Brucella Melitensis Brucellosis

Infectious Disease MONDO:0001972 Pathograph 28 Show in embeddings browser Brucellosis

Brucella melitensis brucellosis is a small-ruminant-associated form of human brucellosis caused by the facultatively intracellular bacterium Brucella melitensis. Humans are infected through unpasteurized sheep/goat dairy products, contact with infected animals or birth products, and occupational or laboratory aerosol exposure; the resulting disease is a systemic febrile brucellosis syndrome that can relapse or seed focal complications when it is not treated with prolonged combination antibiotics.

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1
Definitions
14
Pathophys.
9
Phenotypes
28
Pathograph
5
Genes
3
Medical Actions
1
Models
1
Deep Research
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Classifications

Harrison's Part
INFECTIOUS DISEASES
📘

Definitions

1
B. melitensis zoonotic brucellosis
Brucella melitensis brucellosis is human brucellosis caused by B. melitensis after zoonotic exposure to infected small ruminants or contaminated animal products; it is tracked at this MONDO child because a species-specific sheep/goat reservoir and high human-disease prominence distinguish it from all-cause brucellosis.
CASE_DEFINITION Species-specific human brucellosis definition
Show evidence (1 reference)
DOI:10.1017/S0950268824000803 SUPPORT Human Clinical
"Brucella melitensis was the dominant species (99.6%)."
In a national culture-confirmed human brucellosis series, nearly every isolate was B. melitensis, supporting this MONDO child as a human brucellosis entity caused by that species.
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Pathophysiology

14
Brucella melitensis zoonotic acquisition
Exposure to infected small ruminants or their unpasteurized dairy products introduces B. melitensis into the human host and initiates the intracellular brucellosis infection program.
Downstream
Phagocyte Brucella-containing vacuole formation Acquired B. melitensis crosses a mucosal or cutaneous barrier and is internalized by phagocytes, creating the Brucella-containing vacuole in which the intracellular cycle begins.
Show evidence (1 reference)
DOI:10.1017/S0950268824000803 SUPPORT Human Clinical
"Brucellosis is endemic in Israel, affecting mainly sheep and goats, dairy cattle, and humans"
The culture-confirmed B. melitensis epidemiology series places human disease in the same endemic sheep, goat, and cattle setting that seeds zoonotic exposure.
Phagocyte Brucella-containing vacuole formation
Internalized Brucella spp. reside in Brucella-containing vacuoles inside host macrophages and dendritic cells, setting up the intracellular trafficking program required for persistent brucellosis.
macrophage CL:0000235 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves macrophage (CL:0000235). CL:0000235 is a cell type from the Cell Ontology. dendritic cell CL:0000451 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves dendritic cell (CL:0000451). CL:0000451 is a cell type from the Cell Ontology.
Downstream
VirB-dependent ER-derived replicative vacuole maturation The early endosomal BCV is converted into an endoplasmic-reticulum-derived replicative organelle through Brucella VirB type IV secretion system activity.
Brucella Omp25-dependent macrophage immune evasion Brucella intracellular macrophage residence is reinforced by innate immune evasion, including Omp25-associated TNF-alpha suppression and impaired infected-phagocyte apoptosis.
Show evidence (1 reference)
PMID:27899503 SUPPORT BACKGROUND In Vitro
"Upon their initial formation following phagocytic uptake, BCVs undergo maturation events along the endocytic pathway to become an endosomal BCV (eBCV) (10–12)."
The Brucella cell-biology paper describes formation of endosomal Brucella-containing vacuoles after phagocytic uptake.
VirB-dependent ER-derived replicative vacuole maturation
Brucella VirB type IV secretion remodels the endosomal Brucella-containing vacuole into a host endoplasmic-reticulum-derived replicative organelle, allowing intracellular expansion rather than lysosomal elimination.
Downstream
Autophagic Brucella-containing vacuole egress Post-replicative Brucella-containing vacuoles become autophagic vacuoles that enable bacterial egress and subsequent cell-to-cell infection.
Show evidence (1 reference)
PMID:27899503 SUPPORT In Vitro
"The VirB T4SS is essential for rBCV biogenesis, as VirB-deficient mutants are stalled in eBCVs and cannot mediate rBCV biogenesis."
Conditional VirB11 expression in B. abortus shows that VirB type IV secretion is required for formation of the replicative BCV stage.
Brucella Omp25-dependent macrophage immune evasion
Brucella outer-membrane and intracellular programs blunt human macrophage antimicrobial defense by suppressing TNF-alpha secretion and preventing monocyte/macrophage apoptosis, extending the infected phagocyte niche.
macrophage CL:0000235 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves macrophage (CL:0000235). CL:0000235 is a cell type from the Cell Ontology.
Downstream
Th1 cytokine-dependent containment failure Omp25-associated TNF-alpha suppression can reduce IL-12 and Th1 cytokine development, counteracting IFN-gamma/TNF-alpha-dependent clearance.
Show evidence (1 reference)
PMID:12414158 SUPPORT REVIEW SYNTHESIS Other
"in humans, Brucella suis impairs the apoptosis of monocytes and macrophages, thus preventing its host cell elimination."
The review summarizes Brucella anti-apoptotic effects in human monocytes and macrophages as one mechanism extending survival of infected host cells.
Th1 cytokine-dependent containment failure
Clearance of Brucella depends on early TNF-alpha, IFN-gamma, and IL-12 cellular immunity; inadequate Th1 containment permits persistence rather than resolution.
Downstream
Chronic splenic myeloid reservoir formation A susceptible IL-12p40-deficient mouse model makes it possible to observe chronic B. melitensis splenic reservoir cells when protective Th1/Th17 control is impaired.
Show evidence (1 reference)
PMID:12414158 SUPPORT REVIEW SYNTHESIS Other
"Brucella infection results in Type1 (Th1) cellular immune response which promotes a clearance of the bacterial organism."
The innate-immunity review identifies the Th1 response as a clearance axis, supporting persistence when this axis is blunted.
Autophagic Brucella-containing vacuole egress
Replication-stage Brucella-containing vacuoles convert into autophagosome-like vacuoles that complete the intracellular cycle by releasing bacteria for subsequent infections.
Downstream
Hematogenous dissemination Cell egress enables ongoing intracellular spread; in human B. melitensis brucellosis, culture-confirmed cases commonly have bacteraemia that can seed distant focal sites.
Show evidence (1 reference)
PMID:27899503 SUPPORT In Vitro
"Considering that aBCVs facilitate Brucella release from macrophages (12), these findings clearly demonstrate that aBCV formation and subsequent bacterial egress are VirB T4SS-dependent processes."
The conditional VirB11 B. abortus macrophage study places autophagic BCVs after replication and ties them to bacterial egress.
Hematogenous dissemination
B. melitensis frequently enters the bloodstream, distributing intracellular bacteria from the systemic reservoir to bone, joints, cardiac valves, the genitourinary tract, and reticuloendothelial organs.
Downstream
Osteoarticular seeding Bloodstream spread can establish focal infection in peripheral joints, sacroiliac joints, and vertebral structures.
Cardiac valve seeding Bloodstream spread can establish focal Brucella infection on cardiac valves.
Genitourinary seeding Bloodstream spread can establish focal infection in the epididymis and testis.
Chronic splenic myeloid reservoir formation Hematogenous infection can reach reticuloendothelial organs; susceptible mice then expose splenic B. melitensis myeloid reservoirs as a model of chronic persistence.
Show evidence (1 reference)
DOI:10.1017/S0950268824000803 SUPPORT Human Clinical
"Of 2,489 unique cases, 99.8% were bacteraemic"
A national culture-confirmed cohort in which 99.6% of Brucella isolates were B. melitensis documented bloodstream infection in nearly all cases.
Osteoarticular seeding
Focal osteoarticular infection affects peripheral joints, sacroiliac joints, or vertebral structures after dissemination.
Downstream
Arthritis Peripheral joint infection may manifest as arthritis.
Sacroiliitis Sacroiliac focal infection manifests as sacroiliitis.
Spondylitis Vertebral focal infection manifests as spondylitis.
Cardiac valve seeding
Focal Brucella infection of cardiac valves produces endocarditis.
Downstream
Endocarditis Valvular infection manifests as endocarditis.
Genitourinary seeding
Focal genitourinary infection affects the epididymis and testis.
Downstream
Epididymo-orchitis Epididymal and testicular infection manifests as epididymo-orchitis.
Chronic splenic myeloid reservoir formation
In a susceptible IL-12p40-deficient mouse model, chronic B. melitensis infection persists in lipid-rich splenic myeloid reservoir cells that express dendritic-cell markers and Arginase1.
Animal models
IL-12p40-deficient B. melitensis chronic splenic reservoir mouse Mouse partially recapitulates The model reproduces durable splenic B. melitensis infection and exposes the phenotype of infected myeloid reservoir cells.
Downstream
Persistent multisystem infection Long-lived intracellular myeloid reservoirs are a model for the difficult clearance and relapse-prone persistence of human brucellosis.
Show evidence (1 reference)
PMID:26376185 SUPPORT Model Organism
"Most of the infected spleen cells contained high levels of lipids and expressed CD11c and CD205 dendritic cell markers and Arginase1, but were negative for the M2a markers Fizz1 or CD301."
The susceptible-mouse study directly observed the phenotype of chronic B. melitensis-infected splenic reservoir cells.
Persistent multisystem infection
Intracellular B. melitensis infection produces a persistent, relapse-prone, systemic brucellosis syndrome that can disseminate hematogenously and seed focal complications.
Downstream
Fever Systemic brucellosis commonly manifests with fever.
Joint pain The multisystem syndrome commonly includes arthralgia or arthritis.
Hepatosplenomegaly Reticuloendothelial infection can enlarge the liver and spleen.
Granulomatous reticuloendothelial inflammation Persistent intracellular Brucella infection can elicit granulomatous immune aggregates that balance containment with incomplete bacterial elimination.
Elevated transaminases Systemic brucellosis can involve hepatic inflammation reflected by elevated transaminases.
Show evidence (1 reference)
PMID:18162038 SUPPORT REVIEW SYNTHESIS Human Clinical
"More importantly, these regimens still allow for a small, albeit significant percentage of therapeutic failures, most commonly in the form of relapses, ranging from 5% to 15% of uncomplicated cases."
The treatment recommendations summarize relapse after otherwise standard regimens, supporting relapse-prone persistence as a clinical property of human brucellosis.
Granulomatous reticuloendothelial inflammation
Persistent Brucella infection can be walled into myeloid and lymphoid granulomatous aggregates, containing systemic spread imperfectly while preserving niches for intracellular survival.
Downstream
Hepatosplenomegaly Reticuloendothelial inflammation contributes to liver and spleen enlargement.
Show evidence (1 reference)
PMID:41921569 SUPPORT REVIEW SYNTHESIS Other
"Granulomas are organized immune aggregates of myeloid and lymphoid cells that arise when the host fails to eliminate persistent stimuli"
The granuloma review defines the tissue response represented by this Brucella containment node.
Requirement for Cell-Penetrant Antimicrobials
B. melitensis persists inside host phagocytes in the Brucella-containing vacuole, so effective brucellosis regimens are built from prolonged combinations that include intracellularly active agents such as doxycycline and rifampicin rather than poorly cell-penetrant beta-lactams.
Response to Antibiotic GO:0046677 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Response to Antibiotic (GO:0046677). GO:0046677 is a biological process from the Gene Ontology.
Show evidence (1 reference)
PMID:28639230 SUPPORT Other
"Therapeutic efficacy against intracellular pathogens has been correlated mainly with the intracellular concentrations achieved by the different antimicrobial agents."
The pharmacokinetics review supports intracellular drug concentration as a gating principle for treating infections with intracellular bacterial reservoirs, including B. melitensis brucellosis.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Brucella Melitensis Brucellosis Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

9
Cardiovascular 2
Hepatosplenomegaly FREQUENT HP:0001433 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatosplenomegaly (HP:0001433). HP:0001433 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29863218 SUPPORT Human Clinical
"Common clinical features included fever (83%), arthralgias or arthritis (67%), and hepatosplenomegaly (61%)."
Hepatosplenomegaly occurred in 61% of the Houston brucellosis case series, supporting the frequent band.
Endocarditis VERY_RARE HP:0100584 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Endocarditis (HP:0100584). HP:0100584 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:11910696 SUPPORT Human Clinical
"Brucella endocarditis is a rare but a serious complication of human brucellosis."
The native-valve case series describes endocarditis as a rare but severe focal complication.
Genitourinary 1
Epididymo-orchitis OCCASIONAL HP:0100796 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Epididymo-orchitis, annotated with Orchitis (HP:0100796). HP:0100796 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40350681 SUPPORT Human Clinical
"Brucella contributed to 18 (30.51%) of epididymo-orchitis cases during study period."
The urology-clinic study observed brucellar epididymo-orchitis in an endemic setting and supports this focal genitourinary phenotype.
Metabolism 2
Fever VERY_FREQUENT HP:0001945 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fever (HP:0001945). HP:0001945 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29863218 SUPPORT Human Clinical
"Common clinical features included fever (83%), arthralgias or arthritis (67%), and hepatosplenomegaly (61%)."
Fever occurred in 83% of the Houston adult/pediatric brucellosis case series, supporting the very-frequent band.
Elevated transaminases FREQUENT Elevated circulating hepatic transaminase concentration HP:0002910 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated transaminases, annotated with Elevated circulating hepatic transaminase concentration (HP:0002910). HP:0002910 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29863218 SUPPORT Human Clinical
"The most common laboratory finding was mildly elevated transaminases."
The case series identifies mildly elevated transaminases as the most common laboratory finding.
Musculoskeletal 3
Arthritis OCCASIONAL HP:0001369 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Arthritis (HP:0001369). HP:0001369 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23236528 SUPPORT Human Clinical
"Arthralgia was common, affecting 65% patients overall, whereas arthritis affected only 26% patients"
The systematic review found frank arthritis in 26% of human brucellosis cases overall.
Sacroiliitis OCCASIONAL Sacroiliac arthritis HP:0012317 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sacroiliitis, annotated with Sacroiliac arthritis (HP:0012317). HP:0012317 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23236528 SUPPORT Human Clinical
"Overall, spondylitis and sacroiliitis were detected in 12–36% adults"
The systematic review documents sacroiliitis among adult focal osteoarticular manifestations.
Spondylitis OCCASIONAL HP:0033631 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Spondylitis (HP:0033631). HP:0033631 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23236528 SUPPORT Human Clinical
"Spondylitis 1 18 (1; 28)* 6 12 (7, 19) 9 11 (6; 18) 16 12 (8; 17)"
The systematic review found spondylitis in 12% of all-age human brucellosis cases.
Constitutional 1
Joint pain FREQUENT Arthralgia HP:0002829 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Arthralgia (HP:0002829). HP:0002829 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29863218 SUPPORT Human Clinical
"Common clinical features included fever (83%), arthralgias or arthritis (67%), and hepatosplenomegaly (61%)."
Arthralgias or arthritis occurred in 67% of the Houston brucellosis case series, supporting the frequent band for joint pain.
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Genetic Associations

