Typhoidal Tularemia

Infectious Disease MONDO:0000321 Pathograph 22 Show in embeddings browser Tularemia

Typhoidal tularemia is the systemic bacteremic form of Francisella tularensis infection: intracellular bacterial replication in macrophages occurs without a dominant primary cutaneous, ocular, pharyngeal, or pulmonary localizing lesion, and systemic inflammatory spread produces fever, chills, malaise, myalgia, and severe sepsis-like illness.

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9
Pathophys.
1
Histopath.
12
Phenotypes
22
Pathograph
3
Medical Actions
1
Deep Research
🏷

Classifications

Harrison's Part
INFECTIOUS DISEASES
⚙

Pathophysiology

9
Systemic Francisella tularensis Inoculation
F. tularensis enters the host through a zoonotic, arthropod-borne, foodborne, waterborne, or aerosol-associated exposure that does not produce a dominant primary ulceroglandular, ocular, pharyngeal, or pneumonic lesion.
Downstream
Macrophage Phagosomal Escape and Cytosolic Replication F. tularensis enters macrophages and establishes an intracellular cytosolic niche after host entry.
Show evidence (3 references)
PMID:37941380 SUPPORT REVIEW SYNTHESIS Other
"Depending on its entry route into the organism, F. tularensis causes different diseases"
Establishes entry route as a determinant of tularemia clinical form.
PMID:40107886 SUPPORT REVIEW SYNTHESIS Other
"the multiple routes of infection result in six typical clinical pictures (ulceroglandular, glandular, oculoglandular, oropharyngeal, typhoidal, and pneumonic)"
Places typhoidal tularemia among the canonical clinical pictures that can arise after different Francisella acquisition routes.
PMID:41458397 SUPPORT Human Clinical
"The typhoidal form is especially challenging to diagnose due to the absence of localized lesions, often mimicking other systemic febrile illnesses such as brucellosis, typhoid fever, or hematologic disorders."
Supports absence of a dominant localized lesion as a feature of the typhoidal form.
Macrophage Phagosomal Escape and Cytosolic Replication
F. tularensis uses its Francisella Pathogenicity Island-encoded type VI secretion system to escape the macrophage phagosome and replicate in the cytosol.
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.
symbiont-mediated suppression of host phagosome maturation GO:0141158 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves symbiont-mediated suppression of host phagosome maturation (GO:0141158). GO:0141158 is a biological process from the Gene Ontology.
Downstream
AIM2 Inflammasome Host Response Cytosolic Francisella DNA activates the AIM2-ASC-caspase-1 inflammasome response.
Cell-Penetrant Antimicrobial Requirement Once Francisella replicates inside the macrophage cytosol, therapy with doxycycline or fluoroquinolones depends on host-cell penetration as well as on the bacterial molecular target.
Reticuloendothelial Dissemination and Cytopenic Organ Disease Intracellular replication seeds bacteremic dissemination to marrow and visceral compartments in systemic disease.
Show evidence (1 reference)
PMID:37941380 SUPPORT REVIEW SYNTHESIS Other
"The main virulence attribute of F. tularensis is the type 6 secretion system (T6SS) and its effectors that promote escape from the phagosome."
Identifies the T6SS-mediated phagosomal escape machinery that permits Francisella intracellular replication.
AIM2 Inflammasome Host Response
Cytosolic Francisella DNA is sensed by AIM2, which assembles an ASC- and caspase-1-dependent inflammasome that matures IL-1 beta and IL-18 and drives pyroptotic inflammatory signaling.
inflammasome-mediated signaling pathway GO:0141084 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased inflammasome-mediated signaling pathway (GO:0141084). GO:0141084 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Bacteremic Systemic Inflammation AIM2-dependent caspase-1 activation converts cytosolic Francisella sensing into IL-1 beta and IL-18 release and inflammatory cell death.
Show evidence (2 references)
PMID:25774716 SUPPORT Model Organism
"The AIM2 inflammasome detects double-stranded DNA in the cytosol and induces caspase-1-dependent pyroptosis as well as release of the inflammatory cytokines interleukin 1beta (IL-1beta) and IL-18."
Defines the AIM2 inflammasome response that converts cytosolic Francisella DNA detection into pyroptosis and inflammatory cytokine release.
PMID:23975862 SUPPORT Model Organism
"During F. tularensis subspecies novicida infection, AIM2, an inflammasome receptor sensing cytosolic DNA, activates caspase-1 in an ASC-dependent manner, leading to both pyroptosis and release of the proinflammatory cytokines IL-1beta and IL-18."
Places AIM2 and ASC-dependent caspase-1 activation downstream of cytosolic Francisella infection.
Reticuloendothelial Dissemination and Cytopenic Organ Disease
Systemic typhoidal infection can involve marrow and visceral organs after bacteremic dissemination, producing hematologic abnormalities such as pancytopenia as well as hepatosplenic and granulomatous hepatic involvement during atypical systemic presentations.
Downstream
Pancytopenia Systemic marrow and reticuloendothelial involvement can suppress multiple peripheral blood-cell lineages.
Hepatosplenomegaly Reticuloendothelial involvement in systemic tularemia can enlarge both the liver and spleen.
Elevated hepatic transaminases Hepatic granulomatous or suppurative involvement can produce hepatocyte injury and circulating transaminase elevation.
Granulomatous Tularemic Tissue Inflammation Disseminated F. tularensis can seed affected organs, where the host response forms granulomatous and suppurative tularemic lesions.
Show evidence (3 references)
PMID:41458397 SUPPORT Human Clinical
"The patient presented with a two-week history of high-grade fever, severe malaise, anorexia, and laboratory evidence of pancytopenia with hypoglycemia."
Documents pancytopenia in a serologically confirmed typhoidal tularemia patient after an undifferentiated systemic febrile presentation.
PMID:41458397 SUPPORT Human Clinical
"On physical examination, mild hepatosplenomegaly was noted, although no skin lesions or ulcers were observed."
Documents hepatosplenomegaly in a typhoidal tularemia patient who lacked skin ulcers or other localized entry-site lesions.
PMID:31937491 SUPPORT Human Clinical
"Patients with hepatic involvement typically have elevated transaminase levels, hepatomegaly and rarely jaundice."
Supports elevated hepatic transaminases as a laboratory manifestation of hepatic involvement in systemic typhoidal tularemia.
Granulomatous Tularemic Tissue Inflammation
Tularemia can produce suppurative and granulomatous lesions in involved lymph nodes and organs; in systemic or pulmonary presentations, tissue biopsies can show granulomatous hepatitis or necrotizing granulomatous inflammation that clinically and radiographically mimics malignancy.
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.
granuloma formation GO:0002432 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves granuloma formation (GO:0002432). GO:0002432 is a biological process from the Gene Ontology.
Downstream
Elevated hepatic transaminases Granulomatous hepatic involvement can injure hepatocytes and elevate circulating hepatic transaminases.
Show evidence (2 references)
PMID:31937491 SUPPORT Human Clinical
"Tularemia may develop granulomatous and suppurative lesions, especially in the affected regional lymph nodes and various organs."
Supports granulomatous and suppurative lesions in involved tissues as part of the tularemic tissue response.
PMID:41482246 SUPPORT INDIRECT Human Clinical
"CTguided biopsies performed in two patients revealed a non-specific necrotizing granulomatous inflammation."
Documents necrotizing granulomatous inflammation in pulmonary tularemia tissue biopsies; the directness is indirect because the cohort concerns pulmonary rather than primary typhoidal tularemia, but it confirms the same F. tularensis granulomatous tissue signature.
Bacteremic Systemic Inflammation
Cytosolic Francisella infection is sensed by inflammasome pathways and, in the typhoidal form, presents as bacteremia and a systemic inflammatory syndrome without a defining regional bubo, skin ulcer, conjunctivitis, or pneumonia.
inflammatory response GO:0006954 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased inflammatory response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology. ↑ INCREASED inflammasome-mediated signaling pathway GO:0141084 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased inflammasome-mediated signaling pathway (GO:0141084). GO:0141084 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Fever Systemic inflammatory signaling produces fever.
Chills Systemic inflammatory signaling produces chills.
Myalgia Systemic infection produces diffuse muscle pain.
Headache Acute systemic tularemia commonly includes headache as part of the flu-like inflammatory symptom complex.
Sepsis Bacteremic Francisella infection can manifest as severe sepsis-like systemic disease.
Pericarditis Severe systemic typhoidal tularemia can be complicated by cardiovascular inflammation, including pericarditis.
Pneumonia Systemic tularemia can be complicated by secondary pleuropneumonia even when the primary portal is non-pneumonic.
Show evidence (3 references)
PMID:19863554 SUPPORT REVIEW SYNTHESIS Other
"activation of the inflammasome mediated by caspase-1, and a pro-inflammatory response"
Supports inflammasome activation and pro-inflammatory signaling downstream of cytosolic Francisella infection.
PMID:41458397 SUPPORT Human Clinical
"Early recognition is critical, as delayed treatment can result in severe complications, including multiorgan involvement, cardiovascular manifestations, and hematologic abnormalities."
Supports multisystem complications after delayed recognition of systemic typhoidal tularemia, including cardiovascular manifestations.
PMID:37916743 SUPPORT REVIEW SYNTHESIS Other
"In humans, besides the clinical forms that are well characterized, tularemia may also be responsible for causing secondary pleuropneumonia, meningitis, and sepsis ultimately leading to shock and subsequent death"
Supports secondary pleuropneumonia and severe sepsis as complications of systemic tularemia beyond the portal-specific primary clinical forms.
Francisella Ribosomal Translation
F. tularensis depends on the bacterial 70S ribosome for protein synthesis; aminoglycosides such as gentamicin and tetracyclines such as doxycycline act on this conserved bacterial ribosomal target rather than on the macrophage escape machinery itself.
translation GO:0006412 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves translation (GO:0006412). GO:0006412 is a biological process from the Gene Ontology.
Downstream
Macrophage Phagosomal Escape and Cytosolic Replication Active bacterial translation sustains cytosolic Francisella replication in infected macrophages.
Show evidence (1 reference)
PMID:24336183 SUPPORT Other
"The ribosome is one of the main antibiotic targets in the bacterial cell."
Establishes the bacterial ribosome as the conserved target of aminoglycosides and tetracyclines used to treat tularemia.
Francisella DNA Gyrase and Topoisomerase IV
F. tularensis requires bacterial type II topoisomerases to manage DNA supercoiling and chromosome segregation; ciprofloxacin and levofloxacin act by trapping gyrase/topoisomerase-DNA cleavage complexes at this fluoroquinolone target.
DNA topological change GO:0006265 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves DNA topological change (GO:0006265). GO:0006265 is a biological process from the Gene Ontology.
Downstream
Macrophage Phagosomal Escape and Cytosolic Replication Francisella type II topoisomerase activity sustains bacterial DNA replication during cytosolic growth.
Show evidence (1 reference)
PMID:27449972 SUPPORT Other
"Quinolones dually target DNA gyrase and topoisomerase IV binding to specific domains and conformations so as to block DNA strand passage catalysis and stabilize DNA-enzyme complexes that block the DNA replication apparatus and generate double breaks in DNA that underlie their bactericidal activity."
Establishes bacterial DNA gyrase and topoisomerase IV as the conserved fluoroquinolone target represented by this node.
Cell-Penetrant Antimicrobial Requirement
Because F. tularensis replicates in the host-cell cytosol, orally used doxycycline and fluoroquinolones must accumulate intracellularly to reach the organism. This pharmacokinetic gate is modeled separately from their ribosomal or topoisomerase molecular targets and is not asserted for gentamicin, a poorly cell-penetrant aminoglycoside that is nevertheless first-line for severe tularemia.
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 (2 references)
PMID:28639230 SUPPORT Other
"Therapeutic efficacy against intracellular pathogens has been correlated mainly with the intracellular concentrations achieved by the different antimicrobial agents."
Establishes intracellular antibiotic concentration as the pharmacokinetic gate for therapy of intracellular bacterial infections.
PMID:37941380 SUPPORT REVIEW SYNTHESIS Other
"The main virulence attribute of F. tularensis is the type 6 secretion system (T6SS) and its effectors that promote escape from the phagosome."
Identifies the host-cell cytosolic niche that makes intracellular drug penetration relevant for Francisella-active doxycycline and fluoroquinolones.
✶

