Israeli tick typhus is an acute tick-borne spotted-fever-group rickettsiosis caused by the obligately intracellular bacterium Rickettsia conorii subsp. israelensis. Rhipicephalus sanguineus ticks transmit the ISF strain into skin, after which Sca-family rickettsial invasion factors seed endothelial infection, disseminated small-vessel vasculitis, thromboxane-dependent platelet activation, fever, rash, eschar-poor presentations, and potentially fulminant neurologic, renal, and shock complications.
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name: Israeli Tick Typhus
creation_date: "2026-09-28T06:28:43Z"
category: Infectious Disease
description: >-
Israeli tick typhus is an acute tick-borne spotted-fever-group rickettsiosis
caused by the obligately intracellular bacterium Rickettsia conorii subsp.
israelensis. Rhipicephalus sanguineus ticks transmit the ISF strain into
skin, after which Sca-family rickettsial invasion factors seed endothelial
infection, disseminated small-vessel vasculitis, thromboxane-dependent
platelet activation, fever, rash, eschar-poor presentations, and potentially
fulminant neurologic, renal, and shock complications.
disease_term:
preferred_term: Israeli tick typhus
term:
id: MONDO:0000230
label: Israeli tick typhus
parents:
- Spotted fever rickettsiosis
synonyms:
- Israeli spotted fever
- Rickettsia conorii subsp. israelensis infection
- Israeli spotted fever rickettsiosis
references:
- reference: PMID:15766388
title: >-
Proposal to create subspecies of Rickettsia conorii based on multi-locus
sequence typing and an emended description of Rickettsia conorii.
findings:
- statement: >-
Multilocus sequence typing separated Israeli spotted fever rickettsia as
the ISFR type and established R. conorii subsp. israelensis with ISTT CDC1
as the type strain.
supporting_text: >-
We propose the names R. conorii subsp. conorii subsp. nov. (type strain =
Malish, ATCC VR-613), R. conorii subspecies indica subsp. nov. (type
strain = ATCC VR-597), R. conorii subspecies caspia subsp. nov. (type
strain = A-167), and R. conorii subspecies israelensis subsp. nov. (type
strain = ISTT CDC1).
- reference: PMID:19421877
title: >-
Incongruent effects of two isolates of Rickettsia conorii on the survival
of Rhipicephalus sanguineus ticks.
findings:
- statement: >-
R. sanguineus is the recognized R. conorii vector in the Mediterranean
region, and experimental ISTT exposure infected 35-66% of surviving
R. sanguineus ticks.
supporting_text: >-
In the Mediterranean region, the brown dog tick, Rhipicephalus
sanguineus, is the recognized vector of R. conorii.
- reference: PMID:34286684
title: Spotted Fever Group Rickettsioses in Israel, 2010-2019.
findings:
- statement: >-
A nationwide hospitalized Israeli spotted-fever cohort found the Israeli
tick typhus strain in 33 of 42 patients, with 52% intensive-care use, 30%
fatality, only 5% tick-bite history, and eschar in 12%.
supporting_text: >-
The most prevalent species was the Rickettsia conorii Israeli tick typhus
strain (n = 33, 79%); infection with this species necessitated intensive
care for 52% of patients and was associated with a 30% fatality rate. A
history of tick bite was rare, found for only 5% of patients; eschar was
found in 12%; and leukocytosis was more common than leukopenia.
- reference: PMID:18582199
title: >-
Host- and microbe-related risk factors for and pathophysiology of fatal
Rickettsia conorii infection in Portuguese patients.
findings:
- statement: >-
In a 140-patient Portuguese strain-identified R. conorii cohort, fatal
outcome was significantly more likely with the Israeli spotted fever
strain, and alcoholism was a host risk factor.
supporting_text: >-
A fatal outcome was significantly more likely for patients infected with
the ISF strain, and alcoholism was a risk factor.
- reference: PMID:2710586
title: Clinical and laboratory findings of spotted fever in Israeli children.
findings:
- statement: >-
A prospective Israeli pediatric spotted-fever cohort documented fever,
rash, myalgia, vomiting, thrombocytopenia, and hyponatremia as common
manifestations.
supporting_text: >-
In a prospective study of 70 Israeli children with spotted fever the major
clinical features were fever (100%), skin rash (98.5%), myalgia (54%) and
vomiting (40%). Thrombocytopenia (75%) and hyponatremia (62.5%) were
common, but were not associated with increased mortality.
- reference: PMID:8286624
title: Fatal Israeli spotted fever in children.
findings:
- statement: >-
Fatal pediatric Israeli spotted fever can present without tick-bite
history or tache noire and progress to shock, encephalopathy, renal
failure, and bleeding with death within 24 hours of admission.
supporting_text: >-
Clinical disease was characterized by irreversible shock, encephalopathy,
renal failure, bleeding tendency, and death within 24 hours of admission.
None of the patients had a history of tick bite, and no tache noire was
noted.
- reference: PMID:22612237
title: >-
Identification and characterization of the mammalian association and
actin-nucleating domains in the Rickettsia conorii autotransporter protein,
Sca2.
findings:
- statement: >-
R. conorii Sca2 is sufficient for adherence and invasion of human
endothelial cells and participates in intracellular actin-based motility.
supporting_text: >-
A rickettsial autotransporter from Rickettsia conorii, Sca2, has been
shown to be sufficient to mediate both adherence and invasion of human
endothelial cells and to participate in intracellular actin-based motility.
- reference: PMID:8584998
title: >-
Demonstration of Rickettsia Conorii-induced coagulative and platelet
activation in vivo in patients with Mediterranean spotted fever.
findings:
- statement: >-
Human R. conorii infection can drive TXA2-dependent platelet activation,
thrombin generation, endothelial dysfunction, vasculitis, and focal
microthrombus formation.
supporting_text: >-
Our results provide biochemical evidence for the occurrence of
TXA2-dependent platelet activation and thrombin generation in vivo,
together with endothelial dysfunction. These phenomena could account for
clinical manifestations of MSF, such as vasculitis and focal microthrombus
formation.
- reference: PMID:23168048
title: Mediterranean spotted fever in the Trakya region of Turkey.
findings:
- statement: >-
In confirmed R. conorii Mediterranean spotted fever, IFA demonstrated
seroconversion or a fourfold titer rise in 77% of patients and skin-biopsy
PCR was positive in 72.6% of tested biopsies.
supporting_text: >-
Using IFA, seroconversion or a fourfold or greater rise in titre was
observed in 97 (77%) patients, whereas a single high titre was
demonstrated in 16 (12.7%) patients. According to PCR analysis, 77 (72.6%)
of 106 biopsy samples showed positive results.
- reference: PMID:2193627
title: Randomized trial of doxycycline versus josamycin for Mediterranean spotted fever.
findings:
- statement: >-
One-day doxycycline and five-day josamycin both achieved uneventful
recovery in a Mediterranean spotted-fever randomized trial.
supporting_text: >-
We undertook a randomized clinical trial comparing therapeutic efficacy of
the 1-day doxycycline regimen with the 5-day josamycin regimen for
Mediterranean spotted fever. All 59 patients recovered uneventfully, and
results did not significantly differ between the two schedules.
- reference: PMID:26711765
title: Randomized Trial of Clarithromycin for Mediterranean Spotted Fever.
findings:
- statement: >-
Clarithromycin is an oral macrolide alternative to doxycycline or
josamycin for Mediterranean spotted fever.
supporting_text: >-
There were no adverse reactions to treatment or relapses in either group.
In conclusion, clarithromycin is a good alternative to doxycycline or
josamycin in the treatment of MSF.