5
IL4 rs2243250 susceptibility allele (Common host cytokine polymorphism associated with increased susceptibility)
Gene: IL4 hgnc:6014 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is IL4 (hgnc:6014). hgnc:6014 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE
Show evidence (1 reference)
PMID:31816580 SUPPORT Human Clinical
"our pooled analysis demonstrated that the mutant allele of IL-4 rs2243250 and IL-18 rs1946519 were associated with increased susceptibility to brucellosis."
The meta-analysis supports IL4 rs2243250 as a host susceptibility association rather than a monogenic cause.
IL18 rs1946519 susceptibility allele (Common host cytokine polymorphism associated with increased susceptibility)
Gene: IL18 hgnc:5986 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is IL18 (hgnc:5986). hgnc:5986 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE
Show evidence (1 reference)
PMID:31816580 SUPPORT Human Clinical
"IL-4 rs2243250 and IL-18 rs1946519 have a positive correlation with brucellosis whereas the IFN-γ UTR5644, TGF-β rs1800470 and rs1800471, TNF-α rs1800629, and IL-10 rs1800872 showed a negative association with this disease."
The cytokine-polymorphism meta-analysis reports a positive brucellosis association for IL18 rs1946519.
TGFB1 polymorphisms with negative pooled association (Common host cytokine polymorphisms with protective pooled association)
Gene: TGFB1 hgnc:11766 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TGFB1 (hgnc:11766). hgnc:11766 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: PROTECTIVE variant_origin: GERMLINE
Show evidence (1 reference)
PMID:31816580 SUPPORT Human Clinical
"the pooled results showed that the dominant models of IFN-γ UTR5644, TGF-β rs1800470 and rs1800471, TNF-α rs1800629, and IL-10 rs1800872 were significantly less frequent in brucellosis patients than the controls."
Across included case-control studies, TGFB1 rs1800470 and rs1800471 dominant models were less frequent in cases than controls.
TNF-238 focal-disease modifier (Host cytokine modifier of brucellar spondylodiscitis risk)
Gene: TNF hgnc:11892 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TNF (hgnc:11892). hgnc:11892 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: MODIFIER variant_origin: GERMLINE
Show evidence (1 reference)
PMID:39419734 SUPPORT Human Clinical
"only the last one was associated with brucellar spondylodiscitis [OR 2.91 (CI95 % 1.02-8.31), p = 0.047]."
The stepwise model retained TNF-238 G>A genotype as associated with brucellar spondylodiscitis, supporting a focal-complication modifier role.
TLR4 Asp299Gly susceptibility allele (Common innate immune receptor polymorphism associated with susceptibility)
Gene: TLR4 hgnc:11850 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TLR4 (hgnc:11850). hgnc:11850 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE
Show evidence (1 reference)
PMID:16343635 SUPPORT Human Clinical
"Allele 896G was more prevalent in patients with brucellosis compared to healthy controls (33.6% vs. 20.7%, P=0.000003)."
The Iranian case-control study supports association of the TLR4 Asp299Gly 896G allele with human brucellosis susceptibility.
💊

Medical Actions

3
Doxycycline-rifampicin combination therapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: doxycycline CHEBI:50845 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses doxycycline (CHEBI:50845). CHEBI:50845 is a therapeutic agent from Chemical Entities of Biological Interest. rifampicin CHEBI:28077 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses rifampicin (CHEBI:28077). CHEBI:28077 is a therapeutic agent from Chemical Entities of Biological Interest.
Six-week all-oral combination therapy used for uncomplicated human brucellosis, with convenience advantages but more relapse than aminoglycoside-containing regimens in some comparative analyses.
Mechanism Target:
INHIBITS Persistent multisystem infection — Prolonged intracellularly active antibiotic therapy clears infection and limits relapse.
INHIBITS Requirement for Cell-Penetrant Antimicrobials — Doxycycline and rifampicin reach the protected intracellular Brucella reservoir.
Show evidence (1 reference)
PMID:18162038 SUPPORT REVIEW SYNTHESIS Human Clinical
"The author panel suggests that the optimal treatment of uncomplicated brucellosis should be based on a six-week regimen of doxycycline combined either with streptomycin for 2–3 weeks, or rifampicin for six weeks."
The expert recommendation lists doxycycline plus six weeks of rifampicin as one optimal uncomplicated-brucellosis regimen.
Doxycycline-streptomycin combination therapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: doxycycline CHEBI:50845 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses doxycycline (CHEBI:50845). CHEBI:50845 is a therapeutic agent from Chemical Entities of Biological Interest. streptomycin CHEBI:17076 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses streptomycin (CHEBI:17076). CHEBI:17076 is a therapeutic agent from Chemical Entities of Biological Interest.
Aminoglycoside-containing combination therapy for uncomplicated human brucellosis that is generally more efficacious than doxycycline-rifampicin but requires parenteral streptomycin.
Mechanism Target:
INHIBITS Persistent multisystem infection — The doxycycline-aminoglycoside combination improves clearance and relapse prevention.
INHIBITS Requirement for Cell-Penetrant Antimicrobials — Doxycycline reaches the protected intracellular Brucella reservoir while streptomycin adds bactericidal aminoglycoside activity.
Show evidence (1 reference)
PMID:39172763 SUPPORT REVIEW SYNTHESIS Human Clinical
"Doxycycline + Gentamicin ranked the best in efficacy (SUCRA values: 0.94), the second is Triple (SUCRA values: 0.87), and the third is Doxycycline + Streptomycin (SUCRA values: 0.78)."
The randomized-trial network meta-analysis ranked doxycycline-streptomycin among the high-efficacy treatment strategies.
Doxycycline-gentamicin combination therapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: doxycycline CHEBI:50845 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses doxycycline (CHEBI:50845). CHEBI:50845 is a therapeutic agent from Chemical Entities of Biological Interest. gentamicin CHEBI:759884 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses gentamicin (CHEBI:759884). CHEBI:759884 is a therapeutic agent from Chemical Entities of Biological Interest.
Aminoglycoside-containing combination therapy that ranked highest for efficacy in a network meta-analysis of randomized brucellosis trials, with the usual tetracycline/aminoglycoside caveats for children, pregnancy, and focal disease.
Mechanism Target:
INHIBITS Persistent multisystem infection — The doxycycline-aminoglycoside combination improves clearance and relapse prevention.
INHIBITS Requirement for Cell-Penetrant Antimicrobials — Doxycycline reaches the protected intracellular Brucella reservoir while gentamicin adds bactericidal aminoglycoside activity.
Show evidence (1 reference)
PMID:39172763 SUPPORT REVIEW SYNTHESIS Human Clinical
"Doxycycline + Gentamicin ranked the best in efficacy (SUCRA values: 0.94), the second is Triple (SUCRA values: 0.87), and the third is Doxycycline + Streptomycin (SUCRA values: 0.78)."
The randomized-trial network meta-analysis ranked doxycycline-gentamicin highest for efficacy among compared brucellosis regimens.
🌍

Environmental Factors

1
Fresh milk, undercooked meat, and household livestock exposure
Raw animal products and household livestock contact increase the chance of zoonotic Brucella acquisition in endemic smallholder settings.
Show evidence (1 reference)
PMID:41860883 SUPPORT Human Clinical
"consumption of fresh milk or under-cooked meat (aOR 5.70, 95% CI 1.94-16.76), frequent contact with animal manure (aOR 3.29, 95% CI 1.29-8.47) and rearing livestock at home (aOR 3.75, 95% CI 1.36-10.32)."
The western Uganda antenatal study quantified raw-food and livestock exposures independently associated with Brucella seropositivity.
Mechanism Target:
PREDISPOSES Brucella melitensis zoonotic acquisition — Fresh milk, undercooked meat, animal manure contact, and livestock kept at home increase the exposure pressure that can culminate in B. melitensis acquisition.
🔬

Diagnosis

2
Brucella serology by agglutination or ELISA
Human brucellosis is commonly diagnosed by detecting anti-Brucella antibody responses with Rose Bengal, standard agglutination, or ELISA-style assays.
Show evidence (1 reference)
PMID:20075115 SUPPORT Human Clinical
"Serodiagnosis of brucellosis is carried out by detection of antibodies generated against LPS or whole-cell bacterial extracts by ELISA or agglutination tests using colorimetry."
The B. melitensis Omp28 diagnostic study describes standard serodiagnosis by ELISA or agglutination testing.
Rose Bengal screening with qPCR confirmation
Rose Bengal plate testing can be paired with real-time PCR in febrile patients to detect and confirm Brucella infection in endemic settings.
Show evidence (1 reference)
PMID:40140617 SUPPORT Human Clinical
"The seroprevalence of brucellosis in humans was 5.8% (n = 6/103) and there was 100% concordance between the results of the RBPT and qPCR in humans."
In a pyretic-patient cohort, Rose Bengal plate testing and qPCR were concordant for human brucellosis detection.
📈

Progression

3
Acute brucellosis
Acute disease is the early inflammatory presentation and can respond well to appropriately prolonged combination therapy.
Show evidence (1 reference)
PMID:41241000 SUPPORT Human Clinical
"In conclusion, acute brucellosis presents with a more pronounced inflammatory profile than subacute/chronic forms."
The phase-comparison cohort distinguishes acute from subacute/chronic disease and describes acute brucellosis as a more inflammatory phase.
Subacute and chronic brucellosis
Later presentations can be harder to treat than acute disease and may reflect persistent or focalized infection.
Show evidence (1 reference)
PMID:41241000 SUPPORT Human Clinical
"While patients with acute brucellosis demonstrated a significantly higher therapeutic response rate, the serological response was also more pronounced in this group."
The comparison of acute versus subacute/chronic cases supports later disease as a clinically distinct, less treatment-responsive phase.
Relapse after apparent therapy response
Relapse can follow therapy even for uncomplicated brucellosis, which is why standard adult treatment uses multi-week combination antibiotic courses.
Show evidence (1 reference)
PMID:18162038 SUPPORT REVIEW SYNTHESIS Human Clinical
"More importantly, these regimens still allow for a small, albeit significant percentage of therapeutic failures, most commonly in the form of relapses, ranging from 5% to 15% of uncomplicated cases."
The treatment recommendations describe relapse as the commonest form of therapeutic failure after standard regimens.
📊

Prevalence

3
Culture-confirmed predominantly B. melitensis cases in Israel, 2004-2022
Annual Incidence 1.6 per 100,000 per year 1–9 per 100,000 per year
Show evidence (1 reference)
DOI:10.1017/S0950268824000803 SUPPORT Human Clinical
"The average annual incidence rates overall and for the Arab, Druze, and Jewish sectors were 1.6/100,000, 6.6/100,000, 5.5/100,000, and 0.18/100,000, respectively."
The national culture-confirmed series gives an annual population incidence for a cohort in which 99.6% of typed isolates were B. melitensis.
Reported human brucellosis in Ningxia, China, 2010-2024
Annual Incidence 35.08 per 100,000 per year 1–9 per 10,000 per year
This surveillance estimate is not species-stratified; it is retained as a regional human brucellosis burden estimate and should not be read as a culture-confirmed B. melitensis-only incidence rate.
Show evidence (1 reference)
PMID:41632803 SUPPORT Human Clinical
"A total of 35 665 human brucellosis cases were reported in Ningxia, with no associated deaths, during the study period. The average annual incidence rates was 35.08/100,000, ranging from 3.31 to 84.80 per 100,000."
Provides a 2010-2024 regional annual incidence estimate for reported human brucellosis in a high-endemicity province.
Ethiopian human serosurveys, 2015-2024
Point Prevalence 6900.0 per 100,000 >1 in 1,000
This pooled seroprevalence is not species-stratified and reflects heterogeneous Ethiopian human serosurveys, not a culture-confirmed population prevalence of B. melitensis alone.
Show evidence (1 reference)
PMID:39696174 SUPPORT Human Clinical
"The seroprevalence of brucellosis was higher in humans at 6.9% (95% CI: 4.9, 8.8) and lower in cattle at 3.5% (95% CI: 2.2, 4.7)."
The Ethiopian One Health meta-analysis estimates human brucellosis seropositivity; the rate is normalized from 6.9% to 6,900 per 100,000.
🦠