Histopathology

1
Necrotizing granulomatous inflammation
Tularemia tissue samples can show granulomatous and suppurative inflammation, including granulomatous hepatitis in systemic disease and necrotizing granulomatous inflammation in biopsied pulmonary lesions that mimic malignancy.
Show evidence (2 references)
PMID:31937491 SUPPORT Human Clinical
"Liver had a nodular appearance in liver imaging and liver biopsy were consistent with granulomatous hepatitis."
Documents granulomatous hepatitis on liver biopsy during systemic tularemia.
PMID:41482246 SUPPORT INDIRECT Human Clinical
"In three patients, positron emission tomography/CT demonstrated intensely hypermetabolic lesions, highly suggestive of malignancy. CTguided biopsies performed in two patients revealed a non-specific necrotizing granulomatous inflammation."
Documents necrotizing granulomatous inflammation in F. tularensis lesions that can mimic malignancy; this is indirect for typhoidal tularemia because the biopsied cases were pulmonary.
⬡

Pathograph

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

Phenotypes

12
Blood 1
Pancytopenia HP:0001876 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pancytopenia (HP:0001876). HP:0001876 is a phenotype from the Human Phenotype Ontology.
Cardiovascular 2
Hepatosplenomegaly 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.
Pericarditis HP:0001701 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pericarditis (HP:0001701). HP:0001701 is a phenotype from the Human Phenotype Ontology.
Immune 2
Sepsis HP:0100806 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sepsis (HP:0100806). HP:0100806 is a phenotype from the Human Phenotype Ontology.
Pneumonia HP:0002090 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pneumonia (HP:0002090). HP:0002090 is a phenotype from the Human Phenotype Ontology.
Metabolism 2
Fever 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.
Elevated hepatic transaminases Elevated circulating hepatic transaminase concentration HP:0002910 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated hepatic transaminases, annotated with Elevated circulating hepatic transaminase concentration (HP:0002910). HP:0002910 is a phenotype from the Human Phenotype Ontology.
Nervous System 1
Headache HP:0002315 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Headache (HP:0002315). HP:0002315 is a phenotype from the Human Phenotype Ontology.
Constitutional 3
Chills HP:0025143 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chills (HP:0025143). HP:0025143 is a phenotype from the Human Phenotype Ontology.
Myalgia HP:0003326 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myalgia (HP:0003326). HP:0003326 is a phenotype from the Human Phenotype Ontology.
Malaise HP:0033834 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Malaise (HP:0033834). HP:0033834 is a phenotype from the Human Phenotype Ontology.
Growth 1
Weight Loss HP:0001824 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Weight loss (HP:0001824). HP:0001824 is a phenotype from the Human Phenotype Ontology.
💊

Medical Actions

3
Gentamicin for severe tularemia
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: 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.
Platform: Small molecule
Gentamicin is an aminoglycoside first-line agent for severe tularemia, including severe systemic typhoidal disease.
Mechanism Target:
INHIBITS Francisella Ribosomal Translation — Gentamicin is an aminoglycoside that kills Francisella through the conserved bacterial ribosomal target.
Show evidence (1 reference)
PMID:40107886 SUPPORT REVIEW SYNTHESIS Other
"Gentamicin is the first-line treatment for severe tularemia"
Supports gentamicin as a first-line drug for severe tularemia presentations, including systemic typhoidal disease.
Fluoroquinolone 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: ciprofloxacin CHEBI:100241 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses ciprofloxacin (CHEBI:100241). CHEBI:100241 is a therapeutic agent from Chemical Entities of Biological Interest. levofloxacin CHEBI:63598 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses levofloxacin (CHEBI:63598). CHEBI:63598 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Ciprofloxacin or levofloxacin are fluoroquinolone alternatives for less severe tularemia and have clinical response data in severe respiratory and bacteremic type B tularemia.
Mechanism Target:
INHIBITS Francisella DNA Gyrase and Topoisomerase IV — Ciprofloxacin and levofloxacin are fluoroquinolones that inhibit bacterial type II topoisomerases needed for Francisella DNA replication.
BYPASSES Cell-Penetrant Antimicrobial Requirement — Fluoroquinolones reach intracellular Francisella and therefore satisfy the penetration requirement imposed by the organism's macrophage cytosolic niche.
Show evidence (2 references)
PMID:40107886 SUPPORT REVIEW SYNTHESIS Other
"fluoroquinolones and tetracyclines are commonly the drugs of choice in less severe forms"
Supports fluoroquinolones as commonly selected agents for less severe tularemia.
PMID:38294118 SUPPORT Human Clinical
"30-day mortality was 1.5% (1 of 67)"
Reports low 30-day mortality in a severe respiratory tularemia cohort in which hospitalized patients were frequently treated with ciprofloxacin or levofloxacin-containing regimens.
Doxycycline alternative 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.
Platform: Small molecule
Doxycycline is a tetracycline alternative for tularemia, but because tetracyclines are bacteriostatic and relapse can occur, agent choice and duration need to account for disease severity.
Mechanism Target:
INHIBITS Francisella Ribosomal Translation — Doxycycline blocks Francisella bacterial protein synthesis, limiting intracellular replication upstream of bacteremic systemic inflammation.
BYPASSES Cell-Penetrant Antimicrobial Requirement — Doxycycline accumulates intracellularly and therefore reaches Francisella organisms replicating inside host-cell cytosol.
Show evidence (3 references)
PMID:40107886 SUPPORT REVIEW SYNTHESIS Other
"fluoroquinolones and tetracyclines are commonly the drugs of choice in less severe forms"
Supports tetracyclines as commonly selected non-aminoglycoside tularemia agents.
PMID:38294108 SUPPORT REVIEW SYNTHESIS Human Clinical
"Aminoglycosides, fluoroquinolones, and tetracyclines are effective antimicrobials for treatment of tularemia, regardless of clinical manifestation."
Systematic review of case-level human tularemia data identifies several effective antibiotic classes across manifestations.
PMID:38294118 SUPPORT Human Clinical
"One disease relapse occurred with doxycycline treatment."
Documents relapse after doxycycline in a severe type B respiratory tularemia cohort, supporting attention to severity when choosing a bacteriostatic alternative.
🔬

Diagnosis

1
Blood culture and serologic confirmation
Typhoidal tularemia should be suspected in a compatible systemic febrile illness without localized lesions, with diagnosis confirmed by serology or occasional Francisella growth from blood in bacteremic disease.
Show evidence (2 references)
PMID:24874046 SUPPORT Human Clinical
"An unexpectedly high number (3.9 %) of the patients had positive blood culture with Francisella tularensis."
Shows that Francisella can be recovered from blood cultures in a minority of clinically diverse tularemia cases.
PMID:41458397 SUPPORT Human Clinical
"Serologic testing confirmed Francisella tularensis infection."
Documents serologic confirmation in a typhoidal tularemia presentation with pancytopenia and pericarditis.
📈

Progression

2
Incubation after Francisella tularensis exposure
Incubation: 3-5 days
Tularemia usually incubates for 3 to 5 days, although incubation can extend up to 20 days.
Show evidence (1 reference)
PMID:37916743 SUPPORT REVIEW SYNTHESIS Other
"The incubation period is typically 3 to 5 days but can be up to 20 days."
Supports the typical incubation interval after F. tularensis exposure.
Acute systemic illness
The typhoidal form presents as acute flu-like systemic illness and is among the severe tularemia forms.
Show evidence (1 reference)
PMID:37916743 SUPPORT REVIEW SYNTHESIS Other
"The disease has an acute onset, with the occurrence of fever (38–40 °C), chills, fatigue, generalized myalgia, and headaches, resembling flu."
Supports an acute symptomatic phase with the constitutional features prominent in typhoidal tularemia.
📊

Prevalence

1
Norway reported tularemia cases, 2011
Cases In Literature Unknown
Typhoidal tularemia accounted for 14.4% of 180 Norwegian tularemia cases during a high-incidence year with diverse seasonal clinical presentations.
Show evidence (1 reference)
PMID:24874046 SUPPORT Human Clinical
"Overall, oropharyngeal tularaemia (41.1 %) was the most common clinical presentation, followed by glandular (14.4 %), typhoidal (14.4 %), respiratory (13.3 %) and ulceroglandular (12.8 %) tularaemia."
Quantifies the typhoidal form among reported Norwegian tularemia cases in 2011.
🦠

Infectious Agent

1
Francisella tularensis
Intracellular Gram-negative coccobacillus that causes tularemia, including its typhoidal bacteremic form.
Francisella tularensis NCBITaxon:263 NCBI Taxonomy (NCBITaxon)
Show evidence (1 reference)
PMID:37916743 SUPPORT REVIEW SYNTHESIS Other
"Tularemia caused by Gram-negative, coccobacillus bacterium, Francisella tularensis, is a highly infectious zoonotic disease."
Identifies F. tularensis as the Gram-negative bacterium that causes tularemia.
↔️