- reference: PMID:7511715
title: >-
Rickettsia conorii infection of C3H/HeN mice. A model of
endothelial-target rickettsiosis.
findings:
- statement: >-
R. conorii Malish infection in C3H/HeN mice produces disseminated
endothelial infection and vascular injury.
supporting_text: >-
Mice inoculated with a high dose of rickettsiae established disseminated
endothelial infection on day 1, became ill with progressive increase in
rickettsiae on day 4, and died with vascular injury-based
meningoencephalitis and interstitial pneumonia on day 5 or 6.
classifications:
harrisons_chapter:
- classification_value: INFECTIOUS_DISEASES
evidence:
- reference: PMID:15766388
reference_title: >-
Proposal to create subspecies of Rickettsia conorii based on
multi-locus sequence typing and an emended description of Rickettsia
conorii.
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Rickettsiae closely related to the Malish strain, the reference
Rickettsia conorii strain, include Indian tick typhus rickettsia (ITTR),
Israeli spotted fever rickettsia (ISFR), and Astrakhan fever rickettsia
(AFR).
explanation: >-
The taxonomic study identifies Israeli tick typhus as a rickettsial
bacterial infection, placing it in Harrison's Infectious Diseases Part.
infectious_agent:
- name: Rickettsia conorii subsp. israelensis
infectious_agent_term:
preferred_term: Rickettsia conorii subsp. israelensis
term:
id: NCBITaxon:45258
label: Rickettsia conorii subsp. israelensis
description: >-
Obligate intracellular spotted-fever-group rickettsial subspecies that
causes Israeli tick typhus.
evidence:
- reference: PMID:15766388
reference_title: >-
Proposal to create subspecies of Rickettsia conorii based on multi-locus
sequence typing and an emended description of Rickettsia conorii.
supports: SUPPORT
evidence_source: OTHER
snippet: >-
We propose the names R. conorii subsp. conorii subsp. nov. (type strain =
Malish, ATCC VR-613), R. conorii subspecies indica subsp. nov. (type
strain = ATCC VR-597), R. conorii subspecies caspia subsp. nov. (type
strain = A-167), and R. conorii subspecies israelensis subsp. nov. (type
strain = ISTT CDC1).
explanation: >-
Multilocus taxonomy formally placed Israeli spotted fever rickettsia
inside R. conorii as subsp. israelensis.
transmission:
- name: Rhipicephalus sanguineus tick bite inoculation
description: >-
Humans acquire Israeli tick typhus when infected brown dog ticks bite and
inoculate R. conorii subsp. israelensis into skin.
evidence:
- reference: PMID:19421877
reference_title: >-
Incongruent effects of two isolates of Rickettsia conorii on the survival
of Rhipicephalus sanguineus ticks.
supports: SUPPORT
evidence_source: OTHER
quote_role: BACKGROUND
snippet: >-
In the Mediterranean region, the brown dog tick, Rhipicephalus
sanguineus, is the recognized vector of R. conorii.
explanation: >-
The experimental tick study identifies R. sanguineus as the recognized
vector for R. conorii in the Mediterranean setting.
- reference: PMID:19421877
reference_title: >-
Incongruent effects of two isolates of Rickettsia conorii on the survival
of Rhipicephalus sanguineus ticks.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
On the other hand, exposure to ISTT strain had lesser effect on tick
survival and resulted in 35-66% prevalence of infection.
explanation: >-
R. sanguineus ticks experimentally exposed to the Israeli tick typhus
strain sustain infection, supporting biological compatibility between the
pathogen and vector.
epidemiology:
- name: Israel and Mediterranean brown-dog-tick exposure
description: >-
Hospitalized Israeli cases are dominated by the Israeli tick typhus strain,
cluster near the Mediterranean shoreline, and often lack a recalled tick
bite or visible eschar.
factors:
- Israel exposure
- Rhipicephalus sanguineus tick exposure
- Mediterranean shoreline exposure
evidence:
- reference: PMID:34286684
reference_title: Spotted Fever Group Rickettsioses in Israel, 2010-2019.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In a multicenter, nationwide, retrospective study of patients hospitalized
with spotted fever group rickettsiosis in Israel during 2010-2019, we
identified 42 cases, of which 36 were autochthonous.
explanation: >-
The national series documents modern autochthonous spotted-fever-group
rickettsiosis in hospitalized Israeli patients.
- reference: PMID:34286684
reference_title: Spotted Fever Group Rickettsioses in Israel, 2010-2019.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The most prevalent species was the Rickettsia conorii Israeli tick typhus
strain (n = 33, 79%); infection with this species necessitated intensive
care for 52% of patients and was associated with a 30% fatality rate.
explanation: >-
Species-identified hospitalized cases show that the Israeli tick typhus
strain was the dominant local agent and that it caused severe disease in a
selected hospitalized cohort.
clinical_burden:
burden_level: HIGH
rationale: >-
Israeli tick typhus imposes high acute burden because selected hospitalized
cohorts have high intensive-care use and double-digit fatality, and the ISF
strain was associated with fatal outcome in a strain-identified Portuguese
cohort.
evidence:
- reference: PMID:34286684
reference_title: Spotted Fever Group Rickettsioses in Israel, 2010-2019.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The most prevalent species was the Rickettsia conorii Israeli tick typhus
strain (n = 33, 79%); infection with this species necessitated intensive
care for 52% of patients and was associated with a 30% fatality rate.
explanation: >-
The nationwide hospitalized Israeli series documents intensive-care use
and fatality among patients infected with the Israeli tick typhus strain.
- reference: PMID:18582199
reference_title: >-
Host- and microbe-related risk factors for and pathophysiology of fatal
Rickettsia conorii infection in Portuguese patients.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A fatal outcome was significantly more likely for patients infected with
the ISF strain, and alcoholism was a risk factor.
explanation: >-
The prospective strain-identified Portuguese cohort links the ISF strain
to fatal spotted-fever outcome.
pathophysiology:
- name: Brown Dog Tick ISF Inoculation
role: trigger
biological_scale: ORGANISM
description: >-
A feeding R. sanguineus tick inoculates R. conorii subsp. israelensis into
skin, seeding a local dermal focus that may form an eschar and can
disseminate to vascular endothelium.
biological_processes:
- preferred_term: inflammatory response
modifier: INCREASED
term:
id: GO:0006954
label: inflammatory response
evidence:
- reference: PMID:19421877
reference_title: >-
Incongruent effects of two isolates of Rickettsia conorii on the survival
of Rhipicephalus sanguineus ticks.
supports: SUPPORT
evidence_source: OTHER
quote_role: BACKGROUND
snippet: >-
In the Mediterranean region, the brown dog tick, Rhipicephalus
sanguineus, is the recognized vector of R. conorii.
explanation: >-
R. sanguineus is the recognized tick vector for the Mediterranean
R. conorii complex.
downstream:
- target: Inoculation Eschar
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: Local dermal rickettsial infection produces the necrotic eschar.
- target: Sca2-Dependent Endothelial Invasion and Actin Motility
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: Disseminating organisms use Sca-family host-cell entry machinery.
- target: Rickettsial Endothelial Infection
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: Inoculated organisms disseminate to vascular endothelium.
- name: Sca2-Dependent Endothelial Invasion and Actin Motility
role: host_cell_invasion
biological_scale: CELLULAR
description: >-
R. conorii Sca2 is a multifunctional surface autotransporter that mediates
mammalian host-cell association, invasion of human endothelial cells, and
actin-based motility; these shared spotted-fever-group functions are placed
upstream of systemic Israeli tick typhus endothelial infection.
cell_types:
- preferred_term: endothelial cell of vascular tree
term:
id: CL:0002139
label: endothelial cell of vascular tree
biological_processes:
- preferred_term: symbiont entry into host
modifier: INCREASED
term:
id: GO:0044409
label: symbiont entry into host
- preferred_term: actin filament polymerization
modifier: INCREASED
term:
id: GO:0030041
label: actin filament polymerization
evidence:
- reference: PMID:22612237
reference_title: >-
Identification and characterization of the mammalian association and
actin-nucleating domains in the Rickettsia conorii autotransporter
protein, Sca2.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
A rickettsial autotransporter from Rickettsia conorii, Sca2, has been
shown to be sufficient to mediate both adherence and invasion of human
endothelial cells and to participate in intracellular actin-based motility.
explanation: >-
R. conorii Sca2 provides a direct bacterial mechanism for endothelial
adhesion, invasion, and actin-linked spread.
downstream:
- target: Rickettsial Endothelial Infection
causal_link_type: DIRECT
description: Rickettsial uptake and cytosolic motility seed endothelial infection.
