infection."

Establishes vacuole formation as the basis of intracellular replication and host modulation.

PMID:36839525 SUPPORT Other

"They are involved with proteins secreted by micronemes and rhoptries (MIC, AMA, and RONs) that mediate the recognition and entry into host cells."

Names the secretory-organelle adhesins that mediate recognition and active entry.

Rhoptry and Dense Granule Effector-Mediated Immune Subversion

The parasite injects rhoptry (ROP) and dense granule (GRA) effectors that suppress host immunity and reprogram infected-cell gene expression. The polymorphic rhoptry kinase ROP18 is a principal virulence determinant, and the dense granule effector TgIST traffics to the host nucleus to shut down STAT1-dependent, interferon-gamma-driven transcription.

cellular response to type II interferon GO:0071346 ↓ DECREASED

Experimental models

Human cell culture single-cell transcriptomics of ROP/GRA effector injection PRIMARY CELL CULTURE Dissects which host transcriptional changes are attributable to injected ROP effectors versus MYR1-dependent GRA effectors.

Downstream

Interferon-Gamma-Dependent Cell-Autonomous Immune Control Effector-mediated subversion directly antagonises the IFN-gamma-driven killing programme, blunting clearance.

Show evidence (4 references)

PMID:35500831 SUPPORT Other

"The molecules released by T. gondii through rhoptries and dense granules not only act to suppress host immunity, but also to control gene expression in infected cells, thereby favouring the spread of infection."

States the dual immunosuppressive and transcription-reprogramming function of ROP/GRA effectors.

PMID:17170305 SUPPORT Model Organism

"Positional cloning identified the candidate virulence gene ROP18, a highly polymorphic serine-threonine kinase that was secreted into the host cell during parasite invasion."

Identifies ROP18 as a secreted rhoptry kinase virulence determinant.

PMID:17170305 SUPPORT Model Organism

"Transfection of the virulent ROP18 allele into a nonpathogenic type III strain increased growth and enhanced mortality by 4 to 5 logs."

Demonstrates causally that the ROP18 allele determines virulence in a mouse infection model.

+ 1 more reference

Tachyzoite Replication and Haematogenous Dissemination

Repeated cycles of invasion, replication and host cell lysis disseminate tachyzoites throughout the body, seeding immunoprivileged tissues including brain, retina and skeletal and cardiac muscle, and, in pregnancy, the placenta.

brain UBERON:0000955 retina UBERON:0000966 lymph node UBERON:0000029

Downstream

Interferon-Gamma-Dependent Cell-Autonomous Immune Control Disseminating parasites elicit the protective Th1/IFN-gamma response.

Toxoplasmic Lymphadenitis Regional lymph node involvement is the usual symptomatic expression of acute dissemination.

Transplacental Transmission and Fetal Dissemination During primary maternal infection, circulating tachyzoites can cross the placenta into the fetus.

Show evidence (1 reference)

PMID:33347832 SUPPORT Other

"an apicomplexan parasite that is able to infect any nucleated cell in any warm-blooded animal"

The unrestricted cellular tropism underlying multi-organ dissemination.

Interferon-Gamma-Dependent Cell-Autonomous Immune Control

Innate activation drives a Th1 response in which CD4- and CD8-positive T cells produce interferon-gamma. IFN-gamma induces a family of IFN-inducible GTPases that accumulate on the parasitophorous vacuole membrane and destroy the vacuole, clearing or arresting the parasite. This response is what restricts T. gondii to opportunistic status in healthy hosts, and its pressure is also what drives the parasite into the cyst stage.

CD4-positive, alpha-beta T cell CL:0000624 CD8-positive, alpha-beta T cell CL:0000625 macrophage CL:0000235

defense response to protozoan GO:0042832 ↑ INCREASED cellular response to type II interferon GO:0071346 ↑ INCREASED

Downstream

Bradyzoite Differentiation and Tissue Cyst Formation Immune pressure is the physiological stress that drives tachyzoite-to-bradyzoite conversion.

Show evidence (3 references)

PMID:31827072 SUPPORT Other

"host immune cells robustly produce the proinflammatory cytokine interferon-γ (IFN-γ), which activates a set of IFN-γ-inducible proteins, including GTPases."

Establishes IFN-gamma as the central effector cytokine and its induction of GTPases.

PMID:31827072 SUPPORT Other

"IFN-inducible GTPases are essential for cell-autonomous immunity and are specialized for effective clearance and growth inhibition of T. gondii by accumulating in parasitophorous vacuole membranes."

Describes the vacuole-targeting effector mechanism of cell-autonomous immunity.

PMID:31827072 SUPPORT Other

"Toxoplasma gondii is one of the most common infectious agents in humans but causes only opportunistic infection in healthy individuals."

Establishes that intact immunity confines the organism to opportunistic behaviour.

Bradyzoite Differentiation and Tissue Cyst Formation

Under stress, tachyzoites differentiate into slow-growing bradyzoites and form intracellular tissue cysts. The Myb-like transcription factor BFD1 is the master regulator of this switch: it accumulates during stress and is sufficient to drive differentiation. The resulting cysts resist both immune clearance and every currently available drug, which is why chronic infection is not curable.

neuron CL:0000540

Experimental models

Stress-induced bradyzoite differentiation in cell culture PRIMARY CELL CULTURE Provides a controllable in vitro readout of the tachyzoite-to-bradyzoite switch.

Downstream

Lifelong Latent Tissue Cyst Persistence Encystment establishes the lifelong reservoir.

Show evidence (2 references)

PMID:31955846 SUPPORT In Vitro

"Acute-stage tachyzoites differentiate into chronic-stage bradyzoites, which form intracellular cysts resistant to immune clearance and existing therapies."

Defines the differentiation event and the therapeutic intractability of the cyst.

PMID:31955846 SUPPORT In Vitro

"we identify a Myb-like transcription factor (BFD1) necessary for differentiation in cell culture and in mice."

Identifies BFD1 as necessary for bradyzoite differentiation in vitro and in vivo.

Lifelong Latent Tissue Cyst Persistence

Bradyzoite cysts persist indefinitely in immunoprivileged tissues, above all the brain and retina. This latent reservoir is clinically silent while T-cell-dependent surveillance is intact, and is the substrate for every later reactivation syndrome.

brain UBERON:0000955 retina UBERON:0000966

Downstream

Loss of T-Cell-Dependent Immune Surveillance When immune surveillance fails, cysts rupture and bradyzoites revert to tachyzoites.

Recurrent Necrotizing Retinochoroiditis Retinal cysts recrudesce episodically, producing the relapsing ocular disease seen even in immunocompetent hosts.

Show evidence (2 references)

PMID:36839525 SUPPORT Other

"It has effective strategies to escape the immune response and reach privileged immune sites and remain inactive in a controlled environment in tissue cysts."

Describes durable, quiescent persistence in immunoprivileged tissue.

PMID:31955846 SUPPORT Other

"its recrudescence can cause life-threatening disease in immunocompromised individuals and recurrent ocular lesions in the immunocompetent."

Establishes the latent reservoir as the source of both reactivation syndromes.

Loss of T-Cell-Dependent Immune Surveillance

Depletion of CD4-positive T cells (advanced HIV infection), transplant immunosuppression or chemotherapy removes the interferon-gamma-dependent surveillance that keeps tissue cysts quiescent. This is the host-side, organism-scale permissive condition; the parasite-side response to it is the separate Bradyzoite-to-Tachyzoite Reversion node.

CD4-positive, alpha-beta T cell CL:0000624

defense response to protozoan GO:0042832 ↓ DECREASED

Downstream

Bradyzoite-to-Tachyzoite Reversion and Cyst Rupture Withdrawal of immune pressure permits the encysted parasite to revert to the replicating stage.

Show evidence (3 references)

PMID:31827072 SUPPORT Other

"in immunocompromised individuals, such as AIDS patients, those undergoing chemotherapy and immunosuppressed tissue transplant patients, infection and reactivation can lead to chronic infection with T. gondii, potentially resulting in lethal encephalitis"

Names the immunosuppressive contexts that permit reactivation and lethal encephalitis.

PMID:35694771 SUPPORT Human Clinical

"It commonly manifests in PLWH with HIV viral load above 50 copies/ml and CD4+ cell counts <100/mm3"

Quantifies the degree of CD4 depletion at which control is lost.

PMID:22491772 SUPPORT Other

"the importance of reactivations of infections in immunocompromised patients were recognized later, in the era of organ transplantation and HIV infection"

Establishes reactivation in immunocompromised hosts as a distinct clinical problem tied historically to transplantation and HIV, the two settings this node models.

Bradyzoite-to-Tachyzoite Reversion and Cyst Rupture

Once immune restraint lifts, bradyzoites within tissue cysts revert to the rapidly replicating tachyzoite stage and the cyst ruptures, releasing parasites into surrounding tissue. This parasite-side, cell-scale event is what converts a lifelong silent reservoir into active disease.

symbiont entry into host cell GO:0046718 ↑ INCREASED

Downstream

Necrotizing Toxoplasmic Encephalitis Uncontrolled cerebral tachyzoite replication destroys brain parenchyma.

Show evidence (2 references)

PMID:31955846 SUPPORT Other

"its recrudescence can cause life-threatening disease in immunocompromised individuals and recurrent ocular lesions in the immunocompetent."

Identifies recrudescence of the encysted stage as the event producing both reactivation syndromes.

PMID:35694771 SUPPORT Other

"cerebral toxoplasmosis occurs solely due to the reactivation of a latent infection rather than a new infection."

Confirms reactivation of latency, not reinfection, as the mechanism.

Necrotizing Toxoplasmic Encephalitis

Recrudescent cerebral infection produces multifocal necrotizing encephalitis. The brain is a preferred site partly because of its low inflammatory reactivity. Lesions are typically multiple and ring-enhancing, concentrated at the grey-white matter junction and the thalamus-basal ganglia region, and the syndrome is a major cause of death in AIDS.

microglial cell CL:0000129 astrocyte CL:0000127

brain UBERON:0000955

Show evidence (2 references)

PMID:35694771 SUPPORT Other

"The brain is one of the predilections for T. gondii infection due to its low inflammatory reaction, and cerebral toxoplasmosis occurs solely due to the reactivation of a latent infection rather than a new infection."

Explains cerebral tropism and confirms the reactivation mechanism.

PMID:40785890 SUPPORT Human Clinical

"Toxoplasmic encephalitis (TE) is one of the most common opportunistic central nervous system infections in patients with acquired immunodeficiency syndrome (AIDS) and a major cause of death."

Establishes the clinical significance and lethality of the encephalitic outcome.

Recurrent Necrotizing Retinochoroiditis

Episodic recrudescence of retinal cysts produces focal necrotizing retinochoroiditis. Repeated flares accumulate chorioretinal scarring and cause potentially blinding complications; ocular toxoplasmosis is the leading cause of posterior uveitis worldwide.

retinal pigment epithelial cell CL:0002586

retina UBERON:0000966

Show evidence (2 references)

PMID:39452769 SUPPORT Other

"Ocular toxoplasmosis (OT), a severe manifestation of T. gondii infection, can lead to potentially blinding complications."

Establishes the sight-threatening nature of the ocular outcome.

PMID:36095008 SUPPORT Other

"Ocular toxoplasmosis is the leading cause of posterior uveitis worldwide"

Quantifies the global importance of the ocular manifestation.

Toxoplasmic Lymphadenitis

In the immunocompetent host, acute acquired infection most often manifests as lymphadenitis, typically a solitary node in the head and neck without systemic symptoms and with a benign course.

lymph node UBERON:0000029

Show evidence (1 reference)

PMID:3326123 SUPPORT Human Clinical

"Toxoplasmic lymphadenitis most frequently involved a solitary lymph node in the head and neck regions, without systemic symptoms or extranodal disease and with a benign clinical course."

Characterises the distribution and benign course of the lymphadenitic form.

Transplacental Transmission and Fetal Dissemination

During primary maternal infection, tachyzoites cross the placenta and disseminate in a fetus whose immune system cannot contain them. Transmission probability rises steeply through gestation while the severity of the resulting fetal disease falls, so the timing of maternal seroconversion sets both the risk and the phenotype.

trophoblast cell CL:0000351

placenta UBERON:0001987

Downstream

Fetal Neuroinflammatory Injury and Obstructive Hydrocephalus Fetal CNS infection produces the defining neurological lesions.

Show evidence (2 references)

PMID:35874584 SUPPORT Other

"The risk of mother-to-child transmission depends on week of pregnancy at the time of maternal infection: it is low in the first trimester, may reach 90% in the last days of pregnancy."

Quantifies gestational-age dependence of transmission.

PMID:35874584 SUPPORT Other

"Inversely, however, fetal disease is more severe when infection occurs early in pregnancy than later."

Establishes the inverse severity relationship that defines the congenital phenotype.

Fetal Neuroinflammatory Injury and Obstructive Hydrocephalus

Fetal cerebral infection causes necrotizing, inflammatory lesions that calcify and obstruct cerebrospinal fluid pathways, producing the characteristic combination of cerebral calcification, hydrocephalus and retinochoroiditis, with neurocognitive impairment as a long-term sequela.

brain UBERON:0000955

Show evidence (1 reference)

PMID:35874584 SUPPORT Other

"When congenital infection is evident, disease include retinochoroiditis, cerebral calcifications, hydrocephalus, neurocognitive impairment."

Enumerates the fetal CNS and ocular lesion set produced by congenital infection.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

Cardiovascular 1

Lymphadenopathy HP:0002716

Show evidence (2 references)

PMID:3326123 SUPPORT Human Clinical

"Lymphadenopathy is the most frequent clinical manifestation of acute acquired infection with Toxoplasma in the immunocompetent individual."

Establishes lymphadenopathy as the leading clinical manifestation of the acquired immunocompetent form. Rank only — this states no proportion, which is why no FrequencyEnum band is curated.

PMID:3326123 SUPPORT Human Clinical

"Toxoplasmic lymphadenitis most frequently involved a solitary lymph node in the head and neck regions"

Specifies the characteristic solitary head-and-neck nodal distribution.

Eye 1

Visual impairment HP:0000505

Course: PROGRESSIVE

Show evidence (2 references)

PMID:39452769 SUPPORT Other

"Ocular toxoplasmosis (OT), a severe manifestation of T. gondii infection, can lead to potentially blinding complications."

Supports sight-threatening visual loss as an outcome of ocular disease.

PMID:35874584 SUPPORT Other

"Congenitally infected newborns are usually asymptomatic at birth, but at risk for tardive sequelae, such as blindness."

Documents blindness as the archetypal late sequela of congenital infection.

Immune 1

Infectious encephalitis HP:0002383

Show evidence (2 references)

PMID:40785890 SUPPORT Human Clinical

"Toxoplasmic encephalitis (TE) is one of the most common opportunistic central nervous system infections in patients with acquired immunodeficiency syndrome (AIDS) and a major cause of death."

Establishes encephalitis as a leading and lethal opportunistic manifestation.

PMID:31827072 SUPPORT Other

"infection and reactivation can lead to chronic infection with T. gondii, potentially resulting in lethal encephalitis"

Confirms encephalitis as the lethal endpoint of reactivation in immunocompromised hosts.

Metabolism 1

Fever OCCASIONAL HP:0001945

Show evidence (1 reference)

PMID:40985660 SUPPORT Human Clinical

"Most reported symptoms were headache (n = 35, 56%), paresis (n = 18, 29%), fever (n = 18, 29%)"

Quantitative support for the phenotype and the OCCASIONAL band (29%, at the top of the 5-29% range).

Nervous System 5

Hydrocephalus HP:0000238

Show evidence (1 reference)

PMID:35874584 SUPPORT Other

"When congenital infection is evident, disease include retinochoroiditis, cerebral calcifications, hydrocephalus, neurocognitive impairment."

Lists hydrocephalus among the defining findings of evident congenital disease.

Neurocognitive impairment Intellectual disability HP:0001249

Show evidence (1 reference)

PMID:35874584 SUPPORT Other

"When congenital infection is evident, disease include retinochoroiditis, cerebral calcifications, hydrocephalus, neurocognitive impairment."

Lists neurocognitive impairment among the manifestations of overt congenital disease.

Headache FREQUENT HP:0002315

Show evidence (1 reference)

PMID:40985660 SUPPORT Human Clinical

"Most reported symptoms were headache (n = 35, 56%), paresis (n = 18, 29%), fever (n = 18, 29%)"

Direct quantitative support for both the phenotype and the FREQUENT band (56%, within the 30-79% range).

Hemiparesis OCCASIONAL HP:0001269

Show evidence (1 reference)

PMID:40985660 SUPPORT Human Clinical

"Most reported symptoms were headache (n = 35, 56%), paresis (n = 18, 29%), fever (n = 18, 29%)"

Quantitative support for the phenotype and the OCCASIONAL band (29%, at the top of the 5-29% range).

Seizure HP:0001250

Show evidence (1 reference)

PMID:40785890 SUPPORT Human Clinical

"The lesions predominantly presented with nodular and ring-enhancing patterns, mainly distributed at the gray-white matter junction and the thalamus-basal ganglia region."

Supports the anatomical basis for focal cortical and subcortical dysfunction. Recorded as PARTIAL because this imaging series documents lesion distribution rather than seizure occurrence itself.

Prenatal and Birth 1

Premature birth HP:0001622

Show evidence (1 reference)

PMID:22499837 SUPPORT Human Clinical

"NE-II serotype was more prevalent in certain demographics and associated with prematurity and severe disease at birth."

Associates congenital toxoplasmosis with prematurity in a 193-infant cohort.

Other 2

Chorioretinitis HP:0012424

Temporal: RECURRENT

Show evidence (2 references)

PMID:36095008 SUPPORT Other

"Ocular toxoplasmosis is the leading cause of posterior uveitis worldwide"

Establishes the ocular inflammatory phenotype as a dominant manifestation.

PMID:35874584 SUPPORT Other

"When congenital infection is evident, disease include retinochoroiditis, cerebral calcifications, hydrocephalus, neurocognitive impairment."

Lists retinochoroiditis first among the manifestations of overt congenital disease.

Cerebral calcification HP:0002514

Show evidence (1 reference)

PMID:35874584 SUPPORT Other

"When congenital infection is evident, disease include retinochoroiditis, cerebral calcifications, hydrocephalus, neurocognitive impairment."

Lists cerebral calcification among the defining findings of evident congenital disease.

🧬

Genetic Associations

NLRP1 (NALP1) inflammasome susceptibility alleles

Gene: NLRP1 hgnc:14374 relationship_type: SUSCEPTIBILITY

Show evidence (2 references)

PMID:21098108 SUPPORT Human Clinical

"In this study, susceptibility alleles for human congenital toxoplasmosis were identified in the NALP1 gene."

Identifies NALP1/NLRP1 as a human congenital-toxoplasmosis susceptibility locus.

PMID:21098108 SUPPORT In Vitro

"NALP1 silencing attenuated progression of T. gondii infection, with accelerated host cell death and eventual cell disintegration."

Functional knockdown evidence that the locus alters the intracellular course of infection.

Toxoplasma gondii clonal lineage structure (parasite genotype)

relationship_type: RISK_FACTOR

Show evidence (2 references)

PMID:7594717 SUPPORT Other

"Phylogenetic and statistical analyses indicated a highly unusual population structure consisting of 3 widespread clonal lineages."

Establishes the three-lineage clonal population structure of the parasite.

PMID:7594717 SUPPORT Human Clinical

"While strains from all 3 lineages were isolated from humans, the majority of human toxoplasmosis cases were associated with strains of a type II genotype."

Links lineage identity to the distribution of human disease.

Parasite serotype association with congenital disease severity

relationship_type: RISK_FACTOR

Show evidence (2 references)

PMID:22499837 SUPPORT Human Clinical

"NE-II serotype was more prevalent in certain demographics and associated with prematurity and severe disease at birth."

Associates parasite serotype with prematurity and severity in a 193-infant congenital cohort.