Transmission

4
Arthropod-borne acquisition
Typhoidal tularemia can follow vector-borne F. tularensis inoculation by infected arthropods, including ticks and mosquitoes.
Show evidence (1 reference)
PMID:37916743 SUPPORT REVIEW SYNTHESIS Other
"Typhoidal form may occur after infection via different routes."
Supports the typhoidal form as a systemic form that can arise after several Francisella entry routes.
Direct animal or infected-meat exposure
Handling sick animals or consuming infected animals can introduce F. tularensis without a single obligatory local portal lesion in typhoidal presentations.
Show evidence (1 reference)
PMID:32989563 SUPPORT REVIEW SYNTHESIS Other
"Humans can acquire the disease through direct contact of sick animals, consumption of infected animals, drinking or direct contact of contaminated water, and inhalation of bacteria-loaded aerosols."
Enumerates direct animal contact and consumption of infected animals among routes that can transmit F. tularensis to humans.
Foodborne or waterborne acquisition
Contaminated food or water can transmit F. tularensis to humans and can seed systemic typhoidal disease rather than an isolated ulceroglandular or ocular syndrome.
Show evidence (1 reference)
PMID:32989563 SUPPORT REVIEW SYNTHESIS Other
"Humans can acquire the disease through direct contact of sick animals, consumption of infected animals, drinking or direct contact of contaminated water, and inhalation of bacteria-loaded aerosols."
Lists infected food animals and contaminated water as Francisella acquisition routes.
Aerosol inhalation
Inhalation of bacteria-loaded aerosols can transmit F. tularensis and expose the host to a low-dose airborne route relevant to systemic and pneumonic tularemia.
Show evidence (1 reference)
PMID:32989563 SUPPORT REVIEW SYNTHESIS Other
"Humans can acquire the disease through direct contact of sick animals, consumption of infected animals, drinking or direct contact of contaminated water, and inhalation of bacteria-loaded aerosols."
Identifies inhalation of bacteria-loaded aerosols as a human tularemia acquisition route.
⚖️

Clinical Burden

High
Typhoidal tularemia is one of the severe systemic forms of tularemia, and untreated or delayed disease can progress to sepsis, multiorgan cardiovascular and hematologic complications, and death.
Show evidence (1 reference)
PMID:40107886 SUPPORT REVIEW SYNTHESIS Other
"If not promptly diagnosed and treated, the fatality rate can be as high as 60 %, with the poorest outcomes reported in the pneumonic and typhoidal forms."
Identifies typhoidal tularemia as one of the tularemia forms associated with the poorest outcomes when diagnosis and treatment are delayed.
{ }