- name: Rickettsial Endothelial Infection
role: cellular_infection
description: >-
R. conorii subsp. israelensis belongs to the R. conorii complex of
endotheliotropic spotted-fever rickettsiae; systemic infection of small
vascular endothelium is the cellular lesion that transduces infection into
vasculitis, vascular leak, and severe end-organ injury.
cell_types:
- preferred_term: endothelial cell of vascular tree
term:
id: CL:0002139
label: endothelial cell of vascular tree
biological_processes:
- preferred_term: biological process involved in interaction with host
term:
id: GO:0051701
label: biological process involved in interaction with host
evidence:
- reference: PMID:7511715
reference_title: >-
Rickettsia conorii infection of C3H/HeN mice. A model of
endothelial-target rickettsiosis.
supports: SUPPORT
evidence_source: OTHER
quote_role: BACKGROUND
snippet: >-
Rickettsial diseases result from disseminated intraendothelial cell
infection.
explanation: >-
The R. conorii C3H/HeN model paper summarizes the conserved
intraendothelial infection lesion of rickettsial disease.
- reference: PMID:8584998
reference_title: >-
Demonstration of Rickettsia Conorii-induced coagulative and platelet
activation in vivo in patients with Mediterranean spotted fever.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Our results provide biochemical evidence for the occurrence of
TXA2-dependent platelet activation and thrombin generation in vivo,
together with endothelial dysfunction.
explanation: >-
Human R. conorii infection includes endothelial dysfunction during acute
Mediterranean spotted fever, supporting the conserved endothelial lesion.
downstream:
- target: Rickettsial Vasculitis
causal_link_type: DIRECT
description: Endothelial infection drives disseminated vascular inflammation.
- name: Rickettsial Vasculitis
role: vascular_response
description: >-
Endothelial infection and inflammation produce a systemic small-vessel
vasculitis that clinically manifests as fever, rash, severe vascular leak,
neurologic involvement, renal failure, and shock in fulminant Israeli tick
typhus.
cell_types:
- preferred_term: endothelial cell of vascular tree
term:
id: CL:0002139
label: endothelial cell of vascular tree
biological_processes:
- preferred_term: inflammatory response
modifier: INCREASED
term:
id: GO:0006954
label: inflammatory response
- preferred_term: positive regulation of vascular permeability
modifier: INCREASED
term:
id: GO:0043117
label: positive regulation of vascular permeability
evidence:
- reference: PMID:8584998
reference_title: >-
Demonstration of Rickettsia Conorii-induced coagulative and platelet
activation in vivo in patients with Mediterranean spotted fever.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
These phenomena could account for clinical manifestations of MSF, such as
vasculitis and focal microthrombus formation.
explanation: >-
The acute R. conorii platelet, coagulation and endothelial-dysfunction
findings are linked to vasculitis and focal microthrombus formation.
downstream:
- target: Fever
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: Systemic rickettsial inflammation produces fever.
- target: Skin Rash
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: Cutaneous vasculitis produces the characteristic rash.
- target: Myalgia
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: Acute systemic inflammation commonly causes myalgia.
- target: Vomiting
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: Systemic Israeli spotted fever commonly includes gastrointestinal symptoms.
- target: Hyponatremia
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: Systemic rickettsial disease can include hyponatremia.
- target: Encephalopathy
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: Severe CNS microvascular injury can produce encephalopathy.
- target: Acute Kidney Injury
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: Fulminant vasculitic injury can progress to renal failure.
- target: Shock
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: Fulminant systemic vasculitis and vascular leak can produce shock.
- target: Platelet Activation and Microthrombus Formation
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: Endothelial injury can activate platelets and coagulation.
- name: Platelet Activation and Microthrombus Formation
role: consumptive_coagulation
biological_scale: CELLULAR
description: >-
R. conorii endothelial injury is accompanied by TXA2-dependent platelet
activation and thrombin generation in vivo, providing a route to platelet
consumption, thrombocytopenia, microthrombi, and bleeding in severe Israeli
tick typhus.
cell_types:
- preferred_term: platelet
term:
id: CL:0000233
label: platelet
biological_processes:
- preferred_term: platelet activation
modifier: INCREASED
term:
id: GO:0030168
label: platelet activation
- preferred_term: blood coagulation
modifier: INCREASED
term:
id: GO:0007596
label: blood coagulation
evidence:
- reference: PMID:8584998
reference_title: >-
Demonstration of Rickettsia Conorii-induced coagulative and platelet
activation in vivo in patients with Mediterranean spotted fever.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Our results provide biochemical evidence for the occurrence of
TXA2-dependent platelet activation and thrombin generation in vivo,
together with endothelial dysfunction. These phenomena could account for
clinical manifestations of MSF, such as vasculitis and focal microthrombus
formation.
explanation: >-
Human R. conorii infection activates platelet and coagulation pathways
downstream of endothelial dysfunction.
downstream:
- target: Thrombocytopenia
causal_link_type: DIRECT
description: Consumptive platelet activation lowers circulating platelet counts.
- target: Abnormal Bleeding
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: Platelet consumption and coagulation activation can produce bleeding.
- name: Rickettsial Ribosomal Translation
role: therapeutic_vulnerability
conforms_to: "bacterial_protein_synthesis_inhibition#Bacterial mRNA Translation by the Ribosome"
description: >-
R. conorii subsp. israelensis, like other bacteria, depends on ribosomal
translation of its mRNA, making the bacterial ribosome the conserved target
for doxycycline and macrolide antibacterial therapy.
biological_processes:
- preferred_term: Translation
term:
id: GO:0006412
label: translation
evidence:
- reference: PMID:24336183
reference_title: Ribosome-targeting antibiotics and mechanisms of bacterial resistance.
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: The ribosome is one of the main antibiotic targets in the bacterial cell.
explanation: >-
Review evidence establishes the bacterial ribosome as the conserved target
class for tetracyclines and macrolides.
phenotypes:
- name: Fever
category: Constitutional
frequency: VERY_FREQUENT
description: Fever is a core acute manifestation of Israeli tick typhus.
phenotype_term:
preferred_term: Fever
term:
id: HP:0001945
label: Fever
evidence:
- reference: PMID:2710586
reference_title: Clinical and laboratory findings of spotted fever in Israeli children.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In a prospective study of 70 Israeli children with spotted fever the major
clinical features were fever (100%), skin rash (98.5%), myalgia (54%) and
vomiting (40%).
explanation: >-
The Israeli pediatric cohort reported fever in all cases, supporting the
very-frequent fever band.
- name: Skin Rash
category: Dermatologic
frequency: VERY_FREQUENT
description: A rash accompanies nearly all Israeli pediatric spotted-fever cases.
phenotype_term:
preferred_term: Skin rash
term:
id: HP:0000988
label: Skin rash
evidence:
- reference: PMID:2710586
reference_title: Clinical and laboratory findings of spotted fever in Israeli children.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In a prospective study of 70 Israeli children with spotted fever the major
clinical features were fever (100%), skin rash (98.5%), myalgia (54%) and
vomiting (40%).
explanation: >-
The Israeli pediatric cohort reported skin rash in 98.5% of cases.
- name: Inoculation Eschar
category: Dermatologic
frequency: OCCASIONAL
description: >-
Israeli tick typhus is eschar-poor compared with some spotted fevers, but a
minority of hospitalized Israeli cases have an eschar.
phenotype_term:
preferred_term: Eschar
term:
id: HP:6000793
label: Eschar
evidence:
- reference: PMID:34286684
reference_title: Spotted Fever Group Rickettsioses in Israel, 2010-2019.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A history of tick bite was rare, found for only 5% of patients; eschar was
found in 12%; and leukocytosis was more common than leukopenia.
explanation: >-
The national hospitalized Israeli series found eschar in the occasional
range.