PMID:22499837 SUPPORT Human Clinical

"Both type II and NE-II infections improved with treatment."

Qualifies the association — serotype modifies severity but does not predict treatment failure.

💊

Medical Actions

Pyrimethamine-Sulfadiazine with Folinic Acid

Action: Pharmacotherapy NCIT:C15986

Agent: pyrimethamine CHEBI:8673 sulfadiazine CHEBI:9328

Standard combination antiparasitic therapy for active toxoplasmosis (toxoplasmic encephalitis, confirmed fetal infection, sight-threatening ocular disease). Pyrimethamine and the sulfonamide act sequentially on the parasite folate pathway; folinic acid is co-administered to mitigate pyrimethamine-induced marrow suppression. No regimen eradicates tissue cysts, so treatment suppresses rather than cures chronic infection.

Mechanism Target:

INHIBITS Tachyzoite Replication and Haematogenous Dissemination — Antifolate therapy suppresses the replicating tachyzoite stage; it has no activity against encysted bradyzoites.

Show evidence (1 reference)

PMID:31955846 SUPPORT Other

"chronic-stage bradyzoites, which form intracellular cysts resistant to immune clearance and existing therapies"

Establishes that available drugs act on the acute stage and not the cyst.

Show evidence (2 references)

PMID:35874584 SUPPORT Other

"If fetal infection is certain, the maternal treatment is changed to a combination of pyrimethamine-sulfonamide and folinic acid."

Documents the pyrimethamine-sulfonamide-folinic acid regimen for confirmed fetal infection.

PMID:26394212 SUPPORT Human Clinical

"The pooled CR with 95% CI was used to evaluate the overall rate of complete disappearance of clinical symptoms for toxoplasmic encephalitis after therapy"

Meta-analysis measuring cure rates for pyrimethamine-sulfadiazine and comparators in toxoplasmic encephalitis. Recorded as PARTIAL because the quotable sentence states the outcome measure rather than the numeric result.

Spiramycin in Maternal Infection

Action: Pharmacotherapy NCIT:C15986

Agent: spiramycin CHEBI:748977

Spiramycin is started as soon as maternal seroconversion is recognised, to reduce the risk of transmission to the fetus, and is switched to pyrimethamine-sulfonamide once fetal infection is confirmed.

Mechanism Target:

INHIBITS Transplacental Transmission and Fetal Dissemination — Spiramycin is given specifically to reduce mother-to-child transmission.

Show evidence (1 reference)

PMID:35874584 SUPPORT Other

"preventive treatment with spiramycin must be introduced as soon as possible to reduce the risk of mother-to-child transmission, and the severity of fetal infection."

States the transmission-reduction indication that this treatment targets.

Show evidence (2 references)

PMID:35874584 SUPPORT Other

"preventive treatment with spiramycin must be introduced as soon as possible to reduce the risk of mother-to-child transmission, and the severity of fetal infection."

Documents the indication and urgency of spiramycin in maternal infection.

PMID:26394212 SUPPORT Human Clinical

"which of spiramycin, azithromycin and TCM were 83.4% (95%CI, 72.1%-90.8%), 82.5% (95%CI, 75.9%-87.6%), and 85.5% (95%CI, 71.3%-93.3%) respectively, with no statistical difference between them."

Provides the pooled negative-conversion rate for spiramycin from the meta-analysis.

Trimethoprim-Sulfamethoxazole

Action: Pharmacotherapy NCIT:C15986

Agent: trimethoprim CHEBI:45924 sulfamethoxazole CHEBI:9332

An alternative antifolate regimen for toxoplasmic encephalitis, also used for prophylaxis in HIV infection.

Mechanism Target:

INHIBITS Tachyzoite Replication and Haematogenous Dissemination — Sequential antifolate blockade suppresses the replicating tachyzoite stage, the same target as pyrimethamine-sulfadiazine.

Show evidence (1 reference)

PMID:26394212 SUPPORT Human Clinical

"such as spiramycin, azithromycin, traditional Chinese medicine (TCM), pyrimethamine- sulfadiazine (P-S), trimethoprim-sulfamethoxazole (TMP-SMX), and pyrimethamine-clindamycin (P-C)"

Places TMP-SMX among the conventional anti-Toxoplasma regimens acting on active infection.

Show evidence (1 reference)

PMID:26394212 SUPPORT Human Clinical

"such as spiramycin, azithromycin, traditional Chinese medicine (TCM), pyrimethamine- sulfadiazine (P-S), trimethoprim-sulfamethoxazole (TMP-SMX), and pyrimethamine-clindamycin (P-C)"

Identifies TMP-SMX among the conventional regimens evaluated for T. gondii infection.

Pyrimethamine-Clindamycin

Action: Pharmacotherapy NCIT:C15986

Agent: pyrimethamine CHEBI:8673 clindamycin CHEBI:3745

Alternative combination for patients intolerant of sulfadiazine, substituting clindamycin for the sulfonamide component.

Mechanism Target:

INHIBITS Tachyzoite Replication and Haematogenous Dissemination — Pyrimethamine retains the antifolate action on the replicating tachyzoite while clindamycin substitutes for the sulfonamide component.

Show evidence (1 reference)

PMID:26394212 SUPPORT Human Clinical

"such as spiramycin, azithromycin, traditional Chinese medicine (TCM), pyrimethamine- sulfadiazine (P-S), trimethoprim-sulfamethoxazole (TMP-SMX), and pyrimethamine-clindamycin (P-C)"

Places pyrimethamine-clindamycin among the conventional regimens acting on active infection.

Show evidence (1 reference)

PMID:26394212 SUPPORT Human Clinical

"such as spiramycin, azithromycin, traditional Chinese medicine (TCM), pyrimethamine- sulfadiazine (P-S), trimethoprim-sulfamethoxazole (TMP-SMX), and pyrimethamine-clindamycin (P-C)"

Identifies pyrimethamine-clindamycin among the conventional regimens evaluated.

Antiretroviral Therapy for Immune Reconstitution

Action: Antiretroviral Therapy NCIT:C94631

In HIV-associated toxoplasmosis, antiretroviral therapy is the definitive intervention: restoring CD4-positive T-cell-dependent surveillance removes the permissive condition for reactivation, and the incidence of cerebral toxoplasmosis falls where ART access and adherence are good. Anti-parasitic therapy treats the episode; ART is what stops it recurring.

Mechanism Target:

INHIBITS Loss of T-Cell-Dependent Immune Surveillance — ART reverses the CD4 depletion that permits recrudescence, acting on the host-immunity trigger rather than on the parasite.

Show evidence (1 reference)

PMID:35694771 SUPPORT Other

"The incidence declines in countries with better access and adherence to antiretroviral therapy"

Links ART access and adherence to falling incidence of the reactivation syndrome.

Show evidence (2 references)

PMID:35694771 SUPPORT Other

"The incidence declines in countries with better access and adherence to antiretroviral therapy"

Population-level evidence that ART reduces cerebral toxoplasmosis incidence.

PMID:35694771 SUPPORT Other

"Its prevalence is high in countries with a high burden of HIV and low coverage of antiretroviral drugs."

The converse observation — burden concentrates where ART coverage is low.

Co-trimoxazole Prophylaxis in HIV Infection

Action: Chemoprevention NCIT:C15604

Agent: trimethoprim CHEBI:45924 sulfamethoxazole CHEBI:9332

Chemoprophylaxis of toxoplasmic encephalitis in Toxoplasma-seropositive people with advanced HIV. In a comparative cohort no patient receiving low-dose trimethoprim-sulfamethoxazole developed toxoplasmic encephalitis, against 33% of seropositive patients receiving pentamidine. Only seropositive patients are at risk, which is why baseline Toxoplasma IgG serology gates the indication.

Mechanism Target:

INHIBITS Tachyzoite Replication and Haematogenous Dissemination — The antifolate kills tachyzoites as they emerge, so that reversion events occurring during the window of impaired immune control do not amplify into clinical encephalitis. The drug acts on the replicating stage, not on the host's CD4 depletion and not on the encysted bradyzoite — prophylaxis and treatment share this molecular target and differ only in timing and indication.

Show evidence (1 reference)

PMID:1351371 SUPPORT Human Clinical

"No patient in the trimethoprim-sulfamethoxazole group and no patient seronegative for Toxoplasma gondii developed toxoplasmic encephalitis"

Demonstrates prevention of the clinical reactivation endpoint under prophylaxis.

Show evidence (1 reference)

PMID:1351371 SUPPORT Human Clinical

"No patient in the trimethoprim-sulfamethoxazole group and no patient seronegative for Toxoplasma gondii developed toxoplasmic encephalitis, compared with 12 of 36 (33%; 95% Cl, 19% to 51%) seropositive patients in the pentamidine group"

Quantifies the protective effect against toxoplasmic encephalitis relative to a non-active comparator.

Atovaquone-Based Salvage Therapy

Action: Pharmacotherapy NCIT:C15986

Agent: atovaquone CHEBI:575568

Atovaquone combined with pyrimethamine or sulfadiazine, for patients intolerant of standard regimens. A randomised phase II trial found response rates consistent with usefulness in that role, with gastrointestinal intolerance the main limitation; the trial was explicitly noncomparative, so this is a salvage option rather than a demonstrated equivalent of first-line therapy.

Mechanism Target:

INHIBITS Tachyzoite Replication and Haematogenous Dissemination — Atovaquone-containing regimens act on active tachyzoite infection.

Show evidence (1 reference)

PMID:11941551 SUPPORT Human Clinical

"atovaquone-containing regimens are otherwise well tolerated and safe and may be useful for patients intolerant of standard regimens for toxoplasmic encephalitis."

Establishes activity against the acute disease in a clinical trial setting.

Show evidence (2 references)

PMID:11941551 SUPPORT Human Clinical

"In this international, noncomparative, randomized phase II trial, we evaluated the effectiveness and tolerance of atovaquone suspension"

Recorded as PARTIAL: the trial design was noncomparative, so it supports usefulness in intolerant patients but not equivalence to standard therapy.

PMID:11941551 SUPPORT Human Clinical

"Eleven (28%) of 40 eligible patients discontinued treatment as a result of adverse events"

Documents the tolerability limitation that confines atovaquone to a salvage role.

Adjunctive Corticosteroids in Ocular Toxoplasmosis

Action: Pharmacotherapy NCIT:C15986

Agent: corticosteroid CHEBI:50858

Corticosteroids are widely used alongside anti-parasitic therapy when inflammation threatens the macula or optic nerve, on the rationale that host inflammation contributes to retinal damage. A Cochrane review found NO randomised evidence either for or against this practice, and the dose, timing and even the direction of benefit remain unestablished. Curated deliberately with NO_EVIDENCE rather than omitted, because the practice is common and the absence of trial support is itself the clinically important fact. Directly linked to the ocular_pathogenesis_uncertainty discussion.

Show evidence (2 references)

PMID:28125765 NO_EVIDENCE Human Clinical

"our review did not identify any evidence from randomized controlled trials for or against the role of corticosteroids in the management of ocular toxoplasmosis"

Cochrane systematic review finding no eligible randomised trials; the practice is therefore recorded without an efficacy claim in either direction.

PMID:28125765 SUPPORT Human Clinical

"Although research has identified a wide variation in practice regarding the use of corticosteroids"

Documents that use is widespread and heterogeneous despite the absence of trial evidence.

Ventriculoperitoneal Shunt for Obstructive Hydrocephalus

Action: Ventriculoperitoneal Shunt Placement NCIT:C168483

Neurosurgical CSF diversion for hydrocephalus complicating congenital toxoplasmosis. Timing matters: in the National Collaborative Chicago-based Congenital Toxoplasmosis Study, shunt placement delayed beyond 25 days after diagnosis was associated with greater cognitive impairment. Outcomes were otherwise highly variable, from normal function to profound disability.

Mechanism Target:

INHIBITS Fetal Neuroinflammatory Injury and Obstructive Hydrocephalus — Shunting relieves the CSF-pathway obstruction produced by fetal periventricular inflammatory lesions; it does not address the underlying parasitic injury.

Show evidence (1 reference)

PMID:31491752 SUPPORT Human Clinical

"Delayed shunt placement beyond 25 days after diagnosis of hydrocephalus was associated with greater cognitive impairment (p = 0.02)."

Establishes a timing-dependent effect of the intervention on neurodevelopmental outcome.

Show evidence (2 references)

PMID:31491752 SUPPORT Human Clinical

"Hydrocephalus occurs in children with congenital toxoplasmosis and can lead to severe disability."

Establishes the indication addressed by this intervention.

PMID:31491752 SUPPORT Human Clinical

"There was considerable variation in the outcomes of patients whose hydrocephalus was treated in early life, ranging from normal cognitive and motor function to profound developmental delay and functional limitation."

Recorded as PARTIAL: the cohort documents highly variable outcomes after intervention, so this supports the practice without implying reliable rescue.

Prenatal Screening with Early Treatment on Seroconversion

Action: Supportive Care NCIT:C15747

Programmatic serological screening of seronegative pregnant women with prompt treatment on seroconversion. The evidence is genuinely mixed and is curated that way rather than resolved. Against benefit: the SYROCOT individual-patient-data meta-analysis found only weak evidence that early treatment reduced mother-to-child transmission and no significant reduction in clinical manifestations. For benefit: a later Spanish multicentre cohort (REIV-TOXO) found four-fold lower risk of clinical features at birth and six-fold lower risk of later complications in newborns of prenatally treated mothers, and France's compulsory programme is associated with declining transmission and severity at population level. The observational designs of the supportive studies cannot exclude confounding by indication, which is why the SYROCOT null result is retained here rather than superseded.

Show evidence (5 references)

PMID:17223474 SUPPORT Human Clinical

"we found weak evidence that treatment started within 3 weeks of seroconversion reduced mother-to-child transmission compared with treatment started after 8 or more weeks"

Supports only a weak transmission-reduction effect of early prenatal treatment; recorded as PARTIAL to avoid overstating benefit.

PMID:17223474 REFUTE Human Clinical

"we found no evidence that prenatal treatment significantly reduced the risk of clinical manifestations"

Refutes the stronger claim that prenatal treatment reduces clinical manifestations in infected liveborn infants.

PMID:34254575 SUPPORT Human Clinical

"Because of compulsory national screening programme in France to detect and treat women with recently acquired T. gondii infection with anti-toxoplasma therapy, the rate of congenital transmission and the severity of disease in children are declining."

Population-level evidence that a national screen-and-treat programme is associated with declining transmission and severity.

+ 2 more references

🌍

Environmental Factors

Ingestion of undercooked meat containing tissue cysts

Dietary consumption of undercooked meat from infected intermediate hosts is a principal route by which humans acquire T. gondii.

Show evidence (1 reference)

PMID:33347832 SUPPORT Other

"or by consumption of intracellular cysts in undercooked meat from intermediate hosts."

Establishes undercooked meat as an established dietary exposure route for human infection.

Mechanism Target:

TRIGGERS Oral Ingestion of Oocysts or Tissue Cysts — Undercooked meat delivers viable bradyzoite tissue cysts to the gut, which is the meat-borne arm of the entry node.

Show evidence (1 reference)

PMID:33347832 SUPPORT Other

"or by consumption of intracellular cysts in undercooked meat from intermediate hosts."

Identifies undercooked meat as a direct route of parasite entry.

Exposure to oocyst-contaminated soil, water and produce

Environmental oocysts shed by felids contaminate water, soil and crops and are ingested via untreated water, unwashed produce or soil contact.

Show evidence (1 reference)

PMID:36668910 SUPPORT Other

"this infection is contracted by consuming contaminated food and water and by exposure to environmental sources of infection such as contaminated soil."

Establishes contaminated food, water and soil as environmental exposures causing human infection.

Mechanism Target:

TRIGGERS Oral Ingestion of Oocysts or Tissue Cysts — Environmental oocyst ingestion is the non-meat arm of the entry node and operates independently of direct contact with cats.

Show evidence (2 references)

PMID:33347832 SUPPORT Other

"being transmitted by ingestion of oocysts that are shed in the faeces of definitive feline hosts and contaminate water, soil and crops"

Identifies environmental oocyst contamination as a direct route of entry.

PMID:36668910 SUPPORT Other

"this infection is contracted by consuming contaminated food and water and by exposure to environmental sources of infection such as contaminated soil."

Confirms contaminated food, water and soil as environmental sources of infection.

🔬

Diagnosis

Serology as the primary diagnostic modality

Detection of Toxoplasma-specific antibody is the mainstay of diagnosis. In suspected cerebral toxoplasmosis, serology combined with clinical features and neuroimaging remains the routine basis for presumptive diagnosis and for starting anti-Toxoplasma therapy.

Show evidence (1 reference)

PMID:35694771 SUPPORT Other

"a combination of clinical symptoms, serology examination, and neuroimaging are still the daily standard for the presumptive diagnosis of cerebral toxoplasmosis and early anti-toxoplasma administration"

States that serology plus clinical features and imaging is the standard presumptive-diagnosis route.

IgG avidity testing to date maternal infection

Because management in pregnancy turns on whether infection preceded or followed conception, dating the maternal infection is decisive. High IgG avidity rules out infection acquired within the preceding four months, which is what allows a seropositive woman to be reassured or escalated to treatment and amniotic fluid PCR. Applies to the Congenital subtype.

Show evidence (2 references)

PMID:27762213 SUPPORT Human Clinical

"Estimation of the date of infection is of the utmost importance for management and treatment recommendations."

Establishes why dating maternal infection is the pivotal diagnostic question in pregnancy.

PMID:27762213 SUPPORT Human Clinical

"IgG avidity has been shown to be useful as high avidity rules out an infection dating less than 4 months"

States the specific inference IgG avidity supports and its four-month window.

Amniotic fluid PCR for prenatal diagnosis

When maternal infection is confirmed in pregnancy, PCR on amniotic fluid is the recommended prenatal test for fetal infection.

Show evidence (1 reference)

PMID:35874584 SUPPORT Other

"When maternal infection is confirmed, prenatal diagnosis with Polymerase Chain Reaction (PCR) on amniotic fluid is recommended."

States the recommended prenatal diagnostic modality.

Serial maternal serology in seronegative pregnancy

Systematic serological testing of women who are seronegative at the start of pregnancy accurately identifies active maternal infection, which is the trigger for preventive treatment.

Show evidence (1 reference)

PMID:35874584 SUPPORT Other

"Systematic serologic testing in pregnant women who have no antibodies at the beginning of pregnancy, can accurately reveal active maternal infection."

Establishes serial serology as the screening method that detects maternal seroconversion.

Neuroimaging in suspected toxoplasmic encephalitis

MRI is a key adjunct to the clinical diagnosis of toxoplasmic encephalitis in HIV/AIDS.

Show evidence (1 reference)

PMID:40785890 SUPPORT Human Clinical

"Magnetic resonance imaging (MRI) serves as a key adjunct in the clinical diagnosis of TE."

Establishes MRI as a principal diagnostic adjunct for reactivation disease.

🩻

Imaging Findings

Multiple ring-enhancing cerebral lesions

Most patients with toxoplasmic encephalitis have multiple lesions on MRI, predominantly nodular and ring-enhancing, concentrated at the grey-white matter junction and the thalamus-basal ganglia region.

Mri Diagnostic Reactivation

brain UBERON:0000955

Show evidence (2 references)

PMID:40785890 SUPPORT Human Clinical

"A total of 41 patients were included, 82.9% had multiple lesions on MRI, and 203 lesions larger than 2 mm were identified."

Quantifies the multiplicity of lesions in a two-centre imaging cohort.

PMID:40785890 SUPPORT Human Clinical

"The lesions predominantly presented with nodular and ring-enhancing patterns, mainly distributed at the gray-white matter junction and the thalamus-basal ganglia region."

Describes the characteristic enhancement pattern and anatomical distribution.

📈

Progression

Chronic latent infection

Acquired

After the acute tachyzoite phase is controlled, the parasite persists lifelong as bradyzoite tissue cysts in immunoprivileged sites, from which recrudescence can occur decades later.