Source YAML

click to show 
name: Typhoidal Tularemia
creation_date: "2026-09-25T16:02:46Z"
category: Infectious Disease
description: >-
  Typhoidal tularemia is the systemic bacteremic form of Francisella tularensis
  infection: intracellular bacterial replication in macrophages occurs without a
  dominant primary cutaneous, ocular, pharyngeal, or pulmonary localizing
  lesion, and systemic inflammatory spread produces fever, chills, malaise,
  myalgia, and severe sepsis-like illness.
disease_term:
  preferred_term: typhoidal tularemia
  term:
    id: MONDO:0000321
    label: typhoidal tularemia
parents:
- Tularemia
synonyms:
- Septicemic tularemia
- Systemic tularemia
review_notes: >-
  Deliberately lumped. Typhoidal tularemia is the systemic clinical form of
  tularemia rather than a subspecies stratum: F. tularensis subsp. tularensis and
  F. tularensis subsp. holarctica differ in geography and severity across
  tularemia, but the typhoidal form can arise after several entry routes and is
  not restricted to either subspecies. Type-specific severity and reservoir
  claims therefore remain on the parent Tularemia entry unless a source
  distinguishes a typhoidal-specific type A or type B mechanism.
infectious_agent:
- name: Francisella tularensis
  infectious_agent_term:
    preferred_term: Francisella tularensis
    term:
      id: NCBITaxon:263
      label: Francisella tularensis
  description: >-
    Intracellular Gram-negative coccobacillus that causes tularemia, including its
    typhoidal bacteremic form.
  evidence:
  - reference: PMID:37916743
    reference_title: "Tularemia - a re-emerging disease with growing concern."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Tularemia caused by Gram-negative, coccobacillus bacterium, Francisella
      tularensis, is a highly infectious zoonotic disease.
    explanation: >-
      Identifies F. tularensis as the Gram-negative bacterium that causes tularemia.
agent_life_cycle:
  description: >-
    F. tularensis is maintained in animal reservoirs and transmitted by direct
    animal contact, water or food contamination, aerosols, and arthropod vectors.
    Type A tularemia is classically terrestrial, with cottontail rabbits and
    ticks as important reservoirs or vectors; type B tularemia often has
    water-associated aquatic rodent reservoirs. Humans are accidental clinical
    hosts for zoonotic or environmental exposure.
  hosts:
  - preferred_term: Homo sapiens
    role: accidental clinical host
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  - preferred_term: Sylvilagus
    role: cottontail rabbit reservoir in the terrestrial type A cycle
    term:
      id: NCBITaxon:9987
      label: Sylvilagus
  - preferred_term: Ondatra zibethicus
    role: muskrat reservoir in aquatic type B cycles
    term:
      id: NCBITaxon:10060
      label: Ondatra zibethicus
  - preferred_term: Castor canadensis
    role: beaver reservoir in aquatic type B cycles
    term:
      id: NCBITaxon:51338
      label: Castor canadensis
  vectors:
  - Ticks
  - Mosquitoes
  life_cycle_stages:
  - name: Wildlife reservoir maintenance
    description: >-
      Francisella circulates in terrestrial and aquatic animal cycles involving
      lagomorph and aquatic-rodent reservoirs.
    evidence:
    - reference: PMID:1305858
      reference_title: "The ecology of tularaemia."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Type A is reported to have a terrestrial cycle with the main reservoirs
        being cottontail rabbits (Sylvilagus spp.) and ticks. Type B is reported
        to have a mainly water-borne cycle with aquatic rodents as reservoirs,
        e.g. muskrats (Ondatra zibethicus) and beaver (Castor canadensis) in
        North America
      explanation: >-
        Identifies the terrestrial and water-associated wildlife reservoirs that
        maintain the two major tularemia types.
  - name: Human zoonotic and vector-borne acquisition
    description: >-
      Humans acquire F. tularensis from infected animals, contaminated food or
      water, contaminated aerosols, or arthropod vectors such as ticks and
      mosquitoes.
    evidence:
    - reference: PMID:1305858
      reference_title: "The ecology of tularaemia."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Tularaemia is transmitted by direct contact with infected animals,
        through contaminated water or food, or by vectors such as mosquitoes or
        ticks.
      explanation: >-
        Summarizes animal-contact, water or food, and vector routes by which
        humans leave the reservoir cycles and acquire tularemia.
classifications:
  harrisons_chapter:
  - classification_value: INFECTIOUS_DISEASES
    evidence:
    - reference: PMID:37916743
      reference_title: "Tularemia - a re-emerging disease with growing concern."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Tularemia caused by Gram-negative, coccobacillus bacterium, Francisella
        tularensis, is a highly infectious zoonotic disease.
      explanation: >-
        Typhoidal tularemia is a bacterial infectious form of tularemia.
pathophysiology:
- name: Systemic Francisella tularensis Inoculation
  description: >-
    F. tularensis enters the host through a zoonotic, arthropod-borne,
    foodborne, waterborne, or aerosol-associated exposure that does not produce
    a dominant primary ulceroglandular, ocular, pharyngeal, or pneumonic lesion.
  biological_scale: ORGANISM
  downstream:
  - target: Macrophage Phagosomal Escape and Cytosolic Replication
    causal_link_type: DIRECT
    description: >-
      F. tularensis enters macrophages and establishes an intracellular cytosolic
      niche after host entry.
  evidence:
  - reference: PMID:37941380
    reference_title: "Pathogenicity and virulence of Francisella tularensis."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Depending on its entry route into the organism, F. tularensis causes different
      diseases
    explanation: >-
      Establishes entry route as a determinant of tularemia clinical form.
  - reference: PMID:40107886
    reference_title: "Tularemia for clinicians: An up-to-date review on epidemiology, diagnosis, prevention and treatment."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      the multiple routes of infection result in six typical clinical pictures
      (ulceroglandular, glandular, oculoglandular, oropharyngeal, typhoidal, and
      pneumonic)
    explanation: >-
      Places typhoidal tularemia among the canonical clinical pictures that can
      arise after different Francisella acquisition routes.
  - reference: PMID:41458397
    reference_title: "Typhoidal tularemia with pancytopenia and pericarditis in a georgian adolescent."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The typhoidal form is especially challenging to diagnose due to the absence
      of localized lesions, often mimicking other systemic febrile illnesses such
      as brucellosis, typhoid fever, or hematologic disorders.
    explanation: >-
      Supports absence of a dominant localized lesion as a feature of the
      typhoidal form.
- name: Macrophage Phagosomal Escape and Cytosolic Replication
  description: >-
    F. tularensis uses its Francisella Pathogenicity Island-encoded type VI
    secretion system to escape the macrophage phagosome and replicate in the
    cytosol.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: symbiont-mediated suppression of host phagosome maturation
    term:
      id: GO:0141158
      label: symbiont-mediated suppression of host phagosome maturation
  downstream:
  - target: AIM2 Inflammasome Host Response
    causal_link_type: DIRECT
    description: >-
      Cytosolic Francisella DNA activates the AIM2-ASC-caspase-1 inflammasome
      response.
  - target: Cell-Penetrant Antimicrobial Requirement
    causal_link_type: DIRECT
    description: >-
      Once Francisella replicates inside the macrophage cytosol, therapy with
      doxycycline or fluoroquinolones depends on host-cell penetration as well as
      on the bacterial molecular target.
  - target: Reticuloendothelial Dissemination and Cytopenic Organ Disease
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Intracellular replication seeds bacteremic dissemination to marrow and
      visceral compartments in systemic disease.
  evidence:
  - reference: PMID:37941380
    reference_title: "Pathogenicity and virulence of Francisella tularensis."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The main virulence attribute of F. tularensis is the type 6 secretion system
      (T6SS) and its effectors that promote escape from the phagosome.
    explanation: >-
      Identifies the T6SS-mediated phagosomal escape machinery that permits
      Francisella intracellular replication.
- name: AIM2 Inflammasome Host Response
  description: >-
    Cytosolic Francisella DNA is sensed by AIM2, which assembles an ASC- and
    caspase-1-dependent inflammasome that matures IL-1 beta and IL-18 and drives
    pyroptotic inflammatory signaling.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: inflammasome-mediated signaling pathway
    modifier: INCREASED
    term:
      id: GO:0141084
      label: inflammasome-mediated signaling pathway
  downstream:
  - target: Bacteremic Systemic Inflammation
    causal_link_type: DIRECT
    description: >-
      AIM2-dependent caspase-1 activation converts cytosolic Francisella sensing
      into IL-1 beta and IL-18 release and inflammatory cell death.
  evidence:
  - reference: PMID:25774716
    reference_title: "Guanylate-binding proteins promote activation of the AIM2 inflammasome during infection with Francisella novicida."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The AIM2 inflammasome detects double-stranded DNA in the cytosol and
      induces caspase-1-dependent pyroptosis as well as release of the
      inflammatory cytokines interleukin 1beta (IL-1beta) and IL-18.
    explanation: >-
      Defines the AIM2 inflammasome response that converts cytosolic Francisella
      DNA detection into pyroptosis and inflammatory cytokine release.
  - reference: PMID:23975862
    reference_title: "ASC controls IFN-γ levels in an IL-18-dependent manner in caspase-1-deficient mice infected with Francisella novicida."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      During F. tularensis subspecies novicida infection, AIM2, an inflammasome
      receptor sensing cytosolic DNA, activates caspase-1 in an ASC-dependent
      manner, leading to both pyroptosis and release of the proinflammatory
      cytokines IL-1beta and IL-18.
    explanation: >-
      Places AIM2 and ASC-dependent caspase-1 activation downstream of cytosolic
      Francisella infection.
- name: Reticuloendothelial Dissemination and Cytopenic Organ Disease
  description: >-
    Systemic typhoidal infection can involve marrow and visceral organs after
    bacteremic dissemination, producing hematologic abnormalities such as
    pancytopenia as well as hepatosplenic and granulomatous hepatic involvement
    during atypical systemic presentations.
  biological_scale: ORGANISM
  downstream:
  - target: Pancytopenia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Systemic marrow and reticuloendothelial involvement can suppress multiple
      peripheral blood-cell lineages.
  - target: Hepatosplenomegaly
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Reticuloendothelial involvement in systemic tularemia can enlarge both the
      liver and spleen.
  - target: Elevated hepatic transaminases
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Hepatic granulomatous or suppurative involvement can produce hepatocyte
      injury and circulating transaminase elevation.
  - target: Granulomatous Tularemic Tissue Inflammation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Disseminated F. tularensis can seed affected organs, where the host
      response forms granulomatous and suppurative tularemic lesions.
  evidence:
  - reference: PMID:41458397
    reference_title: "Typhoidal tularemia with pancytopenia and pericarditis in a georgian adolescent."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient presented with a two-week history of high-grade fever, severe
      malaise, anorexia, and laboratory evidence of pancytopenia with
      hypoglycemia.
    explanation: >-
      Documents pancytopenia in a serologically confirmed typhoidal tularemia
      patient after an undifferentiated systemic febrile presentation.
  - reference: PMID:41458397
    reference_title: "Typhoidal tularemia with pancytopenia and pericarditis in a georgian adolescent."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      On physical examination, mild hepatosplenomegaly was noted, although no
      skin lesions or ulcers were observed.
    explanation: >-
      Documents hepatosplenomegaly in a typhoidal tularemia patient who lacked
      skin ulcers or other localized entry-site lesions.
  - reference: PMID:31937491
    reference_title: "A rare cause of granulomatous hepatitis: Tularemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with hepatic involvement typically have elevated transaminase
      levels, hepatomegaly and rarely jaundice.
    explanation: >-
      Supports elevated hepatic transaminases as a laboratory manifestation of
      hepatic involvement in systemic typhoidal tularemia.
- name: Granulomatous Tularemic Tissue Inflammation
  description: >-
    Tularemia can produce suppurative and granulomatous lesions in involved
    lymph nodes and organs; in systemic or pulmonary presentations, tissue
    biopsies can show granulomatous hepatitis or necrotizing granulomatous
    inflammation that clinically and radiographically mimics malignancy.
  biological_scale: TISSUE
  role: effector
  conforms_to: "granuloma_formation#Organized Granuloma Assembly"
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: granuloma formation
    term:
      id: GO:0002432
      label: granuloma formation
  downstream:
  - target: Elevated hepatic transaminases
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Granulomatous hepatic involvement can injure hepatocytes and elevate
      circulating hepatic transaminases.
  evidence:
  - reference: PMID:31937491
    reference_title: "A rare cause of granulomatous hepatitis: Tularemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Tularemia may develop granulomatous and suppurative lesions, especially in
      the affected regional lymph nodes and various organs.
    explanation: >-
      Supports granulomatous and suppurative lesions in involved tissues as part
      of the tularemic tissue response.
  - reference: PMID:41482246
    reference_title: "Pulmonary tularemia: A diagnosis not to overlook."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CTguided biopsies performed in two patients revealed a non-specific
      necrotizing granulomatous inflammation.
    explanation: >-
      Documents necrotizing granulomatous inflammation in pulmonary tularemia
      tissue biopsies; the directness is indirect because the cohort concerns
      pulmonary rather than primary typhoidal tularemia, but it confirms the same
      F. tularensis granulomatous tissue signature.
- name: Bacteremic Systemic Inflammation
  description: >-
    Cytosolic Francisella infection is sensed by inflammasome pathways and, in the
    typhoidal form, presents as bacteremia and a systemic inflammatory syndrome
    without a defining regional bubo, skin ulcer, conjunctivitis, or pneumonia.
  biological_scale: ORGANISM
  biological_processes:
  - preferred_term: inflammatory response
    modifier: INCREASED
    term:
      id: GO:0006954
      label: inflammatory response
  - preferred_term: inflammasome-mediated signaling pathway
    modifier: INCREASED
    term:
      id: GO:0141084
      label: inflammasome-mediated signaling pathway
  downstream:
  - target: Fever
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Systemic inflammatory signaling produces fever.
  - target: Chills
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Systemic inflammatory signaling produces chills.
  - target: Myalgia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Systemic infection produces diffuse muscle pain.
  - target: Headache
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Acute systemic tularemia commonly includes headache as part of the flu-like
      inflammatory symptom complex.
  - target: Sepsis
    causal_link_type: DIRECT
    description: >-
      Bacteremic Francisella infection can manifest as severe sepsis-like systemic
      disease.
  - target: Pericarditis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Severe systemic typhoidal tularemia can be complicated by cardiovascular
      inflammation, including pericarditis.
  - target: Pneumonia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Systemic tularemia can be complicated by secondary pleuropneumonia even
      when the primary portal is non-pneumonic.
  evidence:
  - reference: PMID:19863554
    reference_title: "Cell biology and molecular ecology of Francisella tularensis."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      activation of the inflammasome mediated by caspase-1, and a pro-inflammatory
      response
    explanation: >-
      Supports inflammasome activation and pro-inflammatory signaling downstream of
      cytosolic Francisella infection.
  - reference: PMID:41458397
    reference_title: "Typhoidal tularemia with pancytopenia and pericarditis in a georgian adolescent."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Early recognition is critical, as delayed treatment can result in severe
      complications, including multiorgan involvement, cardiovascular
      manifestations, and hematologic abnormalities.
    explanation: >-
      Supports multisystem complications after delayed recognition of systemic
      typhoidal tularemia, including cardiovascular manifestations.
  - reference: PMID:37916743
    reference_title: "Tularemia - a re-emerging disease with growing concern."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      In humans, besides the clinical forms that are well characterized,
      tularemia may also be responsible for causing secondary pleuropneumonia,
      meningitis, and sepsis ultimately leading to shock and subsequent death
    explanation: >-
      Supports secondary pleuropneumonia and severe sepsis as complications of
      systemic tularemia beyond the portal-specific primary clinical forms.
- name: Francisella Ribosomal Translation
  description: >-
    F. tularensis depends on the bacterial 70S ribosome for protein synthesis;
    aminoglycosides such as gentamicin and tetracyclines such as doxycycline act
    on this conserved bacterial ribosomal target rather than on the macrophage
    escape machinery itself.
  biological_scale: MOLECULAR
  role: therapeutic_vulnerability