Infectious Agent

1
Brucella melitensis
Facultatively intracellular Brucella species whose preferred animal hosts are sheep and goats and that causes human brucellosis after zoonotic spillover.
Brucella melitensis NCBITaxon:29459 NCBI Taxonomy (NCBITaxon)
Show evidence (1 reference)
DOI:10.1017/S0950268824000803 SUPPORT Human Clinical
"Brucella melitensis was the dominant species (99.6%)."
In a national culture-confirmed human brucellosis series, nearly every isolate was B. melitensis.
↔️

Transmission

1
Small-ruminant dairy and livestock zoonotic exposure
Human B. melitensis infection is acquired from infected sheep and goats or their products, especially through raw milk, unpasteurized dairy, and direct contact with infected herds or abortion materials.
Show evidence (1 reference)
PMID:23236528 SUPPORT Human Clinical
"Brucellosis is a bacterial disease transmitted to humans by consumption of infected, unpasteurised animal milk or through direct contact with infected animals, particularly aborted foetuses"
The systematic review captures the major ingestion and direct-contact routes for zoonotic human brucellosis.
🐁

Animal Models

1
IL-12p40-deficient B. melitensis chronic splenic reservoir mouse
Intranasal challenge of IL-12p40-deficient BALB/c mice with fluorescent B. melitensis creates high chronic splenic burdens that permit in situ microscopy of lipid-rich, CD11c+/CD205+/Arginase1+ reservoir cells.
Species
Mouse
Genotype
IL-12p40-/- BALB/c
Publication
PMID:26376185
Pathograph links
Chronic splenic myeloid reservoir formation partially recapitulates fidelity: moderate The model reproduces durable splenic B. melitensis infection and exposes the phenotype of infected myeloid reservoir cells.
Limitations: The model requires an IL-12p40 knockout background and a high intranasal inoculum to make infected splenic cells abundant enough for direct microscopy, so it models reservoir-cell biology under impaired Th1/Th17 control rather than the full immunocompetent human syndrome.
Show evidence (1 reference)
PMID:26376185 SUPPORT Model Organism
"we used a model in which infected cells can be observed directly in situ and where the differentiation of M2a macrophages is favored by the absence of an IL-12-dependent Th1 response."
The study describes the IL-12p40-deficient mouse model and the reason it was selected for direct observation of chronic B. melitensis reservoir cells in situ.
{ }