- name: Myalgia
category: Musculoskeletal
frequency: FREQUENT
description: Myalgia can accompany acute Israeli pediatric spotted fever.
phenotype_term:
preferred_term: Myalgia
term:
id: HP:0003326
label: Myalgia
evidence:
- reference: PMID:2710586
reference_title: Clinical and laboratory findings of spotted fever in Israeli children.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In a prospective study of 70 Israeli children with spotted fever the major
clinical features were fever (100%), skin rash (98.5%), myalgia (54%) and
vomiting (40%).
explanation: The Israeli pediatric cohort reported myalgia in 54% of cases.
- name: Vomiting
category: Digestive System
frequency: FREQUENT
description: Vomiting can accompany acute Israeli pediatric spotted fever.
phenotype_term:
preferred_term: Vomiting
term:
id: HP:0002013
label: Vomiting
evidence:
- reference: PMID:2710586
reference_title: Clinical and laboratory findings of spotted fever in Israeli children.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In a prospective study of 70 Israeli children with spotted fever the major
clinical features were fever (100%), skin rash (98.5%), myalgia (54%) and
vomiting (40%).
explanation: The Israeli pediatric cohort reported vomiting in 40% of cases.
- name: Thrombocytopenia
category: Hematologic
frequency: FREQUENT
description: Thrombocytopenia is common in acute Israeli pediatric spotted fever.
phenotype_term:
preferred_term: Thrombocytopenia
term:
id: HP:0001873
label: Thrombocytopenia
evidence:
- reference: PMID:2710586
reference_title: Clinical and laboratory findings of spotted fever in Israeli children.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Thrombocytopenia (75%) and hyponatremia (62.5%) were common, but were not
associated with increased mortality.
explanation: >-
The Israeli pediatric cohort reported thrombocytopenia in the frequent
range.
- name: Hyponatremia
category: Endocrine
frequency: FREQUENT
description: Hyponatremia is common in acute Israeli pediatric spotted fever.
phenotype_term:
preferred_term: Hyponatremia
term:
id: HP:0002902
label: Hyponatremia
evidence:
- reference: PMID:2710586
reference_title: Clinical and laboratory findings of spotted fever in Israeli children.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Thrombocytopenia (75%) and hyponatremia (62.5%) were common, but were not
associated with increased mortality.
explanation: >-
The Israeli pediatric cohort reported hyponatremia in the frequent range.
- name: Encephalopathy
category: Neurologic
description: Encephalopathy can occur in fulminant Israeli spotted fever.
phenotype_term:
preferred_term: Encephalopathy
term:
id: HP:0001298
label: Encephalopathy
evidence:
- reference: PMID:8286624
reference_title: Fatal Israeli spotted fever in children.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Clinical disease was characterized by irreversible shock, encephalopathy,
renal failure, bleeding tendency, and death within 24 hours of admission.
explanation: >-
The fatal pediatric series documents encephalopathy as part of fulminant
Israeli spotted fever.
- name: Acute Kidney Injury
category: Genitourinary
description: Acute renal failure can occur in fulminant Israeli spotted fever.
phenotype_term:
preferred_term: Acute kidney injury
term:
id: HP:0001919
label: Acute kidney injury
evidence:
- reference: PMID:8286624
reference_title: Fatal Israeli spotted fever in children.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Clinical disease was characterized by irreversible shock, encephalopathy,
renal failure, bleeding tendency, and death within 24 hours of admission.
explanation: >-
The fatal pediatric series documents renal failure as part of fulminant
Israeli spotted fever.
- name: Shock
category: Cardiovascular
description: Shock can occur in fulminant Israeli spotted fever.
phenotype_term:
preferred_term: Shock
term:
id: HP:0031273
label: Shock
evidence:
- reference: PMID:8286624
reference_title: Fatal Israeli spotted fever in children.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Clinical disease was characterized by irreversible shock, encephalopathy,
renal failure, bleeding tendency, and death within 24 hours of admission.
explanation: >-
The fatal pediatric series documents shock as part of fulminant Israeli
spotted fever.
- name: Abnormal Bleeding
category: Hematologic
description: A bleeding tendency can occur in fulminant Israeli spotted fever.
phenotype_term:
preferred_term: Abnormal bleeding
term:
id: HP:0001892
label: Abnormal bleeding
evidence:
- reference: PMID:8286624
reference_title: Fatal Israeli spotted fever in children.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Clinical disease was characterized by irreversible shock, encephalopathy,
renal failure, bleeding tendency, and death within 24 hours of admission.
explanation: >-
The fatal pediatric series documents bleeding tendency as part of
fulminant Israeli spotted fever.
diagnosis:
- name: Indirect immunofluorescence assay serology
description: >-
Paired indirect immunofluorescence serology demonstrating seroconversion or
a fourfold titer rise can confirm recent R. conorii infection.
results: Seroconversion, a fourfold titer rise, or a single high titer supports diagnosis.
evidence:
- reference: PMID:23168048
reference_title: Mediterranean spotted fever in the Trakya region of Turkey.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Using IFA, seroconversion or a fourfold or greater rise in titre was
observed in 97 (77%) patients, whereas a single high titre was
demonstrated in 16 (12.7%) patients.
explanation: >-
R. conorii Mediterranean spotted fever data establish IFA serology as a
practical confirmatory test for the R. conorii complex.
- name: Skin biopsy rickettsial PCR and sequencing
description: >-
PCR amplification and sequencing of skin biopsy material from eschar or rash
can detect R. conorii DNA and identify the infecting strain.
diagnosis_term:
preferred_term: polymerase chain reaction
term:
id: NCIT:C17003
label: Polymerase Chain Reaction
results: Positive rickettsial PCR with sequencing supports R. conorii strain identification.
evidence:
- reference: PMID:23168048
reference_title: Mediterranean spotted fever in the Trakya region of Turkey.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
According to PCR analysis, 77 (72.6%) of 106 biopsy samples showed
positive results.
explanation: >-
Skin-biopsy PCR was positive in most confirmed Mediterranean spotted fever
cases, including biopsies from both eschar and maculopapular rash.
treatments:
- name: Doxycycline
description: >-
Doxycycline is first-line antibacterial therapy for Israeli tick typhus and
related R. conorii infections because it blocks rickettsial ribosomal
translation.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: doxycycline
term:
id: CHEBI:50845
label: doxycycline
target_mechanisms:
- target: Rickettsial Ribosomal Translation
treatment_effect: INHIBITS
description: >-
Doxycycline inhibits bacterial protein synthesis through the conserved
tetracycline-class ribosomal target.
evidence:
- reference: PMID:2193627
reference_title: Randomized trial of doxycycline versus josamycin for Mediterranean spotted fever.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
All 59 patients recovered uneventfully, and results did not significantly
differ between the two schedules. One-day doxycycline therapy is an
effective, easy, and inexpensive treatment.
explanation: >-
A randomized Mediterranean spotted-fever trial supports doxycycline
efficacy in the R. conorii complex.
- name: Clarithromycin
description: >-
Clarithromycin is an oral macrolide alternative for Mediterranean
spotted-fever-group rickettsioses when tetracyclines or josamycin are not
suitable.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: clarithromycin
term:
id: CHEBI:3732
label: clarithromycin
target_mechanisms:
- target: Rickettsial Ribosomal Translation
treatment_effect: INHIBITS
description: Clarithromycin targets bacterial ribosomal translation.
evidence:
- reference: PMID:26711765
reference_title: Randomized Trial of Clarithromycin for Mediterranean Spotted Fever.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
There were no adverse reactions to treatment or relapses in either group.
In conclusion, clarithromycin is a good alternative to doxycycline or
josamycin in the treatment of MSF.
explanation: >-
A randomized MSF trial identifies clarithromycin as a macrolide
alternative in the R. conorii complex.