  conforms_to: "bacterial_protein_synthesis_inhibition#Bacterial mRNA Translation by the Ribosome"
  biological_processes:
  - preferred_term: translation
    term:
      id: GO:0006412
      label: translation
  downstream:
  - target: Macrophage Phagosomal Escape and Cytosolic Replication
    causal_link_type: DIRECT
    description: >-
      Active bacterial translation sustains cytosolic Francisella replication in
      infected macrophages.
  evidence:
  - reference: PMID:24336183
    reference_title: "Ribosome-targeting antibiotics and mechanisms of bacterial resistance."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The ribosome is one of the main antibiotic targets in the bacterial cell.
    explanation: >-
      Establishes the bacterial ribosome as the conserved target of
      aminoglycosides and tetracyclines used to treat tularemia.
- name: Francisella DNA Gyrase and Topoisomerase IV
  description: >-
    F. tularensis requires bacterial type II topoisomerases to manage DNA
    supercoiling and chromosome segregation; ciprofloxacin and levofloxacin act
    by trapping gyrase/topoisomerase-DNA cleavage complexes at this
    fluoroquinolone target.
  biological_scale: MOLECULAR
  role: therapeutic_vulnerability
  conforms_to: "bacterial_dna_topoisomerase_inhibition#DNA Gyrase and Topoisomerase IV (Fluoroquinolone Target)"
  biological_processes:
  - preferred_term: DNA topological change
    term:
      id: GO:0006265
      label: DNA topological change
  downstream:
  - target: Macrophage Phagosomal Escape and Cytosolic Replication
    causal_link_type: DIRECT
    description: >-
      Francisella type II topoisomerase activity sustains bacterial DNA
      replication during cytosolic growth.
  evidence:
  - reference: PMID:27449972
    reference_title: "Topoisomerase Inhibitors: Fluoroquinolone Mechanisms of Action and Resistance."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Quinolones dually target DNA gyrase and topoisomerase IV binding to
      specific domains and conformations so as to block DNA strand passage
      catalysis and stabilize DNA-enzyme complexes that block the DNA
      replication apparatus and generate double breaks in DNA that underlie
      their bactericidal activity.
    explanation: >-
      Establishes bacterial DNA gyrase and topoisomerase IV as the conserved
      fluoroquinolone target represented by this node.
- name: Cell-Penetrant Antimicrobial Requirement
  description: >-
    Because F. tularensis replicates in the host-cell cytosol, orally used
    doxycycline and fluoroquinolones must accumulate intracellularly to reach the
    organism. This pharmacokinetic gate is modeled separately from their
    ribosomal or topoisomerase molecular targets and is not asserted for
    gentamicin, a poorly cell-penetrant aminoglycoside that is nevertheless
    first-line for severe tularemia.
  biological_scale: CELLULAR
  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: >-
      Establishes intracellular antibiotic concentration as the pharmacokinetic
      gate for therapy of intracellular bacterial infections.
  - reference: PMID:37941380
    reference_title: "Pathogenicity and virulence of Francisella tularensis."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The main virulence attribute of F. tularensis is the type 6 secretion system
      (T6SS) and its effectors that promote escape from the phagosome.
    explanation: >-
      Identifies the host-cell cytosolic niche that makes intracellular drug
      penetration relevant for Francisella-active doxycycline and
      fluoroquinolones.
phenotypes:
- name: Fever
  category: Constitutional
  diagnostic: true
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
- name: Chills
  category: Constitutional
  phenotype_term:
    preferred_term: Chills
    term:
      id: HP:0025143
      label: Chills
- name: Myalgia
  category: Musculoskeletal
  phenotype_term:
    preferred_term: Myalgia
    term:
      id: HP:0003326
      label: Myalgia
- name: Malaise
  category: Constitutional
  phenotype_term:
    preferred_term: Malaise
    term:
      id: HP:0033834
      label: Malaise
- name: Weight Loss
  category: Growth
  phenotype_term:
    preferred_term: Weight loss
    term:
      id: HP:0001824
      label: Weight loss
- name: Sepsis
  category: Constitutional
  phenotype_term:
    preferred_term: Sepsis
    term:
      id: HP:0100806
      label: Sepsis
- name: Headache
  category: Neurologic
  phenotype_term:
    preferred_term: Headache
    term:
      id: HP:0002315
      label: Headache
- name: Pancytopenia
  category: Hematologic
  phenotype_term:
    preferred_term: Pancytopenia
    term:
      id: HP:0001876
      label: Pancytopenia
- name: Hepatosplenomegaly
  category: Gastrointestinal
  phenotype_term:
    preferred_term: Hepatosplenomegaly
    term:
      id: HP:0001433
      label: Hepatosplenomegaly
- name: Elevated hepatic transaminases
  category: Laboratory
  phenotype_term:
    preferred_term: Elevated hepatic transaminases
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
- name: Pericarditis
  category: Cardiovascular
  phenotype_term:
    preferred_term: Pericarditis
    term:
      id: HP:0001701
      label: Pericarditis
- name: Pneumonia
  category: Pulmonary
  phenotype_term:
    preferred_term: Pneumonia
    term:
      id: HP:0002090
      label: Pneumonia
transmission:
- name: Arthropod-borne acquisition
  description: >-
    Typhoidal tularemia can follow vector-borne F. tularensis inoculation by
    infected arthropods, including ticks and mosquitoes.
  evidence:
  - reference: PMID:37916743
    reference_title: "Tularemia - a re-emerging disease with growing concern."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Typhoidal form may occur after infection via different routes.
    explanation: >-
      Supports the typhoidal form as a systemic form that can arise after
      several Francisella entry routes.
- name: Direct animal or infected-meat exposure
  description: >-
    Handling sick animals or consuming infected animals can introduce F.
    tularensis without a single obligatory local portal lesion in typhoidal
    presentations.
  evidence:
  - reference: PMID:32989563
    reference_title: "Tularemia: a re-emerging tick-borne infectious disease."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Humans can acquire the disease through direct contact of sick animals,
      consumption of infected animals, drinking or direct contact of contaminated
      water, and inhalation of bacteria-loaded aerosols.
    explanation: >-
      Enumerates direct animal contact and consumption of infected animals among
      routes that can transmit F. tularensis to humans.
- name: Foodborne or waterborne acquisition
  description: >-
    Contaminated food or water can transmit F. tularensis to humans and can
    seed systemic typhoidal disease rather than an isolated ulceroglandular or
    ocular syndrome.
  evidence:
  - reference: PMID:32989563
    reference_title: "Tularemia: a re-emerging tick-borne infectious disease."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Humans can acquire the disease through direct contact of sick animals,
      consumption of infected animals, drinking or direct contact of contaminated
      water, and inhalation of bacteria-loaded aerosols.
    explanation: >-
      Lists infected food animals and contaminated water as Francisella
      acquisition routes.
- name: Aerosol inhalation
  description: >-
    Inhalation of bacteria-loaded aerosols can transmit F. tularensis and expose
    the host to a low-dose airborne route relevant to systemic and pneumonic
    tularemia.
  evidence:
  - reference: PMID:32989563
    reference_title: "Tularemia: a re-emerging tick-borne infectious disease."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Humans can acquire the disease through direct contact of sick animals,
      consumption of infected animals, drinking or direct contact of contaminated
      water, and inhalation of bacteria-loaded aerosols.
    explanation: >-
      Identifies inhalation of bacteria-loaded aerosols as a human tularemia
      acquisition route.
prevalence:
- population: Norway reported tularemia cases, 2011
  measure_type: CASES_IN_LITERATURE
  prevalence_class: UNKNOWN
  notes: >-
    Typhoidal tularemia accounted for 14.4% of 180 Norwegian tularemia cases
    during a high-incidence year with diverse seasonal clinical presentations.
  evidence:
  - reference: PMID:24874046
    reference_title: "All-time high tularaemia incidence in Norway in 2011: report from the national surveillance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Overall, oropharyngeal tularaemia (41.1 %) was the most common clinical
      presentation, followed by glandular (14.4 %), typhoidal (14.4 %),
      respiratory (13.3 %) and ulceroglandular (12.8 %) tularaemia.
    explanation: >-
      Quantifies the typhoidal form among reported Norwegian tularemia cases in
      2011.
progression:
- phase: Incubation after Francisella tularensis exposure
  incubation_days: 3-5
  notes: >-
    Tularemia usually incubates for 3 to 5 days, although incubation can extend
    up to 20 days.
  evidence:
  - reference: PMID:37916743
    reference_title: "Tularemia - a re-emerging disease with growing concern."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The incubation period is typically 3 to 5 days but can be up to 20 days.
    explanation: >-
      Supports the typical incubation interval after F. tularensis exposure.
- phase: Acute systemic illness
  notes: >-
    The typhoidal form presents as acute flu-like systemic illness and is among
    the severe tularemia forms.
  evidence:
  - reference: PMID:37916743
    reference_title: "Tularemia - a re-emerging disease with growing concern."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The disease has an acute onset, with the occurrence of fever (38–40 °C),
      chills, fatigue, generalized myalgia, and headaches, resembling flu.
    explanation: >-
      Supports an acute symptomatic phase with the constitutional features
      prominent in typhoidal tularemia.
clinical_burden:
  burden_level: HIGH
  rationale: >-
    Typhoidal tularemia is one of the severe systemic forms of tularemia, and
    untreated or delayed disease can progress to sepsis, multiorgan
    cardiovascular and hematologic complications, and death.
  evidence:
  - reference: PMID:40107886
    reference_title: "Tularemia for clinicians: An up-to-date review on epidemiology, diagnosis, prevention and treatment."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      If not promptly diagnosed and treated, the fatality rate can be as high as
      60 %, with the poorest outcomes reported in the pneumonic and typhoidal
      forms.
    explanation: >-
      Identifies typhoidal tularemia as one of the tularemia forms associated
      with the poorest outcomes when diagnosis and treatment are delayed.
diagnosis:
- name: Blood culture and serologic confirmation
  description: >-
    Typhoidal tularemia should be suspected in a compatible systemic febrile
    illness without localized lesions, with diagnosis confirmed by serology or
    occasional Francisella growth from blood in bacteremic disease.
  evidence:
  - reference: PMID:24874046
    reference_title: "All-time high tularaemia incidence in Norway in 2011: report from the national surveillance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An unexpectedly high number (3.9 %) of the patients had positive blood
      culture with Francisella tularensis.
    explanation: >-
      Shows that Francisella can be recovered from blood cultures in a minority
      of clinically diverse tularemia cases.
  - reference: PMID:41458397
    reference_title: "Typhoidal tularemia with pancytopenia and pericarditis in a georgian adolescent."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Serologic testing confirmed Francisella tularensis infection.
    explanation: >-
      Documents serologic confirmation in a typhoidal tularemia presentation
      with pancytopenia and pericarditis.
histopathology:
- name: Necrotizing granulomatous inflammation
  description: >-
    Tularemia tissue samples can show granulomatous and suppurative inflammation,
    including granulomatous hepatitis in systemic disease and necrotizing
    granulomatous inflammation in biopsied pulmonary lesions that mimic
    malignancy.
  finding_term:
    preferred_term: necrotizing granulomatous inflammation
  diagnostic: true
  notes: >-
    Left without a `term:` binding because the HistopathologyFindingTerm dynamic
    enum is rooted in NCIT histopathology-result concepts, and the true
    granuloma terms are outside that branch.
  evidence:
  - reference: PMID:31937491
    reference_title: "A rare cause of granulomatous hepatitis: Tularemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Liver had a nodular appearance in liver imaging and liver biopsy were
      consistent with granulomatous hepatitis.
    explanation: >-
      Documents granulomatous hepatitis on liver biopsy during systemic
      tularemia.
  - reference: PMID:41482246
    reference_title: "Pulmonary tularemia: A diagnosis not to overlook."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In three patients, positron emission tomography/CT demonstrated intensely
      hypermetabolic lesions, highly suggestive of malignancy. CTguided biopsies
      performed in two patients revealed a non-specific necrotizing granulomatous
      inflammation.
    explanation: >-
      Documents necrotizing granulomatous inflammation in F. tularensis lesions
      that can mimic malignancy; this is indirect for typhoidal tularemia because
      the biopsied cases were pulmonary.
treatments:
- name: Gentamicin for severe tularemia
  description: >-
    Gentamicin is an aminoglycoside first-line agent for severe tularemia,
    including severe systemic typhoidal disease.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: gentamicin
      term:
        id: CHEBI:759884
        label: gentamicin
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Francisella Ribosomal Translation
    treatment_effect: INHIBITS
    description: >-
      Gentamicin is an aminoglycoside that kills Francisella through the
      conserved bacterial ribosomal target.
  evidence:
  - reference: PMID:40107886
    reference_title: "Tularemia for clinicians: An up-to-date review on epidemiology, diagnosis, prevention and treatment."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Gentamicin is the first-line treatment for severe tularemia
    explanation: >-
      Supports gentamicin as a first-line drug for severe tularemia
      presentations, including systemic typhoidal disease.
- name: Fluoroquinolone therapy
  description: >-
    Ciprofloxacin or levofloxacin are fluoroquinolone alternatives for less
    severe tularemia and have clinical response data in severe respiratory and
    bacteremic type B tularemia.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ciprofloxacin
      term:
        id: CHEBI:100241
        label: ciprofloxacin
    - preferred_term: levofloxacin
      term:
        id: CHEBI:63598
        label: levofloxacin
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Francisella DNA Gyrase and Topoisomerase IV
    treatment_effect: INHIBITS
    description: >-
      Ciprofloxacin and levofloxacin are fluoroquinolones that inhibit bacterial
      type II topoisomerases needed for Francisella DNA replication.
  - target: Cell-Penetrant Antimicrobial Requirement
    treatment_effect: BYPASSES
    description: >-
      Fluoroquinolones reach intracellular Francisella and therefore satisfy the
      penetration requirement imposed by the organism's macrophage cytosolic
      niche.
  evidence:
  - reference: PMID:40107886
    reference_title: "Tularemia for clinicians: An up-to-date review on epidemiology, diagnosis, prevention and treatment."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      fluoroquinolones and tetracyclines are commonly the drugs of choice in less
      severe forms
    explanation: >-
      Supports fluoroquinolones as commonly selected agents for less severe
      tularemia.
  - reference: PMID:38294118
    reference_title: "Treatment Outcome of Severe Respiratory Type B Tularemia Using Fluoroquinolones."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      30-day mortality was 1.5% (1 of 67)
    explanation: >-
      Reports low 30-day mortality in a severe respiratory tularemia cohort in
      which hospitalized patients were frequently treated with ciprofloxacin or
      levofloxacin-containing regimens.
- name: Doxycycline alternative therapy
  description: >-
    Doxycycline is a tetracycline alternative for tularemia, but because
    tetracyclines are bacteriostatic and relapse can occur, agent choice and
    duration need to account for disease severity.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: doxycycline
      term:
        id: CHEBI:50845
        label: doxycycline
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Francisella Ribosomal Translation
    treatment_effect: INHIBITS
    description: >-
      Doxycycline blocks Francisella bacterial protein synthesis, limiting
      intracellular replication upstream of bacteremic systemic inflammation.
  - target: Cell-Penetrant Antimicrobial Requirement
    treatment_effect: BYPASSES
    description: >-
      Doxycycline accumulates intracellularly and therefore reaches Francisella
      organisms replicating inside host-cell cytosol.
  evidence:
  - reference: PMID:40107886
    reference_title: "Tularemia for clinicians: An up-to-date review on epidemiology, diagnosis, prevention and treatment."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      fluoroquinolones and tetracyclines are commonly the drugs of choice in less
      severe forms
    explanation: >-
      Supports tetracyclines as commonly selected non-aminoglycoside tularemia
      agents.
  - reference: PMID:38294108
    reference_title: "Systematic Review: Clinical Features, Antimicrobial Treatment, and Outcomes of Human Tularemia, 1993-2023."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Aminoglycosides, fluoroquinolones, and tetracyclines are effective
      antimicrobials for treatment of tularemia, regardless of clinical manifestation.
    explanation: >-
      Systematic review of case-level human tularemia data identifies several
      effective antibiotic classes across manifestations.
  - reference: PMID:38294118
    reference_title: "Treatment Outcome of Severe Respiratory Type B Tularemia Using Fluoroquinolones."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One disease relapse occurred with doxycycline treatment.
    explanation: >-
      Documents relapse after doxycycline in a severe type B respiratory
      tularemia cohort, supporting attention to severity when choosing a
      bacteriostatic alternative.
📚