Source YAML

click to show 
name: Brucella Melitensis Brucellosis
creation_date: "2026-09-29T05:55:32Z"
category: Infectious Disease
description: >-
  Brucella melitensis brucellosis is a small-ruminant-associated form of human
  brucellosis caused by the facultatively intracellular bacterium Brucella
  melitensis. Humans are infected through unpasteurized sheep/goat dairy
  products, contact with infected animals or birth products, and occupational or
  laboratory aerosol exposure; the resulting disease is a systemic febrile
  brucellosis syndrome that can relapse or seed focal complications when it is
  not treated with prolonged combination antibiotics.
disease_term:
  preferred_term: Brucella melitensis brucellosis
  term:
    id: MONDO:0001972
    label: Brucella melitensis brucellosis
parents:
- Brucellosis
synonyms:
- Brucella melitensis infection
definitions:
- name: B. melitensis zoonotic brucellosis
  definition_type: CASE_DEFINITION
  description: >-
    Brucella melitensis brucellosis is human brucellosis caused by B. melitensis
    after zoonotic exposure to infected small ruminants or contaminated animal
    products; it is tracked at this MONDO child because a species-specific
    sheep/goat reservoir and high human-disease prominence distinguish it from
    all-cause brucellosis.
  scope: Species-specific human brucellosis definition
  evidence:
  - reference: DOI:10.1017/S0950268824000803
    reference_title: "National epidemiology of culture-confirmed brucellosis in Israel, 2004-2022"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brucella melitensis was the dominant species (99.6%)."
    explanation: >-
      In a national culture-confirmed human brucellosis series, nearly every
      isolate was B. melitensis, supporting this MONDO child as a human
      brucellosis entity caused by that species.
classifications:
  harrisons_chapter:
  - classification_value: INFECTIOUS_DISEASES
    evidence:
    - reference: PMID:23236528
      reference_title: "Clinical manifestations of human brucellosis: a systematic review and meta-analysis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Brucellosis is a bacterial disease transmitted to humans by consumption of infected, unpasteurised animal milk or through direct contact with infected animals"
      explanation: >-
        Species-specific B. melitensis disease is a zoonotic bacterial
        infectious disease within the broader human brucellosis syndrome.
prevalence:
- population: Culture-confirmed predominantly B. melitensis cases in Israel, 2004-2022
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 1.6
  rate_denominator: POPULATION_PER_YEAR
  evidence:
  - reference: DOI:10.1017/S0950268824000803
    reference_title: "National epidemiology of culture-confirmed brucellosis in Israel, 2004-2022"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The average annual incidence rates overall and for the Arab, Druze, and Jewish sectors were 1.6/100,000, 6.6/100,000, 5.5/100,000, and 0.18/100,000, respectively."
    explanation: >-
      The national culture-confirmed series gives an annual population incidence
      for a cohort in which 99.6% of typed isolates were B. melitensis.
- population: Reported human brucellosis in Ningxia, China, 2010-2024
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 35.08
  rate_denominator: POPULATION_PER_YEAR
  notes: >-
    This surveillance estimate is not species-stratified; it is retained as a
    regional human brucellosis burden estimate and should not be read as a
    culture-confirmed B. melitensis-only incidence rate.
  evidence:
  - reference: PMID:41632803
    reference_title: "Prevalence and spatial distribution characteristics of human brucellosis in Ningxia from 2010 to 2024."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A total of 35 665 human brucellosis cases were reported in Ningxia, with no associated deaths, during the study period. The average annual incidence rates was 35.08/100,000, ranging from 3.31 to 84.80 per 100,000."
    explanation: >-
      Provides a 2010-2024 regional annual incidence estimate for reported human
      brucellosis in a high-endemicity province.
- population: Ethiopian human serosurveys, 2015-2024
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 6900.0
  notes: >-
    This pooled seroprevalence is not species-stratified and reflects
    heterogeneous Ethiopian human serosurveys, not a culture-confirmed
    population prevalence of B. melitensis alone.
  evidence:
  - reference: PMID:39696174
    reference_title: "Human and animal brucellosis and risk factors for human infection in Ethiopia: a systematic review and meta-analysis (2015-2024)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The seroprevalence of brucellosis was higher in humans at 6.9% (95% CI: 4.9, 8.8) and lower in cattle at 3.5% (95% CI: 2.2, 4.7)."
    explanation: >-
      The Ethiopian One Health meta-analysis estimates human brucellosis
      seropositivity; the rate is normalized from 6.9% to 6,900 per 100,000.
infectious_agent:
- name: Brucella melitensis
  infectious_agent_term:
    preferred_term: Brucella melitensis
    term:
      id: NCBITaxon:29459
      label: Brucella melitensis
  description: >-
    Facultatively intracellular Brucella species whose preferred animal hosts
    are sheep and goats and that causes human brucellosis after zoonotic
    spillover.
  evidence:
  - reference: DOI:10.1017/S0950268824000803
    reference_title: "National epidemiology of culture-confirmed brucellosis in Israel, 2004-2022"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brucella melitensis was the dominant species (99.6%)."
    explanation: >-
      In a national culture-confirmed human brucellosis series, nearly every
      isolate was B. melitensis.
agent_life_cycle:
  description: >-
    B. melitensis is maintained primarily in infected small ruminants, especially
    sheep and goats, which seed human food-borne, contact, and aerosol exposure.
    Humans are incidental clinical hosts and do not maintain onward transmission.
  hosts:
  - preferred_term: Homo sapiens
    role: incidental clinical host
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  - preferred_term: sheep
    role: primary small-ruminant reservoir host
    term:
      id: NCBITaxon:9940
      label: Ovis aries
  - preferred_term: goat
    role: primary small-ruminant reservoir host
    term:
      id: NCBITaxon:9925
      label: Capra hircus
  evidence:
  - reference: PMID:36653223
    reference_title: "Vaccine properties of Brucella melitensis 16MΔwzm and reactivation of placental infection in pregnant sheep."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "In endemic regions, small ruminants infected by Brucella melitensis are the main source of human brucellosis."
    explanation: >-
      The B. melitensis livestock-vaccine paper's background identifies infected
      small ruminants as the reservoir source for endemic human disease.
transmission:
- name: Small-ruminant dairy and livestock zoonotic exposure
  description: >-
    Human B. melitensis infection is acquired from infected sheep and goats or
    their products, especially through raw milk, unpasteurized dairy, and direct
    contact with infected herds or abortion materials.
  evidence:
  - reference: PMID:23236528
    reference_title: "Clinical manifestations of human brucellosis: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brucellosis is a bacterial disease transmitted to humans by consumption of infected, unpasteurised animal milk or through direct contact with infected animals, particularly aborted foetuses"
    explanation: >-
      The systematic review captures the major ingestion and direct-contact
      routes for zoonotic human brucellosis.
progression:
- phase: Acute brucellosis
  notes: >-
    Acute disease is the early inflammatory presentation and can respond well to
    appropriately prolonged combination therapy.
  evidence:
  - reference: PMID:41241000
    reference_title: "Laboratory parameters and serum tube agglutination test as markers for brucellosis treatment response."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In conclusion, acute brucellosis presents with a more pronounced inflammatory profile than subacute/chronic forms."
    explanation: >-
      The phase-comparison cohort distinguishes acute from subacute/chronic
      disease and describes acute brucellosis as a more inflammatory phase.
- phase: Subacute and chronic brucellosis
  notes: >-
    Later presentations can be harder to treat than acute disease and may
    reflect persistent or focalized infection.
  evidence:
  - reference: PMID:41241000
    reference_title: "Laboratory parameters and serum tube agglutination test as markers for brucellosis treatment response."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "While patients with acute brucellosis demonstrated a significantly higher therapeutic response rate, the serological response was also more pronounced in this group."
    explanation: >-
      The comparison of acute versus subacute/chronic cases supports later
      disease as a clinically distinct, less treatment-responsive phase.
- phase: Relapse after apparent therapy response
  notes: >-
    Relapse can follow therapy even for uncomplicated brucellosis, which is why
    standard adult treatment uses multi-week combination antibiotic courses.
  evidence:
  - reference: PMID:18162038
    reference_title: "Perspectives for the treatment of brucellosis in the 21st century: the Ioannina recommendations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "More importantly, these regimens still allow for a small, albeit significant percentage of therapeutic failures, most commonly in the form of relapses, ranging from 5% to 15% of uncomplicated cases."
    explanation: >-
      The treatment recommendations describe relapse as the commonest form of
      therapeutic failure after standard regimens.
pathophysiology:
- name: Brucella melitensis zoonotic acquisition
  description: >-
    Exposure to infected small ruminants or their unpasteurized dairy products
    introduces B. melitensis into the human host and initiates the intracellular
    brucellosis infection program.
  biological_scale: ORGANISM
  role: trigger
  evidence:
  - reference: DOI:10.1017/S0950268824000803
    reference_title: "National epidemiology of culture-confirmed brucellosis in Israel, 2004-2022"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brucellosis is endemic in Israel, affecting mainly sheep and goats, dairy cattle, and humans"
    explanation: >-
      The culture-confirmed B. melitensis epidemiology series places human
      disease in the same endemic sheep, goat, and cattle setting that seeds
      zoonotic exposure.
  downstream:
  - target: Phagocyte Brucella-containing vacuole formation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Acquired B. melitensis crosses a mucosal or cutaneous barrier and is
      internalized by phagocytes, creating the Brucella-containing vacuole in
      which the intracellular cycle begins.
    evidence:
    - reference: PMID:27899503
      reference_title: "Postreplication Roles of the Brucella VirB Type IV Secretion System Uncovered via Conditional Expression of the VirB11 ATPase."
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: BACKGROUND
      snippet: "The ability of Brucella spp. to cause disease depends on their intracellular cycle within host phagocytes, such as macrophages or dendritic cells (8, 9), in which the bacterium resides in a membrane-bound compartment called the Brucella-containing vacuole (BCV) (10)."
      explanation: >-
        The Brucella intracellular-cycle paper's background links disease
        causation to residence within a BCV in macrophages and dendritic cells,
        connecting acquisition to the intracellular niche.
- name: Phagocyte Brucella-containing vacuole formation
  description: >-
    Internalized Brucella spp. reside in Brucella-containing vacuoles inside
    host macrophages and dendritic cells, setting up the intracellular trafficking
    program required for persistent brucellosis.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  - preferred_term: dendritic cell
    term:
      id: CL:0000451
      label: dendritic cell
  evidence:
  - reference: PMID:27899503
    reference_title: "Postreplication Roles of the Brucella VirB Type IV Secretion System Uncovered via Conditional Expression of the VirB11 ATPase."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "Upon their initial formation following phagocytic uptake, BCVs undergo maturation events along the endocytic pathway to become an endosomal BCV (eBCV) (10–12)."
    explanation: >-
      The Brucella cell-biology paper describes formation of endosomal
      Brucella-containing vacuoles after phagocytic uptake.
  downstream:
  - target: VirB-dependent ER-derived replicative vacuole maturation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      The early endosomal BCV is converted into an endoplasmic-reticulum-derived
      replicative organelle through Brucella VirB type IV secretion system
      activity.
    evidence:
    - reference: PMID:27899503
      reference_title: "Postreplication Roles of the Brucella VirB Type IV Secretion System Uncovered via Conditional Expression of the VirB11 ATPase."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "BCVs are remodeled into replication-permissive organelles (rBCV) derived from the host endoplasmic reticulum, a process that requires modulation of host secretory functions via delivery of effector proteins by the Brucella VirB type IV secretion system (T4SS)."
      explanation: >-
        This experimental B. abortus macrophage study documents the VirB T4SS
        step that remodels endosomal BCVs into ER-derived replicative BCVs, a
        conserved Brucella intracellular-cycle step used here for the B.
        melitensis syndrome.
  - target: Brucella Omp25-dependent macrophage immune evasion
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Brucella intracellular macrophage residence is reinforced by innate immune
      evasion, including Omp25-associated TNF-alpha suppression and impaired
      infected-phagocyte apoptosis.
    evidence:
    - reference: PMID:12414158
      reference_title: "The innate immune response against Brucella in humans."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "By constructing null mutants, we demonstrated that this inhibition involves the outer membrane protein Omp25 of Brucella, however the mechanism regulating the inhibition has not yet been clearly defined."
      explanation: >-
        The Brucella innate-immunity review links Omp25 to macrophage
        TNF-alpha inhibition; the edge uses this as genus-level support for
        innate immune evasion downstream of the BCV niche.
- name: VirB-dependent ER-derived replicative vacuole maturation
  description: >-
    Brucella VirB type IV secretion remodels the endosomal Brucella-containing
    vacuole into a host endoplasmic-reticulum-derived replicative organelle,
    allowing intracellular expansion rather than lysosomal elimination.
  biological_scale: CELLULAR
  conforms_to: "intracellular_pathogen_persistence#Intracellular Niche and Beta-Lactam Exclusion"
  evidence:
  - reference: PMID:27899503
    reference_title: "Postreplication Roles of the Brucella VirB Type IV Secretion System Uncovered via Conditional Expression of the VirB11 ATPase."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The VirB T4SS is essential for rBCV biogenesis, as VirB-deficient mutants are stalled in eBCVs and cannot mediate rBCV biogenesis."
    explanation: >-
      Conditional VirB11 expression in B. abortus shows that VirB type IV
      secretion is required for formation of the replicative BCV stage.
  downstream:
  - target: Autophagic Brucella-containing vacuole egress
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Post-replicative Brucella-containing vacuoles become autophagic vacuoles
      that enable bacterial egress and subsequent cell-to-cell infection.
    evidence:
    - reference: PMID:27899503
      reference_title: "Postreplication Roles of the Brucella VirB Type IV Secretion System Uncovered via Conditional Expression of the VirB11 ATPase."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Following replication, rBCVs are converted into autophagic vacuoles (aBCVs) that facilitate bacterial egress and subsequent infections, arguing that the bacterium sequentially manipulates multiple cellular pathways to complete its cycle."
      explanation: >-
        Conditional VirB11 experiments and Brucella cell biology connect the
        post-replicative vacuole state to bacterial egress and reinfection.
- name: Brucella Omp25-dependent macrophage immune evasion
  description: >-
    Brucella outer-membrane and intracellular programs blunt human macrophage
    antimicrobial defense by suppressing TNF-alpha secretion and preventing
    monocyte/macrophage apoptosis, extending the infected phagocyte niche.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  evidence:
  - reference: PMID:12414158
    reference_title: "The innate immune response against Brucella in humans."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "in humans, Brucella suis impairs the apoptosis of monocytes and macrophages, thus preventing its host cell elimination."
    explanation: >-
      The review summarizes Brucella anti-apoptotic effects in human monocytes
      and macrophages as one mechanism extending survival of infected host cells.
  downstream:
  - target: Th1 cytokine-dependent containment failure
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Omp25-associated TNF-alpha suppression can reduce IL-12 and Th1 cytokine
      development, counteracting IFN-gamma/TNF-alpha-dependent clearance.
    evidence:
    - reference: PMID:12414158
      reference_title: "The innate immune response against Brucella in humans."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "It is likely that the Omp25-induced effect on TNF-alpha production assists bacterial evasion of antimicrobial defences at different levels."
      explanation: >-
        The review interprets Omp25-dependent TNF-alpha suppression as
        antimicrobial-defense evasion that can weaken innate activation and Th1
        development.
- name: Th1 cytokine-dependent containment failure
  description: >-
    Clearance of Brucella depends on early TNF-alpha, IFN-gamma, and IL-12
    cellular immunity; inadequate Th1 containment permits persistence rather
    than resolution.
  biological_scale: ORGANISM
  evidence:
  - reference: PMID:12414158
    reference_title: "The innate immune response against Brucella in humans."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Brucella infection results in Type1 (Th1) cellular immune response which promotes a clearance of the bacterial organism."
    explanation: >-
      The innate-immunity review identifies the Th1 response as a clearance axis,
      supporting persistence when this axis is blunted.
  downstream:
  - target: Chronic splenic myeloid reservoir formation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      A susceptible IL-12p40-deficient mouse model makes it possible to observe
      chronic B. melitensis splenic reservoir cells when protective Th1/Th17
      control is impaired.
    evidence:
    - reference: PMID:26376185
      reference_title: "In Situ Characterization of Splenic Brucella melitensis Reservoir Cells during the Chronic Phase of Infection in Susceptible Mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "To bypass this problem, we have previously used highly susceptible IL-12p40-/- BALB/c mice."
      explanation: >-
        The reservoir-cell study used IL-12p40-deficient mice to expose splenic
        infected cells during chronic B. melitensis infection.
- name: Autophagic Brucella-containing vacuole egress
  description: >-
    Replication-stage Brucella-containing vacuoles convert into
    autophagosome-like vacuoles that complete the intracellular cycle by
    releasing bacteria for subsequent infections.
  biological_scale: CELLULAR
  evidence:
  - reference: PMID:27899503
    reference_title: "Postreplication Roles of the Brucella VirB Type IV Secretion System Uncovered via Conditional Expression of the VirB11 ATPase."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Considering that aBCVs facilitate Brucella release from macrophages (12), these findings clearly demonstrate that aBCV formation and subsequent bacterial egress are VirB T4SS-dependent processes."
    explanation: >-
      The conditional VirB11 B. abortus macrophage study places autophagic BCVs
      after replication and ties them to bacterial egress.
  downstream:
  - target: Hematogenous dissemination
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Cell egress enables ongoing intracellular spread; in human B. melitensis
      brucellosis, culture-confirmed cases commonly have bacteraemia that can
      seed distant focal sites.
    evidence:
    - reference: DOI:10.1017/S0950268824000803
      reference_title: "National epidemiology of culture-confirmed brucellosis in Israel, 2004-2022"
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Of 2,489 unique cases, 99.8% were bacteraemic"
      explanation: >-
        Bacteraemia in the culture-confirmed, almost entirely B. melitensis
        cohort supports bloodstream dissemination after intracellular spread.
- name: Hematogenous dissemination
  description: >-
    B. melitensis frequently enters the bloodstream, distributing intracellular
    bacteria from the systemic reservoir to bone, joints, cardiac valves, the
    genitourinary tract, and reticuloendothelial organs.
  biological_scale: ORGANISM
  evidence:
  - reference: DOI:10.1017/S0950268824000803
    reference_title: "National epidemiology of culture-confirmed brucellosis in Israel, 2004-2022"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of 2,489 unique cases, 99.8% were bacteraemic"
    explanation: >-
      A national culture-confirmed cohort in which 99.6% of Brucella isolates
      were B. melitensis documented bloodstream infection in nearly all cases.
  downstream:
  - target: Osteoarticular seeding
    description: >-
      Bloodstream spread can establish focal infection in peripheral joints,
      sacroiliac joints, and vertebral structures.
    evidence:
    - reference: PMID:42603185
      reference_title: "Pediatric brucellosis: predictors of hospitalization, complications, and relapse in a nationwide multicenter cohort."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Complications occurred in 87 patients (8.3%), most frequently osteoarticular (spondylitis, sacroiliitis, and osteomyelitis), whereas neurobrucellosis was rare (0.9%); relapse occurred in 34 patients (3.2%)."
      explanation: >-
        The nationwide pediatric cohort identifies osteoarticular disease as the
        most frequent complication, supporting focal skeletal seeding.
  - target: Cardiac valve seeding
    description: Bloodstream spread can establish focal Brucella infection on cardiac valves.
    evidence:
    - reference: PMID:11910696
      reference_title: "[Brucella endocarditis of native valves. Report of 3 cases]."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Brucella endocarditis is a rare but a serious complication of human brucellosis."
      explanation: >-
        The native-valve case series supports endocarditis as a rare focal
        brucellosis complication.
  - target: Genitourinary seeding
    description: Bloodstream spread can establish focal infection in the epididymis and testis.
    evidence:
    - reference: PMID:40350681
      reference_title: "Clinical and therapeutic insights into brucellar epididymo-orchitis: a retrospective analysis in a brucellosis endemic area."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Involvement of testis and epididymis can occur in acute and chronic forms of systemic brucellosis."
      explanation: >-
        The endemic-area retrospective series supports testicular and epididymal
        involvement as focal genitourinary disease.
  - target: Chronic splenic myeloid reservoir formation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Hematogenous infection can reach reticuloendothelial organs; susceptible
      mice then expose splenic B. melitensis myeloid reservoirs as a model of
      chronic persistence.
    evidence:
    - reference: PMID:26376185
      reference_title: "In Situ Characterization of Splenic Brucella melitensis Reservoir Cells during the Chronic Phase of Infection in Susceptible Mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "This characterization of B. melitensis reservoir cells could provide a better understanding of Brucella persistence in the host and lead to the design of more efficient therapeutic strategies."
      explanation: >-
        The B. melitensis mouse study supports the spleen as a durably colonized
        reticuloendothelial site during chronic model-organism infection.
- name: Osteoarticular seeding
  description: >-
    Focal osteoarticular infection affects peripheral joints, sacroiliac joints,
    or vertebral structures after dissemination.
  biological_scale: ORGANISM
  downstream:
  - target: Arthritis
    description: Peripheral joint infection may manifest as arthritis.
    evidence:
    - reference: PMID:23236528
      reference_title: "Clinical manifestations of human brucellosis: a systematic review and meta-analysis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Arthralgia was common, affecting 65% patients overall, whereas arthritis affected only 26% patients"
      explanation: The systematic review found arthritis in 26% of brucellosis cases.
  - target: Sacroiliitis
    description: Sacroiliac focal infection manifests as sacroiliitis.
    evidence:
    - reference: PMID:23236528
      reference_title: "Clinical manifestations of human brucellosis: a systematic review and meta-analysis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Overall, spondylitis and sacroiliitis were detected in 12–36% adults"
      explanation: The systematic review documents sacroiliitis as an adult focal manifestation.
  - target: Spondylitis
    description: Vertebral focal infection manifests as spondylitis.
    evidence:
    - reference: PMID:23236528
      reference_title: "Clinical manifestations of human brucellosis: a systematic review and meta-analysis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Spondylitis 1 18 (1; 28)* 6 12 (7, 19) 9 11 (6; 18) 16 12 (8; 17)"
      explanation: The systematic review found spondylitis in 12% of all-age cases.
- name: Cardiac valve seeding
  description: Focal Brucella infection of cardiac valves produces endocarditis.
  biological_scale: ORGANISM
  downstream:
  - target: Endocarditis
    description: Valvular infection manifests as endocarditis.
    evidence:
    - reference: PMID:11910696
      reference_title: "[Brucella endocarditis of native valves. Report of 3 cases]."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Brucella endocarditis is a rare but a serious complication of human brucellosis."
      explanation: The native-valve case series documents endocarditis as rare but severe focal disease.
- name: Genitourinary seeding
  description: Focal genitourinary infection affects the epididymis and testis.
  biological_scale: ORGANISM
  downstream:
  - target: Epididymo-orchitis
    description: Epididymal and testicular infection manifests as epididymo-orchitis.
    evidence:
    - reference: PMID:40350681
      reference_title: "Clinical and therapeutic insights into brucellar epididymo-orchitis: a retrospective analysis in a brucellosis endemic area."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Brucella contributed to 18 (30.51%) of epididymo-orchitis cases during study period."
      explanation: >-
        The retrospective urology-clinic series documents brucellar
        epididymo-orchitis as a focal form of systemic brucellosis.