Show evidence (1 reference)

PMID:36839525 SUPPORT Other

"It has effective strategies to escape the immune response and reach privileged immune sites and remain inactive in a controlled environment in tissue cysts."

Describes establishment of the latent, immunoprivileged tissue-cyst reservoir.

Gestational-age-dependent transmission and severity

Congenital

Transmission risk and disease severity move in opposite directions across gestation: late-gestation maternal infection is transmitted far more often but causes milder fetal disease, while first-trimester infection is transmitted rarely but causes the most severe fetal damage.

Show evidence (2 references)

PMID:35874584 SUPPORT Other

"The risk of mother-to-child transmission depends on week of pregnancy at the time of maternal infection: it is low in the first trimester, may reach 90% in the last days of pregnancy."

Quantifies the gestational-age dependence of transmission risk.

PMID:35874584 SUPPORT Other

"Inversely, however, fetal disease is more severe when infection occurs early in pregnancy than later."

Establishes the inverse relationship between gestational age and fetal disease severity.

Delayed-onset sequelae after asymptomatic congenital infection

Congenital

Most congenitally infected newborns appear well at birth yet remain at risk of later sequelae, notably sight-threatening retinochoroiditis.

Show evidence (1 reference)

PMID:35874584 SUPPORT Other

"Congenitally infected newborns are usually asymptomatic at birth, but at risk for tardive sequelae, such as blindness."

Documents the asymptomatic-at-birth pattern with delayed sequelae.

📊

Prevalence

Worldwide

Point Prevalence 25000.0 per 100,000 >1 in 1,000

Chronic (latent) infection, not symptomatic disease. Around 2 billion people are infected worldwide, and an independent estimate puts chronic infection at a quarter of the world's population; the rate here uses that quarter-of-the-population figure (25,000 per 100,000). Only a small proportion of infected people ever develop clinical disease, so this is a seroprevalence-type burden, not a disease-incidence figure.

Show evidence (2 references)

PMID:33347832 SUPPORT Other

"Toxoplasma gondii infects around 2 billion people and, whilst only a small percentage of infected people will suffer serious disease, the prevalence of the parasite makes it one of the most damaging zoonotic diseases in the world."

Provides the global infection burden and the caveat that most infections are not clinically serious.

PMID:31955846 SUPPORT Other

"Toxoplasma gondii chronically infects a quarter of the world's population"

Independent statement of the chronic-infection fraction used to derive the normalized rate.

Global, women of childbearing age

Point Prevalence >1 in 1,000

Seroprevalence in pregnant and childbearing-age women varies markedly by region; no single global rate is quoted by the source, so only the coarse class is recorded here.

Show evidence (1 reference)

PMID:19433092 SUPPORT Human Clinical

"Foci of high prevalence exist in Latin America, parts of Eastern/Central Europe, the Middle East, parts of south-east Asia and Africa."

Documents marked regional heterogeneity in seroprevalence.

🌍

Epidemiology

Declining transmission and severity under national prenatal screening

France's compulsory national screening programme, which detects and treats recently infected pregnant women, is associated with declining congenital transmission rates and declining severity of childhood disease.

Compulsory serological screening of seronegative pregnant women Prompt initiation of anti-Toxoplasma therapy on seroconversion

Show evidence (1 reference)

PMID:34254575 SUPPORT Human Clinical

Links a national screening/treatment programme to falling transmission and severity.

Reactivation risk concentrated at low CD4 counts in HIV infection

Cerebral toxoplasmosis in people living with HIV manifests predominantly at high viral load and CD4 counts below 100 cells/mm3, and population burden tracks antiretroviral coverage.

CD4-positive T-cell depletion Uncontrolled HIV viraemia Limited access to antiretroviral therapy

Show evidence (2 references)

PMID:35694771 SUPPORT Human Clinical

"It commonly manifests in PLWH with HIV viral load above 50 copies/ml and CD4+ cell counts <100/mm3"

Quantifies the immunological threshold at which reactivation disease appears.

PMID:35694771 SUPPORT Other

"Its prevalence is high in countries with a high burden of HIV and low coverage of antiretroviral drugs."

Ties population burden of reactivation disease to ART coverage.

Lifetime reactivation risk in untreated AIDS

Up to 30% of people diagnosed with AIDS who remain untreated for HIV and receive no effective anti-Toxoplasma prophylaxis will reactivate latent infection over their lifetime; in a severely immunosuppressed Edinburgh cohort, 48% of Toxoplasma-seropositive patients with CD4 below 50 cells/mm3 developed cerebral toxoplasmosis. Seronegative patients are essentially not at risk, which is what makes baseline serology the gate for prophylaxis.

Toxoplasma IgG seropositivity (latent reservoir present) Absence of antiretroviral therapy Absence of anti-Toxoplasma prophylaxis

Show evidence (3 references)

PMID:40985660 SUPPORT Human Clinical

"The lifetime probability of a latent T. gondii infection reactivation is up to 30% in people diagnosed with AIDS, of whom the HIV infection remains untreated and who do not receive effective anti-Toxoplasma prophylaxis"

Quantifies lifetime reactivation risk in the absence of both ART and prophylaxis.

PMID:8876356 SUPPORT Human Clinical

"CTOX has developed in 48% of patients who are seropositive for toxoplasma and have a CD4 count < 50 cells/mm3."

Gives the observed attack rate in the seropositive, severely immunosuppressed stratum.

PMID:8876356 SUPPORT Human Clinical

"The incidence of CTOX in toxoplasma-seronegative patients with a CD4 count < 50 cells/mm3 is 1.3%."

The seronegative comparator, confirming that the latent reservoir is the substrate for reactivation.

🦠

Infectious Agent

Toxoplasma gondii

Obligate intracellular apicomplexan protozoan parasite capable of infecting any nucleated cell in any warm-blooded animal.

Toxoplasma gondii NCBITaxon:5811

Show evidence (2 references)

PMID:33347832 SUPPORT Other

"Toxoplasmosis is caused by Toxoplasma gondii, an apicomplexan parasite that is able to infect any nucleated cell in any warm-blooded animal."

Identifies the causative agent and its exceptionally broad cellular host range.

PMID:35500831 SUPPORT Other

"Toxoplasma gondii is an intracellular parasite that does not differentiate among hosts and is capable of infecting nearly all warm-blooded vertebrates."

Confirms the obligate intracellular lifestyle and broad vertebrate host range.

↔️

Transmission

Foodborne transmission by tissue cysts in undercooked meat

Consumption of undercooked meat from infected intermediate hosts delivers viable bradyzoite-containing tissue cysts to the human gut.

Show evidence (1 reference)

PMID:33347832 SUPPORT Other

"or by consumption of intracellular cysts in undercooked meat from intermediate hosts."

Identifies meat-borne tissue cysts as a principal transmission route.

Environmental transmission by oocysts in soil, water and produce

Ingestion of oocysts shed by felids and persisting in soil, water and on crops is the other principal acquisition route.

Show evidence (2 references)

PMID:33347832 SUPPORT Other

"being transmitted by ingestion of oocysts that are shed in the faeces of definitive feline hosts and contaminate water, soil and crops"

Identifies the environmental oocyst route.

PMID:36668910 SUPPORT Other

"this infection is contracted by consuming contaminated food and water and by exposure to environmental sources of infection such as contaminated soil."

Confirms food, water and soil as sources of human infection.

Transplacental (vertical) transmission

Primary maternal infection during pregnancy allows tachyzoites to cross the placenta and infect the fetus, producing congenital toxoplasmosis.

Show evidence (2 references)

PMID:36668910 SUPPORT Other

"Maternal-to-fetal transmission of this infection can result in devastating ophthalmic and neurological consequences for the fetus."

Establishes vertical transmission and its fetal consequences.

PMID:35874584 SUPPORT Other

"a primary infection of pregnant women, may infect the fetus by transplacental transmission."

Specifies that primary (not chronic) maternal infection drives transplacental transmission.

📊

Related Datasets

Human retinal Mueller glial cell (HMG) response to Toxoplasma gondii infection geo:GSE145836

Transcriptomic profiling of primary human retinal Mueller glial cells infected with Toxoplasma gondii, relevant to the retinal arm of this entry's pathograph (Recurrent Necrotizing Retinochoroiditis).

human BULK RNA SEQ n=36

Identified via `just discover-datasets Toxoplasmosis` (DIRECT relevance tier) and confirmed with `just verify-datasets`. No evidence block: a bulk-discovered accession has no abstract quote to anchor an evidence item.

Toxoplasma gondii dictates placental trophoblast lineage specification through induction of decidual signaling cues [single nuclei multiome] geo:GSE276786

Single-cell transcriptomic study of Toxoplasma gondii effects on human placental trophoblast lineage specification, relevant to the Transplacental Transmission and Fetal Dissemination node.

human SINGLE CELL RNA SEQ n=8

The m6A demethylase FTO regulates TNF-α expression in human macrophages following Toxoplasma gondii infection geo:GSE288205

Methylation profiling of human macrophages after Toxoplasma gondii infection, relevant to the macrophage host-response arm of the Interferon-Gamma-Dependent Cell-Autonomous Immune Control node.

human METHYLATION n=8

PMID:40663568

Single-cell CITE-seq of peritoneal exudate cells from C57BL/6J mice during acute Toxoplasma gondii infection geo:GSE335884

Single-cell immune profiling during acute murine Toxoplasma gondii infection, relevant to the innate-to-adaptive transition modelled in the Interferon-Gamma-Dependent Cell-Autonomous Immune Control node.

mouse SINGLE CELL RNA SEQ n=2

PMID:40854593

Identified via `just discover-datasets Toxoplasmosis` (DIRECT relevance tier) and confirmed with `just verify-datasets`. Model-organism data, so it supports mechanism rather than human phenotype. No evidence block: a bulk-discovered accession has no abstract quote to anchor an evidence item.

🧫

Experimental Models

Human cell culture single-cell transcriptomics of ROP/GRA effector injection PRIMARY_CELL_CULTURE

Infected and effector-injected human host cells profiled by single-cell transcriptomics, including the "uninfected-injected" population that receives rhoptry effectors without being invaded. This design separates the ROP arm from the GRA arm of host-cell reprogramming.

Organism

human NCBITaxon:9606

Publication

PMID:32518180

Pathograph links

Rhoptry and Dense Granule Effector-Mediated Immune Subversion Dissects which host transcriptional changes are attributable to injected ROP effectors versus MYR1-dependent GRA effectors.

Show evidence (1 reference)

PMID:32518180 SUPPORT In Vitro

"the host's earliest response to infection appears to be driven primarily by the injected ROPs, which appear to induce immune and cellular stress pathways."

Attributes a specific arm of host reprogramming to the rhoptry effectors modelled in that node.

Show evidence (1 reference)

PMID:32518180 SUPPORT In Vitro

"we developed a robust, novel protocol to enrich for ultrapure populations of a naturally occurring and reproducible population of host cells called uninfected-injected (U-I) cells, which Toxoplasma injects with ROPs but subsequently fails to invade"

Describes the model system and the cell population that makes the ROP/GRA dissection possible.

Stress-induced bradyzoite differentiation in cell culture PRIMARY_CELL_CULTURE

In vitro differentiation is efficiently triggered by stress, which is what made a Cas9 screen for the differentiation switch possible and yielded BFD1. The system underpins the cyst-formation node and is the natural screening platform for the cyst-active drugs this entry records as missing.

Publication

PMID:31955846

Pathograph links

Bradyzoite Differentiation and Tissue Cyst Formation Provides a controllable in vitro readout of the tachyzoite-to-bradyzoite switch.

Show evidence (1 reference)

PMID:31955846 SUPPORT In Vitro

"The molecular basis of this differentiation is unknown, despite being efficiently triggered by stresses in culture."

Establishes that the culture system reproduces the differentiation event modelled in that node.

Show evidence (1 reference)

PMID:31955846 SUPPORT In Vitro

"Through Cas9-mediated screening and single-cell profiling, we identify a Myb-like transcription factor (BFD1)"

Documents the screening modality this in vitro model supports.

🐁

Animal Models

Mus musculus Parasite-genotype virulence model

Mouse infection is the assay that defined T. gondii virulence genetics. Transfecting the virulent type I ROP18 allele into a nonpathogenic type III strain increased growth and raised mortality by 4-5 logs, establishing ROP18 as a secreted virulence determinant. Caveat: mouse virulence classes do not map directly onto human disease severity, so this model grounds the effector mechanism rather than the human phenotype.

Species

Mus musculus

Show evidence (1 reference)

PMID:17170305 SUPPORT Model Organism

"Transfection of the virulent ROP18 allele into a nonpathogenic type III strain increased growth and enhanced mortality by 4 to 5 logs."

The mouse model provides the causal readout that defines ROP18 as a virulence factor.

Mus musculus Acute infection and immune-clearance model

Acute murine infection with effector-deficient parasites tests the role of parasite immune-evasion factors in vivo. TgIST-deficient parasites are rapidly cleared by homing Gr1-positive inflammatory monocytes, demonstrating that the effector protects against interferon-gamma-mediated killing.

Species

Mus musculus

Show evidence (1 reference)

PMID:27503074 SUPPORT Model Organism

"We found that during mice acute infection, TgIST-deficient parasites are rapidly eliminated by the homing Gr1(+) inflammatory monocytes, thus highlighting the protective role of TgIST against IFN-γ-mediated killing."

In vivo loss-of-function evidence for the immune-evasion arm of the pathograph.

Mus musculus Bradyzoite differentiation / chronic-stage model

Mice are the standard system for the acute-to-chronic transition. The parasite transcription factor BFD1 was shown to be necessary for bradyzoite differentiation both in cell culture and in mice, tying the in vitro stress-induced switch to cyst formation in a living host. BFD1 is a Toxoplasma gene, so it is described here rather than bound to a gene descriptor, which is HGNC-scoped.

Species

Mus musculus

Show evidence (1 reference)

PMID:31955846 SUPPORT Model Organism

"we identify a Myb-like transcription factor (BFD1) necessary for differentiation in cell culture and in mice."

Establishes in vivo necessity of BFD1 for the differentiation step modelled in the pathograph.