- name: Josamycin
description: >-
Josamycin is an oral macrolide alternative for Mediterranean
spotted-fever-group rickettsioses when tetracycline-class therapy is
unsuitable.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: josamycin
term:
id: CHEBI:31739
label: josamycin
target_mechanisms:
- target: Rickettsial Ribosomal Translation
treatment_effect: INHIBITS
description: Josamycin targets bacterial ribosomal translation.
evidence:
- reference: PMID:2193627
reference_title: Randomized trial of doxycycline versus josamycin for Mediterranean spotted fever.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Josamycin is a useful therapeutic alternative that may be particularly
convenient for pregnant women and patients with a history of allergy to
tetracyclines.
explanation: >-
A randomized Mediterranean spotted-fever trial identifies josamycin as a
macrolide alternative in the R. conorii complex.
animal_models:
- name: C3H/HeN Rickettsia conorii Malish infection mouse
species: Mouse
genotype: Wild-type C3H/HeN
publication: PMID:7511715
description: >-
Intravenous R. conorii Malish 7 infection in C3H/HeN mice produces
disseminated endothelial infection and vascular-injury outcomes, modeling
the endotheliotropic vasculitis shared across R. conorii spotted-fever
infections.
modeled_mechanisms:
- target: Rickettsial Endothelial Infection
relationship: PARTIALLY_RECAPITULATES
fidelity: MODERATE
description: >-
High-dose infection establishes disseminated endothelial infection and
vascular-injury-based meningoencephalitis and interstitial pneumonia.
limitations: >-
The model uses the R. conorii Malish 7 strain associated with
Mediterranean spotted fever, not R. conorii subsp. israelensis, so it
supports the shared endotheliotropic rickettsial mechanism rather than an
israelensis-specific virulence program.
evidence:
- reference: PMID:7511715
reference_title: >-
Rickettsia conorii infection of C3H/HeN mice. A model of
endothelial-target rickettsiosis.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Mice inoculated with a high dose of rickettsiae established
disseminated endothelial infection on day 1, became ill with
progressive increase in rickettsiae on day 4, and died with vascular
injury-based meningoencephalitis and interstitial pneumonia on day 5 or
6.
explanation: >-
The C3H/HeN model directly measures the endothelial infection and
vascular-injury phenotypes central to spotted-fever pathogenesis.
evidence:
- reference: PMID:7511715
reference_title: >-
Rickettsia conorii infection of C3H/HeN mice. A model of
endothelial-target rickettsiosis.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
This experimental infection provides the best available model for
rickettsial disease with endothelial infection and injury, immune
rickettsial clearance, regeneration of endothelium, and repair of the
vascular lesions.
explanation: >-
The authors frame C3H/HeN R. conorii infection as an endothelial-target
rickettsiosis model.
Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.
Create Israeli tick typhus · 2026-09-28T07:05:15Z · View source
Created a de novo Israeli tick typhus entry from the OpenScientist deep-research report, with Rickettsia conorii subsp. israelensis identity, Rhipicephalus sanguineus transmission, Sca2-to-endothelium invasion biology, TXA2-dependent platelet activation and microthrombus formation, cohort-backed Israeli phenotypes, IFA and PCR diagnostics, doxycycline and clarithromycin treatments, and a C3H/HeN R. conorii Malish infection mouse model. Addressed initial review by marking PMID:19421877 vector-background quotes as BACKGROUND, replacing load-bearing endothelial and vasculitis snippets with sentences that directly support the node claims, adding a human endothelial-dysfunction anchor, adding shock and abnormal bleeding phenotypes from the fatal pediatric series, and adding a clinical_burden block for the ISF ICU/fatality and strain-severity data. Left the non-blocking vascular-permeability split, environmental tick-exposure block, reservoir/incubation additions, and Hyponatremia category cleanup for later rather than expanding this review fix beyond the blocking findings.
Disease: Israeli Tick Typhus / Israeli Spotted Fever (ISF) MONDO ID: MONDO:0000230 Category: Infectious Disease (tick-borne spotted-fever-group rickettsiosis) Causative agent: Rickettsia conorii subsp. israelensis Identifiers: MONDO:0000230 · ICD-10 A77.1 · ICD-11 1C30.0 · MeSH D001907 (Boutonneuse Fever)
Israeli Tick Typhus, more precisely termed Israeli Spotted Fever (ISF), is a tick-borne, spotted-fever-group (SFG) rickettsiosis caused by the obligate intracellular Gram-negative bacterium Rickettsia conorii subsp. *israelensis. It is a clinical and etiological variant of Mediterranean spotted fever (MSF) / boutonneuse fever, distinguished from the classic R. conorii subsp. conorii (Malish) strain by multi-locus sequence typing (MLST) and by a more virulent clinical phenotype. The disease is transmitted by the brown dog tick, Rhipicephalus sanguineus***, which serves as both vector and reservoir, with domestic dogs acting as amplifying/sentinel hosts. This report synthesizes 16 confirmed findings drawn from 61 papers reviewed across a five-iteration investigation.
The core pathophysiology is a disseminated small-vessel vasculitis: rickettsiae enter through the dermis at the tick-bite site, spread hematogenously, and infect vascular endothelial cells—most critically in the brain and lungs—driving increased microvascular permeability, edema, platelet/coagulation activation, and multi-organ dysfunction. Clinically, fever and maculopapular rash are near-universal, but unlike classic MSF the diagnostic eschar (tache noire) is frequently absent, and a history of tick bite is often lacking, which contributes to diagnostic delay. The ISF strain is associated with a case-fatality of ~20–30% in hospitalized/severe cohorts, with older age, alcoholism, G6PD deficiency, and delayed treatment as major prognostic risk factors.
Management is straightforward and highly effective when timely: doxycycline is the drug of choice and is curative even as a single-day 200 mg course, with josamycin, clarithromycin, and (historically) chloramphenicol as alternatives for children and pregnant women. There is no vaccine; prevention rests on tick-bite avoidance and integrated Rhipicephalus sanguineus vector control on dogs and premises. ISF is a zoonosis whose geographic range—historically the Mediterranean basin (Israel, Italy, Portugal)—is now documented across multiple continents (Iran, Uganda, Ghana), reflecting the global spread of the brown dog tick.
Multi-locus sequence typing of 39 isolates/tick amplicons resolved four R. conorii genotypes: the Malish type, Indian tick typhus (ITTR) type, Astrakhan fever (AFR) type, and the Israeli spotted fever (ISFR) type. Pairwise similarity across the 16S rRNA, gltA, ompA, ompB, and sca4 loci ranged 98.2–100%, supporting classification at the subspecies (not species) rank (PMID: 15766388). ISF is therefore R. conorii subsp. israelensis, a member of the R. conorii complex and a variant of Mediterranean spotted fever / boutonneuse fever (PMID: 28408252).
"Among the 39 isolates or tick amplicons studied, four MLST genotypes were identified: i) the Malish type; ii) the ITTR type; iii) the AFR type; and iv) the ISFR type." — PMID: 15766388
Key identifiers: MONDO:0000230; ICD-10 A77.1 (Spotted fever due to Rickettsia conorii; includes Boutonneuse/Marseilles/Mediterranean tick fever); ICD-11 1C30.0; MeSH D001907 (Boutonneuse Fever); NCBI Taxonomy pathogen Rickettsia conorii subsp. israelensis. Synonyms: Israeli spotted fever, Israeli tick typhus, a form of Mediterranean spotted fever / boutonneuse fever / fièvre boutonneuse. Information is derived from aggregated disease-level sources (case series, cohorts, case reports), not single-patient EHR data.
A prospective Portuguese study of 140 strain-identified R. conorii patients (1994–2006; 71 Malish, 69 ISF) found that 29 adults (21%) died, and that fatal outcome was significantly more likely with the ISF strain, with alcoholism identified as a risk factor (PMID: 18582199). The pathophysiology of fatal disease involved significantly greater incidence of petechial rash, gastrointestinal symptoms, obtundation/confusion, dehydration, tachypnea, hepatomegaly, leukocytosis, coagulopathy, azotemia, hyperbilirubinemia, and elevated hepatic enzymes and creatine kinase.