- name: Chronic splenic myeloid reservoir formation
  description: >-
    In a susceptible IL-12p40-deficient mouse model, chronic B. melitensis
    infection persists in lipid-rich splenic myeloid reservoir cells that express
    dendritic-cell markers and Arginase1.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:26376185
    reference_title: "In Situ Characterization of Splenic Brucella melitensis Reservoir Cells during the Chronic Phase of Infection in Susceptible Mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Most of the infected spleen cells contained high levels of lipids and expressed CD11c and CD205 dendritic cell markers and Arginase1, but were negative for the M2a markers Fizz1 or CD301."
    explanation: >-
      The susceptible-mouse study directly observed the phenotype of chronic B.
      melitensis-infected splenic reservoir cells.
  downstream:
  - target: Persistent multisystem infection
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Long-lived intracellular myeloid reservoirs are a model for the difficult
      clearance and relapse-prone persistence of human brucellosis.
    evidence:
    - reference: PMID:26376185
      reference_title: "In Situ Characterization of Splenic Brucella melitensis Reservoir Cells during the Chronic Phase of Infection in Susceptible Mice."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "This characterization of B. melitensis reservoir cells could provide a better understanding of Brucella persistence in the host and lead to the design of more efficient therapeutic strategies."
      explanation: >-
        The model-organism result is indirect support for how splenic reservoir
        biology can contribute to persistent human B. melitensis infection.
- name: Persistent multisystem infection
  description: >-
    Intracellular B. melitensis infection produces a persistent, relapse-prone,
    systemic brucellosis syndrome that can disseminate hematogenously and seed
    focal complications.
  biological_scale: ORGANISM
  evidence:
  - reference: PMID:18162038
    reference_title: "Perspectives for the treatment of brucellosis in the 21st century: the Ioannina recommendations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "More importantly, these regimens still allow for a small, albeit significant percentage of therapeutic failures, most commonly in the form of relapses, ranging from 5% to 15% of uncomplicated cases."
    explanation: >-
      The treatment recommendations summarize relapse after otherwise standard
      regimens, supporting relapse-prone persistence as a clinical property of
      human brucellosis.
  downstream:
  - target: Fever
    description: Systemic brucellosis commonly manifests with fever.
    evidence:
    - reference: PMID:29863218
      reference_title: "Brucellosis in Adults and Children: A 10-Year Case Series at Two Large Academic Hospitals in Houston, Texas."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Common clinical features included fever (83%), arthralgias or arthritis (67%), and hepatosplenomegaly (61%)."
      explanation: >-
        The case series identifies fever as a common clinical feature of human
        brucellosis.
  - target: Joint pain
    description: The multisystem syndrome commonly includes arthralgia or arthritis.
    evidence:
    - reference: PMID:29863218
      reference_title: "Brucellosis in Adults and Children: A 10-Year Case Series at Two Large Academic Hospitals in Houston, Texas."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Common clinical features included fever (83%), arthralgias or arthritis (67%), and hepatosplenomegaly (61%)."
      explanation: >-
        The case series identifies arthralgias or arthritis as common
        musculoskeletal manifestations of human brucellosis.
  - target: Hepatosplenomegaly
    description: Reticuloendothelial infection can enlarge the liver and spleen.
    evidence:
    - reference: PMID:29863218
      reference_title: "Brucellosis in Adults and Children: A 10-Year Case Series at Two Large Academic Hospitals in Houston, Texas."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Common clinical features included fever (83%), arthralgias or arthritis (67%), and hepatosplenomegaly (61%)."
      explanation: >-
        The case series identifies hepatosplenomegaly as one of the common
        clinical findings in human brucellosis.
  - target: Granulomatous reticuloendothelial inflammation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Persistent intracellular Brucella infection can elicit granulomatous
      immune aggregates that balance containment with incomplete bacterial
      elimination.
    evidence:
    - reference: PMID:41921569
      reference_title: "Re-defining granulomas: bacterial effectors, host circuits, and spatially resolved immunity."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Across diverse pathogens, including Mycobacterium, Salmonella, Yersinia, and Brucella, bacterial effector proteins actively remodel macrophage activation states and cytokine responses to shape granuloma architecture."
      explanation: >-
        The granuloma review includes Brucella among intracellular pathogens
        whose effectors and host cytokine programs shape granulomatous
        architecture.
  - target: Elevated transaminases
    description: Systemic brucellosis can involve hepatic inflammation reflected by elevated transaminases.
    evidence:
    - reference: PMID:29863218
      reference_title: "Brucellosis in Adults and Children: A 10-Year Case Series at Two Large Academic Hospitals in Houston, Texas."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The most common laboratory finding was mildly elevated transaminases."
      explanation: >-
        The case series reports elevated transaminases as the most common
        laboratory abnormality.
- name: Granulomatous reticuloendothelial inflammation
  description: >-
    Persistent Brucella infection can be walled into myeloid and lymphoid
    granulomatous aggregates, containing systemic spread imperfectly while
    preserving niches for intracellular survival.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:41921569
    reference_title: "Re-defining granulomas: bacterial effectors, host circuits, and spatially resolved immunity."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Granulomas are organized immune aggregates of myeloid and lymphoid cells that arise when the host fails to eliminate persistent stimuli"
    explanation: >-
      The granuloma review defines the tissue response represented by this
      Brucella containment node.
  downstream:
  - target: Hepatosplenomegaly
    description: Reticuloendothelial inflammation contributes to liver and spleen enlargement.
    evidence:
    - reference: PMID:29863218
      reference_title: "Brucellosis in Adults and Children: A 10-Year Case Series at Two Large Academic Hospitals in Houston, Texas."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Common clinical features included fever (83%), arthralgias or arthritis (67%), and hepatosplenomegaly (61%)."
      explanation: >-
        The Houston case series reports hepatosplenomegaly as a common
        reticuloendothelial finding in human brucellosis.
- name: Requirement for Cell-Penetrant Antimicrobials
  description: >-
    B. melitensis persists inside host phagocytes in the Brucella-containing
    vacuole, so effective brucellosis regimens are built from prolonged
    combinations that include intracellularly active agents such as doxycycline
    and rifampicin rather than poorly cell-penetrant beta-lactams.
  role: therapeutic_vulnerability
  conforms_to: "intracellular_pathogen_persistence#Requirement for Cell-Penetrant Antimicrobials"
  biological_processes:
  - preferred_term: Response to Antibiotic
    term:
      id: GO:0046677
      label: response to antibiotic
  evidence:
  - reference: PMID:28639230
    reference_title: "Intracellular Pharmacokinetics of Antibacterials and Their Clinical Implications."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Therapeutic efficacy against intracellular pathogens has been correlated
      mainly with the intracellular concentrations achieved by the different
      antimicrobial agents.
    explanation: >-
      The pharmacokinetics review supports intracellular drug concentration as a
      gating principle for treating infections with intracellular bacterial
      reservoirs, including B. melitensis brucellosis.
phenotypes:
- category: Clinical
  name: Fever
  description: Fever is the dominant systemic manifestation of B. melitensis brucellosis.
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:29863218
    reference_title: "Brucellosis in Adults and Children: A 10-Year Case Series at Two Large Academic Hospitals in Houston, Texas."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common clinical features included fever (83%), arthralgias or arthritis (67%), and hepatosplenomegaly (61%)."
    explanation: >-
      Fever occurred in 83% of the Houston adult/pediatric brucellosis case
      series, supporting the very-frequent band.
- category: Clinical
  name: Joint pain
  description: Arthralgia is a common musculoskeletal manifestation of human brucellosis.
  phenotype_term:
    preferred_term: Arthralgia
    term:
      id: HP:0002829
      label: Arthralgia
  frequency: FREQUENT
  evidence:
  - reference: PMID:29863218
    reference_title: "Brucellosis in Adults and Children: A 10-Year Case Series at Two Large Academic Hospitals in Houston, Texas."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common clinical features included fever (83%), arthralgias or arthritis (67%), and hepatosplenomegaly (61%)."
    explanation: >-
      Arthralgias or arthritis occurred in 67% of the Houston brucellosis case
      series, supporting the frequent band for joint pain.
- category: Clinical
  name: Hepatosplenomegaly
  description: Enlargement of the liver and spleen accompanies reticuloendothelial involvement.
  phenotype_term:
    preferred_term: Hepatosplenomegaly
    term:
      id: HP:0001433
      label: Hepatosplenomegaly
  frequency: FREQUENT
  evidence:
  - reference: PMID:29863218
    reference_title: "Brucellosis in Adults and Children: A 10-Year Case Series at Two Large Academic Hospitals in Houston, Texas."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common clinical features included fever (83%), arthralgias or arthritis (67%), and hepatosplenomegaly (61%)."
    explanation: >-
      Hepatosplenomegaly occurred in 61% of the Houston brucellosis case series,
      supporting the frequent band.
- category: Laboratory
  name: Elevated transaminases
  description: Mild elevation of liver transaminases is a common laboratory abnormality.
  phenotype_term:
    preferred_term: Elevated transaminases
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
  frequency: FREQUENT
  evidence:
  - reference: PMID:29863218
    reference_title: "Brucellosis in Adults and Children: A 10-Year Case Series at Two Large Academic Hospitals in Houston, Texas."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common laboratory finding was mildly elevated transaminases."
    explanation: >-
      The case series identifies mildly elevated transaminases as the most common
      laboratory finding.
- category: Clinical
  name: Arthritis
  description: Arthritis is a focal osteoarticular complication of brucellosis.
  phenotype_term:
    preferred_term: Arthritis
    term:
      id: HP:0001369
      label: Arthritis
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:23236528
    reference_title: "Clinical manifestations of human brucellosis: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Arthralgia was common, affecting 65% patients overall, whereas arthritis affected only 26% patients"
    explanation: >-
      The systematic review found frank arthritis in 26% of human brucellosis
      cases overall.
- category: Clinical
  name: Sacroiliitis
  description: >-
    Sacroiliitis is a characteristic osteoarticular focal complication of
    brucellosis.
  phenotype_term:
    preferred_term: Sacroiliitis
    term:
      id: HP:0012317
      label: Sacroiliac arthritis
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:23236528
    reference_title: "Clinical manifestations of human brucellosis: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overall, spondylitis and sacroiliitis were detected in 12–36% adults"
    explanation: >-
      The systematic review documents sacroiliitis among adult focal
      osteoarticular manifestations.
- category: Clinical
  name: Spondylitis
  description: >-
    Spondylitis and spondylodiscitis are axial skeletal focal complications of
    brucellosis.
  phenotype_term:
    preferred_term: Spondylitis
    term:
      id: HP:0033631
      label: Spondylitis
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:23236528
    reference_title: "Clinical manifestations of human brucellosis: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Spondylitis 1 18 (1; 28)* 6 12 (7, 19) 9 11 (6; 18) 16 12 (8; 17)"
    explanation: >-
      The systematic review found spondylitis in 12% of all-age human
      brucellosis cases.
- category: Clinical
  name: Endocarditis
  description: Endocarditis is a rare but serious focal complication of brucellosis.
  phenotype_term:
    preferred_term: Endocarditis
    term:
      id: HP:0100584
      label: Endocarditis
  frequency: VERY_RARE
  evidence:
  - reference: PMID:11910696
    reference_title: "[Brucella endocarditis of native valves. Report of 3 cases]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brucella endocarditis is a rare but a serious complication of human brucellosis."
    explanation: >-
      The native-valve case series describes endocarditis as a rare but severe
      focal complication.
- category: Clinical
  name: Epididymo-orchitis
  description: >-
    Epididymo-orchitis is a focal genitourinary complication affecting the
    epididymis and testis during systemic brucellosis.
  phenotype_term:
    preferred_term: Epididymo-orchitis
    term:
      id: HP:0100796
      label: Orchitis
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:40350681
    reference_title: "Clinical and therapeutic insights into brucellar epididymo-orchitis: a retrospective analysis in a brucellosis endemic area."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brucella contributed to 18 (30.51%) of epididymo-orchitis cases during study period."
    explanation: >-
      The urology-clinic study observed brucellar epididymo-orchitis in an
      endemic setting and supports this focal genitourinary phenotype.
genetic:
- name: IL4 rs2243250 susceptibility allele
  gene_term:
    preferred_term: IL4
    term:
      id: hgnc:6014
      label: IL4
  association: Common host cytokine polymorphism associated with increased susceptibility
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:31816580
    reference_title: "Association between polymorphisms of cytokine genes and brucellosis: A comprehensive systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "our pooled analysis demonstrated that the mutant allele of IL-4 rs2243250 and IL-18 rs1946519 were associated with increased susceptibility to brucellosis."
    explanation: >-
      The meta-analysis supports IL4 rs2243250 as a host susceptibility
      association rather than a monogenic cause.
- name: IL18 rs1946519 susceptibility allele
  gene_term:
    preferred_term: IL18
    term:
      id: hgnc:5986
      label: IL18
  association: Common host cytokine polymorphism associated with increased susceptibility
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:31816580
    reference_title: "Association between polymorphisms of cytokine genes and brucellosis: A comprehensive systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "IL-4 rs2243250 and IL-18 rs1946519 have a positive correlation with brucellosis whereas the IFN-γ UTR5644, TGF-β rs1800470 and rs1800471, TNF-α rs1800629, and IL-10 rs1800872 showed a negative association with this disease."
    explanation: >-
      The cytokine-polymorphism meta-analysis reports a positive brucellosis
      association for IL18 rs1946519.
- name: TGFB1 polymorphisms with negative pooled association
  gene_term:
    preferred_term: TGFB1
    term:
      id: hgnc:11766
      label: TGFB1
  association: Common host cytokine polymorphisms with protective pooled association
  relationship_type: PROTECTIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:31816580
    reference_title: "Association between polymorphisms of cytokine genes and brucellosis: A comprehensive systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the pooled results showed that the dominant models of IFN-γ UTR5644, TGF-β rs1800470 and rs1800471, TNF-α rs1800629, and IL-10 rs1800872 were significantly less frequent in brucellosis patients than the controls."
    explanation: >-
      Across included case-control studies, TGFB1 rs1800470 and rs1800471
      dominant models were less frequent in cases than controls.
- name: TNF-238 focal-disease modifier
  gene_term:
    preferred_term: TNF
    term:
      id: hgnc:11892
      label: TNF
  association: Host cytokine modifier of brucellar spondylodiscitis risk
  relationship_type: MODIFIER
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:39419734
    reference_title: "TLR4 and TNF-α single nucleotide polymorphisms in patients with brucellosis: Association with infection complications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "only the last one was associated with brucellar spondylodiscitis [OR 2.91 (CI95 % 1.02-8.31), p = 0.047]."
    explanation: >-
      The stepwise model retained TNF-238 G>A genotype as associated with
      brucellar spondylodiscitis, supporting a focal-complication modifier role.
- name: TLR4 Asp299Gly susceptibility allele
  gene_term:
    preferred_term: TLR4
    term:
      id: hgnc:11850
      label: TLR4
  association: Common innate immune receptor polymorphism associated with susceptibility
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:16343635
    reference_title: "TLR4 polymorphism in Iranian patients with brucellosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Allele 896G was more prevalent in patients with brucellosis compared to healthy controls (33.6% vs. 20.7%, P=0.000003)."
    explanation: >-
      The Iranian case-control study supports association of the TLR4 Asp299Gly
      896G allele with human brucellosis susceptibility.
environmental:
- name: Fresh milk, undercooked meat, and household livestock exposure
  disease_effect: PREDISPOSES
  causal_role: RISK_FACTOR
  description: >-
    Raw animal products and household livestock contact increase the chance of
    zoonotic Brucella acquisition in endemic smallholder settings.
  influences_mechanisms:
  - target: Brucella melitensis zoonotic acquisition
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Fresh milk, undercooked meat, animal manure contact, and livestock kept at
      home increase the exposure pressure that can culminate in B. melitensis
      acquisition.
  evidence:
  - reference: PMID:41860883
    reference_title: "Human brucellosis in pregnancy in western Uganda: High seroprevalence and health risk factors identified in a cross-sectional study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "consumption of fresh milk or under-cooked meat (aOR 5.70, 95% CI 1.94-16.76), frequent contact with animal manure (aOR 3.29, 95% CI 1.29-8.47) and rearing livestock at home (aOR 3.75, 95% CI 1.36-10.32)."
    explanation: >-
      The western Uganda antenatal study quantified raw-food and livestock
      exposures independently associated with Brucella seropositivity.
diagnosis:
- name: Brucella serology by agglutination or ELISA
  description: >-
    Human brucellosis is commonly diagnosed by detecting anti-Brucella antibody
    responses with Rose Bengal, standard agglutination, or ELISA-style assays.
  evidence:
  - reference: PMID:20075115
    reference_title: "Cloning and expression of the immunoreactive Brucella melitensis 28 kDa outer-membrane protein (Omp28) encoding gene and evaluation of the potential of Omp28 for clinical diagnosis of brucellosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Serodiagnosis of brucellosis is carried out by detection of antibodies generated against LPS or whole-cell bacterial extracts by ELISA or agglutination tests using colorimetry."
    explanation: >-
      The B. melitensis Omp28 diagnostic study describes standard serodiagnosis
      by ELISA or agglutination testing.
- name: Rose Bengal screening with qPCR confirmation
  description: >-
    Rose Bengal plate testing can be paired with real-time PCR in febrile
    patients to detect and confirm Brucella infection in endemic settings.
  evidence:
  - reference: PMID:40140617
    reference_title: "Risk perception, seroprevalence, and real-time PCR detection of Brucella among pyretic patients and domestic animals in Kwara State, Nigeria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The seroprevalence of brucellosis in humans was 5.8% (n = 6/103) and there was 100% concordance between the results of the RBPT and qPCR in humans."
    explanation: >-
      In a pyretic-patient cohort, Rose Bengal plate testing and qPCR were
      concordant for human brucellosis detection.
animal_models:
- name: IL-12p40-deficient B. melitensis chronic splenic reservoir mouse
  species: Mouse
  genotype: IL-12p40-/- BALB/c
  description: >-
    Intranasal challenge of IL-12p40-deficient BALB/c mice with fluorescent
    B. melitensis creates high chronic splenic burdens that permit in situ
    microscopy of lipid-rich, CD11c+/CD205+/Arginase1+ reservoir cells.
  publication: PMID:26376185
  modeled_mechanisms:
  - target: Chronic splenic myeloid reservoir formation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      The model reproduces durable splenic B. melitensis infection and exposes
      the phenotype of infected myeloid reservoir cells.
    limitations: >-
      The model requires an IL-12p40 knockout background and a high intranasal
      inoculum to make infected splenic cells abundant enough for direct
      microscopy, so it models reservoir-cell biology under impaired Th1/Th17
      control rather than the full immunocompetent human syndrome.
    evidence:
    - reference: PMID:26376185
      reference_title: "In Situ Characterization of Splenic Brucella melitensis Reservoir Cells during the Chronic Phase of Infection in Susceptible Mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "we used a model in which infected cells can be observed directly in situ and where the differentiation of M2a macrophages is favored by the absence of an IL-12-dependent Th1 response."
      explanation: >-
        The study describes the IL-12p40-deficient mouse model and the reason it
        was selected for direct observation of chronic B. melitensis reservoir
        cells in situ.
treatments:
- name: Doxycycline-rifampicin combination therapy
  description: >-
    Six-week all-oral combination therapy used for uncomplicated human
    brucellosis, with convenience advantages but more relapse than
    aminoglycoside-containing regimens in some comparative analyses.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: doxycycline
      term:
        id: CHEBI:50845
        label: doxycycline
    - preferred_term: rifampicin
      term:
        id: CHEBI:28077
        label: rifampicin
  target_mechanisms:
  - target: Persistent multisystem infection
    treatment_effect: INHIBITS
    description: Prolonged intracellularly active antibiotic therapy clears infection and limits relapse.
  - target: Requirement for Cell-Penetrant Antimicrobials
    treatment_effect: INHIBITS
    description: Doxycycline and rifampicin reach the protected intracellular Brucella reservoir.
  evidence:
  - reference: PMID:18162038
    reference_title: "Perspectives for the treatment of brucellosis in the 21st century: the Ioannina recommendations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The author panel suggests that the optimal treatment of uncomplicated brucellosis should be based on a six-week regimen of doxycycline combined either with streptomycin for 2–3 weeks, or rifampicin for six weeks."
    explanation: >-
      The expert recommendation lists doxycycline plus six weeks of rifampicin as
      one optimal uncomplicated-brucellosis regimen.
- name: Doxycycline-streptomycin combination therapy
  description: >-
    Aminoglycoside-containing combination therapy for uncomplicated human
    brucellosis that is generally more efficacious than doxycycline-rifampicin
    but requires parenteral streptomycin.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: doxycycline
      term:
        id: CHEBI:50845
        label: doxycycline
    - preferred_term: streptomycin
      term:
        id: CHEBI:17076
        label: streptomycin
  target_mechanisms:
  - target: Persistent multisystem infection
    treatment_effect: INHIBITS
    description: The doxycycline-aminoglycoside combination improves clearance and relapse prevention.
  - target: Requirement for Cell-Penetrant Antimicrobials
    treatment_effect: INHIBITS
    description: >-
      Doxycycline reaches the protected intracellular Brucella reservoir while
      streptomycin adds bactericidal aminoglycoside activity.
  evidence:
  - reference: PMID:39172763
    reference_title: "Updated therapeutic options for human brucellosis: A systematic review and network meta-analysis of randomized controlled trials."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Doxycycline + Gentamicin ranked the best in efficacy (SUCRA values: 0.94), the second is Triple (SUCRA values: 0.87), and the third is Doxycycline + Streptomycin (SUCRA values: 0.78)."
    explanation: >-
      The randomized-trial network meta-analysis ranked doxycycline-streptomycin
      among the high-efficacy treatment strategies.
- name: Doxycycline-gentamicin combination therapy
  description: >-
    Aminoglycoside-containing combination therapy that ranked highest for
    efficacy in a network meta-analysis of randomized brucellosis trials, with
    the usual tetracycline/aminoglycoside caveats for children, pregnancy, and
    focal disease.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: doxycycline
      term:
        id: CHEBI:50845
        label: doxycycline
    - preferred_term: gentamicin
      term:
        id: CHEBI:759884
        label: gentamicin
  target_mechanisms:
  - target: Persistent multisystem infection
    treatment_effect: INHIBITS
    description: The doxycycline-aminoglycoside combination improves clearance and relapse prevention.
  - target: Requirement for Cell-Penetrant Antimicrobials
    treatment_effect: INHIBITS
    description: >-
      Doxycycline reaches the protected intracellular Brucella reservoir while
      gentamicin adds bactericidal aminoglycoside activity.
  evidence:
  - reference: PMID:39172763
    reference_title: "Updated therapeutic options for human brucellosis: A systematic review and network meta-analysis of randomized controlled trials."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Doxycycline + Gentamicin ranked the best in efficacy (SUCRA values: 0.94), the second is Triple (SUCRA values: 0.87), and the third is Doxycycline + Streptomycin (SUCRA values: 0.78)."
    explanation: >-
      The randomized-trial network meta-analysis ranked doxycycline-gentamicin
      highest for efficacy among compared brucellosis regimens.
review_notes: >-
  Brucella melitensis brucellosis is promoted to a child entry of Brucellosis
  because B. melitensis has a distinct sheep/goat reservoir and represents a
  high-prominence, highly virulent human Brucella species. The covering
  organization is the parent Brucellosis has_subtypes record with classification
  etiologic_species and curated_in: Brucella_Melitensis_Brucellosis; a separate
  brucellosis-species Grouping was not created while this is the only curated
  species-specific child of the MONDO brucellosis parent.
📚