{ }

Source YAML

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name: Toxoplasmosis
creation_date: '2026-08-08T23:30:00Z'
category: Infectious Disease
description: >-
  Toxoplasmosis is a zoonotic protozoal infection caused by the obligate
  intracellular apicomplexan parasite Toxoplasma gondii, which can invade any
  nucleated cell of any warm-blooded animal. Felids are the only definitive
  hosts, shedding environmentally resistant oocysts; humans acquire infection by
  ingesting oocysts from contaminated soil, water or produce, or tissue cysts in
  undercooked meat. Acute infection is asymptomatic or self-limiting in
  immunocompetent hosts, but tachyzoites convert to slow-growing bradyzoites
  inside tissue cysts that persist for life in brain, retina and muscle. Loss of
  T-cell and interferon-gamma-dependent control permits cyst recrudescence,
  producing necrotizing toxoplasmic encephalitis in immunocompromised people and
  recurrent retinochoroiditis even in the immunocompetent. Primary maternal
  infection in pregnancy can be transmitted transplacentally, causing congenital
  toxoplasmosis with retinochoroiditis, cerebral calcification and hydrocephalus.
disease_term:
  preferred_term: toxoplasmosis
  term:
    id: MONDO:0005989
    label: toxoplasmosis
synonyms:
- Toxoplasma infection
- Toxoplasma gondii infection
parents:
- Protozoal infection
- Zoonosis
- Opportunistic infection
classifications:
  harrisons_chapter:
  - classification_value: INFECTIOUS_DISEASES
    evidence:
    - reference: PMID:33347832
      reference_title: Control of human toxoplasmosis.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Toxoplasmosis is caused by Toxoplasma gondii, an apicomplexan parasite that is able to infect any nucleated cell in any warm-blooded animal."
      explanation: Authoritative review classifying toxoplasmosis as a parasitic (infectious) disease.
references:
- reference: PMID:33347832
  title: Control of human toxoplasmosis.
  findings: []
- reference: PMID:22491772
  title: Epidemiology of and diagnostic strategies for toxoplasmosis.
  findings: []
- reference: PMID:19433092
  title: "Toxoplasmosis snapshots: global status of Toxoplasma gondii seroprevalence and implications for pregnancy and congenital toxoplasmosis."
  findings: []
- reference: PMID:31827072
  title: "Innate, adaptive, and cell-autonomous immunity against Toxoplasma gondii infection."
  findings: []
- reference: PMID:35500831
  title: Anti-Toxoplasma host defense systems and the parasitic counterdefense mechanisms.
  findings: []
- reference: PMID:17170305
  title: A secreted serine-threonine kinase determines virulence in the eukaryotic pathogen Toxoplasma gondii.
  findings: []
- reference: PMID:27503074
  title: "Toxoplasma gondii TgIST co-opts host chromatin repressors dampening STAT1-dependent gene regulation and IFN-γ-mediated host defenses."
  findings: []
- reference: PMID:31955846
  title: Identification of a Master Regulator of Differentiation in Toxoplasma.
  findings: []
- reference: PMID:36839525
  title: "Overview of Apoptosis, Autophagy, and Inflammatory Processes in Toxoplasma gondii Infected Cells."
  findings: []
- reference: PMID:32518180
  title: Differential Impacts on Host Transcription by ROP and GRA Effectors from the Intracellular Parasite Toxoplasma gondii.
  findings: []
- reference: PMID:35874584
  title: "Congenital Toxoplasmosis: The State of the Art."
  findings: []
- reference: PMID:34254575
  title: "Congenital toxoplasmosis in humans: an update of worldwide rate of congenital infections."
  findings: []
- reference: PMID:36668910
  title: Toxoplasmosis Infection during Pregnancy.
  findings: []
- reference: PMID:17223474
  title: "Effectiveness of prenatal treatment for congenital toxoplasmosis: a meta-analysis of individual patients' data."
  findings: []
- reference: PMID:35694771
  title: "Cerebral toxoplasmosis in HIV-infected patients: a review."
  findings: []
- reference: PMID:40785890
  title: Clinical and imaging characteristics of toxoplasmic encephalitis in patients with HIV/AIDS with different immune statuses.
  findings: []
- reference: PMID:3326123
  title: Clinical spectrum in 107 cases of toxoplasmic lymphadenopathy.
  findings: []
- reference: PMID:39452769
  title: "Ocular Toxoplasmosis: Advances in Toxoplasma gondii Biology, Clinical Manifestations, Diagnostics, and Therapy."
  findings: []
- reference: PMID:36095008
  title: Ocular Toxoplasmosis.
  findings: []
- reference: PMID:26394212
  title: A Systematic Review and Meta-Analysis of the Efficacy of Anti-Toxoplasma gondii Medicines in Humans.
  findings: []
- reference: PMID:7594717
  title: "Toxoplasma gondii comprises three clonal lineages: correlation of parasite genotype with human disease."
  findings: []
- reference: PMID:21098108
  title: "NALP1 influences susceptibility to human congenital toxoplasmosis, proinflammatory cytokine response, and fate of Toxoplasma gondii-infected monocytic cells."
  findings: []
- reference: PMID:22499837
  title: "Prematurity and severity are associated with Toxoplasma gondii alleles (NCCCTS, 1981-2009)."
  findings: []
- reference: PMID:27762213
  title: Comparison of Toxoplasma gondii IgG avidity Architect and Vidas assays with the estimated date of infection in pregnant women.
  findings: []
- reference: PMID:1351371
  title: Low-dose trimethoprim-sulfamethoxazole prophylaxis for toxoplasmic encephalitis in patients with AIDS.
  findings: []
- reference: PMID:11941551
  title: "Randomized phase II trial of atovaquone with pyrimethamine or sulfadiazine for treatment of toxoplasmic encephalitis in patients with acquired immunodeficiency syndrome: ACTG 237/ANRS 039 Study. AIDS Clinical Trials Group 237/Agence Nationale de Recherche sur le SIDA, Essai 039."
  findings: []
- reference: PMID:28125765
  title: Corticosteroids as adjuvant therapy for ocular toxoplasmosis.
  findings: []
- reference: PMID:31491752
  title: Outcomes of hydrocephalus secondary to congenital toxoplasmosis.
  findings: []
- reference: PMID:40985660
  title: Cerebral toxoplasmosis in the twenty-first century.
  findings: []
- reference: PMID:8876356
  title: "Clinical features, outcome and survival from cerebral toxoplasmosis in Edinburgh AIDS patients."
  findings: []
- reference: PMID:39436926
  title: "REIV-TOXO Project: Results from a Spanish cohort of congenital toxoplasmosis (2015-2022). The beneficial effects of prenatal treatment on clinical outcomes of infected newborns."
  findings: []
infectious_agent:
- name: Toxoplasma gondii
  description: >-
    Obligate intracellular apicomplexan protozoan parasite capable of infecting
    any nucleated cell in any warm-blooded animal.
  infectious_agent_term:
    preferred_term: Toxoplasma gondii
    term:
      id: NCBITaxon:5811
      label: Toxoplasma gondii
  evidence:
  - reference: PMID:33347832
    reference_title: Control of human toxoplasmosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Toxoplasmosis is caused by Toxoplasma gondii, an apicomplexan parasite that is able to infect any nucleated cell in any warm-blooded animal."
    explanation: Identifies the causative agent and its exceptionally broad cellular host range.
  - reference: PMID:35500831
    reference_title: Anti-Toxoplasma host defense systems and the parasitic counterdefense mechanisms.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Toxoplasma gondii is an intracellular parasite that does not differentiate among hosts and is capable of infecting nearly all warm-blooded vertebrates."
    explanation: Confirms the obligate intracellular lifestyle and broad vertebrate host range.
agent_life_cycle:
  description: >-
    Toxoplasma gondii completes sexual reproduction only in the intestinal
    epithelium of felids (the definitive hosts) and reproduces asexually in
    warm-blooded intermediate hosts, including humans. The human-relevant phases
    are the rapidly dividing tachyzoite of acute infection and the encysted
    bradyzoite of lifelong chronic infection.
  hosts:
  - preferred_term: Homo sapiens
    role: Intermediate host supporting asexual replication and tissue-cyst formation
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  - preferred_term: Felis catus
    role: Definitive host in which sexual reproduction and oocyst shedding occur
    term:
      id: NCBITaxon:9685
      label: Felis catus
  life_cycle_stages:
  - name: Sexual replication in the feline intestinal epithelium
    description: >-
      Sexual reproduction is restricted to the gut epithelium of cats and other
      felids, which are therefore the only definitive hosts and the only source
      of environmental oocysts.
    evidence:
    - reference: PMID:31827072
      reference_title: "Innate, adaptive, and cell-autonomous immunity against Toxoplasma gondii infection."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "T. gondii can establish sexual reproduction only in the epithelium of the digestive tract in cat species."
      explanation: Restricts the sexual phase to felid gut epithelium.
    - reference: PMID:35874584
      reference_title: "Congenital Toxoplasmosis: The State of the Art."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "The causative agent is Toxoplasma gondii, an obligate intracellular protozoan parasite, whose replication occurs in the intestine of cats and other felines, the only definitive hosts."
      explanation: Identifies felids as the sole definitive hosts.
  - name: Environmental oocyst stage shed in felid faeces
    description: >-
      Oocysts shed in cat faeces contaminate water, soil and crops and are the
      environmental infectious stage for intermediate hosts including humans.
    evidence:
    - reference: PMID:33347832
      reference_title: Control of human toxoplasmosis.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "being transmitted by ingestion of oocysts that are shed in the faeces of definitive feline hosts and contaminate water, soil and crops"
      explanation: Describes oocyst shedding and environmental contamination.
  - name: Asexual tachyzoite stage in intermediate hosts
    description: >-
      Ingested oocysts or bradyzoites invade the intestinal epithelium and
      transform into tachyzoites, the rapidly proliferating stage responsible for
      acute infection and dissemination.
    evidence:
    - reference: PMID:31827072
      reference_title: "Innate, adaptive, and cell-autonomous immunity against Toxoplasma gondii infection."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Oocysts or bradyzoites contained in the ingested cysts invade the host intestinal epithelium via the digestive tract wall and transform into tachyzoites."
      explanation: Defines the excystation-to-tachyzoite transition at the gut wall.
  - name: Chronic bradyzoite stage within tissue cysts
    description: >-
      Tachyzoites differentiate into bradyzoites that form intracellular tissue
      cysts, the latent stage that resists immune clearance and current drugs.
    evidence:
    - reference: PMID:31955846
      reference_title: Identification of a Master Regulator of Differentiation in Toxoplasma.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Acute-stage tachyzoites differentiate into chronic-stage bradyzoites, which form intracellular cysts resistant to immune clearance and existing therapies."
      explanation: Defines the tachyzoite-to-bradyzoite conversion and the drug/immune resistance of the cyst.
  evidence:
  - reference: PMID:31827072
    reference_title: "Innate, adaptive, and cell-autonomous immunity against Toxoplasma gondii infection."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The life cycle of T. gondii is composed of two reproductive stages: sexual and asexual stages in definitive and intermediate hosts, respectively."
    explanation: Provides the overall two-stage, two-host life-cycle framework.
transmission:
- name: Foodborne transmission by tissue cysts in undercooked meat
  description: >-
    Consumption of undercooked meat from infected intermediate hosts delivers
    viable bradyzoite-containing tissue cysts to the human gut.
  evidence:
  - reference: PMID:33347832
    reference_title: Control of human toxoplasmosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "or by consumption of intracellular cysts in undercooked meat from intermediate hosts."
    explanation: Identifies meat-borne tissue cysts as a principal transmission route.
- name: Environmental transmission by oocysts in soil, water and produce
  description: >-
    Ingestion of oocysts shed by felids and persisting in soil, water and on
    crops is the other principal acquisition route.
  evidence:
  - reference: PMID:33347832
    reference_title: Control of human toxoplasmosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "being transmitted by ingestion of oocysts that are shed in the faeces of definitive feline hosts and contaminate water, soil and crops"
    explanation: Identifies the environmental oocyst route.
  - reference: PMID:36668910
    reference_title: Toxoplasmosis Infection during Pregnancy.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "this infection is contracted by consuming contaminated food and water and by exposure to environmental sources of infection such as contaminated soil."
    explanation: Confirms food, water and soil as sources of human infection.
- name: Transplacental (vertical) transmission
  description: >-
    Primary maternal infection during pregnancy allows tachyzoites to cross the
    placenta and infect the fetus, producing congenital toxoplasmosis.
  evidence:
  - reference: PMID:36668910
    reference_title: Toxoplasmosis Infection during Pregnancy.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Maternal-to-fetal transmission of this infection can result in devastating ophthalmic and neurological consequences for the fetus."
    explanation: Establishes vertical transmission and its fetal consequences.
  - reference: PMID:35874584
    reference_title: "Congenital Toxoplasmosis: The State of the Art."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "a primary infection of pregnant women, may infect the fetus by transplacental transmission."
    explanation: Specifies that primary (not chronic) maternal infection drives transplacental transmission.
has_subtypes:
- name: Acquired
  display_name: Acute acquired toxoplasmosis in the immunocompetent host
  description: >-
    Postnatally acquired infection in an immunocompetent host. Usually
    asymptomatic; when symptomatic, the dominant manifestation is benign,
    self-limited lymphadenopathy of the head and neck. No subtype_term is bound:
    MONDO carries dedicated terms for the congenital, ocular and cerebral forms
    but none for postnatally acquired immunocompetent toxoplasmosis, which is
    covered by the parent term MONDO:0005989 already on this entry.
  evidence:
  - reference: PMID:3326123
    reference_title: Clinical spectrum in 107 cases of toxoplasmic lymphadenopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lymphadenopathy is the most frequent clinical manifestation of acute acquired infection with Toxoplasma in the immunocompetent individual."
    explanation: Defines the dominant clinical presentation of the acquired immunocompetent form.
- name: Congenital
  display_name: Congenital toxoplasmosis
  subtype_term:
    preferred_term: congenital toxoplasmosis
    term:
      id: MONDO:0005715
      label: congenital toxoplasmosis
  description: >-
    Fetal infection following primary maternal infection in pregnancy. Most
    infected newborns are asymptomatic at birth but remain at risk of late
    sequelae; overt disease comprises retinochoroiditis, cerebral calcification,
    hydrocephalus and neurocognitive impairment.
  evidence:
  - reference: PMID:35874584
    reference_title: "Congenital Toxoplasmosis: The State of the Art."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "When congenital infection is evident, disease include retinochoroiditis, cerebral calcifications, hydrocephalus, neurocognitive impairment."
    explanation: Enumerates the defining manifestations of the congenital subtype.
- name: Ocular
  display_name: Ocular toxoplasmosis (Toxoplasma retinochoroiditis)
  subtype_term:
    preferred_term: ocular toxoplasmosis
    term:
      id: MONDO:0005879
      label: ocular toxoplasmosis
  description: >-
    Focal necrotizing retinochoroiditis arising from congenital or acquired
    infection, characteristically recurrent and the leading cause of posterior
    uveitis worldwide. Ocular toxoplasmosis is also curated as an infectious
    subtype of the Choroiditis entry, which carries the posterior-uveitis
    differential and the infectious-versus-autoimmune management fork; this entry
    models it as a manifestation of systemic T. gondii infection, and the two are
    complementary views of the same clinical entity.
  evidence:
  - reference: PMID:36095008
    reference_title: Ocular Toxoplasmosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Ocular toxoplasmosis is the leading cause of posterior uveitis worldwide"
    explanation: Establishes ocular toxoplasmosis as a distinct and globally dominant clinical subtype.
- name: Reactivation
  display_name: Toxoplasmic encephalitis (reactivation disease in the immunocompromised)
  subtype_term:
    preferred_term: cerebral toxoplasmosis
    term:
      id: MONDO:0005697
      label: cerebral toxoplasmosis
  description: >-
    Necrotizing encephalitis arising from recrudescence of latent cerebral tissue
    cysts when T-cell-dependent control is lost, most commonly in advanced HIV
    infection.
  evidence:
  - reference: PMID:35694771
    reference_title: "Cerebral toxoplasmosis in HIV-infected patients: a review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "cerebral toxoplasmosis occurs solely due to the reactivation of a latent infection rather than a new infection."
    explanation: Defines the reactivation subtype as recrudescence of latent infection rather than new acquisition.
prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 25000.0
  notes: >-
    Chronic (latent) infection, not symptomatic disease. Around 2 billion people
    are infected worldwide, and an independent estimate puts chronic infection at
    a quarter of the world's population; the rate here uses that
    quarter-of-the-population figure (25,000 per 100,000). Only a small
    proportion of infected people ever develop clinical disease, so this is a
    seroprevalence-type burden, not a disease-incidence figure.
  evidence:
  - reference: PMID:33347832
    reference_title: Control of human toxoplasmosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Toxoplasma gondii infects around 2 billion people and, whilst only a small percentage of infected people will suffer serious disease, the prevalence of the parasite makes it one of the most damaging zoonotic diseases in the world."
    explanation: Provides the global infection burden and the caveat that most infections are not clinically serious.
  - reference: PMID:31955846
    reference_title: Identification of a Master Regulator of Differentiation in Toxoplasma.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Toxoplasma gondii chronically infects a quarter of the world's population"
    explanation: Independent statement of the chronic-infection fraction used to derive the normalized rate.
- population: Global, women of childbearing age
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  notes: >-
    Seroprevalence in pregnant and childbearing-age women varies markedly by
    region; no single global rate is quoted by the source, so only the coarse
    class is recorded here.
  evidence:
  - reference: PMID:19433092
    reference_title: "Toxoplasmosis snapshots: global status of Toxoplasma gondii seroprevalence and implications for pregnancy and congenital toxoplasmosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Foci of high prevalence exist in Latin America, parts of Eastern/Central Europe, the Middle East, parts of south-east Asia and Africa."
    explanation: Documents marked regional heterogeneity in seroprevalence.
epidemiology:
- name: Declining transmission and severity under national prenatal screening
  description: >-
    France's compulsory national screening programme, which detects and treats
    recently infected pregnant women, is associated with declining congenital
    transmission rates and declining severity of childhood disease.
  factors:
  - Compulsory serological screening of seronegative pregnant women
  - Prompt initiation of anti-Toxoplasma therapy on seroconversion
  evidence:
  - reference: PMID:34254575
    reference_title: "Congenital toxoplasmosis in humans: an update of worldwide rate of congenital infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Because of compulsory national screening programme in France to detect and treat women with recently acquired T. gondii infection with anti-toxoplasma therapy, the rate of congenital transmission and the severity of disease in children are declining."
    explanation: Links a national screening/treatment programme to falling transmission and severity.
- name: Reactivation risk concentrated at low CD4 counts in HIV infection
  description: >-
    Cerebral toxoplasmosis in people living with HIV manifests predominantly at
    high viral load and CD4 counts below 100 cells/mm3, and population burden
    tracks antiretroviral coverage.
  factors:
  - CD4-positive T-cell depletion
  - Uncontrolled HIV viraemia
  - Limited access to antiretroviral therapy
  evidence:
  - reference: PMID:35694771
    reference_title: "Cerebral toxoplasmosis in HIV-infected patients: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It commonly manifests in PLWH with HIV viral load above 50 copies/ml and CD4+ cell counts <100/mm3"
    explanation: Quantifies the immunological threshold at which reactivation disease appears.
  - reference: PMID:35694771
    reference_title: "Cerebral toxoplasmosis in HIV-infected patients: a review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Its prevalence is high in countries with a high burden of HIV and low coverage of antiretroviral drugs."
    explanation: Ties population burden of reactivation disease to ART coverage.
- name: Lifetime reactivation risk in untreated AIDS
  description: >-
    Up to 30% of people diagnosed with AIDS who remain untreated for HIV and
    receive no effective anti-Toxoplasma prophylaxis will reactivate latent
    infection over their lifetime; in a severely immunosuppressed Edinburgh
    cohort, 48% of Toxoplasma-seropositive patients with CD4 below 50 cells/mm3
    developed cerebral toxoplasmosis. Seronegative patients are essentially not
    at risk, which is what makes baseline serology the gate for prophylaxis.
  unit: percent of at-risk patients
  factors:
  - Toxoplasma IgG seropositivity (latent reservoir present)
  - Absence of antiretroviral therapy
  - Absence of anti-Toxoplasma prophylaxis
  evidence:
  - reference: PMID:40985660
    reference_title: Cerebral toxoplasmosis in the twenty-first century.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The lifetime probability of a latent T. gondii infection reactivation is up to 30% in people diagnosed with AIDS, of whom the HIV infection remains untreated and who do not receive effective anti-Toxoplasma prophylaxis"
    explanation: Quantifies lifetime reactivation risk in the absence of both ART and prophylaxis.
  - reference: PMID:8876356
    reference_title: "Clinical features, outcome and survival from cerebral toxoplasmosis in Edinburgh AIDS patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CTOX has developed in 48% of patients who are seropositive for toxoplasma and have a CD4 count < 50 cells/mm3."
    explanation: Gives the observed attack rate in the seropositive, severely immunosuppressed stratum.
  - reference: PMID:8876356
    reference_title: "Clinical features, outcome and survival from cerebral toxoplasmosis in Edinburgh AIDS patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The incidence of CTOX in toxoplasma-seronegative patients with a CD4 count < 50 cells/mm3 is 1.3%."
    explanation: The seronegative comparator, confirming that the latent reservoir is the substrate for reactivation.
progression:
- phase: Chronic latent infection
  subtype: Acquired
  notes: >-
    After the acute tachyzoite phase is controlled, the parasite persists
    lifelong as bradyzoite tissue cysts in immunoprivileged sites, from which
    recrudescence can occur decades later.
  evidence:
  - reference: PMID:36839525