"A fatal outcome was significantly more likely for patients infected with the ISF strain, and alcoholism was a risk factor." — PMID: 18582199
Note a nuance: a separate Portuguese analysis (n=94) found that neither eschar presence (Malish 49% vs ISF 39%) nor fatality differed statistically between strains (PMID: 16481514), suggesting the "greater severity" concept, while supported by the larger prospective cohort and Israeli national data, should be interpreted with the caveat of cohort-dependent effect sizes.
In MSF patients, in vivo biochemical evidence showed TXA2-dependent platelet activation (urinary 11-dehydro-TXB2), thrombin generation (prothrombin fragment 1+2), and endothelial dysfunction (plasma endothelin-1) (PMID: 8584998). In R. conorii-infected mice, rickettsiae localize to the endothelium and selectively modulate antioxidant enzymes (GPx, GR, G6PD, SOD); the antioxidant alpha-lipoic acid was protective, implicating oxidative injury (PMID: 15120155). Severe ISF can progress to purpura fulminans and DIC (PMID: 29664383).
"Our results provide biochemical evidence for the occurrence of TXA2-dependent platelet activation and thrombin generation in vivo, together with endothelial dysfunction." — PMID: 8584998
In 70 Israeli children, fever occurred in 100%, rash 98.5%, myalgia 54%, vomiting 40%; thrombocytopenia 75%, hyponatremia 62.5%; 16% hospitalized; 1 death (PMID: 2710586). Fatal Israeli pediatric cases showed irreversible shock, encephalopathy, renal failure, and bleeding, with death within 24 h, often with no eschar and no tick-bite history (PMID: 8286624). A Palestinian pediatric cohort (n=18) reported fever and rash 100%, eschar rare (6%), GI 44%, neurological 28%, arthralgia/myalgia 33%, thrombocytopenia 56%, and universally good outcomes with prompt doxycycline (PMID: 41795239).
"the major clinical features were fever (100%), skin rash (98.5%), myalgia (54%) and vomiting (40%). Thrombocytopenia (75%) and hyponatremia (62.5%) were common" — PMID: 2710586
"None of the patients had a history of tick bite, and no tache noire was noted. One child presented without rash" — PMID: 8286624
Documented complications: hemophagocytic lymphohistiocytosis/HLH (PMID: 35169573, PMID: 40693676), purpura fulminans (PMID: 29664383, PMID: 40580427), Guillain-Barré syndrome (PMID: 41768953), and multi-organ failure in children (PMID: 26905298).
Suggested HPO terms: HP:0001945 (Fever), HP:0000988 (Skin rash), HP:0003326 (Myalgia), HP:0002013 (Vomiting), HP:0001873 (Thrombocytopenia), HP:0002902 (Hyponatremia), HP:0002240 (Hepatomegaly), HP:0001298 (Encephalopathy), HP:0001919 (Acute kidney injury), HP:0031137 (Abnormal circulating coagulation protein concentration), HP:0002624 (vasculitis-related manifestations).
The ISF strain is documented in Israel, Italy (Sicily, Sardinia), and Portugal (PMID: 28408252), and R. conorii subsp. israelensis has been detected in ticks/patients in Iran (PMID: 38254000, PMID: 35365079), Uganda (PMID: 37498943), Ghana (first record) (PMID: 41958159), and ticks in Israel (PMID: 35816829). Seasonality is late spring/summer, linked to Rhipicephalus sanguineus activity and climate variability/low precipitation (PMID: 17114701). Dogs serve as a reservoir: 38.5% of 400 healthy Portuguese dogs were seropositive, and the ISF strain was detected in dog blood (PMID: 21771547).
"R. conorii subsp. israelensis, which belongs to the R. conorii complex, is the agent of Israeli spotted fever (ISF); apart from Israel, it has also been found in Italy (Sicily and Sardinia) and in different regions of Portugal." — PMID: 28408252
Surface cell antigen (Sca) autotransporters—Sca0/OmpA, Sca5/OmpB, and Sca2—mediate host-cell adhesion, invasion, and intracellular motility. Sca2 (~1800-aa monomeric autotransporter) is sufficient to mediate adherence and invasion of human endothelial cells and drives assembly of long, unbranched actin tails for intracellular movement; it is the only known functional mimic of eukaryotic formins (PMID: 22612237). Cryo-EM shows Sca2 forms a formin FH2-dimer-like "doughnut" encircling two actin subunits (PMID: 37028467).
"A rickettsial autotransporter from Rickettsia conorii, Sca2, has been shown to be sufficient to mediate both adherence and invasion of human endothelial cells and to participate in intracellular actin-based motility." — PMID: 22612237
"Sca2... is the only known functional mimic of eukaryotic formins" — PMID: 37028467
Suggested GO terms: GO:0007155 (cell adhesion), GO:0070358 (actin polymerization-dependent cell motility), GO:0030036 (actin cytoskeleton organization).
SFG rickettsial infection of microvascular endothelial cells activates tyrosine phosphorylation of VE-cadherin (peak ~72 h post-infection), reducing VE-cadherin junctional interactions and increasing permeability (PMID: 22720111). Increased permeability is partly due to intracellular rickettsiae and partly to host pro-inflammatory defenses, with dissociation of endothelial adherens junctions (PMID: 17957455); nitric oxide from infected ECs both limits rickettsial proliferation and alters barrier integrity (PMID: 16481520). The full pathogenetic sequence—dermal entry → hematogenous spread to endothelium (esp. brain and lungs) → increased permeability, edema, and immunity via NK cells, IFN-γ, TNF-α, RANTES, antibodies, and CTLs—is defined in the SFG rickettsioses (PMID: 12860594).
"infection of R. montanensis significantly activated tyrosine phosphorylation of VE-cadherin beginning at 48 hr and reaching a peak at 72 hr p.i." — PMID: 22720111
"The pathogenetic sequence includes rickettsial entry into the dermis, hematogenous dissemination to vascular endothelial cells (most critically in brain and lungs), increased vascular permeability, edema, and immunity mediated by NK cells, IFN-gamma, TNF-alpha, RANTES, antibodies, and cytotoxic T lymphocytes." — PMID: 12860594
The microvascular/vascular endothelial cell is the primary target; disseminated endothelial infection produces increased permeability and edema most critically in brain and lungs (PMID: 12860594, PMID: 22720111). Documented organ involvement in ISF/MSF spans skin (rash, eschar, edema), CNS (encephalopathy, meningoencephalitis, Guillain-Barré), lungs (tachypnea, non-cardiogenic pulmonary edema), kidney (azotemia, acute tubular necrosis), liver (hepatomegaly, transaminitis, hyperbilirubinemia), GI tract, spleen, and the hematologic system (thrombocytopenia, coagulopathy, DIC, purpura fulminans) (PMID: 18582199, PMID: 8286624, PMID: 29664383).
"hematogenous dissemination to vascular endothelial cells (most critically in brain and lungs), increased vascular permeability, edema" — PMID: 12860594
Suggested UBERON/CL/GO terms: UBERON:0001981 (blood vessel), UBERON:0001986 (endothelium), CL:0000115 (endothelial cell), CL:0002139 (endothelial cell of vascular tree); UBERON:0002097 (skin), UBERON:0000955 (brain), UBERON:0002048 (lung), UBERON:0002113 (kidney), UBERON:0002107 (liver); GO:0005912 (adherens junction), GO:0005923 (bicellular tight junction), GO:0005911 (cell-cell junction).
No licensed human vaccine exists for R. conorii/SFG rickettsiae; prevention depends on avoiding tick bites and controlling the brown dog tick. Integrated vector control (surveillance, residual acaricide spraying, dog tick collars, public outreach) substantially reduced Rhipicephalus sanguineus populations and rickettsial risk in a California program (PMID: 41146265). Effective canine ectoparasiticides include isoxazolines (e.g., lotilaner) and combination endectocides (PMID: 42045933); pyrethroid acaricides target the tick voltage-gated sodium channel but resistance is emerging (PMID: 41272771). Early empiric doxycycline is the key secondary-prevention measure against fatal outcomes.