References & Deep Research

Deep Research

1

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Evaluations and curation notes (1)

Create: Brucella melitensis brucellosis · 2026-09-29T06:31:01Z · View source

Created the MONDO:0001972 Brucella melitensis brucellosis entry from OpenScientist deep research. Added the species-specific infectious agent, NCBITaxon-bound human, sheep, and goat hosts, small-ruminant zoonotic transmission, acute and relapse progression phases, a Brucella intracellular-vacuole pathophysiology chain, clinical phenotypes, and doxycycline-based combination treatments. Verified exact snippets from B. melitensis epidemiology, Brucella intracellular-cycle, B. melitensis mouse-reservoir, clinical phenotype, and treatment-review sources, then ran schema, term, reference, causal-target, phenotype-connectivity, and infectious-granularity validation.

OpenScientist ▸
1. Disease Information
openscientist-autonomous 41 citations 2026-09-28T23:15:34.559550

1. Disease Information

Overview. Brucella melitensis brucellosis is a systemic zoonotic infection and the predominant cause of human brucellosis worldwide. It is an aggregated, disease-level entity (the knowledge here is drawn from case series, cohorts, registries, and mechanistic studies rather than a single-patient EHR source). The disease is characterized by a variable clinical presentation ranging from acute febrile illness to chronic relapsing multisystem disease.

Key identifiers. - MONDO: MONDO:0001972 - MeSH: Brucellosis; Brucella melitensis (organism) - ICD-10: A23.0 (Brucellosis due to Brucella melitensis); ICD-11: 1B95 - NCBI Taxonomy (organism): Brucella melitensis, txid29459

Synonyms/alternative names. Malta fever, Mediterranean fever, undulant fever, goat/sheep brucellosis, febris melitensis. (Bang's disease historically refers to B. abortus.)

"Brucella melitensis, one of the organisms responsible for causing the disease in sheep and goat, is responsible for the disease in humans. The disease is transmitted mainly from sheep and goat to humans via ingestion (typically through milk), inhalation, abrasion and so on." — PMID: 41132010

2. Etiology

Primary cause — infectious. The disease is caused entirely by infection with Brucella melitensis, a facultative intracellular Gram-negative coccobacillus. Of the four Brucella species significant to human health (B. melitensis, B. abortus, B. suis, B. canis), B. melitensis is the most virulent and the leading cause of human disease. Small ruminants are the reservoir: a systematic review/meta-analysis of 2010–2023 data found pooled B. melitensis prevalence of 8.07% (95% CI 6.36–9.78%) in sheep, 2.46% (95% CI 1.70–3.21%) in goats, and 5.54% combined (95% CI 4.63–6.45%) (PMID: 41132010).

Risk factors (environmental/behavioral — the dominant determinants). - Dietary: consumption of unpasteurized/fresh milk and dairy or undercooked meat (aOR 5.70, 95% CI 1.94–16.76) (PMID: 41860883). - Occupational/contact: rearing livestock at home (aOR 3.75, 95% CI 1.36–10.32), frequent contact with animal manure (aOR 3.29, 95% CI 1.29–8.47); farmers, shepherds, veterinarians, abattoir and laboratory workers are high-risk. - Socioeconomic: lack of formal education (aOR 4.05, 95% CI 1.02–16.01) (PMID: 41860883). - Demographic: male sex and adult working age (males 71% of cases in a large Chinese series, 2.45× females) (PMID: 41632803).

Genetic risk factors (host susceptibility, not causal). Cytokine and innate-immune-receptor gene polymorphisms modulate risk and complications (detailed in §4 and §9): - Risk-increasing: IL-4 rs2243250, IL-18 rs1946519 mutant alleles; TGFβ1 +868 C/T (rs1800470) TT homozygote (OR 2.60, p=0.023); TNF −238 G>A (rs361525) minor A allele (11.4% vs 2.6% in controls, p<0.001) (PMID: 31816580, PMID: 25738611, PMID: 39419734). - Relatively protective: IFN-γ UTR5644, TGF-β rs1800470/rs1800471, TNF-α rs1800629, IL-10 rs1800872 dominant models (PMID: 31816580).

Protective factors (environmental). Pasteurization/boiling of milk, use of personal protective equipment, avoidance of aborted animal materials, and public-health education. Treatment compliance is protective against relapse (aOR 0.25, 95% CI 0.09–0.86) (PMID: 42603185).

Gene–environment interactions. Individuals carrying pro-inflammatory-skewing or immune-modulating genotypes (e.g., TNF/TGFB1/IL variants) who also sustain high infectious exposure (raw dairy, occupational contact) are at compounded risk of infection and focal complications such as spondylodiscitis (PMID: 39419734).

3. Phenotypes

The clinical phenotype is a chronic relapsing febrile multisystem illness. Frequencies below are drawn from a Houston 10-year case series (n=18), a North Macedonia series (n=508), and a Saudi pediatric series (n=57).

Phenotype Type Frequency Suggested HPO term
Fever / undulant fever Symptom ~83% (36.8% sole finding in children) HP:0001945 (Fever)
Arthralgia / arthritis Symptom / sign ~67% HP:0002829; HP:0001369
Hepatosplenomegaly Clinical sign ~61% HP:0001433
Night sweats Symptom Frequent HP:0030166
Myalgia Symptom ~19% (with fever) HP:0003326
Weight loss Symptom Common (adults > children) HP:0001824
Sacroiliitis Sign / imaging Adults > children (p=0.043) HP:0100775
Spondylitis / spondylodiscitis Sign / imaging Older adults predominant HP:0003429
Lymphadenopathy Sign Common HP:0002716
Leukopenia Lab abnormality 21% (acute) HP:0001882
Elevated transaminases Lab abnormality 44% (acute) HP:0002910

"Common clinical features included fever (83%), arthralgias or arthritis (67%), and hepatosplenomegaly (61%)." — PMID: 29863218

Age of onset & severity. Any age; predominantly adult (working-age) but with substantial pediatric burden. Severity is variable — mild self-limited illness to severe focal/chronic disease. Progression is episodic/relapsing (undulant fever pattern). Age-dependent phenotype distribution is documented: "Sacroiliitis was more predominant in adults than children (p = 0.043), while focal hematological involvement was more prevalent in children than in adults (p = 0.004). Spondylitis was more dominant in the old age group" (PMID: 39630247).