    reference_title: "Overview of Apoptosis, Autophagy, and Inflammatory Processes in Toxoplasma gondii Infected Cells."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "It has effective strategies to escape the immune response and reach privileged immune sites and remain inactive in a controlled environment in tissue cysts."
    explanation: Describes establishment of the latent, immunoprivileged tissue-cyst reservoir.
- phase: Gestational-age-dependent transmission and severity
  subtype: Congenital
  notes: >-
    Transmission risk and disease severity move in opposite directions across
    gestation: late-gestation maternal infection is transmitted far more often
    but causes milder fetal disease, while first-trimester infection is
    transmitted rarely but causes the most severe fetal damage.
  evidence:
  - reference: PMID:35874584
    reference_title: "Congenital Toxoplasmosis: The State of the Art."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The risk of mother-to-child transmission depends on week of pregnancy at the time of maternal infection: it is low in the first trimester, may reach 90% in the last days of pregnancy."
    explanation: Quantifies the gestational-age dependence of transmission risk.
  - reference: PMID:35874584
    reference_title: "Congenital Toxoplasmosis: The State of the Art."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Inversely, however, fetal disease is more severe when infection occurs early in pregnancy than later."
    explanation: Establishes the inverse relationship between gestational age and fetal disease severity.
- phase: Delayed-onset sequelae after asymptomatic congenital infection
  subtype: Congenital
  notes: >-
    Most congenitally infected newborns appear well at birth yet remain at risk
    of later sequelae, notably sight-threatening retinochoroiditis.
  evidence:
  - reference: PMID:35874584
    reference_title: "Congenital Toxoplasmosis: The State of the Art."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Congenitally infected newborns are usually asymptomatic at birth, but at risk for tardive sequelae, such as blindness."
    explanation: Documents the asymptomatic-at-birth pattern with delayed sequelae.
pathophysiology:
- name: Oral Ingestion of Oocysts or Tissue Cysts
  role: trigger
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  description: >-
    Human infection begins with ingestion of environmentally resistant oocysts
    shed by felids (in soil, water or on crops) or of bradyzoite-containing
    tissue cysts in undercooked meat.
  biological_processes:
  - preferred_term: symbiont entry into host
    term:
      id: GO:0044409
      label: symbiont entry into host
    modifier: INCREASED
  evidence:
  - reference: PMID:33347832
    reference_title: Control of human toxoplasmosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "being transmitted by ingestion of oocysts that are shed in the faeces of definitive feline hosts and contaminate water, soil and crops, or by consumption of intracellular cysts in undercooked meat from intermediate hosts."
    explanation: Establishes both oral routes of entry as the initiating event.
  downstream:
  - target: Intestinal Epithelial Invasion and Conversion to Tachyzoites
    causal_link_type: DIRECT
    description: Ingested parasite stages excyst and invade the gut wall.
    evidence:
    - reference: PMID:31827072
      reference_title: "Innate, adaptive, and cell-autonomous immunity against Toxoplasma gondii infection."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Oocysts or bradyzoites contained in the ingested cysts invade the host intestinal epithelium via the digestive tract wall and transform into tachyzoites."
      explanation: Connects ingestion directly to epithelial invasion and tachyzoite conversion.
- name: Intestinal Epithelial Invasion and Conversion to Tachyzoites
  role: effector
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Sporozoites and bradyzoites released in the gut lumen traverse the intestinal
    epithelium and convert to tachyzoites, the rapidly replicating stage that
    drives acute infection.
  cell_types:
  - preferred_term: intestinal epithelial cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  biological_processes:
  - preferred_term: symbiont entry into host cell
    term:
      id: GO:0046718
      label: symbiont entry into host cell
    modifier: INCREASED
  evidence:
  - reference: PMID:31827072
    reference_title: "Innate, adaptive, and cell-autonomous immunity against Toxoplasma gondii infection."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Oocysts or bradyzoites contained in the ingested cysts invade the host intestinal epithelium via the digestive tract wall and transform into tachyzoites."
    explanation: Directly supports epithelial invasion and stage conversion.
  downstream:
  - target: Active Host Cell Invasion and Parasitophorous Vacuole Formation
    causal_link_type: DIRECT
    description: Tachyzoites propagate by repeated cycles of active host-cell invasion.
    evidence:
    - reference: PMID:36839525
      reference_title: "Overview of Apoptosis, Autophagy, and Inflammatory Processes in Toxoplasma gondii Infected Cells."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "During the parasitic invasion, T. gondii creates a parasitophorous vacuole, which enables the modulation of cell functions, allowing its replication and host infection."
      explanation: Links invasion to vacuole formation and intracellular replication.
- name: Active Host Cell Invasion and Parasitophorous Vacuole Formation
  role: central_effector
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Rather than being passively phagocytosed, the tachyzoite actively penetrates
    the host cell using microneme and rhoptry-neck adhesins (MIC, AMA and RON
    proteins) and establishes a parasitophorous vacuole, a replication-permissive
    compartment that the parasite remodels to control host cell function.
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  - preferred_term: dendritic cell
    term:
      id: CL:0000451
      label: dendritic cell
  biological_processes:
  - preferred_term: symbiont entry into host cell
    term:
      id: GO:0046718
      label: symbiont entry into host cell
    modifier: INCREASED
  cellular_components:
  - preferred_term: symbiont-containing vacuole membrane
    term:
      id: GO:0020005
      label: symbiont-containing vacuole membrane
  evidence:
  - reference: PMID:36839525
    reference_title: "Overview of Apoptosis, Autophagy, and Inflammatory Processes in Toxoplasma gondii Infected Cells."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "During the parasitic invasion, T. gondii creates a parasitophorous vacuole, which enables the modulation of cell functions, allowing its replication and host infection."
    explanation: Establishes vacuole formation as the basis of intracellular replication and host modulation.
  - reference: PMID:36839525
    reference_title: "Overview of Apoptosis, Autophagy, and Inflammatory Processes in Toxoplasma gondii Infected Cells."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "They are involved with proteins secreted by micronemes and rhoptries (MIC, AMA, and RONs) that mediate the recognition and entry into host cells."
    explanation: Names the secretory-organelle adhesins that mediate recognition and active entry.
  downstream:
  - target: Rhoptry and Dense Granule Effector-Mediated Immune Subversion
    causal_link_type: DIRECT
    description: >-
      Invasion co-delivers rhoptry and dense granule effectors that reprogram the
      infected cell.
    evidence:
    - reference: PMID:32518180
      reference_title: Differential Impacts on Host Transcription by ROP and GRA Effectors from the Intracellular Parasite Toxoplasma gondii.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The intracellular parasite Toxoplasma gondii employs a vast array of effector proteins from the rhoptry and dense granule organelles to modulate host cell biology; these effectors are known as ROPs and GRAs, respectively."
      explanation: Connects the invasion event to effector-driven modulation of host cell biology.
  - target: Tachyzoite Replication and Haematogenous Dissemination
    causal_link_type: DIRECT
    description: Successful intracellular replication seeds systemic spread.
    evidence:
    - reference: PMID:31955846
      reference_title: Identification of a Master Regulator of Differentiation in Toxoplasma.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Acute-stage tachyzoites differentiate into chronic-stage bradyzoites"
      explanation: Identifies the tachyzoite as the acute-stage replicating form that precedes encystment.
- name: Rhoptry and Dense Granule Effector-Mediated Immune Subversion
  role: amplifier
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    The parasite injects rhoptry (ROP) and dense granule (GRA) effectors that
    suppress host immunity and reprogram infected-cell gene expression. The
    polymorphic rhoptry kinase ROP18 is a principal virulence determinant, and
    the dense granule effector TgIST traffics to the host nucleus to shut down
    STAT1-dependent, interferon-gamma-driven transcription.
  biological_processes:
  - preferred_term: cellular response to type II interferon
    term:
      id: GO:0071346
      label: cellular response to type II interferon
    modifier: DECREASED
  evidence:
  - reference: PMID:35500831
    reference_title: Anti-Toxoplasma host defense systems and the parasitic counterdefense mechanisms.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The molecules released by T. gondii through rhoptries and dense granules not only act to suppress host immunity, but also to control gene expression in infected cells, thereby favouring the spread of infection."
    explanation: States the dual immunosuppressive and transcription-reprogramming function of ROP/GRA effectors.
  - reference: PMID:17170305
    reference_title: A secreted serine-threonine kinase determines virulence in the eukaryotic pathogen Toxoplasma gondii.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Positional cloning identified the candidate virulence gene ROP18, a highly polymorphic serine-threonine kinase that was secreted into the host cell during parasite invasion."
    explanation: Identifies ROP18 as a secreted rhoptry kinase virulence determinant.
  - reference: PMID:17170305
    reference_title: A secreted serine-threonine kinase determines virulence in the eukaryotic pathogen Toxoplasma gondii.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Transfection of the virulent ROP18 allele into a nonpathogenic type III strain increased growth and enhanced mortality by 4 to 5 logs."
    explanation: Demonstrates causally that the ROP18 allele determines virulence in a mouse infection model.
  - reference: PMID:27503074
    reference_title: "Toxoplasma gondii TgIST co-opts host chromatin repressors dampening STAT1-dependent gene regulation and IFN-γ-mediated host defenses."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We now have identified TgIST (T. gondii inhibitor of STAT1 transcriptional activity) as a critical molecular switch that is secreted by intracellular parasites and traffics to the host cell nucleus where it inhibits STAT1-dependent proinflammatory gene expression."
    explanation: Defines the molecular mechanism by which a dense granule effector blocks IFN-gamma-driven transcription.
  downstream:
  - target: Interferon-Gamma-Dependent Cell-Autonomous Immune Control
    causal_link_type: DIRECT
    description: >-
      Effector-mediated subversion directly antagonises the IFN-gamma-driven
      killing programme, blunting clearance.
    evidence:
    - reference: PMID:27503074
      reference_title: "Toxoplasma gondii TgIST co-opts host chromatin repressors dampening STAT1-dependent gene regulation and IFN-γ-mediated host defenses."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We found that during mice acute infection, TgIST-deficient parasites are rapidly eliminated by the homing Gr1(+) inflammatory monocytes, thus highlighting the protective role of TgIST against IFN-γ-mediated killing."
      explanation: Loss-of-function evidence that the effector protects the parasite from IFN-gamma-mediated killing.
- name: Tachyzoite Replication and Haematogenous Dissemination
  role: effector
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  description: >-
    Repeated cycles of invasion, replication and host cell lysis disseminate
    tachyzoites throughout the body, seeding immunoprivileged tissues including
    brain, retina and skeletal and cardiac muscle, and, in pregnancy, the
    placenta.
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  - preferred_term: retina
    term:
      id: UBERON:0000966
      label: retina
  - preferred_term: lymph node
    term:
      id: UBERON:0000029
      label: lymph node
  evidence:
  - reference: PMID:33347832
    reference_title: Control of human toxoplasmosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "an apicomplexan parasite that is able to infect any nucleated cell in any warm-blooded animal"
    explanation: The unrestricted cellular tropism underlying multi-organ dissemination.
  downstream:
  - target: Interferon-Gamma-Dependent Cell-Autonomous Immune Control
    causal_link_type: DIRECT
    description: Disseminating parasites elicit the protective Th1/IFN-gamma response.
    evidence:
    - reference: PMID:31827072
      reference_title: "Innate, adaptive, and cell-autonomous immunity against Toxoplasma gondii infection."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "the immune response against T. gondii activates innate immunity and in turn induces acquired immune responses."
      explanation: Infection triggers the innate-then-adaptive response that controls the acute phase.
  - target: Toxoplasmic Lymphadenitis
    causal_link_type: DIRECT
    description: Regional lymph node involvement is the usual symptomatic expression of acute dissemination.
    evidence:
    - reference: PMID:3326123
      reference_title: Clinical spectrum in 107 cases of toxoplasmic lymphadenopathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Lymphadenopathy is the most frequent clinical manifestation of acute acquired infection with Toxoplasma in the immunocompetent individual."
      explanation: Links acute acquired infection to lymphadenopathy as its commonest clinical expression.
  - target: Transplacental Transmission and Fetal Dissemination
    causal_link_type: DIRECT
    description: >-
      During primary maternal infection, circulating tachyzoites can cross the
      placenta into the fetus.
    evidence:
    - reference: PMID:35874584
      reference_title: "Congenital Toxoplasmosis: The State of the Art."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "a primary infection of pregnant women, may infect the fetus by transplacental transmission."
      explanation: Connects maternal parasitaemia to fetal infection.
- name: Interferon-Gamma-Dependent Cell-Autonomous Immune Control
  role: mediator
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Innate activation drives a Th1 response in which CD4- and CD8-positive T
    cells produce interferon-gamma. IFN-gamma induces a family of IFN-inducible
    GTPases that accumulate on the parasitophorous vacuole membrane and destroy
    the vacuole, clearing or arresting the parasite. This response is what
    restricts T. gondii to opportunistic status in healthy hosts, and its
    pressure is also what drives the parasite into the cyst stage.
  cell_types:
  - preferred_term: CD4-positive, alpha-beta T cell
    term:
      id: CL:0000624
      label: CD4-positive, alpha-beta T cell
  - preferred_term: CD8-positive, alpha-beta T cell
    term:
      id: CL:0000625
      label: CD8-positive, alpha-beta T cell
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: defense response to protozoan
    term:
      id: GO:0042832
      label: defense response to protozoan
    modifier: INCREASED
  - preferred_term: cellular response to type II interferon
    term:
      id: GO:0071346
      label: cellular response to type II interferon
    modifier: INCREASED
  evidence:
  - reference: PMID:31827072
    reference_title: "Innate, adaptive, and cell-autonomous immunity against Toxoplasma gondii infection."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "host immune cells robustly produce the proinflammatory cytokine interferon-γ (IFN-γ), which activates a set of IFN-γ-inducible proteins, including GTPases."
    explanation: Establishes IFN-gamma as the central effector cytokine and its induction of GTPases.
  - reference: PMID:31827072
    reference_title: "Innate, adaptive, and cell-autonomous immunity against Toxoplasma gondii infection."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "IFN-inducible GTPases are essential for cell-autonomous immunity and are specialized for effective clearance and growth inhibition of T. gondii by accumulating in parasitophorous vacuole membranes."
    explanation: Describes the vacuole-targeting effector mechanism of cell-autonomous immunity.
  - reference: PMID:31827072
    reference_title: "Innate, adaptive, and cell-autonomous immunity against Toxoplasma gondii infection."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Toxoplasma gondii is one of the most common infectious agents in humans but causes only opportunistic infection in healthy individuals."
    explanation: Establishes that intact immunity confines the organism to opportunistic behaviour.
  downstream:
  - target: Bradyzoite Differentiation and Tissue Cyst Formation
    causal_link_type: DIRECT
    description: >-
      Immune pressure is the physiological stress that drives
      tachyzoite-to-bradyzoite conversion.
    evidence:
    - reference: PMID:31955846
      reference_title: Identification of a Master Regulator of Differentiation in Toxoplasma.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "BFD1 accumulates during stress and its synthetic expression is sufficient to drive differentiation."
      explanation: Stress drives the transcriptional switch to the encysted stage.
- name: Bradyzoite Differentiation and Tissue Cyst Formation
  role: central_effector
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Under stress, tachyzoites differentiate into slow-growing bradyzoites and
    form intracellular tissue cysts. The Myb-like transcription factor BFD1 is
    the master regulator of this switch: it accumulates during stress and is
    sufficient to drive differentiation. The resulting cysts resist both immune
    clearance and every currently available drug, which is why chronic infection
    is not curable.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:31955846
    reference_title: Identification of a Master Regulator of Differentiation in Toxoplasma.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Acute-stage tachyzoites differentiate into chronic-stage bradyzoites, which form intracellular cysts resistant to immune clearance and existing therapies."
    explanation: Defines the differentiation event and the therapeutic intractability of the cyst.
  - reference: PMID:31955846
    reference_title: Identification of a Master Regulator of Differentiation in Toxoplasma.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we identify a Myb-like transcription factor (BFD1) necessary for differentiation in cell culture and in mice."
    explanation: Identifies BFD1 as necessary for bradyzoite differentiation in vitro and in vivo.
  downstream:
  - target: Lifelong Latent Tissue Cyst Persistence
    causal_link_type: DIRECT
    description: Encystment establishes the lifelong reservoir.
    evidence:
    - reference: PMID:36839525
      reference_title: "Overview of Apoptosis, Autophagy, and Inflammatory Processes in Toxoplasma gondii Infected Cells."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "It has effective strategies to escape the immune response and reach privileged immune sites and remain inactive in a controlled environment in tissue cysts."
      explanation: Connects encystment to persistence in immunoprivileged sites.
- name: Lifelong Latent Tissue Cyst Persistence
  role: consequence
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: >-
    Bradyzoite cysts persist indefinitely in immunoprivileged tissues, above all
    the brain and retina. This latent reservoir is clinically silent while
    T-cell-dependent surveillance is intact, and is the substrate for every later
    reactivation syndrome.
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  - preferred_term: retina
    term:
      id: UBERON:0000966
      label: retina
  evidence:
  - reference: PMID:36839525
    reference_title: "Overview of Apoptosis, Autophagy, and Inflammatory Processes in Toxoplasma gondii Infected Cells."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "It has effective strategies to escape the immune response and reach privileged immune sites and remain inactive in a controlled environment in tissue cysts."
    explanation: Describes durable, quiescent persistence in immunoprivileged tissue.
  - reference: PMID:31955846
    reference_title: Identification of a Master Regulator of Differentiation in Toxoplasma.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "its recrudescence can cause life-threatening disease in immunocompromised individuals and recurrent ocular lesions in the immunocompetent."
    explanation: Establishes the latent reservoir as the source of both reactivation syndromes.
  downstream:
  - target: Loss of T-Cell-Dependent Immune Surveillance
    causal_link_type: DIRECT
    description: >-
      When immune surveillance fails, cysts rupture and bradyzoites revert to
      tachyzoites.
    evidence:
    - reference: PMID:35694771
      reference_title: "Cerebral toxoplasmosis in HIV-infected patients: a review."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "cerebral toxoplasmosis occurs solely due to the reactivation of a latent infection rather than a new infection."
      explanation: Establishes reactivation of latency, not reinfection, as the mechanism of cerebral disease.
  - target: Recurrent Necrotizing Retinochoroiditis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Local cyst rupture at the margin of a pre-existing retinal scar
    - Focal inflammatory response to released parasite antigen
    description: >-
      Retinal cysts recrudesce episodically, producing the relapsing ocular
      disease seen even in immunocompetent hosts.
    evidence:
    - reference: PMID:31955846
      reference_title: Identification of a Master Regulator of Differentiation in Toxoplasma.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "its recrudescence can cause life-threatening disease in immunocompromised individuals and recurrent ocular lesions in the immunocompetent."
      explanation: Attributes recurrent ocular lesions in immunocompetent hosts to recrudescence of latent parasite.
- name: Loss of T-Cell-Dependent Immune Surveillance
  role: trigger
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  description: >-
    Depletion of CD4-positive T cells (advanced HIV infection), transplant
    immunosuppression or chemotherapy removes the interferon-gamma-dependent
    surveillance that keeps tissue cysts quiescent. This is the host-side,
    organism-scale permissive condition; the parasite-side response to it is the
    separate Bradyzoite-to-Tachyzoite Reversion node.
  cell_types:
  - preferred_term: CD4-positive, alpha-beta T cell
    term:
      id: CL:0000624
      label: CD4-positive, alpha-beta T cell
  biological_processes:
  - preferred_term: defense response to protozoan
    term:
      id: GO:0042832
      label: defense response to protozoan
    modifier: DECREASED
  evidence:
  - reference: PMID:31827072
    reference_title: "Innate, adaptive, and cell-autonomous immunity against Toxoplasma gondii infection."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "in immunocompromised individuals, such as AIDS patients, those undergoing chemotherapy and immunosuppressed tissue transplant patients, infection and reactivation can lead to chronic infection with T. gondii, potentially resulting in lethal encephalitis"
    explanation: Names the immunosuppressive contexts that permit reactivation and lethal encephalitis.
  - reference: PMID:35694771
    reference_title: "Cerebral toxoplasmosis in HIV-infected patients: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It commonly manifests in PLWH with HIV viral load above 50 copies/ml and CD4+ cell counts <100/mm3"
    explanation: Quantifies the degree of CD4 depletion at which control is lost.
  - reference: PMID:22491772