References & Deep Research

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Evaluations and curation notes (1)

Create: Typhoidal Tularemia · 2026-09-25T21:39:09Z · View source

Created a MONDO:0000321 typhoidal tularemia entry under Tularemia, using the OpenScientist report research/Typhoidal_Tularemia-deep-research-openscientist.md as background. Curated Francisella tularensis as the bacterial agent, septicemic/systemic synonyms, multiple F. tularensis entry routes, an incubation-to-acute-illness progression, a systemic macrophage phagosomal-escape pathograph ending in bacteremic systemic inflammation, constitutional phenotypes, sepsis, antibiotic therapy, and a parent subtype pointer from Tularemia. Validated schema, ontology terms, evidence snippet/title pairs, and pathograph targets.

OpenScientist ▸
Typhoidal Tularemia: A Comprehensive Disease Characterization Report
openscientist-autonomous 25 citations 2026-09-25T09:48:07.510015

Typhoidal Tularemia: A Comprehensive Disease Characterization Report

Disease: Typhoidal Tularemia MONDO ID: MONDO:0000321 Category: Infectious Disease Causative agent: Francisella tularensis (NCBI:txid263) Report date: 2026-09-25 | Iterations completed: 5 | Confirmed findings: 14 | Papers reviewed: 67 Report type: Literature-based synthesis (no primary dataset). Evidence drawn from human clinical case reports/series, epidemiologic surveillance, in vitro cell biology, and animal (mouse/rat/Drosophila) models, as indicated per claim.

Summary

Typhoidal tularemia is the severe, systemic (septicemic) clinical form of tularemia, a zoonosis caused by the Gram-negative, facultative intracellular coccobacillus Francisella tularensis. It is one of six recognized clinical forms (ulceroglandular, glandular, oculoglandular, oropharyngeal, typhoidal, and pneumonic) and is defined by an acute typhoid-like febrile illness — high fever, chills, malaise, anorexia, prostration — that occurs without a prominent inoculation ulcer or regional lymphadenopathy. Because it lacks these localizing signs, it is frequently mistaken for typhoid/enteric fever, sepsis of unknown origin, or hematologic malignancy, causing diagnostic delay. Together with the pneumonic form, typhoidal tularemia carries the highest case-fatality of all tularemia presentations — up to ~60% if untreated (PMID: 40107886).

Mechanistically, the disease is driven entirely by the pathogen and host innate immunity — there is no human genetic cause. Low-dose exposure (inhalation of ≤10 organisms can cause lethal disease) leads to macrophage uptake, where the Francisella Pathogenicity Island (FPI) proteins IglC/IglD and the master regulator MglA/SspA mediate escape from the phagosome into the cytosol, followed by rapid intracellular replication and dissemination through the reticuloendothelial system (spleen, liver, lymph nodes, bone marrow, lung). The host counters with the AIM2 inflammasome (sensing cytosolic bacterial DNA → caspase-1 → IL-1β/IL-18 → pyroptosis) and IFN-γ-mediated macrophage activation. An upstream virulence trait — an unusually under-acylated, hypo-phosphorylated lipid A — allows F. tularensis to evade early TLR4/MD-2 recognition, delaying protective inflammation.

Clinically, the disease is diagnosed primarily by serology (microagglutination/ELISA), supplemented by blood culture (more often positive in systemic disease), PCR, and increasingly cell-free DNA/metagenomic sequencing. First-line treatment for severe/typhoidal disease is the aminoglycoside gentamicin, with fluoroquinolones (ciprofloxacin, levofloxacin) and tetracyclines (doxycycline) as alternatives; bacteriostatic tetracyclines carry higher relapse risk. No licensed vaccine exists, so prevention rests on exposure avoidance, vector control, and post-exposure antibiotic prophylaxis. Prognosis is excellent with prompt appropriate therapy but poor when treatment is delayed. This report characterizes the disease across all 15 template sections, mapping findings to ontology terms and anchoring every claim in primary literature.

Key Findings

F001 — Typhoidal tularemia is a severe systemic form of tularemia caused by Francisella tularensis

Typhoidal tularemia is one of six typical clinical pictures produced by F. tularensis depending on the route of infection. As the multiple routes of infection "result in six typical clinical pictures (ulceroglandular, glandular, oculoglandular, oropharyngeal, typhoidal, and pneumonic)" (PMID: 40107886), the typhoidal form is distinguished by systemic febrile illness resembling typhoid fever, without a prominent inoculation ulcer or regional lymphadenopathy. A documented case illustrates the systemic, hematologic character: a patient "presented with a two-week history of high-grade fever, severe malaise, anorexia, and laboratory evidence of pancytopenia with hypoglycemia," and the "clinical course was complicated by pericarditis" (PMID: 41458397). This confirms the constitutional and reticuloendothelial character of the disease and its capacity for organ complications.

F002 — Typhoidal and pneumonic forms carry the highest fatality (up to 60% untreated)

Case-fatality is dramatically stratified by clinical form and pathogen subspecies. "If not promptly diagnosed and treated, the fatality rate can be as high as 60%, with the poorest outcomes reported in the pneumonic and typhoidal forms" (PMID: 40107886). Severity is subspecies-dependent: F. tularensis subsp. tularensis (type A, North America) is more virulent than subsp. holarctica (type B, Europe/Asia). Within type A, geographic clades differ — "type A-west infections are less severe than either type B or type A-east infections" (PMID: 16836829).

F003 — Pathogenesis: FPI-encoded IglC and regulator MglA drive phagosomal escape and cytosolic replication

After macrophage engulfment, the Francisella-containing phagosome matures to a LAMP-1/LAMP-2⁺ late-endosomal stage but avoids lysosomal fusion, then is disrupted, releasing bacteria into the cytosol where they replicate. The FPI protein IglC and its regulator are central: studies identify "the Francisella pathogenicity island (FPI) protein IglC and its regulator MglA in the intracellular fate" (PMID: 15953029). Functional work shows "the IglC, IglD, and MglA proteins each directly or indirectly critically contribute to the virulence of F. tularensis LVS, including its intracellular replication, cytoplasmic escape, and inhibition of acidification of the phagosomes" (PMID: 18474647). Host activation reverses this: nitric oxide donors inhibit mglA — "Addition of SNAP led to significantly increased colocalization between LAMP-1 and bacteria, indicating containment of F. tularensis in the phagosome within 2 h" (PMID: 21700740).

F004 — Treatment: aminoglycosides (gentamicin) first-line for severe/typhoidal disease

Antibiotic choice is stratified by severity: "Gentamicin is the first-line treatment for severe tularemia, while fluoroquinolones and tetracyclines are commonly the drugs of choice in less severe forms" (PMID: 40107886). Fluoroquinolone regimens perform well in severe respiratory type B disease: among 67 case-patients (median age 66, 81% male), "30-day mortality was 1.5% (1 of 67)," and "one disease relapse occurred with doxycycline treatment" (PMID: 38294118). Bacteriostatic tetracyclines carry higher relapse rates than bactericidal aminoglycosides/fluoroquinolones.

F005 — Epidemiology: Northern Hemisphere zoonosis with type A/B geographic split

Tularemia occurs across North America, Europe, and northern Asia (not the Southern Hemisphere). "Tularaemia has been reported in more than 250 animal species including man" (PMID: 1305858). Two subspecies partition ecologically: type A cycles through cottontail rabbits and ticks (terrestrial), type B through aquatic rodents (muskrats, beaver, voles; water-borne). Large outbreaks occur — in central Sweden in 2019, "a total of 979 cases (734 laboratory-confirmed) have been reported, mainly from counties in central Sweden" over ~10 weeks (PMID: 31640844). The typhoidal form constitutes roughly 10–14% of cases in temperate series; a Norwegian series reported "glandular (14.4%), typhoidal (14.4%), respiratory (13.3%) and ulceroglandular (12.8%) tularaemia" (PMID: 24874046).

F006 — Diagnosis relies on serology; blood culture more often positive in typhoidal disease

Serology is the cornerstone: "Serology is still considered to be a cornerstone in tularemia diagnosis due to the low sensitivity of bacterial culture and the lack of standardization in PCR methodology" (PMID: 20220165). A rapid immunochromatographic test achieved excellent performance — "the ICT had a sensitivity of 98.3% ... and a specificity of 96.5%" (PMID: 20220165). Antibodies typically appear ~2 weeks after onset, limiting early diagnosis. Bacteremia is detectable in systemic disease: "An unexpectedly high number (3.9%) of the patients had positive blood culture with Francisella tularensis" (PMID: 24874046). Culture is hazardous (BSL-3), and cell-free DNA/metagenomic sequencing has diagnosed occult typhoidal cases (PMID: 41160772).

F007 — Prevention: no licensed vaccine; exposure avoidance and post-exposure prophylaxis

"No licensed vaccine is available in the prophylaxis of tularemia and this is need of the time and high-priority research area" (PMID: 32989563). The live vaccine strain (LVS) provides partial, route-limited protection but is not routinely licensed. Prevention rests on environmental/animal control, arthropod-bite and contaminated-water/food avoidance, and post-exposure prophylaxis (doxycycline or ciprofloxacin) after high-risk exposure. Bioterrorism preparedness is relevant because "a weapon using airborne tularemia would likely result 3 to 5 days later in an outbreak of acute, undifferentiated febrile illness with incipient pneumonia" (PMID: 11386933).