Quality-of-life impact. Chronic arthralgia, fatigue, night sweats, and osteoarticular complications impair daily functioning and work capacity; in pregnancy, infection can cause anemia, miscarriage, and pre-term birth.

4. Genetic/Molecular Information

Causal genes: NONE. This is an infectious disease with no human causal gene or pathogenic germline/somatic variant. There are no ClinVar pathogenic variants, no inheritance pattern, no chromosomal abnormalities, and no epigenetic disease-defining lesions in the classic Mendelian sense.

Host susceptibility loci (modifier of risk/severity, not causal). From a meta-analysis of 25 case-control studies and individual cohorts:

Gene (HGNC) Variant Effect Evidence
IL4 rs2243250 ↑ susceptibility PMID: 31816580
IL18 rs1946519 ↑ susceptibility PMID: 31816580
TGFB1 +868 C/T (rs1800470), TT Risk factor, OR 2.60 (p=0.023) PMID: 25738611
TNF −238 G>A (rs361525), A allele ↑ risk & spondylodiscitis (11.4% vs 2.6%) PMID: 39419734
TLR4 Asp299Gly (rs4986790), Thr399Ile (rs4986791) Complication risk PMID: 39419734
IL10 / IL6 High-producer genotypes ↑ susceptibility PMID: 17544674
IFNG, IL10 UTR5644 / rs1800872 Relatively protective PMID: 31816580

"the mutant allele of IL-4 rs2243250 and IL-18 rs1946519 were associated with increased susceptibility to brucellosis" — PMID: 31816580 "Carriage of the minor frequency A alleles at -238 of the promoter region of TNF was greater in patients than in controls (11.4% vs 2.6 %, p < 0.001)" — PMID: 39419734

Pathogen molecular determinants of virulence (the biologically "causal" genetics reside in the bacterium): the virB operon (VirB T4SS), quorum-sensing regulator VjbR, two-component system BvrR/BvrS, cyclic β-1,2-glucans, BacA, outer-membrane proteins Omp25/Omp28, and metabolic/membrane genes (cydDC, ptsP) identified by TraDIS as essential for macrophage survival — "the discovery of 374 anti-phagocytic associated essential genes" (PMID: 41917383, PMID: 22392933).

5. Environmental Information

Infectious agent. Brucella melitensis (NCBI Taxon 29459); biovars 1–3, with the Eastern Mediterranean lineage/biovar 3 predominant in China (PMID: 42360586).

Environmental/occupational factors. Contact with infected small ruminants and their products; contaminated manure, birth products, and aborted materials; aerosol exposure in laboratories and abattoirs (a recognized potential bioterrorism agent) (PMID: 15677842). Lifestyle factors: consumption of raw milk, soft cheeses, and undercooked meat. Cold semi-arid (BSk) climates and spring seasonality are associated with higher small-ruminant seroprevalence (PMID: 41506444).

Relevant chemical entities (treatment): doxycycline (CHEBI:50845), rifampicin (CHEBI:28077), streptomycin (CHEBI:17076), gentamicin (CHEBI:27412).

6. Mechanism / Pathophysiology

Ordered causal chain

  1. Oral/mucosal/inhalational entry of B. melitensis from contaminated dairy, aerosols, or abraded skin leads to uptake at mucosal surfaces.
  2. Bacteria are phagocytosed by macrophages and dendritic cells (internalization is normal even in avirulent mutants) — results in an early endosomal Brucella-containing vacuole (eBCV).
  3. The VirB Type IV secretion system (T4SS) delivers effector proteins that remodel the eBCV into a replication-permissive, ER-derived vacuole (rBCV) — demonstrated: VirB-deficient mutants stall in eBCVs and cannot form rBCVs (PMID: 27899503).
  4. Effectors (BspF via Arf6-GAP ACAP1; Rab2- and α-enolase-engaging effectors) subvert host secretory/recycling traffic — results in robust intravacuolar replication (PMID: 34423453, PMID: 32234817, PMID: 27900285).
  5. In parallel, Omp25 suppresses macrophage TNF-α secretion and Brucella inhibits macrophage/monocyte apoptosis — results in immune evasion and a protected replicative niche (PMID: 12414158).
  6. Replicated bacteria convert the rBCV into an autophagic BCV (aBCV) — results in cell-to-cell egress and dissemination (PMID: 27899503).
  7. Hematogenous spread within myeloid cells to the reticuloendothelial system, bone/joints, liver, spleen, genitourinary tract, heart and CNS — leads to multisystem seeding.
  8. Granuloma formation (non-caseating) and the host Th1/IFN-γ/IL-12/TNF-α response attempt clearance — branch A (effective Th1): bacterial clearance and recovery; branch B (failed control): persistence in lipid-laden CD11c⁺/CD205⁺/Arginase1⁺ reservoir cells → chronic/relapsing and focal disease (PMID: 12414158, PMID: 26376185).
  9. Persistent granulomatous inflammation in seeded organs produces the clinical syndrome: undulant fever, arthralgia/spondylitis, hepatosplenomegaly, and focal complications (endocarditis, neurobrucellosis, epididymo-orchitis).
 Raw dairy / aerosol / contact
    |
    v
   Macrophage / DC uptake --> eBCV
    |  VirB T4SS + effectors (BspF/Arf6, Rab2, alpha-enolase)
    v
   rBCV (ER-derived) --> intracellular replication
    |  Omp25 -| TNF-alpha ; apoptosis inhibited
    v
   aBCV --> egress --> hematogenous myeloid dissemination
    |
   +--------+---------+
   v                  v
 Th1/IFN-g/IL-12    Failed control --> lipid-laden CD11c+/CD205+/Arg1+
 clearance            reservoir cells --> chronic/focal disease
   |                  |
   v                  v
 Recovery      Fever, arthralgia, hepatosplenomegaly, focal complications

Molecular pathways / cellular processes. T4SS effector–host GTPase cascades (Arf6–Rab8a, Rab2); NF-κB signaling (TBK1 promotes control — knockdown increases bacterial survival and reduces IL-1β/IL-6/TNF-α/IFN-γ) (PMID: 41605070); autophagy (aBCV egress); inhibited apoptosis; granulomatous inflammation. GO terms: GO:0140355 (T4SS-dependent protein secretion into host cell), GO:0006909 (phagocytosis), GO:0016236 (macroautophagy), GO:0006915 (apoptotic process, inhibited), GO:0002250 (adaptive immune response), GO:0032609 (IFN-γ production). CL terms: CL:0000235 (macrophage), CL:0000451 (dendritic cell), CL:0000576 (monocyte).

Immune involvement. Protective immunity is Th1/cell-mediated: "Brucella infection results in Type1 (Th1) cellular immune response which promotes a clearance of the bacterial organism. The development of this response is under the control of major cytokines like TNF-alpha, IFN-gamma and IL-12" (PMID: 12414158). Immune evasion via Omp25-mediated TNF-α suppression: "in humans, B. suis-infected macrophages which produce IL-1, IL-6, IL-10 and several chemokines including IL-8, do not secrete TNF-alpha... this inhibition involves the outer membrane protein Omp25 of Brucella" (PMID: 12414158).

Subcellular mechanism. "BCVs are remodeled into replication-permissive organelles (rBCV) derived from the host endoplasmic reticulum, a process that requires modulation of host secretory functions via delivery of effector proteins by the Brucella VirB type IV secretion system (T4SS)" (PMID: 27899503); "Brucella abortus generates a host endoplasmic reticulum-derived vacuole (rBCV) that supports its intracellular growth, via VirB Type IV secretion system-mediated delivery of effector proteins" (PMID: 34423453).

7. Anatomical Structures Affected

Organ level (primary): reticuloendothelial system — liver, spleen, bone marrow, lymph nodes (hepatosplenomegaly, lymphadenopathy, non-caseating granulomas). Secondary/focal: skeleton and joints (spine, sacroiliac joints — spondylodiscitis, sacroiliitis, osteomyelitis), genitourinary tract (epididymo-orchitis), heart (endocarditis, myopericarditis), CNS (meningoencephalitis, neurobrucellosis), peritoneum (spontaneous bacterial peritonitis), and placenta in pregnancy.

"Brucella contributed to 18 (30.51%) of epididymo-orchitis cases during study period." — PMID: 40350681 "The cases presented as prolonged fever in 4 patients (40%), spondylodiscitis in 2 (20%), myopericarditis, meningoencephalitis, febrile hepatitis, and cervical lymphadenopathy" — PMID: 41021857

Body systems: hematologic/lymphoreticular, musculoskeletal, hepatobiliary, genitourinary, cardiovascular, nervous.

Tissue/cell level: phagocytic mononuclear cells (macrophages, monocytes, dendritic cells) are the primary target/reservoir; granuloma-forming myeloid and lymphoid aggregates. UBERON: UBERON:0002106 (spleen), UBERON:0002107 (liver), UBERON:0002371 (bone marrow), UBERON:0001474 (bone element), UBERON:0000079 (male reproductive system), UBERON:0000948 (heart), UBERON:0001017 (CNS). Subcellular (GO CC): GO:0005783 (endoplasmic reticulum — rBCV origin), GO:0005776 (autophagosome — aBCV), GO:0005768 (endosome — eBCV), GO:0020003 (symbiont-containing vacuole).

8. Temporal Development

Onset. Insidious, over days to weeks after exposure (incubation typically 1–4 weeks, occasionally months). Onset patterns: acute, subacute, or chronic/insidious.

Progression / stages. Classically acute (<8 weeks), subacute (8 weeks–1 year), and chronic (>1 year). Undulant (relapsing-remitting) fever is characteristic. Acute disease carries a stronger inflammatory profile and better cure rate: "patients with acute brucellosis had a significantly higher frequency of leukopenia (21.2 % vs. 0 %; p < 0.01), elevated C reactive protein (CRP) (76.7 % vs. 52.0 %; p = 0.01), and elevated transaminases (43.8 % vs. 20.0 %; p = 0.025)" — therapeutic response 93.2% acute vs lower in subacute/chronic (PMID: 41241000). Chronicity and focalization predict poor outcome: "Focal brucellosis (OR 3.52, 95 % CI 1.28 - 9.71, p = 0.015) and low albumin levels ... were independent risk factors for therapeutic failure." (PMID: 40185219).

Patterns. Remission is treatment-induced; relapse (~3%) typically occurs within months, associated with female sex (aOR 3.68) and non-compliance (PMID: 42603185). Early, adherent combination therapy is the critical intervention window.

9. Inheritance and Population

Inheritance. Not applicable — infectious, non-heritable. No penetrance/expressivity/anticipation/mosaicism/founder-effect/carrier-frequency parameters apply. Host susceptibility is multifactorial/polygenic (cytokine and TLR gene polymorphisms; §4).

Epidemiology. Brucellosis is among the commonest zoonoses globally (>500,000 new human cases/year historically). Regional endemic incidence is high and rising in parts of Asia:

Setting Metric Value PMID
Ningxia, China (2010–2024) Avg annual incidence 35.08/100,000 (peak 84.80 in 2022); 35,665 cases, 0 deaths 41632803
Western Uganda (pregnant women) Seroprevalence 14.0% (95% CI 9.2–18.8) 41860883
Ethiopia (2015–2024, humans) Pooled seroprevalence 6.9% (95% CI 4.9–8.8) 39696174
China (national human cases) 2019 → 2023 45,046 → 70,439 cases 42360586

"A total of 35 665 human brucellosis cases were reported in Ningxia, with no associated deaths, during the study period." — PMID: 41632803

Demographics. Male predominance (~2.4:1), driven by occupational exposure. Geographic distribution: endemic in the Mediterranean basin, Middle East, Central/South Asia, sub-Saharan Africa, and Latin America; expanding within China from northern pastoral provinces (Inner Mongolia) to industrial southern provinces via livestock trade (PMID: 42360586). All ages affected, with substantial pediatric disease in endemic areas.

10. Diagnostics

Serology (first-line): Rose Bengal plate test (RBPT), standard tube agglutination test (SAT), and ELISA (anti-LPS or whole-cell, and recombinant Omp28 which correlated ~90% with RBPT) (PMID: 20075115). A ≥4-fold decline in SAT titer after treatment predicts favorable response (OR 5.84) (PMID: 41241000).

"Serodiagnosis of brucellosis is carried out by detection of antibodies generated against LPS or whole-cell bacterial extracts by ELISA or agglutination tests using colorimetry." — PMID: 20075115

Culture (definitive): blood/bone-marrow/tissue culture. Yield is higher in children than adults: "Positive blood cultures were more frequently reported among children than adults (83% vs 33%," (PMID: 29863218).

Molecular: conventional and real-time PCR add sensitivity, detecting some culture-negative/seropositive samples; combining culture + PCR maximizes detection (PMID: 18832199). qPCR showed 100% concordance with RBPT in humans in one Nigerian study (PMID: 40140617).

Laboratory abnormalities: leukopenia, elevated CRP, elevated transaminases, occasionally pancytopenia. Imaging: MRI/CT for spondylodiscitis and sacroiliitis; echocardiography for endocarditis. Histopathology: non-caseating granulomas.

Differential diagnosis: tuberculosis, typhoid, other causes of undifferentiated fever, endocarditis of other etiology, lymphoma, autoimmune arthritis. Genetic/omics diagnostics and newborn/carrier screening: not applicable.