"the integrated intervention substantially reduced tick populations at the affected site. Both adult and immature stages of Rh. sanguineus s.l. declined following sequential treatments." — PMID: 41146265
R. conorii subsp. israelensis DNA has been detected in Rhipicephalus sanguineus dog ticks in Ghana (first record; 3.95% of pools; PMID: 41958159), Uganda (PMID: 37498943), and Israel (PMID: 35816829); the ISF strain was detected in Portuguese dog blood with 38.5% seropositivity (PMID: 21771547). The tick maintains the agent transovarially/transstadially, and the ISF strain is better tolerated by the tick than Malish (PMID: 19421877). Naturally infected species include domestic dogs (Canis lupus familiaris, NCBI Taxon 9615) and the tick vector (Rhipicephalus sanguineus, NCBI Taxon 34632).
"This study reports the first molecular detection of R. conorii subsp. israelensis in Ghana." — PMID: 41958159
A randomized trial of 1-day doxycycline vs 5-day josamycin in 59 MSF patients showed all recovered uneventfully with no significant difference; single-day doxycycline is effective, easy, and inexpensive (PMID: 2193627). An RCT of clarithromycin vs doxycycline/josamycin (n=40, incl. 13 children <14 y) found no significant difference in time to defervescence (2.67 vs 2.22 d) or symptom resolution, with no adverse reactions or relapses (PMID: 26711765). Josamycin is favored first-choice in children and pregnant women (PMID: 1884779). Chloramphenicol is effective but carries bone-marrow toxicity, so tetracyclines are preferred.
"One-day doxycycline therapy is an effective, easy, and inexpensive treatment. Josamycin is a useful therapeutic alternative that may be particularly convenient for pregnant women and patients with a history of allergy to tetracyclines." — PMID: 2193627
"clarithromycin is a good alternative to doxycycline or josamycin in the treatment of MSF." — PMID: 26711765
Suggested NCIT/CHEBI terms: NCIT:C692 (Doxycycline), NCIT:C1032 (Clarithromycin), NCIT:C376 (Chloramphenicol); CHEBI:50845 (doxycycline), CHEBI:3732 (clarithromycin).
Onset is acute after a short (~5–7 day) incubation; severe ISF can progress to neurologic and multi-organ failure within days, with recovery achievable if appropriate antibiotics start early (PMID: 14964019). Fatal pediatric ISF progressed to shock, encephalopathy, and renal failure with death within 24 h of admission (PMID: 8286624). In the strain-identified Portuguese cohort, 29/140 (21%) adults died, fatality significantly higher for ISF (PMID: 18582199). Prognostic factors for death: ISF strain, older age, alcoholism, delayed treatment, G6PD deficiency, petechial/purpuric rash, obtundation, coagulopathy, azotemia, hepatic dysfunction.
"Clinical disease was characterized by irreversible shock, encephalopathy, renal failure, bleeding tendency, and death within 24 hours of admission." — PMID: 8286624
In 128 confirmed MSF patients, IFA showed seroconversion or ≥4-fold titre rise in 97 (77%) and a single high titre in 16 (12.7%); skin-biopsy PCR was positive in 77/106 (72.6%), with similar yield from eschar (73%) and maculopapular rash (70%) specimens (PMID: 23168048). Real-time PCR of skin biopsy plus DNA sequencing of gltA and ompA enables species/subspecies identification (PMID: 40608626), and ISF has been specifically confirmed by real-time PCR + IFA in case reports (PMID: 38254000).
"Using IFA, seroconversion or a fourfold or greater rise in titre was observed in 97 (77%) patients, whereas a single high titre was demonstrated in 16 (12.7%) patients. According to PCR analysis, 77 (72.6%) of 106 biopsy samples showed positive results." — PMID: 23168048
Common laboratory abnormalities (LOINC-relevant): thrombocytopenia, hyponatremia, elevated transaminases, hyperbilirubinemia, elevated CRP, azotemia, elevated creatine kinase. Differential diagnosis: other SFG rickettsioses (African tick-bite fever — more numerous eschars, PMID: 41244315), meningococcemia, leptospirosis, viral exanthems, and other causes of fever + rash. There is no genetic testing, newborn screening, or omics-based diagnostic relevant to this infectious disease.
C3H/HeN and C3H/HeJ mice are susceptible and develop lethal disseminated infection with endothelial targeting; C57BL/6 mice are resistant (PMID: 17403875). NK-cell depletion enhances susceptibility, and early control is IFN-γ/IL-12 dependent (PMID: 11504408). Susceptible C3H mice show delayed CD4+ Th1/Th2 responses and higher Foxp3+ Tregs. The ISF (ISTT) strain differs from Malish in tick biology: it caused less tick mortality and higher tick infection prevalence (35–66% vs <5%) in Rhipicephalus sanguineus (PMID: 19421877). Tick saliva modulates host inflammation (IL-1β, NF-κB) during transmission (PMID: 26011701).
"depletion of NK cell activity with antibody to asialo GM1 enhanced the susceptibility of C3H/HeN mice to infection with R. conorii" — PMID: 11504408
"exposure to ISTT strain had lesser effect on tick survival and resulted in 35-66% prevalence of infection" — PMID: 19421877
Model organisms: Mus musculus (NCBI Taxon 10090) — inbred C3H/HeN, C3H/HeJ (susceptible), C57BL/6 (resistant); primary human microvascular/umbilical vein endothelial cells for in vitro work. Recapitulation: disseminated endothelial infection, vasculitis, and lethal multi-organ disease are well reproduced in susceptible mice; limitations include that eschar/tache noire formation and the human tick-bite transmission route are incompletely modeled without live tick infestation.
A nationwide Israeli study (2010–2019) identified 42 hospitalized SFG rickettsiosis cases (36 autochthonous); the R. conorii Israeli tick typhus strain was most prevalent (33/42, 79%), required intensive care in 52%, and had a 30% fatality rate. History of tick bite was present in only 5%; eschar in 12%; leukocytosis more common than leukopenia; 72% resided along the Mediterranean shoreline (PMID: 34286684). A seroepidemiologic survey of two Israeli villages found 69/85 (81%) dogs vs 14/136 (10%) humans anti-R. conorii seropositive, establishing canine serology as a sensitive sentinel for human exposure (PMID: 17620644). ISF in Sicily can be traced back to 1987–1991, with 3/5 patients severe and 1 death (PMID: 16333093).
"The most prevalent species was the Rickettsia conorii Israeli tick typhus strain (n = 33, 79%); infection with this species necessitated intensive care for 52% of patients and was associated with a 30% fatality rate. A history of tick bite was rare, found for only 5% of patients; eschar was found in 12%" — PMID: 34286684
"Sixty-nine of 85 (81%) canine sera and 14 of 136 (10%) of human sera had anti-R. conorii antibodies." — PMID: 17620644
ISF is an infectious, not a Mendelian genetic, disease; there are no human causal genes, pathogenic variants, inheritance patterns, penetrance/expressivity considerations, founder effects, carrier frequencies, or chromosomal abnormalities to report. Host genetic modifiers of severity are plausible but under-characterized: G6PD deficiency is repeatedly cited as a risk factor for severe/fatal MSF, consistent with the oxidative-injury mechanism and the selective modulation of G6PD observed in infected tissues (PMID: 15120155). In animal models, host background (C3H vs C57BL/6) strongly determines susceptibility, implying host genetic control of outcome (PMID: 17403875). The relevant "genome" for causal variants is that of the pathogen (sca0/ompA, sca5/ompB, sca2, sca4, gltA, 16S rRNA), which defines strain identity and virulence.