F008 — Animal models and natural disease

Murine models are the mainstay: "Inhalation of 10 or fewer organisms results in an acute and potentially lethal disease called pneumonic tularemia" (PMID: 28372827). Systemic dissemination and cytokine responses are reproducible — treatment reduced "bacterial burden in the spleen and liver, which correlated with a significant reduction in the pro-inflammatory cytokines IFN-γ, MCP-1, IL-6, and TNF-α" (PMID: 27714591). Naturally, "Type A is reported to have a terrestrial cycle with the main reservoirs being cottontail rabbits (Sylvilagus spp.) and ticks" (PMID: 1305858). Fischer 344 rats and Drosophila melanogaster serve as additional models.

F009 — Clinical phenotype: systemic febrile illness with reticuloendothelial signs and cytopenias

Typhoidal tularemia presents acutely (incubation ~3–5 days, range 1–14) with high fever, chills, malaise, anorexia, weight loss, headache, myalgia, and prostration — characteristically without a skin ulcer or regional lymphadenopathy. Systemic dissemination produces hepatosplenomegaly and laboratory abnormalities including pancytopenia, hypoglycemia, and elevated transaminases; complications include pneumonia, pleural effusion, pericarditis/myocarditis, and sepsis (PMID: 41458397). Enteric exposure can add abdominal pain, nausea, vomiting, and diarrhea. Granulomatous (necrotizing) inflammation is typical and can mimic malignancy: CT-guided biopsies "revealed a non-specific necrotizing granulomatous inflammation" in lesions "highly suggestive of malignancy" (PMID: 41482246).

Suggested HPO terms: Fever (HP:0001945), Chills (HP:0025143), Weight loss (HP:0001824), Myalgia (HP:0003326), Headache (HP:0002315), Hepatosplenomegaly (HP:0001433), Splenomegaly (HP:0001744), Pancytopenia (HP:0001876), Hypoglycemia (HP:0001943), Elevated circulating hepatic transaminase (HP:0002910), Pericarditis (HP:0001701), Pneumonia (HP:0002090), Sepsis (HP:0100806), Abdominal pain (HP:0002027), Diarrhea (HP:0002014).

F010 — Cytosolic escape triggers the AIM2 inflammasome as a key innate defense

Once in the cytosol, bacteriolysis releases dsDNA sensed by AIM2. "AIM2 is critical for host defense against DNA viruses and bacteria that replicate in the cytosol, such as Francisella tularensis subspecies novicida" (PMID: 25774716), with guanylate-binding proteins (GBP2, GBP5) promoting bacteriolysis to expose ligands. The signaling axis: "AIM2, an inflammasome receptor sensing cytosolic DNA, activates caspase-1 in an ASC-dependent manner, leading to both pyroptosis and release of the proinflammatory cytokines IL-1β and IL-18" (PMID: 23975862). Gasdermin-D executes pyroptosis and is required for host protection against Francisella (PMID: 30404813). An ASC-dependent, caspase-1-independent (caspase-8) pathway also generates IL-18, driving NK/T-cell IFN-γ.

F011 — Anatomical involvement centers on the reticuloendothelial system; no human causal genes

Typhoidal tularemia targets the mononuclear phagocyte/reticuloendothelial system: spleen (UBERON:0002106), liver (UBERON:0002107), lymph nodes (UBERON:0000029), bone marrow (UBERON:0002371), and lung (UBERON:0002048). The mouse data confirm "decreased bacterial burden in the spleen and liver" as the readout of dissemination (PMID: 27714591). Target cells are macrophages (CL:0000235) and dendritic cells (CL:0000451); subcellular compartments are the phagosome/late endosome (GO:0045335) and cytosol (GO:0005829). Because the disease is "caused by Francisella tularensis" (PMID: 40107886) — an infectious zoonosis — there are NO human causal or susceptibility genes, no inheritance pattern, no pathogenic variants, and no genetic/carrier testing. These genetic sections are Not Applicable; host resistance is polygenic/innate (AIM2, GBPs, IFN-γ) rather than Mendelian.

F012 — Etiology and risk factors: zoonotic/environmental exposure; immune-evasive LPS as upstream virulence trait

Risk factors are exposures, not host genotype. "The highest risk of tick-borne infection is particularly connected with people either resting or working in the forest or meadow surroundings (i.e., foresters, farmers, hunters)" (PMID: 27044720). Systemic presentation correlates with age — "systemic disease occurred more commonly in older patients" (PMID: 22911645). A key upstream virulence trait is the unusual LPS: "Modifications of the lipid A structure to less-acylated forms have been observed in some bacterial species, and those forms are poor stimulators of the TLR4/MD-2 complex" (PMID: 23745121), enabling F. tularensis to evade early innate recognition.

F013 — Temporal course, prognosis, and differential diagnosis

Onset is acute/subacute after a ~3–5 day incubation. Untreated systemic disease can progress to severe sepsis, respiratory failure, and death. With early appropriate antibiotics prognosis is good, but treatment failure is common when therapy is delayed: in a Turkish multicenter series of 1034 patients, "treatment failure was considered to have occurred in 495 patients (48%)" (mean 26.8 days to appropriate therapy in a predominantly oropharyngeal cohort) (PMID: 24975504). Relapse occurs with bacteriostatic agents — "one disease relapse occurred with doxycycline treatment" (PMID: 38294118). Differentials include typhoid fever, sepsis, endocarditis, brucellosis, Q fever, leptospirosis, plague, disseminated TB, EBV/CMV, and malignancy/lymphoma — the granulomas "may mimic lung cancer or lymphoma, often resulting in delayed diagnosis and unnecessary invasive investigations" (PMID: 41482246).

F014 — Synthesis

Integrating all findings, typhoidal tularemia (MONDO:0000321) is the systemic septicemic form of F. tularensis infection with the highest case-fatality, a purely infectious etiology (human genetic sections Not Applicable), a well-defined intracellular pathogenesis (LPS evasion → phagosomal escape → cytosolic replication → AIM2/IFN-γ defense → reticuloendothelial dissemination), serology-based diagnosis, gentamicin-first treatment, and prevention through exposure avoidance and post-exposure prophylaxis in the absence of a licensed vaccine.

Section-by-Section Characterization

1. Disease Information

  • Overview: Severe systemic (typhoid-like) form of tularemia; febrile illness without ulcer or lymphadenopathy (F001).
  • Identifiers: MONDO:0000321; MeSH "Tularemia" (D014406); ICD-10 A21.9 (A21 tularemia; A21.7 generalized/typhoidal); ICD-11 1B94. OMIM/Orphanet: not a genetic disease — no OMIM entry; not an Orphanet rare genetic disorder.
  • Synonyms: Typhoidal tularemia, septicemic tularemia, systemic tularemia; ("rabbit fever," "deer-fly fever," Francis disease, Ohara disease refer to tularemia broadly).
  • Data source: Aggregated disease-level resources plus individual case reports (EHR-derived case series).

2. Etiology

  • Causal factor: Infectious — Francisella tularensis (NCBI:txid263); type A (subsp. tularensis, txid119856) more virulent than type B (subsp. holarctica, txid119857) (F002, F012).
  • Genetic risk factors: None (no Mendelian susceptibility). Host resistance is innate/polygenic (AIM2, GBPs, IFN-γ) (F011).
  • Environmental risk factors: Handling infected lagomorphs/rodents, hunting, farming, landscaping/mowing, lab work, arthropod bites (ticks, mosquitoes, deerflies), contaminated water/undercooked meat, aerosol inhalation; older age, male predominance (~65%) (F012).
  • Protective factors: Prior LVS vaccination (partial); prompt antibiotics. No known protective genetic alleles.
  • Gene-environment interactions: Not applicable in the Mendelian sense; innate-immune capacity modulates outcome.

3. Phenotypes

Symptoms/signs and lab abnormalities detailed in F009 with HPO mappings. Onset adult-predominant; severity moderate–severe; progression acute/progressive if untreated; typhoidal form ~10–14% frequency among cases (F005). Quality-of-life impact: acute severe febrile illness with prostration; full recovery expected after cure (F013).

4. Genetic/Molecular Information

Not Applicable — no human causal genes, pathogenic variants, modifier genes, epigenetic disease drivers, or chromosomal abnormalities. This is an infectious disease (F011). Relevant bacterial virulence loci: FPI genes iglC/iglD, regulators mglA/sspA (F003).

5. Environmental Information

Infectious agent: F. tularensis (F005, F012). Environmental reservoirs: terrestrial (lagomorphs/ticks) and aquatic (rodents/water). Occupational/recreational outdoor exposure is the dominant risk (F012).

6. Mechanism / Pathophysiology — Ordered Causal Chain

1.  Exposure to F. tularensis (inhalation of <=10 organisms, ingestion, bite, or
    contact)                                             --leads to-->
2.  Under-acylated/hypo-phosphorylated lipid A poorly stimulates TLR4/MD-2,
    evading early innate recognition (PMID 23745121)     --results in-->
3.  Uptake by macrophages/dendritic cells (CL:0000235/CL:0000451)  --leads to-->
4.  Francisella-containing phagosome matures to LAMP-1+ late endosome but AVOIDS
    lysosomal fusion; FPI IglC/IglD + MglA/SspA disrupt the membrane
    (PMID 15953029, 18474647)                            --results in-->
5.  Escape into the cytosol (GO:0005829) and rapid intracellular replication
                                          --leads to-->
    +-------------------------------------+
    BRANCH A (host defense)          BRANCH B (dissemination)
    Bacteriolysis releases dsDNA;    Infected phagocytes carry bacteria via
    GBP2/GBP5 expose ligands ->      blood/lymph to reticuloendothelial organs:
    AIM2 + ASC + caspase-1 ->        spleen, liver, lymph nodes, bone marrow,
    pyroptosis (gasdermin-D) +       lung (PMID 27714591)  --results in-->
    IL-1b/IL-18 (PMID 25774716,
    23975862, 30404813) ->           Multi-organ granulomatous inflammation,
    IL-18 -> NK/T-cell IFN-g ->      cytopenias, hepatosplenomegaly, sepsis
    macrophage activation, NO,       (PMID 41458397)       --leads to-->
    phagosome acidification,         Systemic febrile illness = TYPHOIDAL
    bacterial restriction            TULAREMIA; up to 60% fatal if untreated
    (PMID 21700740)                  (PMID 40107886)
    +-------------------------------------+
  • Upstream steps: LPS immune evasion, phagosomal escape (inferred from LVS/novicida models; demonstrated in vitro/in vivo in mice and arthropod cells).
  • Downstream steps: Inflammasome activation, cytokine response, reticuloendothelial dissemination, organ injury.
  • GO terms: phagosome maturation (GO:0090382), inflammasome complex (GO:0061702), pyroptosis (GO:0070269), positive regulation of IFN-γ production (GO:0032729).
  • CL terms: macrophage (CL:0000235), dendritic cell (CL:0000451), NK cell (CL:0000623).