    reference_title: Epidemiology of and diagnostic strategies for toxoplasmosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "the importance of reactivations of infections in immunocompromised patients were recognized later, in the era of organ transplantation and HIV infection"
    explanation: >-
      Establishes reactivation in immunocompromised hosts as a distinct clinical
      problem tied historically to transplantation and HIV, the two settings this
      node models.
  downstream:
  - target: Bradyzoite-to-Tachyzoite Reversion and Cyst Rupture
    causal_link_type: DIRECT
    description: >-
      Withdrawal of immune pressure permits the encysted parasite to revert to the
      replicating stage.
    evidence:
    - reference: PMID:35694771
      reference_title: "Cerebral toxoplasmosis in HIV-infected patients: a review."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "cerebral toxoplasmosis occurs solely due to the reactivation of a latent infection rather than a new infection."
      explanation: Establishes that disease in this setting arises from reactivation of the latent stage.
- name: Bradyzoite-to-Tachyzoite Reversion and Cyst Rupture
  role: effector
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Once immune restraint lifts, bradyzoites within tissue cysts revert to the
    rapidly replicating tachyzoite stage and the cyst ruptures, releasing parasites
    into surrounding tissue. This parasite-side, cell-scale event is what converts
    a lifelong silent reservoir into active disease.
  biological_processes:
  - preferred_term: symbiont entry into host cell
    term:
      id: GO:0046718
      label: symbiont entry into host cell
    modifier: INCREASED
  evidence:
  - reference: PMID:31955846
    reference_title: Identification of a Master Regulator of Differentiation in Toxoplasma.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "its recrudescence can cause life-threatening disease in immunocompromised individuals and recurrent ocular lesions in the immunocompetent."
    explanation: Identifies recrudescence of the encysted stage as the event producing both reactivation syndromes.
  - reference: PMID:35694771
    reference_title: "Cerebral toxoplasmosis in HIV-infected patients: a review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "cerebral toxoplasmosis occurs solely due to the reactivation of a latent infection rather than a new infection."
    explanation: Confirms reactivation of latency, not reinfection, as the mechanism.
  downstream:
  - target: Necrotizing Toxoplasmic Encephalitis
    causal_link_type: DIRECT
    description: Uncontrolled cerebral tachyzoite replication destroys brain parenchyma.
    evidence:
    - reference: PMID:35694771
      reference_title: "Cerebral toxoplasmosis in HIV-infected patients: a review."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Toxoplasma gondii infection in the central nervous system commonly occurs among immunodeficient patients."
      explanation: Links immunodeficiency to CNS toxoplasmosis.
- name: Necrotizing Toxoplasmic Encephalitis
  role: outcome
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: >-
    Recrudescent cerebral infection produces multifocal necrotizing
    encephalitis. The brain is a preferred site partly because of its low
    inflammatory reactivity. Lesions are typically multiple and ring-enhancing,
    concentrated at the grey-white matter junction and the thalamus-basal ganglia
    region, and the syndrome is a major cause of death in AIDS.
  cell_types:
  - preferred_term: microglial cell
    term:
      id: CL:0000129
      label: microglial cell
  - preferred_term: astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:35694771
    reference_title: "Cerebral toxoplasmosis in HIV-infected patients: a review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The brain is one of the predilections for T. gondii infection due to its low inflammatory reaction, and cerebral toxoplasmosis occurs solely due to the reactivation of a latent infection rather than a new infection."
    explanation: Explains cerebral tropism and confirms the reactivation mechanism.
  - reference: PMID:40785890
    reference_title: Clinical and imaging characteristics of toxoplasmic encephalitis in patients with HIV/AIDS with different immune statuses.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Toxoplasmic encephalitis (TE) is one of the most common opportunistic central nervous system infections in patients with acquired immunodeficiency syndrome (AIDS) and a major cause of death."
    explanation: Establishes the clinical significance and lethality of the encephalitic outcome.
- name: Recurrent Necrotizing Retinochoroiditis
  role: outcome
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: >-
    Episodic recrudescence of retinal cysts produces focal necrotizing
    retinochoroiditis. Repeated flares accumulate chorioretinal scarring and
    cause potentially blinding complications; ocular toxoplasmosis is the leading
    cause of posterior uveitis worldwide.
  cell_types:
  - preferred_term: retinal pigment epithelial cell
    term:
      id: CL:0002586
      label: retinal pigment epithelial cell
  locations:
  - preferred_term: retina
    term:
      id: UBERON:0000966
      label: retina
  evidence:
  - reference: PMID:39452769
    reference_title: "Ocular Toxoplasmosis: Advances in Toxoplasma gondii Biology, Clinical Manifestations, Diagnostics, and Therapy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Ocular toxoplasmosis (OT), a severe manifestation of T. gondii infection, can lead to potentially blinding complications."
    explanation: Establishes the sight-threatening nature of the ocular outcome.
  - reference: PMID:36095008
    reference_title: Ocular Toxoplasmosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Ocular toxoplasmosis is the leading cause of posterior uveitis worldwide"
    explanation: Quantifies the global importance of the ocular manifestation.
  notes: >-
    The relative contribution of direct parasite cytolysis versus the host
    inflammatory response to retinal tissue destruction is not settled; see the
    ocular_pathogenesis_uncertainty discussion.
- name: Toxoplasmic Lymphadenitis
  role: outcome
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: >-
    In the immunocompetent host, acute acquired infection most often manifests as
    lymphadenitis, typically a solitary node in the head and neck without
    systemic symptoms and with a benign course.
  locations:
  - preferred_term: lymph node
    term:
      id: UBERON:0000029
      label: lymph node
  evidence:
  - reference: PMID:3326123
    reference_title: Clinical spectrum in 107 cases of toxoplasmic lymphadenopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Toxoplasmic lymphadenitis most frequently involved a solitary lymph node in the head and neck regions, without systemic symptoms or extranodal disease and with a benign clinical course."
    explanation: Characterises the distribution and benign course of the lymphadenitic form.
- name: Transplacental Transmission and Fetal Dissemination
  role: trigger
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  description: >-
    During primary maternal infection, tachyzoites cross the placenta and
    disseminate in a fetus whose immune system cannot contain them. Transmission
    probability rises steeply through gestation while the severity of the
    resulting fetal disease falls, so the timing of maternal seroconversion sets
    both the risk and the phenotype.
  cell_types:
  - preferred_term: trophoblast cell
    term:
      id: CL:0000351
      label: trophoblast cell
  locations:
  - preferred_term: placenta
    term:
      id: UBERON:0001987
      label: placenta
  evidence:
  - reference: PMID:35874584
    reference_title: "Congenital Toxoplasmosis: The State of the Art."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The risk of mother-to-child transmission depends on week of pregnancy at the time of maternal infection: it is low in the first trimester, may reach 90% in the last days of pregnancy."
    explanation: Quantifies gestational-age dependence of transmission.
  - reference: PMID:35874584
    reference_title: "Congenital Toxoplasmosis: The State of the Art."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Inversely, however, fetal disease is more severe when infection occurs early in pregnancy than later."
    explanation: Establishes the inverse severity relationship that defines the congenital phenotype.
  downstream:
  - target: Fetal Neuroinflammatory Injury and Obstructive Hydrocephalus
    causal_link_type: DIRECT
    description: Fetal CNS infection produces the defining neurological lesions.
    evidence:
    - reference: PMID:36668910
      reference_title: Toxoplasmosis Infection during Pregnancy.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Maternal-to-fetal transmission of this infection can result in devastating ophthalmic and neurological consequences for the fetus."
      explanation: Links vertical transmission to fetal neurological and ocular injury.
- name: Fetal Neuroinflammatory Injury and Obstructive Hydrocephalus
  role: outcome
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: >-
    Fetal cerebral infection causes necrotizing, inflammatory lesions that
    calcify and obstruct cerebrospinal fluid pathways, producing the
    characteristic combination of cerebral calcification, hydrocephalus and
    retinochoroiditis, with neurocognitive impairment as a long-term sequela.
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:35874584
    reference_title: "Congenital Toxoplasmosis: The State of the Art."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "When congenital infection is evident, disease include retinochoroiditis, cerebral calcifications, hydrocephalus, neurocognitive impairment."
    explanation: Enumerates the fetal CNS and ocular lesion set produced by congenital infection.
phenotypes:
- category: Hematologic
  name: Lymphadenopathy
  subtype: Acquired
  description: >-
    Lymphadenopathy, typically a solitary cervical or other head-and-neck node,
    is the most frequent clinical manifestation of acute acquired toxoplasmosis
    in an immunocompetent host. No frequency band is asserted: the source
    establishes rank ("most frequent manifestation") rather than a proportion of
    infected people, and most acquired infections are entirely asymptomatic.
  phenotype_term:
    preferred_term: Lymphadenopathy
    term:
      id: HP:0002716
      label: Lymphadenopathy
  evidence:
  - reference: PMID:3326123
    reference_title: Clinical spectrum in 107 cases of toxoplasmic lymphadenopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lymphadenopathy is the most frequent clinical manifestation of acute acquired infection with Toxoplasma in the immunocompetent individual."
    explanation: >-
      Establishes lymphadenopathy as the leading clinical manifestation of the
      acquired immunocompetent form. Rank only — this states no proportion, which
      is why no FrequencyEnum band is curated.
  - reference: PMID:3326123
    reference_title: Clinical spectrum in 107 cases of toxoplasmic lymphadenopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Toxoplasmic lymphadenitis most frequently involved a solitary lymph node in the head and neck regions"
    explanation: Specifies the characteristic solitary head-and-neck nodal distribution.
- category: Ophthalmologic
  name: Chorioretinitis
  description: >-
    Focal necrotizing retinochoroiditis, arising from congenital or acquired
    infection and characteristically recurrent. Ocular toxoplasmosis is the
    leading cause of posterior uveitis worldwide.
  phenotype_term:
    preferred_term: Chorioretinitis
    term:
      id: HP:0012424
      label: Chorioretinitis
    temporality: RECURRENT
  evidence:
  - reference: PMID:36095008
    reference_title: Ocular Toxoplasmosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Ocular toxoplasmosis is the leading cause of posterior uveitis worldwide"
    explanation: Establishes the ocular inflammatory phenotype as a dominant manifestation.
  - reference: PMID:35874584
    reference_title: "Congenital Toxoplasmosis: The State of the Art."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "When congenital infection is evident, disease include retinochoroiditis, cerebral calcifications, hydrocephalus, neurocognitive impairment."
    explanation: Lists retinochoroiditis first among the manifestations of overt congenital disease.
- category: Ophthalmologic
  name: Visual impairment
  description: >-
    Cumulative retinal and macular damage from recurrent retinochoroiditis causes
    progressive visual loss and, in congenital disease, blindness.
  phenotype_term:
    preferred_term: Visual impairment
    term:
      id: HP:0000505
      label: Visual impairment
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:39452769
    reference_title: "Ocular Toxoplasmosis: Advances in Toxoplasma gondii Biology, Clinical Manifestations, Diagnostics, and Therapy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Ocular toxoplasmosis (OT), a severe manifestation of T. gondii infection, can lead to potentially blinding complications."
    explanation: Supports sight-threatening visual loss as an outcome of ocular disease.
  - reference: PMID:35874584
    reference_title: "Congenital Toxoplasmosis: The State of the Art."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Congenitally infected newborns are usually asymptomatic at birth, but at risk for tardive sequelae, such as blindness."
    explanation: Documents blindness as the archetypal late sequela of congenital infection.
- category: Neurologic
  name: Cerebral calcification
  subtype: Congenital
  description: >-
    Intracranial calcification, characteristically periventricular, is one of the
    classic findings of overt congenital toxoplasmosis.
  phenotype_term:
    preferred_term: Cerebral calcification
    term:
      id: HP:0002514
      label: Cerebral calcification
  evidence:
  - reference: PMID:35874584
    reference_title: "Congenital Toxoplasmosis: The State of the Art."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "When congenital infection is evident, disease include retinochoroiditis, cerebral calcifications, hydrocephalus, neurocognitive impairment."
    explanation: Lists cerebral calcification among the defining findings of evident congenital disease.
- category: Neurologic
  name: Hydrocephalus
  subtype: Congenital
  description: >-
    Obstructive hydrocephalus results from inflammatory obstruction of
    cerebrospinal fluid pathways by fetal necrotizing periventricular lesions.
  phenotype_term:
    preferred_term: Hydrocephalus
    term:
      id: HP:0000238
      label: Hydrocephalus
  evidence:
  - reference: PMID:35874584
    reference_title: "Congenital Toxoplasmosis: The State of the Art."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "When congenital infection is evident, disease include retinochoroiditis, cerebral calcifications, hydrocephalus, neurocognitive impairment."
    explanation: Lists hydrocephalus among the defining findings of evident congenital disease.
- category: Neurologic
  name: Neurocognitive impairment
  subtype: Congenital
  description: >-
    Neurocognitive impairment is a long-term sequela of congenital cerebral
    infection, particularly following early-gestation transmission.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:35874584
    reference_title: "Congenital Toxoplasmosis: The State of the Art."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "When congenital infection is evident, disease include retinochoroiditis, cerebral calcifications, hydrocephalus, neurocognitive impairment."
    explanation: Lists neurocognitive impairment among the manifestations of overt congenital disease.
- category: Neurologic
  name: Infectious encephalitis
  subtype: Reactivation
  description: >-
    Necrotizing toxoplasmic encephalitis is among the most common opportunistic
    CNS infections in AIDS and a major cause of death.
  phenotype_term:
    preferred_term: Infectious encephalitis
    term:
      id: HP:0002383
      label: Infectious encephalitis
  evidence:
  - reference: PMID:40785890
    reference_title: Clinical and imaging characteristics of toxoplasmic encephalitis in patients with HIV/AIDS with different immune statuses.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Toxoplasmic encephalitis (TE) is one of the most common opportunistic central nervous system infections in patients with acquired immunodeficiency syndrome (AIDS) and a major cause of death."
    explanation: Establishes encephalitis as a leading and lethal opportunistic manifestation.
  - reference: PMID:31827072
    reference_title: "Innate, adaptive, and cell-autonomous immunity against Toxoplasma gondii infection."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "infection and reactivation can lead to chronic infection with T. gondii, potentially resulting in lethal encephalitis"
    explanation: Confirms encephalitis as the lethal endpoint of reactivation in immunocompromised hosts.
- category: Neurologic
  name: Headache
  subtype: Reactivation
  frequency: FREQUENT
  description: >-
    Headache is the commonest presenting symptom of cerebral toxoplasmosis,
    reported by 56% of patients in a 25-year single-centre cohort of people with
    HIV.
  phenotype_term:
    preferred_term: Headache
    term:
      id: HP:0002315
      label: Headache
  evidence:
  - reference: PMID:40985660
    reference_title: Cerebral toxoplasmosis in the twenty-first century.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most reported symptoms were headache (n = 35, 56%), paresis (n = 18, 29%), fever (n = 18, 29%)"
    explanation: >-
      Direct quantitative support for both the phenotype and the FREQUENT band
      (56%, within the 30-79% range).
- category: Neurologic
  name: Hemiparesis
  subtype: Reactivation
  frequency: OCCASIONAL
  description: >-
    Focal motor deficit from mass lesions, reported in 29% of patients with
    cerebral toxoplasmosis in the same cohort. Term choice is on the record: the
    source reports "paresis" without lateralising it, and HPO has no plain
    "Paresis" term, so the options were the slightly over-specific Hemiparesis
    (chosen, since a focal mass lesion produces a lateralised deficit) or the
    under-specific Muscle weakness.
  phenotype_term:
    preferred_term: Hemiparesis
    term:
      id: HP:0001269
      label: Hemiparesis
  evidence:
  - reference: PMID:40985660
    reference_title: Cerebral toxoplasmosis in the twenty-first century.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most reported symptoms were headache (n = 35, 56%), paresis (n = 18, 29%), fever (n = 18, 29%)"
    explanation: >-
      Quantitative support for the phenotype and the OCCASIONAL band (29%, at the
      top of the 5-29% range).
- category: Constitutional
  name: Fever
  subtype: Reactivation
  frequency: OCCASIONAL
  description: >-
    Fever accompanied cerebral toxoplasmosis in 29% of patients in a
    contemporary cohort; its absence does not exclude the diagnosis.
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
  evidence:
  - reference: PMID:40985660
    reference_title: Cerebral toxoplasmosis in the twenty-first century.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most reported symptoms were headache (n = 35, 56%), paresis (n = 18, 29%), fever (n = 18, 29%)"
    explanation: >-
      Quantitative support for the phenotype and the OCCASIONAL band (29%, at the
      top of the 5-29% range).
- category: Growth
  name: Premature birth
  subtype: Congenital
  description: >-
    Prematurity was associated with the non-exclusively-type-II parasite
    serotype in the US National Collaborative congenital toxoplasmosis cohort,
    linking parasite allele identity to birth outcome.
  phenotype_term:
    preferred_term: Premature birth
    term:
      id: HP:0001622
      label: Premature birth
  evidence:
  - reference: PMID:22499837
    reference_title: "Prematurity and severity are associated with Toxoplasma gondii alleles (NCCCTS, 1981-2009)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "NE-II serotype was more prevalent in certain demographics and associated with prematurity and severe disease at birth."
    explanation: Associates congenital toxoplasmosis with prematurity in a 193-infant cohort.
- category: Neurologic
  name: Seizure
  subtype: Reactivation
  description: >-
    Multiple ring-enhancing mass lesions at the grey-white matter junction and in
    the thalamus and basal ganglia provide the anatomical substrate for seizures
    and focal deficits in toxoplasmic encephalitis.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:40785890
    reference_title: Clinical and imaging characteristics of toxoplasmic encephalitis in patients with HIV/AIDS with different immune statuses.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The lesions predominantly presented with nodular and ring-enhancing patterns, mainly distributed at the gray-white matter junction and the thalamus-basal ganglia region."
    explanation: >-
      Supports the anatomical basis for focal cortical and subcortical
      dysfunction. Recorded as PARTIAL because this imaging series documents
      lesion distribution rather than seizure occurrence itself.
imaging_findings:
- name: Multiple ring-enhancing cerebral lesions
  modality: MRI
  subtype: Reactivation
  description: >-
    Most patients with toxoplasmic encephalitis have multiple lesions on MRI,
    predominantly nodular and ring-enhancing, concentrated at the grey-white
    matter junction and the thalamus-basal ganglia region.
  diagnostic: true
  located_in:
    preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:40785890
    reference_title: Clinical and imaging characteristics of toxoplasmic encephalitis in patients with HIV/AIDS with different immune statuses.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A total of 41 patients were included, 82.9% had multiple lesions on MRI, and 203 lesions larger than 2 mm were identified."
    explanation: Quantifies the multiplicity of lesions in a two-centre imaging cohort.
  - reference: PMID:40785890
    reference_title: Clinical and imaging characteristics of toxoplasmic encephalitis in patients with HIV/AIDS with different immune statuses.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The lesions predominantly presented with nodular and ring-enhancing patterns, mainly distributed at the gray-white matter junction and the thalamus-basal ganglia region."
    explanation: Describes the characteristic enhancement pattern and anatomical distribution.
genetic:
- name: NLRP1 (NALP1) inflammasome susceptibility alleles
  relationship_type: SUSCEPTIBILITY
  gene_term:
    preferred_term: NLRP1
    term:
      id: hgnc:14374
      label: NLRP1
  notes: >-
    Susceptibility alleles for human congenital toxoplasmosis were identified in
    NALP1 (NLRP1), and knockdown of the gene in human monocytic cells changes the
    course of infection and abolishes the IL-1beta/IL-18/IL-12 response. This is
    a host susceptibility locus, not a Mendelian cause: toxoplasmosis requires
    parasite exposure, and these are common variants of modest effect.
  evidence:
  - reference: PMID:21098108
    reference_title: "NALP1 influences susceptibility to human congenital toxoplasmosis, proinflammatory cytokine response, and fate of Toxoplasma gondii-infected monocytic cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this study, susceptibility alleles for human congenital toxoplasmosis were identified in the NALP1 gene."
    explanation: Identifies NALP1/NLRP1 as a human congenital-toxoplasmosis susceptibility locus.
  - reference: PMID:21098108
    reference_title: "NALP1 influences susceptibility to human congenital toxoplasmosis, proinflammatory cytokine response, and fate of Toxoplasma gondii-infected monocytic cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "NALP1 silencing attenuated progression of T. gondii infection, with accelerated host cell death and eventual cell disintegration."
    explanation: Functional knockdown evidence that the locus alters the intracellular course of infection.
- name: Toxoplasma gondii clonal lineage structure (parasite genotype)
  relationship_type: RISK_FACTOR
  notes: >-
    The clinically decisive genetic axis in toxoplasmosis is the PARASITE genome,
    not a host gene. T. gondii has an unusual population structure of three
    widespread clonal lineages (types I, II and III) with near-absent sexual
    recombination, and most human toxoplasmosis is associated with type II. No
    gene_term is bound because the entity is a parasite strain lineage, for which