1. Infected Rhipicephalus sanguineus tick bite inoculates R. conorii subsp. israelensis
into the dermis ──leads to──▶
2. Sca0/OmpA + Sca5/OmpB mediate adhesion to vascular endothelial cells ──results in──▶
3. Receptor-mediated invasion of endothelial cells (Sca2 sufficient for entry) ──leads to──▶
4. Intracellular replication + Sca2 formin-mimic actin-based motility ──drives──▶
5. Cell-to-cell spread and hematogenous dissemination to systemic microvasculature
(brain and lungs most critical) ──results in──▶
6. Endothelial injury:
├── VE-cadherin tyrosine phosphorylation → adherens-junction dissociation
├── Nitric oxide + reactive oxygen species (ROS) → peroxidative membrane damage
└── Pro-inflammatory host response (NK cells, IFN-γ, TNF-α, RANTES, CTLs)
──all converge on──▶
7. Increased microvascular permeability → interstitial edema (cerebral, pulmonary)
+ small-vessel vasculitis ──in parallel with──▶
8. Platelet activation (TXA2) + thrombin generation → procoagulant state, microthrombi
──branches──▶
├── Usual course: self-limited vasculitis → fever + maculopapular rash
│ → RESOLUTION with early doxycycline
└── Severe/ISF-strain course: DIC, purpura fulminans, HLH, shock,
encephalopathy, renal failure, multi-organ failure → DEATH (20–30%)
Steps 1–5 and the endothelial tropism (step 6) are experimentally demonstrated (in vitro human ECs, mouse models, patient biopsies). The relative contribution of intrinsic rickettsial cytotoxicity vs host immunopathology to permeability (step 7) is partly inferred; both are supported (PMID: 17957455). Why the ISF strain is more virulent than Malish at the molecular level is not yet mechanistically resolved—it is an empirical epidemiologic/clinical observation (PMID: 18582199, PMID: 34286684).
| Level | Mechanism | Evidence source | GO/CL suggestion |
|---|---|---|---|
| Upstream (trigger) | Tick inoculation; Sca-mediated adhesion/invasion | In vitro, cryo-EM (PMID: 22612237, PMID: 37028467) | GO:0007155 cell adhesion; CL:0000115 endothelial cell |
| Middle | Actin-based motility; hematogenous spread | In vitro, mouse (PMID: 15120155) | GO:0070358 actin polymerization-based movement |
| Downstream (effector) | VE-cadherin phosphorylation, NO/ROS, permeability | In vitro human ECs (PMID: 22720111, PMID: 16481520) | GO:0005923 tight junction; GO:0034220 ion transmembrane transport |
| Terminal (clinical) | Vasculitis, edema, DIC, multi-organ failure | Patient cohorts (PMID: 18582199, PMID: 34286684) | HP:0002624 vasculitis; HP:0001928 coagulopathy |
| Feature | Malish (R. conorii subsp. conorii) | ISF (R. conorii subsp. israelensis) |
|---|---|---|
| MLST genotype | Malish type | ISFR type (PMID: 15766388) |
| Eschar (tache noire) | ~49% (Portugal) | ~39% (Portugal); ~5–12% (Israel) (PMID: 16481514, PMID: 34286684) |
| Virulence / fatality | Lower | Higher; fatal outcome significantly more likely (PMID: 18582199) |
| Tick infection prevalence | <5% | 35–66%; better tolerated by tick (PMID: 19421877) |
| PMID | Title (abbrev.) | Contribution |
|---|---|---|
| 15766388 | MLST subspecies of R. conorii | Defines ISF as subsp. israelensis; taxonomy backbone |
| 18582199 | Fatal R. conorii risk factors (Portugal) | Core evidence: ISF strain virulence, 21% fatality, alcoholism |
| 34286684 | SFG rickettsioses in Israel 2010–2019 | National epidemiology; 79% ISF, 30% fatality, coastal clustering |
| 12860594 | Pathogenic mechanisms of Rickettsia | Full pathogenetic causal chain and immune mediators |
| 22720111 | Rickettsiae + VE-cadherin (AFM) | Molecular basis of endothelial hyperpermeability |
| 22612237 | Sca2 domains | Sca2 adhesion/invasion/motility |
| 37028467 | Cryo-EM of Sca2 | Formin-like core structure |
| 8584998 | Coagulation/platelet activation in MSF | In vivo procoagulant state, endothelial dysfunction |
| 2710586 | Spotted fever in Israeli children | Symptom/lab frequencies |
| 8286624 | Fatal ISF in children | Absence of eschar/tick history; rapidly fatal course |
| 41795239 | Palestinian pediatric cohort | Modern pediatric phenotype; benign with early Rx |
| 23168048 | MSF in Turkey | Diagnostic yield of IFA + biopsy PCR |
| 40608626 | Rickettsiosis case series | gltA/ompA sequencing for species ID |
| 2193627 | RCT doxycycline vs josamycin | First-line therapy evidence |
| 26711765 | RCT clarithromycin | Macrolide alternative for children |
| 21771547 | R. conorii in Portuguese dogs | Reservoir/sentinel role of dogs |
| 17620644 | Seroepidemiology, Israeli villages | Dogs 81% vs humans 10% seropositive |
| 19421877 | ISTT vs Malish in ticks | Strain difference in vector biology |
| 17403875 | Dendritic cells & susceptibility | C3H susceptible vs C57BL/6 resistant model |
| 11504408 | NK/IFN-γ early immunity | Protective immune mechanism |
| 28408252 | ISF in Sicily | Geographic distribution; disease identity |
| 16481514 | Eschar in ISF patients | Nuance: no statistical eschar/severity difference in one cohort |
| 41146265 | Integrated vector control (California) | Prevention via Rh. sanguineus control |
| 41958159 | ISF agent in Ghana ticks | Expanding geographic range; zoonotic cycle |
Challenging / nuancing evidence: PMID: 16481514 found no statistically significant difference in eschar frequency or fatality between Malish and ISF in a 94-patient Portuguese cohort, tempering the "greater severity" narrative that is otherwise strongly supported by the larger prospective cohort (PMID: 18582199) and Israeli national data (PMID: 34286684). The most likely reconciliation is that strain virulence interacts with host factors (age, alcoholism, G6PD status) and treatment timing, so cohort composition strongly influences the observed effect size.
Israeli Tick Typhus (Israeli spotted fever; MONDO:0000230) is a tick-borne spotted-fever-group rickettsiosis caused by the obligate intracellular bacterium Rickettsia conorii subsp. israelensis, transmitted by the brown dog tick Rhipicephalus sanguineus with dogs as the amplifying reservoir. It infects vascular endothelial cells to produce a disseminated small-vessel vasculitis presenting as fever and maculopapular rash (with the tache noire/eschar frequently absent), and the more virulent ISF strain can progress to severe multi-organ disease with case-fatality reaching ~20–30% in hospitalized/severe cases. Prompt empiric doxycycline is the first-line treatment and is highly effective when started early.
Checked with linkml-reference-validator 0.3.0rc3.
| Outcome | Count |
|---|---|
| References checked | 45 |
| Resolved | 45 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| References weighed for topical relevance | 45 |
| On topic | 24 |
| Off topic | 0 |
All extracted references resolved successfully.
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 | 31 |
| Terms named correctly | 25 |
| Terms named as a different term | 4 |
| Terms whose name is worth a second look | 2 |
These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:
HP:0031137 (1 mention) - the report calls it "Abnormal circulating coagulation protein concentration"; HP calls it Storage in hepatocytesHP:0002624 (2 mentions) - the report calls it "vasculitis-related manifestations"; HP calls it Abnormal venous morphologyNCIT:C692 (1 mention) - the report calls it "Doxycycline"; NCIT calls it NimodipineNCIT:C376 (1 mention) - the report calls it "Chloramphenicol"; NCIT calls it CisplatinThe 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:
UBERON:0002097 (1 mention) - the report calls it "skin"; UBERON calls it skin of body, and lists "skin" among its other namesNCIT:C1032 (1 mention) - the report calls it "Clarithromycin"; NCIT calls it Cactinomycin