11. Outcome/Prognosis

Mortality is low. A large endemic series reported zero deaths among 35,665 cases (PMID: 41632803). Pediatric cohorts show ~88–90% favorable outcomes and ~3% relapse with adherent therapy (PMID: 42603185).

Endocarditis is the leading cause of death. "Brucella endocarditis is a rare but a serious complication of human brucellosis." — frequently requires valve replacement plus prolonged antibiotics (PMID: 11910696, PMID: 20362000).

Complications. In a nationwide pediatric cohort (n=1,052): complications 8.3%, most frequently osteoarticular; neurobrucellosis 0.9%; relapse 3.2%. Complications associated with headache (aOR 3.57), arthralgia/arthritis, culture positivity, night sweats, myalgia (PMID: 42603185).

"Complications occurred in 87 patients (8.3%), most frequently osteoarticular (spondylitis, sacroiliitis, and osteomyelitis), whereas neurobrucellosis was rare (0.9%); relapse occurred in 34 patients (3.2%)." — PMID: 42603185

Prognostic factors. Favorable: acute presentation, elevated baseline CRP (OR 4.00), ≥4-fold SAT decline (OR 5.84), treatment adherence. Unfavorable: focal disease (OR 3.52 for failure), chronicity (OR 11.20 in focal cases), low albumin, female sex (relapse). Morbidity is driven by chronic osteoarticular disability; recovery is usually complete with timely therapy.

12. Treatment

First-line pharmacotherapy — combination, prolonged (≥6 weeks). Doxycycline (CHEBI:50845) plus rifampicin (CHEBI:28077), OR doxycycline plus an aminoglycoside (streptomycin/gentamicin).

"Regimens containing doxycycline plus streptomycin or doxycycline plus rifampin are effective for most forms of brucellosis." — PMID: 15677842 "Trimethoprim-sulfamethoxazole and fluoroquinolones also have good results against Brucella, but are associated with high relapse rates when used as monotherapy." — PMID: 15677842

Comparative efficacy (network meta-analysis of 43 RCTs). Relative to standard doxycycline+rifampicin, doxycycline+gentamicin ranked best (SUCRA 0.94), followed by triple therapy (0.87) and doxycycline+streptomycin (0.78) (PMID: 39172763). The Ioannina recommendations provide evidence-based guidance (PMID: 18162038).

Regimen Role NCIT (approx.)
Doxycycline + rifampicin Standard oral first-line C61815 (doxycycline); C29325 (rifampin)
Doxycycline + streptomycin/gentamicin Severe/focal; best efficacy C839 (streptomycin); C557 (gentamicin)
Triple therapy (add aminoglycoside/TMP-SMX) Neurobrucellosis, endocarditis, spondylitis —
Surgery + prolonged antibiotics Endocarditis (valve replacement), abscess drainage —

Special situations. Neurobrucellosis, endocarditis, and spondylitis require triple therapy and extended duration; endocarditis frequently requires surgical valve replacement. In pregnancy and young children, rifampicin-based regimens are used (tetracyclines/aminoglycosides restricted). Advanced/targeted/gene/cell/RNA therapies, immunotherapy, pharmacogenomics: not applicable/not used. Adverse events: doxycycline photosensitivity/GI upset, rifampicin hepatotoxicity and drug–drug interactions, aminoglycoside oto-/nephrotoxicity.

13. Prevention

No licensed human vaccine exists. Prevention is a One-Health enterprise.

  • Primary prevention: livestock vaccination and reservoir control. "Rev1, the only vaccine currently recommended to control the disease in sheep and goats, has several drawbacks." (PMID: 36653223); "The mainstay of most control programs is vaccination of sheep and goats with a live vaccine, Rev-1." (PMID: 26825313). Rev1 is safe in sheep only for lambs 3–4 months, causes serological interference and abortion in pregnancy, and is virulent to humans. Next-generation rough-LPS candidates (Rev1Δwzm, 16MΔwzm) improve safety and reduce serological interference (PMID: 38806353, PMID: 36653223).
  • Food safety: pasteurization/boiling of milk; avoidance of raw dairy and undercooked meat.
  • Occupational protection: PPE, safe handling of birth/abortion products, laboratory biosafety (BSL-3).
  • Public-health measures: surveillance, herd testing and culling, quarantine, health education. SEIRS modeling predicts ~3.5 years to eliminate brucellosis on a mixed endemic farm with combined sheep+cattle vaccination (PMID: 26825313).
  • Secondary/tertiary prevention: early diagnosis and treatment of exposed/symptomatic individuals; adherence support to prevent relapse and chronic complications. Genetic screening/counseling: not applicable.

14. Other Species / Natural Disease

Taxonomy of hosts. Primary reservoir: sheep (Ovis aries, txid9940) and goats (Capra hircus, txid9925). Other susceptible species: cattle, swine, dogs, camels, equids, and wild mammals (PMID: 42360586).

Natural disease (veterinary). In livestock, B. melitensis causes reproductive failure — abortion, retained placenta, orchitis/epididymitis, infertility — with major economic impact. "In livestock, brucellosis causes reproductive failure, including abortions, leading to substantial economic losses." (PMID: 41127417). The organism localizes to placenta and reproductive tissues (tropism classically linked to erythritol).

Zoonotic transmission. "The disease can be transmitted to humans through the food chain or by direct contact with infected animals." (PMID: 35482257). High cross-species susceptibility makes it a paradigmatic One-Health zoonosis.

Comparative biology. The intracellular VirB T4SS/BCV mechanism is conserved across Brucella species and hosts; granuloma biology parallels other intracellular pathogens (Mycobacterium, Salmonella, Yersinia) (PMID: 41921569).

15. Model Organisms

Mouse (primary model). BALB/c and C57BL/6 mice via intranasal/intraperitoneal B. melitensis establish chronic splenic infection recapitulating the human myeloid reservoir. "Most of the infected spleen cells contained high levels of lipids and expressed CD11c and CD205 dendritic cell markers and Arginase1, but were negative for the M2a markers Fizz1 or CD301." (PMID: 26376185).

Genetic models. IL-12p40⁻/⁻ (Th1-deficient) mice show uncontrolled splenic reservoir persistence; STAT6 deficiency did not affect bacterial growth; TBK1 knockout promotes bacterial survival in vivo (PMID: 26376185, PMID: 41605070).

Cellular/in vitro models. RAW264.7 and J774.A1 murine macrophages, human macrophages/monocytes; used for TraDIS (374 essential intracellular-survival genes) and genome-wide CRISPR host-gene screens (PMID: 41917383, PMID: 42617139).

Recapitulation & limitations. Mouse models faithfully reproduce chronic intracellular persistence, Th1-dependent control, and reservoir-cell biology, but do not reproduce the undulant fever, osteoarticular disease, or endocarditis of human disease. Natural livestock (sheep/goat) infection best models reproductive pathology and vaccine efficacy.

Mechanistic Model / Interpretation

The unifying theme of B. melitensis pathogenesis is stealthy intracellular parasitism of professional phagocytes. Two pathogen programs drive disease: (1) the VirB T4SS, which converts a doomed endosome into a bespoke ER-derived replicative organelle by hijacking host GTPase traffic (Arf6–Rab8a, Rab2) and secretory machinery; and (2) innate-immune subversion, principally Omp25-mediated TNF-α suppression and blockade of macrophage apoptosis. The outcome bifurcates on host immunity: a competent Th1/IFN-γ/IL-12/TNF-α (and TBK1/NF-κB) response clears the organism, whereas failure — influenced by cytokine-gene polymorphisms (IL4, IL18, TNF, TGFB1, IL10, TLR4) — permits persistence in lipid-laden dendritic-cell-like reservoir cells and produces the chronic, relapsing, focal disease that accounts for the clinical morbidity (spondylitis, endocarditis, neurobrucellosis).

This model explains the therapeutic logic: because bacteria hide intracellularly, treatment must use lipophilic, intracellularly-penetrating antibiotics in combination for prolonged courses — hence doxycycline paired with rifampicin or an aminoglycoside, and the high relapse of monotherapy. It also explains prevention strategy: with human immunity difficult to induce safely, breaking the animal-reservoir → food/contact → human chain (Rev1 livestock vaccination, pasteurization, surveillance) is the effective lever.

Evidence Base

PMID Contribution Type
41132010 Etiology, transmission routes, reservoir prevalence Systematic review/meta-analysis
15677842 First-line combination therapy; monotherapy relapse Guidelines
39172763 Comparative regimen efficacy (doxy+gentamicin best) Network meta-analysis, 43 RCTs
22392933 VirB T4SS & VjbR required for intracellular replication In vitro/mouse
27899503 rBCV biogenesis requires VirB T4SS In vitro
34423453 BspF effector–Arf6-Rab8a cascade In vitro
12414158 Omp25/TNF-α evasion; protective Th1 response Human/in vitro review
26376185 Chronic splenic reservoir cell phenotype Mouse model
42603185 Complications, relapse, compliance Nationwide pediatric cohort
29863218 Clinical phenotype frequencies; culture yield 10-year case series
31816580 Host cytokine susceptibility variants Meta-analysis
41632803 Incidence, male predominance, low mortality Registry (Ningxia)
11910696 Endocarditis as serious/fatal complication Case series
36653223 / 26825313 Rev1 livestock vaccine, control modeling Vaccine/modeling
41241000 / 40185219 Acute vs chronic course; prognostic factors Cohorts

Most evidence is human clinical (cohorts, case series, meta-analyses) and model organism/in vitro (mouse, macrophage). No computational-only findings were relied upon for clinical claims.

Limitations and Knowledge Gaps

  1. Host-genetics evidence is early-stage: susceptibility SNP associations derive from modest case-control studies with heterogeneity; few are validated in independent cohorts or functionally confirmed.
  2. Mechanistic effector work is largely in B. abortus/B. suis and murine macrophages; B. melitensis-specific effector repertoires and human-cell validation remain incomplete.
  3. No mouse model reproduces the full human syndrome (undulant fever, osteoarticular disease, endocarditis), limiting translational inference.
  4. Precise global incidence/prevalence for B. melitensis specifically is confounded by under-reporting, serological cross-reactivity, and species-level ambiguity in surveillance.
  5. No human vaccine and no host-directed therapy are available; optimal antibiotic duration for focal disease is not firmly established.
  6. During citation verification, the Ningxia incidence numeric snippet (PMID: 41632803) was flagged as a partial mismatch, while the "zero deaths" quote verified cleanly; incidence figures should be treated as approximate pending source re-check.

Proposed Follow-up Experiments / Actions

  1. Validate host-susceptibility SNPs (IL4, IL18, TNF-238, TGFB1, TLR4) in large, multi-ancestry prospective cohorts with functional (cytokine-response) readouts and stratification by focal complication.
  2. Define the B. melitensis-specific T4SS effector–host interactome in primary human macrophages using proximity labeling and CRISPR host-gene screens (PMID: 42617139), prioritizing druggable nodes (Arf6, Rab2, α-enolase, TBK1/NF-κB).
  3. Advance rough-LPS vaccine candidates (Rev1Δwzm, 16MΔwzm) toward B. melitensis challenge efficacy in pregnant ewes and develop a differentiating (DIVA) serodiagnostic (PMID: 38806353).
  4. Run adequately-powered RCTs confirming doxycycline+gentamicin superiority and defining duration for spondylitis/neurobrucellosis/endocarditis (PMID: 39172763).
  5. Deploy integrated molecular surveillance (MLVA + cgSNP) along livestock-trade corridors to track dominant genotypes and guide region-specific vaccination (PMID: 42093768, PMID: 42360586).
  6. Test host-directed adjuncts (e.g., TBK1/IFN-axis modulation) to accelerate clearance and reduce relapse in chronic disease (PMID: 41605070).

Report compiled from 16 confirmed findings across 5 investigation iterations and 53 reviewed papers. Evidence types are distinguished as human clinical, model organism, or in vitro throughout.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0rc3.

Outcome Count
References checked 42
Resolved 42
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 42
On topic 23
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 37
Resolved 37
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 0
Terms whose name was checked 29
Terms named correctly 15
Terms named as a different term 9
Terms whose name is worth a second look 5

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • HP:0030166 (1 mention) - the report calls it "Frequent"; HP calls it Night sweats
  • HP:0003326 (1 mention) - the report calls it "~19% (with fever)"; HP calls it Myalgia
  • HP:0001824 (1 mention) - the report calls it "Common (adults > children)"; HP calls it Weight loss
  • HP:0100775 (1 mention) - the report calls it "Adults > children (p=0.043)"; HP calls it Dural ectasia
  • HP:0003429 (1 mention) - the report calls it "Older adults predominant"; HP calls it CNS hypomyelination
  • HP:0002716 (1 mention) - the report calls it "Common"; HP calls it Lymphadenopathy
  • HP:0001882 (1 mention) - the report calls it "21% (acute)"; HP calls it Decreased total leukocyte count
  • HP:0002910 (1 mention) - the report calls it "44% (acute)"; HP calls it Elevated circulating hepatic transaminase concentration
  • GO:0140355 (1 mention) - the report calls it "T4SS-dependent protein secretion into host cell"; GO calls it cargo receptor ligand activity

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • GO:0006915 (1 mention) - the report calls it "apoptotic process, inhibited"; GO calls it apoptotic process
  • GO:0032609 (1 mention) - the report calls it "IFN-γ production"; GO calls it type II interferon production, and lists "IFNG production" among its other names
  • GO:0005783 (1 mention) - the report calls it "endoplasmic reticulum — rBCV origin"; GO calls it endoplasmic reticulum
  • GO:0005776 (1 mention) - the report calls it "autophagosome — aBCV"; GO calls it autophagosome
  • GO:0005768 (1 mention) - the report calls it "endosome — eBCV"; GO calls it endosome