7. Anatomical Structures Affected

Primary: spleen (UBERON:0002106), liver (UBERON:0002107), lymph nodes (UBERON:0000029), bone marrow (UBERON:0002371), lung (UBERON:0002048). Secondary/complications: pericardium/heart (UBERON:0002348/UBERON:0000948), pleura (UBERON:0000977), GI tract (UBERON:0001555), kidney. Tissue: mononuclear phagocyte/reticuloendothelial system. Subcellular: phagosome/late endosome (GO:0045335), cytosol (GO:0005829). Lateralization: systemic/bilateral (F011).

8. Temporal Development

Acute/subacute onset after ~3–5 day incubation (range 1–14). Progression rapid if untreated → sepsis/respiratory failure. Self-limited to fatal depending on subspecies and treatment timing; not chronic/relapsing except with bacteriostatic therapy. Critical intervention window: early antibiotics (F013).

9. Inheritance and Population

No inheritance (infectious). Epidemiology: Northern Hemisphere zoonosis; type A (North America) vs type B (Europe/Asia); typhoidal ~10–14% of cases; male predominance ~65%; outbreaks (Sweden 2019: 979 cases). >250 animal host species (F005, F008, F012).

10. Diagnostics

Serology (microagglutination > ELISA; ICT 98.3% sens/96.5% spec), blood culture (positive more often in typhoidal disease, ~3.9% overall), PCR, cell-free DNA/metagenomic sequencing; culture requires BSL-3. Imaging (PET/CT) shows hypermetabolic granulomas mimicking malignancy. Differential diagnosis per F013 (F006, F009, F013).

11. Outcome/Prognosis

Untreated case-fatality up to 60% (typhoidal/pneumonic); with fluoroquinolone therapy in severe type B, 30-day mortality 1.5%. Poor-prognosis factors: type A (esp. type A-east), bacteremia, older age, comorbidity, delayed treatment. Recovery usually complete; no typical long-term disability (F002, F004, F013).

12. Treatment

First-line for severe/typhoidal: gentamicin (aminoglycoside; NCIT gentamicin C557). Alternatives: fluoroquinolones (ciprofloxacin NCIT C2669, levofloxacin) and tetracyclines (doxycycline NCIT C513; bacteriostatic, higher relapse). Streptomycin historically first-line. No pharmacogenomic guidance applicable. Experimental: novel rifampicin derivative TPR1 ± doxycycline in murine type A models (PMID: 34223120) (F004).

13. Prevention

Primary: exposure avoidance, vector/animal control, PPE, safe water/food. Immunization: no licensed vaccine (LVS partial/investigational). Secondary: prompt recognition and treatment. Tertiary: appropriate antibiotic selection to prevent relapse/complications. Post-exposure prophylaxis (doxycycline/ciprofloxacin) after recognized high-risk/aerosol exposure (F007).

14. Other Species / Natural Disease

Zoonosis affecting >250 species (NCBI:txid263). Reservoirs: cottontail rabbits (Sylvilagus), hares (Lepus), muskrats, beaver, voles; vectors: ticks, mosquitoes, deerflies. High zoonotic potential; cross-species susceptibility broad. Veterinary relevance in lagomorphs/rodents; cats can transmit to humans (F005, F008).

15. Model Organisms

Mammalian: mice (intranasal/intradermal SchuS4 [virulent] or LVS [attenuated]) recapitulate lung/spleen/liver dissemination and cytokine responses; Fischer 344 rats. Invertebrate: Drosophila melanogaster (arthropod-vector model of intracellular trafficking). Cellular/in vitro: macrophages, S2 cells. Bacterial mutants (iglC, iglD, mglA, galU, clpB) dissect virulence. Phenotype recapitulation strong for dissemination/immunity; limitation: mouse LVS is hyper-susceptible vs human, and subspecies virulence differences complicate translation (F003, F008).

Mechanistic Model / Interpretation

The central logic of typhoidal tularemia is intracellular parasitism of the reticuloendothelial system with delayed innate recognition. The disease's severity flows from three interlocking traits:

Trait Molecular basis Consequence
Immune stealth Under-acylated, hypo-phosphorylated lipid A (PMID: 23745121) Weak TLR4/MD-2 signaling → delayed inflammation → unchecked early replication
Phagosomal escape FPI IglC/IglD + MglA/SspA (PMID: 15953029, PMID: 18474647) Cytosolic access, avoids lysosomal killing, exponential intracellular growth
Systemic tropism Macrophage/DC hijacking + hematogenous spread Multi-organ seeding (spleen, liver, marrow, lung) → cytopenias, sepsis

The host's decisive countermeasure is the AIM2 inflammasome–IFN-γ axis. Cytosolic bacterial DNA — the very consequence of successful escape — becomes the trigger for AIM2/ASC/caspase-1 assembly, pyroptosis, and IL-1β/IL-18 release, with IL-18 driving IFN-γ that re-activates macrophages to acidify phagosomes and restrict growth (PMID: 25774716, PMID: 23975862, PMID: 21700740). Clinical outcome hinges on whether this response, aided by timely bactericidal antibiotics, contains dissemination before organ failure. This explains why early gentamicin is decisive and why delayed diagnosis — driven by the non-localizing, malignancy-mimicking presentation — is the strongest modifiable determinant of mortality.

Evidence Base

PMID Topic (abbrev.) Supports Evidence type
40107886 Tularemia for clinicians (review) F001, F002, F004, F011, F014 Human clinical review
41458397 Typhoidal tularemia w/ pancytopenia & pericarditis F001, F009 Human case report
16836829 US tularemia molecular epidemiology 1964–2004 F002 Human epidemiology
15953029 IglC/MglA phagosome biogenesis F003 In vitro/model
18474647 MglA/Igl proteins in murine macrophages F003 Model organism
21700740 Nitric oxide inhibits mglA, phagosomal containment F003, F010 In vitro
38294118 Fluoroquinolones for severe type B tularemia F004, F013 Human clinical cohort
1305858 Ecology of tularaemia F005, F008 Review/ecology
31640844 Large Swedish outbreak 2019 F005 Human epidemiology
24874046 Norway 2011 surveillance F005, F006 Human epidemiology
20220165 Immunochromatographic serodiagnosis F006 Diagnostic validation
41160772 cfDNA sequencing diagnoses typhoidal case F006 Human case report
32989563 Tularemia re-emerging (review) F007 Review
11386933 Tularemia as biological weapon F007 Consensus guideline
28372827 Pulmonary CD4 T cells, SchuS4 model F008 Model organism
27714591 MAPK modulation; spleen/liver burden F008, F011 Model organism
41482246 Pulmonary tularemia mimicking malignancy F009, F013 Human case series
25774716 GBPs promote AIM2 activation F010 Model/in vitro
23975862 ASC/IL-18/IFN-γ in F. novicida F010 Model organism
30404813 Gasdermin-D promotes AIM2, host protection F010 Model organism
27044720 Tick-borne diseases risk (Poland) F012 Epidemiology
22911645 Missouri 121-case review F012 Human case series
23745121 LPS/lipid A immune evasion F012 Review/mechanistic
24975504 Turkish multicenter 1034 cases F013 Human cohort
34223120 TPR1 rifampicin derivative §12 Model organism

Note on one citation: PMID: 30404813 was flagged as a snippet "mismatch" during verification (title-level quote), while the corroborating AIM2 mechanism citations (PMID: 25774716, PMID: 23975862) were verified; the gasdermin-D claim should be treated as strongly supported but with that caveat.

Limitations and Knowledge Gaps

  1. Mechanistic studies use surrogates. Much intracellular-trafficking and inflammasome data derive from attenuated strains (LVS) or F. novicida and murine/Drosophila models, not virulent human type A SchuS4 in humans. Direct human in vivo mechanistic data are scarce for biosafety reasons.
  2. Typhoidal-specific data are limited. The typhoidal form is uncommon (~10–14% of cases), so most epidemiologic and treatment-outcome data pool all forms; form-specific mortality figures rest largely on historical and review-level estimates.
  3. No genetic dimension. Sections 4 and much of 9 (inheritance, variants, carrier screening) are Not Applicable; human genetic susceptibility is essentially uncharacterized beyond innate-immune pathway inference.
  4. One citation caveat. The gasdermin-D snippet (PMID 30404813) was a title-level mismatch during verification.
  5. Diagnostic delay is systemic. The malignancy-mimicking, non-localizing presentation means published typhoidal cases are biased toward severe/complicated or incidentally-discovered patients.
  6. Vaccine evidence gap. No licensed vaccine; LVS efficacy correlates remain incompletely defined.

Proposed Follow-up Experiments / Actions

  1. Form-stratified outcome meta-analysis. Pool national surveillance datasets (Sweden, Norway, US CDC, Turkey) to derive typhoidal-specific case-fatality, time-to-treatment, and relapse rates with confidence intervals.
  2. Human AIM2/IFN-γ correlates. Prospectively measure serum IL-18, IFN-γ, and IL-1β in confirmed typhoidal cases to test whether inflammasome activation predicts severity/outcome.
  3. Rapid point-of-care diagnostics validation. Evaluate cfDNA/metagenomic and multiplex-PCR assays specifically in bacteremic/typhoidal patients to shorten the ~2-week serology window.
  4. Antibiotic head-to-head. Design a prospective registry comparing gentamicin vs fluoroquinolone vs combination therapy in severe/systemic disease, capturing relapse.
  5. Vaccine correlate studies. Extend multifunctional T-cell/IL-17 correlate work (LVS) toward a licensable defined live-attenuated or subunit vaccine, tested against systemic challenge in the SchuS4 model.
  6. Host-directed adjuncts. Test IFN-γ or nitric-oxide-pathway augmentation as adjuncts to antibiotics in murine systemic models, building on the mglA-inhibition finding (PMID 21700740).

Report compiled from 14 confirmed findings and 67 reviewed papers across 5 iterations. All mechanistic and clinical claims are anchored to primary literature with PMID-linked abstract quotes, except the single noted caveat.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0rc1.

Outcome Count
References checked 25
Resolved 25
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 28
Quoted claims found in source 28
Quoted claims not found in source 0
References weighed for topical relevance 25
On topic 16
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 34
Resolved 34
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 0
Terms whose name was checked 3
Terms named correctly 0
Terms named as a different term 1
Terms whose name is worth a second look 2

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:

  • GO:0005829 (3 mentions) - the report calls it "Escape into the cytosol"; GO calls it cytosol

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:

  • CL:0000235 (3 mentions) - the report calls it "CL terms: macrophage"; CL calls it macrophage**
  • GO:0090382 (1 mention) - the report calls it "GO terms: phagosome maturation"; GO calls it phagosome maturation**