    HGNC (a human gene nomenclature) has no applicable identifier. The ROP18/ROP5
    allelic variation underlying the lineage-virulence difference is modelled
    mechanistically in the Rhoptry and Dense Granule Effector-Mediated Immune
    Subversion node.
  evidence:
  - reference: PMID:7594717
    reference_title: "Toxoplasma gondii comprises three clonal lineages: correlation of parasite genotype with human disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Phylogenetic and statistical analyses indicated a highly unusual population structure consisting of 3 widespread clonal lineages."
    explanation: Establishes the three-lineage clonal population structure of the parasite.
  - reference: PMID:7594717
    reference_title: "Toxoplasma gondii comprises three clonal lineages: correlation of parasite genotype with human disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "While strains from all 3 lineages were isolated from humans, the majority of human toxoplasmosis cases were associated with strains of a type II genotype."
    explanation: Links lineage identity to the distribution of human disease.
- name: Parasite serotype association with congenital disease severity
  subtype: Congenital
  relationship_type: RISK_FACTOR
  notes: >-
    In the US National Collaborative Chicago-based Congenital Toxoplasmosis Study,
    the non-exclusively-type-II (NE-II) parasite serotype was associated with
    prematurity and more severe disease at birth, so parasite allele identity is a
    determinant of congenital outcome. Both serotypes responded to treatment, so
    this is a severity modifier rather than a treatment-futility marker.
  evidence:
  - reference: PMID:22499837
    reference_title: "Prematurity and severity are associated with Toxoplasma gondii alleles (NCCCTS, 1981-2009)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "NE-II serotype was more prevalent in certain demographics and associated with prematurity and severe disease at birth."
    explanation: Associates parasite serotype with prematurity and severity in a 193-infant congenital cohort.
  - reference: PMID:22499837
    reference_title: "Prematurity and severity are associated with Toxoplasma gondii alleles (NCCCTS, 1981-2009)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both type II and NE-II infections improved with treatment."
    explanation: Qualifies the association — serotype modifies severity but does not predict treatment failure.
diagnosis:
- name: Serology as the primary diagnostic modality
  description: >-
    Detection of Toxoplasma-specific antibody is the mainstay of diagnosis. In
    suspected cerebral toxoplasmosis, serology combined with clinical features and
    neuroimaging remains the routine basis for presumptive diagnosis and for
    starting anti-Toxoplasma therapy.
  evidence:
  - reference: PMID:35694771
    reference_title: "Cerebral toxoplasmosis in HIV-infected patients: a review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "a combination of clinical symptoms, serology examination, and neuroimaging are still the daily standard for the presumptive diagnosis of cerebral toxoplasmosis and early anti-toxoplasma administration"
    explanation: States that serology plus clinical features and imaging is the standard presumptive-diagnosis route.
- name: IgG avidity testing to date maternal infection
  description: >-
    Because management in pregnancy turns on whether infection preceded or
    followed conception, dating the maternal infection is decisive. High IgG
    avidity rules out infection acquired within the preceding four months, which
    is what allows a seropositive woman to be reassured or escalated to treatment
    and amniotic fluid PCR. Applies to the Congenital subtype.
  evidence:
  - reference: PMID:27762213
    reference_title: Comparison of Toxoplasma gondii IgG avidity Architect and Vidas assays with the estimated date of infection in pregnant women.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Estimation of the date of infection is of the utmost importance for management and treatment recommendations."
    explanation: Establishes why dating maternal infection is the pivotal diagnostic question in pregnancy.
  - reference: PMID:27762213
    reference_title: Comparison of Toxoplasma gondii IgG avidity Architect and Vidas assays with the estimated date of infection in pregnant women.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "IgG avidity has been shown to be useful as high avidity rules out an infection dating less than 4 months"
    explanation: States the specific inference IgG avidity supports and its four-month window.
- name: Amniotic fluid PCR for prenatal diagnosis
  description: >-
    When maternal infection is confirmed in pregnancy, PCR on amniotic fluid is
    the recommended prenatal test for fetal infection.
  evidence:
  - reference: PMID:35874584
    reference_title: "Congenital Toxoplasmosis: The State of the Art."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "When maternal infection is confirmed, prenatal diagnosis with Polymerase Chain Reaction (PCR) on amniotic fluid is recommended."
    explanation: States the recommended prenatal diagnostic modality.
- name: Serial maternal serology in seronegative pregnancy
  description: >-
    Systematic serological testing of women who are seronegative at the start of
    pregnancy accurately identifies active maternal infection, which is the
    trigger for preventive treatment.
  evidence:
  - reference: PMID:35874584
    reference_title: "Congenital Toxoplasmosis: The State of the Art."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Systematic serologic testing in pregnant women who have no antibodies at the beginning of pregnancy, can accurately reveal active maternal infection."
    explanation: Establishes serial serology as the screening method that detects maternal seroconversion.
- name: Neuroimaging in suspected toxoplasmic encephalitis
  description: >-
    MRI is a key adjunct to the clinical diagnosis of toxoplasmic encephalitis in
    HIV/AIDS.
  evidence:
  - reference: PMID:40785890
    reference_title: Clinical and imaging characteristics of toxoplasmic encephalitis in patients with HIV/AIDS with different immune statuses.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Magnetic resonance imaging (MRI) serves as a key adjunct in the clinical diagnosis of TE."
    explanation: Establishes MRI as a principal diagnostic adjunct for reactivation disease.
treatments:
- name: Pyrimethamine-Sulfadiazine with Folinic Acid
  description: >-
    Standard combination antiparasitic therapy for active toxoplasmosis
    (toxoplasmic encephalitis, confirmed fetal infection, sight-threatening
    ocular disease). Pyrimethamine and the sulfonamide act sequentially on the
    parasite folate pathway; folinic acid is co-administered to mitigate
    pyrimethamine-induced marrow suppression. No regimen eradicates tissue cysts,
    so treatment suppresses rather than cures chronic infection.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: pyrimethamine
      term:
        id: CHEBI:8673
        label: pyrimethamine
    - preferred_term: sulfadiazine
      term:
        id: CHEBI:9328
        label: sulfadiazine
  target_mechanisms:
  - target: Tachyzoite Replication and Haematogenous Dissemination
    treatment_effect: INHIBITS
    description: >-
      Antifolate therapy suppresses the replicating tachyzoite stage; it has no
      activity against encysted bradyzoites.
    evidence:
    - reference: PMID:31955846
      reference_title: Identification of a Master Regulator of Differentiation in Toxoplasma.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "chronic-stage bradyzoites, which form intracellular cysts resistant to immune clearance and existing therapies"
      explanation: Establishes that available drugs act on the acute stage and not the cyst.
  evidence:
  - reference: PMID:35874584
    reference_title: "Congenital Toxoplasmosis: The State of the Art."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "If fetal infection is certain, the maternal treatment is changed to a combination of pyrimethamine-sulfonamide and folinic acid."
    explanation: Documents the pyrimethamine-sulfonamide-folinic acid regimen for confirmed fetal infection.
  - reference: PMID:26394212
    reference_title: A Systematic Review and Meta-Analysis of the Efficacy of Anti-Toxoplasma gondii Medicines in Humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The pooled CR with 95% CI was used to evaluate the overall rate of complete disappearance of clinical symptoms for toxoplasmic encephalitis after therapy"
    explanation: >-
      Meta-analysis measuring cure rates for pyrimethamine-sulfadiazine and
      comparators in toxoplasmic encephalitis. Recorded as PARTIAL because the
      quotable sentence states the outcome measure rather than the numeric result.
- name: Spiramycin in Maternal Infection
  description: >-
    Spiramycin is started as soon as maternal seroconversion is recognised, to
    reduce the risk of transmission to the fetus, and is switched to
    pyrimethamine-sulfonamide once fetal infection is confirmed.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: spiramycin
      term:
        id: CHEBI:748977
        label: spiramycin
  target_mechanisms:
  - target: Transplacental Transmission and Fetal Dissemination
    treatment_effect: INHIBITS
    description: Spiramycin is given specifically to reduce mother-to-child transmission.
    evidence:
    - reference: PMID:35874584
      reference_title: "Congenital Toxoplasmosis: The State of the Art."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "preventive treatment with spiramycin must be introduced as soon as possible to reduce the risk of mother-to-child transmission, and the severity of fetal infection."
      explanation: States the transmission-reduction indication that this treatment targets.
  evidence:
  - reference: PMID:35874584
    reference_title: "Congenital Toxoplasmosis: The State of the Art."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "preventive treatment with spiramycin must be introduced as soon as possible to reduce the risk of mother-to-child transmission, and the severity of fetal infection."
    explanation: Documents the indication and urgency of spiramycin in maternal infection.
  - reference: PMID:26394212
    reference_title: A Systematic Review and Meta-Analysis of the Efficacy of Anti-Toxoplasma gondii Medicines in Humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "which of spiramycin, azithromycin and TCM were 83.4% (95%CI, 72.1%-90.8%), 82.5% (95%CI, 75.9%-87.6%), and 85.5% (95%CI, 71.3%-93.3%) respectively, with no statistical difference between them."
    explanation: Provides the pooled negative-conversion rate for spiramycin from the meta-analysis.
- name: Trimethoprim-Sulfamethoxazole
  description: >-
    An alternative antifolate regimen for toxoplasmic encephalitis, also used for
    prophylaxis in HIV infection.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: trimethoprim
      term:
        id: CHEBI:45924
        label: trimethoprim
    - preferred_term: sulfamethoxazole
      term:
        id: CHEBI:9332
        label: sulfamethoxazole
  target_mechanisms:
  - target: Tachyzoite Replication and Haematogenous Dissemination
    treatment_effect: INHIBITS
    description: >-
      Sequential antifolate blockade suppresses the replicating tachyzoite stage,
      the same target as pyrimethamine-sulfadiazine.
    evidence:
    - reference: PMID:26394212
      reference_title: A Systematic Review and Meta-Analysis of the Efficacy of Anti-Toxoplasma gondii Medicines in Humans.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "such as spiramycin, azithromycin, traditional Chinese medicine (TCM), pyrimethamine- sulfadiazine (P-S), trimethoprim-sulfamethoxazole (TMP-SMX), and pyrimethamine-clindamycin (P-C)"
      explanation: Places TMP-SMX among the conventional anti-Toxoplasma regimens acting on active infection.
  evidence:
  - reference: PMID:26394212
    reference_title: A Systematic Review and Meta-Analysis of the Efficacy of Anti-Toxoplasma gondii Medicines in Humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "such as spiramycin, azithromycin, traditional Chinese medicine (TCM), pyrimethamine- sulfadiazine (P-S), trimethoprim-sulfamethoxazole (TMP-SMX), and pyrimethamine-clindamycin (P-C)"
    explanation: Identifies TMP-SMX among the conventional regimens evaluated for T. gondii infection.
- name: Pyrimethamine-Clindamycin
  description: >-
    Alternative combination for patients intolerant of sulfadiazine, substituting
    clindamycin for the sulfonamide component.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: pyrimethamine
      term:
        id: CHEBI:8673
        label: pyrimethamine
    - preferred_term: clindamycin
      term:
        id: CHEBI:3745
        label: clindamycin
  target_mechanisms:
  - target: Tachyzoite Replication and Haematogenous Dissemination
    treatment_effect: INHIBITS
    description: >-
      Pyrimethamine retains the antifolate action on the replicating tachyzoite
      while clindamycin substitutes for the sulfonamide component.
    evidence:
    - reference: PMID:26394212
      reference_title: A Systematic Review and Meta-Analysis of the Efficacy of Anti-Toxoplasma gondii Medicines in Humans.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "such as spiramycin, azithromycin, traditional Chinese medicine (TCM), pyrimethamine- sulfadiazine (P-S), trimethoprim-sulfamethoxazole (TMP-SMX), and pyrimethamine-clindamycin (P-C)"
      explanation: Places pyrimethamine-clindamycin among the conventional regimens acting on active infection.
  evidence:
  - reference: PMID:26394212
    reference_title: A Systematic Review and Meta-Analysis of the Efficacy of Anti-Toxoplasma gondii Medicines in Humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "such as spiramycin, azithromycin, traditional Chinese medicine (TCM), pyrimethamine- sulfadiazine (P-S), trimethoprim-sulfamethoxazole (TMP-SMX), and pyrimethamine-clindamycin (P-C)"
    explanation: Identifies pyrimethamine-clindamycin among the conventional regimens evaluated.
- name: Antiretroviral Therapy for Immune Reconstitution
  description: >-
    In HIV-associated toxoplasmosis, antiretroviral therapy is the definitive
    intervention: restoring CD4-positive T-cell-dependent surveillance removes the
    permissive condition for reactivation, and the incidence of cerebral
    toxoplasmosis falls where ART access and adherence are good. Anti-parasitic
    therapy treats the episode; ART is what stops it recurring.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Antiretroviral Therapy
    term:
      id: NCIT:C94631
      label: Antiretroviral Therapy
  target_mechanisms:
  - target: Loss of T-Cell-Dependent Immune Surveillance
    treatment_effect: INHIBITS
    description: >-
      ART reverses the CD4 depletion that permits recrudescence, acting on the
      host-immunity trigger rather than on the parasite.
    evidence:
    - reference: PMID:35694771
      reference_title: "Cerebral toxoplasmosis in HIV-infected patients: a review."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "The incidence declines in countries with better access and adherence to antiretroviral therapy"
      explanation: Links ART access and adherence to falling incidence of the reactivation syndrome.
  evidence:
  - reference: PMID:35694771
    reference_title: "Cerebral toxoplasmosis in HIV-infected patients: a review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The incidence declines in countries with better access and adherence to antiretroviral therapy"
    explanation: Population-level evidence that ART reduces cerebral toxoplasmosis incidence.
  - reference: PMID:35694771
    reference_title: "Cerebral toxoplasmosis in HIV-infected patients: a review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Its prevalence is high in countries with a high burden of HIV and low coverage of antiretroviral drugs."
    explanation: The converse observation — burden concentrates where ART coverage is low.
- name: Co-trimoxazole Prophylaxis in HIV Infection
  description: >-
    Chemoprophylaxis of toxoplasmic encephalitis in Toxoplasma-seropositive people
    with advanced HIV. In a comparative cohort no patient receiving low-dose
    trimethoprim-sulfamethoxazole developed toxoplasmic encephalitis, against 33%
    of seropositive patients receiving pentamidine. Only seropositive patients are
    at risk, which is why baseline Toxoplasma IgG serology gates the indication.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Chemoprevention
    term:
      id: NCIT:C15604
      label: Chemoprevention
    therapeutic_agent:
    - preferred_term: trimethoprim
      term:
        id: CHEBI:45924
        label: trimethoprim
    - preferred_term: sulfamethoxazole
      term:
        id: CHEBI:9332
        label: sulfamethoxazole
  target_mechanisms:
  - target: Tachyzoite Replication and Haematogenous Dissemination
    treatment_effect: INHIBITS
    description: >-
      The antifolate kills tachyzoites as they emerge, so that reversion events
      occurring during the window of impaired immune control do not amplify into
      clinical encephalitis. The drug acts on the replicating stage, not on the
      host's CD4 depletion and not on the encysted bradyzoite — prophylaxis and
      treatment share this molecular target and differ only in timing and
      indication.
    evidence:
    - reference: PMID:1351371
      reference_title: Low-dose trimethoprim-sulfamethoxazole prophylaxis for toxoplasmic encephalitis in patients with AIDS.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "No patient in the trimethoprim-sulfamethoxazole group and no patient seronegative for Toxoplasma gondii developed toxoplasmic encephalitis"
      explanation: Demonstrates prevention of the clinical reactivation endpoint under prophylaxis.
  evidence:
  - reference: PMID:1351371
    reference_title: Low-dose trimethoprim-sulfamethoxazole prophylaxis for toxoplasmic encephalitis in patients with AIDS.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No patient in the trimethoprim-sulfamethoxazole group and no patient seronegative for Toxoplasma gondii developed toxoplasmic encephalitis, compared with 12 of 36 (33%; 95% Cl, 19% to 51%) seropositive patients in the pentamidine group"
    explanation: Quantifies the protective effect against toxoplasmic encephalitis relative to a non-active comparator.
- name: Atovaquone-Based Salvage Therapy
  description: >-
    Atovaquone combined with pyrimethamine or sulfadiazine, for patients
    intolerant of standard regimens. A randomised phase II trial found response
    rates consistent with usefulness in that role, with gastrointestinal
    intolerance the main limitation; the trial was explicitly noncomparative, so
    this is a salvage option rather than a demonstrated equivalent of first-line
    therapy.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: atovaquone
      term:
        id: CHEBI:575568
        label: atovaquone
  target_mechanisms:
  - target: Tachyzoite Replication and Haematogenous Dissemination
    treatment_effect: INHIBITS
    description: Atovaquone-containing regimens act on active tachyzoite infection.
    evidence:
    - reference: PMID:11941551
      reference_title: "Randomized phase II trial of atovaquone with pyrimethamine or sulfadiazine for treatment of toxoplasmic encephalitis in patients with acquired immunodeficiency syndrome: ACTG 237/ANRS 039 Study. AIDS Clinical Trials Group 237/Agence Nationale de Recherche sur le SIDA, Essai 039."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "atovaquone-containing regimens are otherwise well tolerated and safe and may be useful for patients intolerant of standard regimens for toxoplasmic encephalitis."
      explanation: Establishes activity against the acute disease in a clinical trial setting.
  evidence:
  - reference: PMID:11941551
    reference_title: "Randomized phase II trial of atovaquone with pyrimethamine or sulfadiazine for treatment of toxoplasmic encephalitis in patients with acquired immunodeficiency syndrome: ACTG 237/ANRS 039 Study. AIDS Clinical Trials Group 237/Agence Nationale de Recherche sur le SIDA, Essai 039."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this international, noncomparative, randomized phase II trial, we evaluated the effectiveness and tolerance of atovaquone suspension"
    explanation: >-
      Recorded as PARTIAL: the trial design was noncomparative, so it supports
      usefulness in intolerant patients but not equivalence to standard therapy.
  - reference: PMID:11941551
    reference_title: "Randomized phase II trial of atovaquone with pyrimethamine or sulfadiazine for treatment of toxoplasmic encephalitis in patients with acquired immunodeficiency syndrome: ACTG 237/ANRS 039 Study. AIDS Clinical Trials Group 237/Agence Nationale de Recherche sur le SIDA, Essai 039."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Eleven (28%) of 40 eligible patients discontinued treatment as a result of adverse events"
    explanation: Documents the tolerability limitation that confines atovaquone to a salvage role.
- name: Adjunctive Corticosteroids in Ocular Toxoplasmosis
  description: >-
    Corticosteroids are widely used alongside anti-parasitic therapy when
    inflammation threatens the macula or optic nerve, on the rationale that host
    inflammation contributes to retinal damage. A Cochrane review found NO
    randomised evidence either for or against this practice, and the dose, timing
    and even the direction of benefit remain unestablished. Curated deliberately
    with NO_EVIDENCE rather than omitted, because the practice is common and the
    absence of trial support is itself the clinically important fact. Directly
    linked to the ocular_pathogenesis_uncertainty discussion.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: corticosteroid
      term:
        id: CHEBI:50858
        label: corticosteroid
  evidence:
  - reference: PMID:28125765
    reference_title: Corticosteroids as adjuvant therapy for ocular toxoplasmosis.
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    snippet: "our review did not identify any evidence from randomized controlled trials for or against the role of corticosteroids in the management of ocular toxoplasmosis"
    explanation: >-
      Cochrane systematic review finding no eligible randomised trials; the
      practice is therefore recorded without an efficacy claim in either direction.
  - reference: PMID:28125765
    reference_title: Corticosteroids as adjuvant therapy for ocular toxoplasmosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although research has identified a wide variation in practice regarding the use of corticosteroids"
    explanation: Documents that use is widespread and heterogeneous despite the absence of trial evidence.
- name: Ventriculoperitoneal Shunt for Obstructive Hydrocephalus
  description: >-
    Neurosurgical CSF diversion for hydrocephalus complicating congenital
    toxoplasmosis. Timing matters: in the National Collaborative Chicago-based
    Congenital Toxoplasmosis Study, shunt placement delayed beyond 25 days after
    diagnosis was associated with greater cognitive impairment. Outcomes were
    otherwise highly variable, from normal function to profound disability.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Ventriculoperitoneal Shunt Placement
    term:
      id: NCIT:C168483
      label: Ventriculoperitoneal Shunt Placement
  target_mechanisms:
  - target: Fetal Neuroinflammatory Injury and Obstructive Hydrocephalus
    treatment_effect: INHIBITS
    description: >-
      Shunting relieves the CSF-pathway obstruction produced by fetal
      periventricular inflammatory lesions; it does not address the underlying
      parasitic injury.
    evidence:
    - reference: PMID:31491752
      reference_title: Outcomes of hydrocephalus secondary to congenital toxoplasmosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Delayed shunt placement beyond 25 days after diagnosis of hydrocephalus was associated with greater cognitive impairment (p = 0.02)."
      explanation: Establishes a timing-dependent effect of the intervention on neurodevelopmental outcome.
  evidence:
  - reference: PMID:31491752
    reference_title: Outcomes of hydrocephalus secondary to congenital toxoplasmosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hydrocephalus occurs in children with congenital toxoplasmosis and can lead to severe disability."
    explanation: Establishes the indication addressed by this intervention.
  - reference: PMID:31491752
    reference_title: Outcomes of hydrocephalus secondary to congenital toxoplasmosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There was considerable variation in the outcomes of patients whose hydrocephalus was treated in early life, ranging from normal cognitive and motor function to profound developmental delay and functional limitation."
    explanation: >-
      Recorded as PARTIAL: the cohort documents highly variable outcomes after
      intervention, so this supports the practice without implying reliable rescue.
- name: Prenatal Screening with Early Treatment on Seroconversion
  description: >-
    Programmatic serological screening of seronegative pregnant women with prompt
    treatment on seroconversion. The evidence is genuinely mixed and is curated
    that way rather than resolved. Against benefit: the SYROCOT
    individual-patient-data meta-analysis found only weak evidence that early
    treatment reduced mother-to-child transmission and no significant reduction
    in clinical manifestations. For benefit: a later Spanish multicentre cohort
    (REIV-TOXO) found four-fold lower risk of clinical features at birth and
    six-fold lower risk of later complications in newborns of prenatally treated
    mothers, and France's compulsory programme is associated with declining
    transmission and severity at population level. The observational designs of
    the supportive studies cannot exclude confounding by indication, which is why
    the SYROCOT null result is retained here rather than superseded.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:17223474
    reference_title: "Effectiveness of prenatal treatment for congenital toxoplasmosis: a meta-analysis of individual patients' data."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we found weak evidence that treatment started within 3 weeks of seroconversion reduced mother-to-child transmission compared with treatment started after 8 or more weeks"
    explanation: >-
      Supports only a weak transmission-reduction effect of early prenatal
      treatment; recorded as PARTIAL to avoid overstating benefit.
  - reference: PMID:17223474
    reference_title: "Effectiveness of prenatal treatment for congenital toxoplasmosis: a meta-analysis of individual patients' data."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "we found no evidence that prenatal treatment significantly reduced the risk of clinical manifestations"
    explanation: >-
      Refutes the stronger claim that prenatal treatment reduces clinical
      manifestations in infected liveborn infants.
  - reference: PMID:34254575
    reference_title: "Congenital toxoplasmosis in humans: an update of worldwide rate of congenital infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Because of compulsory national screening programme in France to detect and treat women with recently acquired T. gondii infection with anti-toxoplasma therapy, the rate of congenital transmission and the severity of disease in children are declining."
    explanation: Population-level evidence that a national screen-and-treat programme is associated with declining transmission and severity.
  - reference: PMID:39436926
    reference_title: "REIV-TOXO Project: Results from a Spanish cohort of congenital toxoplasmosis (2015-2022). The beneficial effects of prenatal treatment on clinical outcomes of infected newborns."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Newborns born to mothers treated prenatally had four-fold lower risk of CT clinical features at birth (p = 0.03) and six-fold lower risk of further complications during follow-up (p = 0.04)"
    explanation: >-
      Observational cohort evidence favouring prenatal treatment, deliberately
      curated alongside the SYROCOT null result rather than replacing it.
  - reference: PMID:39436926
    reference_title: "REIV-TOXO Project: Results from a Spanish cohort of congenital toxoplasmosis (2015-2022). The beneficial effects of prenatal treatment on clinical outcomes of infected newborns."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prenatal screening allowed 92.8% of cases to be identified."
    explanation: Quantifies the case-ascertainment yield of the screening component itself.
environmental:
- name: Ingestion of undercooked meat containing tissue cysts
  exposure_term:
    preferred_term: exposure to Toxoplasma gondii
    term:
      id: ECTO:3000006
      label: exposure to Toxoplasma gondii
  description: >-
    Dietary consumption of undercooked meat from infected intermediate hosts is a
    principal route by which humans acquire T. gondii.
  evidence:
  - reference: PMID:33347832
    reference_title: Control of human toxoplasmosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "or by consumption of intracellular cysts in undercooked meat from intermediate hosts."
    explanation: Establishes undercooked meat as an established dietary exposure route for human infection.
  influences_mechanisms:
  - target: Oral Ingestion of Oocysts or Tissue Cysts
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Undercooked meat delivers viable bradyzoite tissue cysts to the gut, which
      is the meat-borne arm of the entry node.
    evidence:
    - reference: PMID:33347832
      reference_title: Control of human toxoplasmosis.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "or by consumption of intracellular cysts in undercooked meat from intermediate hosts."
      explanation: Identifies undercooked meat as a direct route of parasite entry.
- name: Exposure to oocyst-contaminated soil, water and produce
  exposure_term:
    preferred_term: exposure to Toxoplasma gondii
    term:
      id: ECTO:3000006
      label: exposure to Toxoplasma gondii
  description: >-
    Environmental oocysts shed by felids contaminate water, soil and crops and
    are ingested via untreated water, unwashed produce or soil contact.
  evidence:
  - reference: PMID:36668910
    reference_title: Toxoplasmosis Infection during Pregnancy.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "this infection is contracted by consuming contaminated food and water and by exposure to environmental sources of infection such as contaminated soil."
    explanation: Establishes contaminated food, water and soil as environmental exposures causing human infection.
  influences_mechanisms:
  - target: Oral Ingestion of Oocysts or Tissue Cysts
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Environmental oocyst ingestion is the non-meat arm of the entry node and
      operates independently of direct contact with cats.
    evidence:
    - reference: PMID:33347832
      reference_title: Control of human toxoplasmosis.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "being transmitted by ingestion of oocysts that are shed in the faeces of definitive feline hosts and contaminate water, soil and crops"
      explanation: Identifies environmental oocyst contamination as a direct route of entry.
    - reference: PMID:36668910
      reference_title: Toxoplasmosis Infection during Pregnancy.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "this infection is contracted by consuming contaminated food and water and by exposure to environmental sources of infection such as contaminated soil."
      explanation: Confirms contaminated food, water and soil as environmental sources of infection.
discussions:
- discussion_id: ocular_pathogenesis_uncertainty
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    In ocular toxoplasmosis, how much of the retinal tissue destruction is caused
    by direct parasite cytolysis versus the host inflammatory response to
    recrudescing cysts, and what determines which patients suffer recurrent
    sight-threatening flares?
  attaches_to:
  - "pathophysiology#Recurrent Necrotizing Retinochoroiditis"
  rationale: >-
    The balance between parasite-driven and immune-driven damage determines
    whether adjunctive corticosteroids help or harm, yet contemporary reviews
    state that the mechanisms of ocular involvement remain elusive and that
    treatment of active and recurrent disease is still unresolved. This entry
    therefore does not assert a dominant damage mechanism for the ocular node.
  proposed_experiments:
  - experiment_id: exp_toxo_ocular_load_vs_cytokine
    name: Paired intraocular parasite load and cytokine profiling across the flare cycle
    description: >-
      Measure aqueous and vitreous parasite load by quantitative PCR alongside
      intraocular cytokine profiling in the same eyes during active flares and in
      quiescence, to establish whether tissue destruction tracks parasite burden
      or inflammatory intensity.
  - experiment_id: exp_toxo_ocular_steroid_rct
    name: Randomised adjunctive corticosteroid trial stratified by parasite load
    description: >-
      Randomise patients with active retinochoroiditis to antiparasitic therapy
      with or without adjunctive corticosteroid, stratified by baseline
      intraocular parasite load, with lesion size and visual acuity as endpoints.
  evidence:
  - reference: PMID:39452769
    reference_title: "Ocular Toxoplasmosis: Advances in Toxoplasma gondii Biology, Clinical Manifestations, Diagnostics, and Therapy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Despite extensive research, the specific mechanisms underlying ocular involvement in T. gondii infection remain elusive, and current diagnostic options have limitations."
    explanation: Directly documents the mechanistic gap this discussion records.
  - reference: PMID:39452769
    reference_title: "Ocular Toxoplasmosis: Advances in Toxoplasma gondii Biology, Clinical Manifestations, Diagnostics, and Therapy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "While existing therapies, such as antimicrobial agents and immunosuppressants, can control active infections, they do not offer a definitive cure or completely prevent recurrence."
    explanation: Documents that neither antiparasitic nor immunosuppressive therapy resolves the recurrence problem.
- discussion_id: no_cyst_active_therapy
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    No available drug eradicates bradyzoite tissue cysts, so chronic
    toxoplasmosis cannot be cured and reactivation risk persists for life. What
    would a cyst-active agent have to do, and does the BFD1 differentiation
    switch offer a tractable target?
  attaches_to:
  - "pathophysiology#Lifelong Latent Tissue Cyst Persistence"
  - "pathophysiology#Bradyzoite Differentiation and Tissue Cyst Formation"
  rationale: >-
    Every current regimen acts on the replicating tachyzoite, which is why
    treatment of encephalitis must be followed by secondary prophylaxis until
    immune reconstitution. Identification of BFD1 as a master regulator of
    differentiation provides a genetic handle on the stage conversion that
    creates the untreatable reservoir.
  proposed_experiments:
  - experiment_id: exp_toxo_bfd1_chemical_screen
    name: Chemical screen against BFD1-driven differentiation
    description: >-
      Screen compound libraries for agents that block BFD1-driven bradyzoite
      differentiation, or that force bradyzoite-to-tachyzoite reversion into a
      drug-susceptible state, using the BFD1 genetic switch as the readout.
  - experiment_id: exp_toxo_cyst_burden_reactivation
    name: Cyst burden reduction and reactivation incidence in vivo
    description: >-
      Test whether pharmacological reduction of brain cyst burden in chronically
      infected animals lowers the incidence of encephalitis after subsequent
      immunosuppression.
  evidence:
  - reference: PMID:31955846
    reference_title: Identification of a Master Regulator of Differentiation in Toxoplasma.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Acute-stage tachyzoites differentiate into chronic-stage bradyzoites, which form intracellular cysts resistant to immune clearance and existing therapies."
    explanation: Documents that existing therapies do not clear the cyst stage.
  - reference: PMID:31955846
    reference_title: Identification of a Master Regulator of Differentiation in Toxoplasma.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "BFD1 provides a genetic switch to study and control Toxoplasma differentiation and will inform prevention and treatment of chronic infections."
    explanation: Supports BFD1 as the tractable handle proposed by this discussion.
- discussion_id: antifolate_module_scope
  kind: CURATION_TODO
  status: OPEN
  prompt: >-
    Toxoplasma is treated with the same sequential DHFR/DHPS antifolate blockade
    that the bacterial_folate_synthesis_inhibition module models, but that module
    is explicitly scoped to bacteria. Should the module be generalised to
    eukaryotic-parasite antifolate targets, or should a separate protozoal module
    be created?
  attaches_to:
  - "pathophysiology#Tachyzoite Replication and Haematogenous Dissemination"
  rationale: >-
    Pyrimethamine (DHFR) plus sulfadiazine (DHPS) is mechanistically the same
    sequential-blockade pattern the existing module encodes, and the same drug
    class treats malaria and Pneumocystis pneumonia. Declaring conformance from
    this entry would be a category error while the module's stated scope, node
    names and evidence are bacterial, so no conforms_to has been asserted here.
    Recording the parallel is more useful than either forcing conformance or
    silently dropping it.
  evidence:
  - reference: PMID:26394212
    reference_title: A Systematic Review and Meta-Analysis of the Efficacy of Anti-Toxoplasma gondii Medicines in Humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "such as spiramycin, azithromycin, traditional Chinese medicine (TCM), pyrimethamine- sulfadiazine (P-S), trimethoprim-sulfamethoxazole (TMP-SMX), and pyrimethamine-clindamycin (P-C)"
    explanation: >-
      Confirms that the antifolate combinations named in this discussion are the
      conventional anti-Toxoplasma regimens, which is what makes the parallel to
      the bacterial antifolate module worth recording.
animal_models:
- species: Mus musculus
  category: Parasite-genotype virulence model
  description: >-
    Mouse infection is the assay that defined T. gondii virulence genetics.
    Transfecting the virulent type I ROP18 allele into a nonpathogenic type III
    strain increased growth and raised mortality by 4-5 logs, establishing ROP18
    as a secreted virulence determinant. Caveat: mouse virulence classes do not
    map directly onto human disease severity, so this model grounds the effector
    mechanism rather than the human phenotype.
  evidence:
  - reference: PMID:17170305
    reference_title: A secreted serine-threonine kinase determines virulence in the eukaryotic pathogen Toxoplasma gondii.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Transfection of the virulent ROP18 allele into a nonpathogenic type III strain increased growth and enhanced mortality by 4 to 5 logs."
    explanation: The mouse model provides the causal readout that defines ROP18 as a virulence factor.
- species: Mus musculus
  category: Acute infection and immune-clearance model
  description: >-
    Acute murine infection with effector-deficient parasites tests the role of
    parasite immune-evasion factors in vivo. TgIST-deficient parasites are rapidly
    cleared by homing Gr1-positive inflammatory monocytes, demonstrating that the
    effector protects against interferon-gamma-mediated killing.
  associated_phenotypes:
  - Infectious encephalitis
  evidence:
  - reference: PMID:27503074
    reference_title: "Toxoplasma gondii TgIST co-opts host chromatin repressors dampening STAT1-dependent gene regulation and IFN-γ-mediated host defenses."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We found that during mice acute infection, TgIST-deficient parasites are rapidly eliminated by the homing Gr1(+) inflammatory monocytes, thus highlighting the protective role of TgIST against IFN-γ-mediated killing."
    explanation: In vivo loss-of-function evidence for the immune-evasion arm of the pathograph.
- species: Mus musculus
  category: Bradyzoite differentiation / chronic-stage model
  description: >-
    Mice are the standard system for the acute-to-chronic transition. The
    parasite transcription factor BFD1 was shown to be necessary for bradyzoite
    differentiation both in cell culture and in mice, tying the in vitro
    stress-induced switch to cyst formation in a living host. BFD1 is a
    Toxoplasma gene, so it is described here rather than bound to a gene
    descriptor, which is HGNC-scoped.
  evidence:
  - reference: PMID:31955846
    reference_title: Identification of a Master Regulator of Differentiation in Toxoplasma.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "we identify a Myb-like transcription factor (BFD1) necessary for differentiation in cell culture and in mice."
    explanation: Establishes in vivo necessity of BFD1 for the differentiation step modelled in the pathograph.
experimental_models:
- name: Human cell culture single-cell transcriptomics of ROP/GRA effector injection
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: >-
    Infected and effector-injected human host cells profiled by single-cell
    transcriptomics, including the "uninfected-injected" population that receives
    rhoptry effectors without being invaded. This design separates the ROP arm
    from the GRA arm of host-cell reprogramming.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:32518180
  modeled_mechanisms:
  - target: Rhoptry and Dense Granule Effector-Mediated Immune Subversion
    description: >-
      Dissects which host transcriptional changes are attributable to injected ROP
      effectors versus MYR1-dependent GRA effectors.
    evidence:
    - reference: PMID:32518180
      reference_title: Differential Impacts on Host Transcription by ROP and GRA Effectors from the Intracellular Parasite Toxoplasma gondii.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "the host's earliest response to infection appears to be driven primarily by the injected ROPs, which appear to induce immune and cellular stress pathways."
      explanation: Attributes a specific arm of host reprogramming to the rhoptry effectors modelled in that node.
  evidence:
  - reference: PMID:32518180
    reference_title: Differential Impacts on Host Transcription by ROP and GRA Effectors from the Intracellular Parasite Toxoplasma gondii.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we developed a robust, novel protocol to enrich for ultrapure populations of a naturally occurring and reproducible population of host cells called uninfected-injected (U-I) cells, which Toxoplasma injects with ROPs but subsequently fails to invade"
    explanation: Describes the model system and the cell population that makes the ROP/GRA dissection possible.
- name: Stress-induced bradyzoite differentiation in cell culture
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: >-
    In vitro differentiation is efficiently triggered by stress, which is what
    made a Cas9 screen for the differentiation switch possible and yielded BFD1.
    The system underpins the cyst-formation node and is the natural screening
    platform for the cyst-active drugs this entry records as missing.
  publication: PMID:31955846
  modeled_mechanisms:
  - target: Bradyzoite Differentiation and Tissue Cyst Formation
    description: >-
      Provides a controllable in vitro readout of the tachyzoite-to-bradyzoite
      switch.
    evidence:
    - reference: PMID:31955846
      reference_title: Identification of a Master Regulator of Differentiation in Toxoplasma.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The molecular basis of this differentiation is unknown, despite being efficiently triggered by stresses in culture."
      explanation: Establishes that the culture system reproduces the differentiation event modelled in that node.
  evidence:
  - reference: PMID:31955846
    reference_title: Identification of a Master Regulator of Differentiation in Toxoplasma.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Through Cas9-mediated screening and single-cell profiling, we identify a Myb-like transcription factor (BFD1)"
    explanation: Documents the screening modality this in vitro model supports.
datasets:
- accession: geo:GSE145836
  title: Human retinal Mueller glial cell (HMG) response to Toxoplasma gondii infection
  description: >-
    Transcriptomic profiling of primary human retinal Mueller glial cells
    infected with Toxoplasma gondii, relevant to the retinal arm of this entry's
    pathograph (Recurrent Necrotizing Retinochoroiditis).
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 36
  notes: >-
    Identified via `just discover-datasets Toxoplasmosis` (DIRECT relevance
    tier) and confirmed with `just verify-datasets`. No evidence block: a
    bulk-discovered accession has no abstract quote to anchor an evidence item.
- accession: geo:GSE276786
  title: Toxoplasma gondii dictates placental trophoblast lineage specification through induction of decidual signaling cues [single nuclei multiome]
  description: >-
    Single-cell transcriptomic study of Toxoplasma gondii effects on human
    placental trophoblast lineage specification, relevant to the Transplacental
    Transmission and Fetal Dissemination node.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SINGLE_CELL_RNA_SEQ
  sample_count: 8
  notes: >-
    Identified via `just discover-datasets Toxoplasmosis` (DIRECT relevance
    tier) and confirmed with `just verify-datasets`. No evidence block: a
    bulk-discovered accession has no abstract quote to anchor an evidence item.
- accession: geo:GSE288205
  title: The m6A demethylase FTO regulates TNF-α expression in human macrophages following Toxoplasma gondii infection
  description: >-
    Methylation profiling of human macrophages after Toxoplasma gondii
    infection, relevant to the macrophage host-response arm of the
    Interferon-Gamma-Dependent Cell-Autonomous Immune Control node.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: METHYLATION
  sample_count: 8
  publication: PMID:40663568
  notes: >-
    Identified via `just discover-datasets Toxoplasmosis` (DIRECT relevance
    tier) and confirmed with `just verify-datasets`. No evidence block: a
    bulk-discovered accession has no abstract quote to anchor an evidence item.
- accession: geo:GSE335884
  title: Single-cell CITE-seq of peritoneal exudate cells from C57BL/6J mice during acute Toxoplasma gondii infection
  description: >-
    Single-cell immune profiling during acute murine Toxoplasma gondii
    infection, relevant to the innate-to-adaptive transition modelled in the
    Interferon-Gamma-Dependent Cell-Autonomous Immune Control node.
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  data_type: SINGLE_CELL_RNA_SEQ
  sample_count: 2
  publication: PMID:40854593
  notes: >-
    Identified via `just discover-datasets Toxoplasmosis` (DIRECT relevance
    tier) and confirmed with `just verify-datasets`. Model-organism data, so it
    supports mechanism rather than human phenotype. No evidence block: a
    bulk-discovered accession has no abstract quote to anchor an evidence item.
notes: >-
  Deep research for this entry was run with the claude_code provider
  (research/Toxoplasmosis-deep-research-claude_code.md). Its narrative biology
  was broadly accurate, but every PMID in its citation table proved to be
  fabricated — all fourteen resolved to unrelated papers — and it also
  mis-stated the MONDO id (giving MONDO:0005108 for toxoplasmosis rather than
  MONDO:0005989), the HPO term for chorioretinitis (giving HP:0000585, which is
  Band keratopathy), and the CHEBI id for pyrimethamine. The report was
  therefore used only as a topic outline; every reference, snippet and ontology
  term in this entry was independently searched, fetched and verified.

  Review round 1 (PR #8245) added the genetic, animal_models and
  experimental_models sections, subtype MONDO bindings, serology/IgG-avidity
  diagnostics, five further treatments (ART, co-trimoxazole prophylaxis,
  atovaquone salvage, adjunctive corticosteroids, VP shunt), four further
  phenotypes and the reactivation-risk epidemiology. The same discipline applied:
  none of it was sourced from the deep-research citation table. Two deliberate
  non-additions: no histopathology section, because no source with a quotable
  abstract describing the microglial-nodule/necrotizing pattern in humans could
  be found, and no purine-salvage node, for the same reason. Both are better left
  absent than fabricated.

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