🏷

Classifications

Harrison's Part

⚙

Pathophysiology

7

Reptile Tick-Borne Rickettsia honei Inoculation

Feeding reptile-associated ticks carrying R. honei inoculate spotted-fever group rickettsiae into the human dermis and initiate local infection at the arthropod attachment site.

symbiont entry into host GO:0044409

Downstream

Dermal Mononuclear Phagocyte Rickettsia honei Infection Tick inoculation deposits R. honei in skin, where early vector-borne rickettsial infection begins in dermal phagocytes.

Show evidence (1 reference)

PMID:14628950 SUPPORT Other

"Rickettsia honei is the etiologic agent of Flinders Island (Australia) spotted fever."

The tick ecology study links the Flinders Island reptile tick reservoir to the etiologic agent of human FISF.

Dermal Mononuclear Phagocyte Rickettsia honei Infection

After tick inoculation, pathogenic rickettsiae enter macrophages or dendritic cells in the dermis before spreading through lymphatics toward systemic endothelial sites.

macrophage CL:0000235 dendritic cell CL:0000451

symbiont entry into host cell GO:0046718

Downstream

Rickettsial Lymphatic Dissemination Rickettsiae disseminate from the skin inoculation site through lymphatics.

Eschar Local inoculation-site infection can necrose into an eschar.

Show evidence (1 reference)

PMID:30148688 SUPPORT REVIEW SYNTHESIS Other

"The pathogenic sequence of events that occur in rickettsial infection begins with the entry of organisms inoculated by the feeding tick or mite or scratched into the skin from infected louse or flea feces deposited on the skin. The initial target cells of infection are CD68+ cells (macrophages..."

The rickettsial pathogenesis review places macrophages or dendritic cells at the start of vector-inoculated spotted-fever infection.

Rickettsial Lymphatic Dissemination

Rickettsiae spread from the skin inoculation site through lymphatic vessels to draining lymph nodes before hematogenous seeding of the vascular endothelium.

biological process involved in interaction with host GO:0051701

Downstream

Endothelial Cell Rickettsia honei Infection Lymphatic spread precedes systemic endothelial seeding.

Regional Lymphadenopathy Drainage from the infected inoculation site enlarges regional lymph nodes.

Show evidence (1 reference)

PMID:30148688 SUPPORT REVIEW SYNTHESIS Other

"The rickettsiae then spread via lymphatic vessels to the regional lymph nodes as has been observed vividly in the lymphangitis associated with R. sibirica mongolitimoniae infection"

The review uses another SFG rickettsiosis to support lymphatic spread between the inoculation eschar and hematogenous endothelial infection.

Endothelial Cell Rickettsia honei Infection

Hematogenously disseminated pathogenic Rickettsia species mainly infect endothelial cells lining the small and medium blood vessels.

endothelial cell of vascular tree CL:0002139

biological process involved in interaction with host GO:0051701

Downstream

Rickettsial Vasculitis Endothelial rickettsial infection drives vascular inflammation.

Show evidence (2 references)

PMID:19327117 SUPPORT REVIEW SYNTHESIS Other

"Some of the most common phenotypic characteristics of Rickettsia include their strict intracellular location and lifecycle association with arthropods."

The review establishes the obligate intracellular lifestyle shared by pathogenic Rickettsia species.

PMID:19327117 SUPPORT REVIEW SYNTHESIS Other

"Although pathogenic Rickettsiae are able to infect and replicate in a number of different cell types in vitro, a unique property during in vivo infection is their affinity for vascular endothelial cells (ECs) lining small and medium-sized blood vessels in humans and in established animal models..."

The review identifies vascular endothelial cells as the main in-vivo target for pathogenic rickettsial infection.

Rickettsial Vasculitis

Rickettsial endothelial infection and activation inflame small vessels and increase vascular permeability, producing the systemic fever and cutaneous rash of Flinders Island spotted fever.

endothelial cell of vascular tree CL:0002139

inflammatory response GO:0006954 ↑ INCREASED positive regulation of vascular permeability GO:0043117 ↑ INCREASED

Downstream

Fever Systemic rickettsial inflammation produces fever.

Maculopapular Rash Cutaneous rickettsial vasculitis produces the exanthem.

Headache Systemic rickettsial inflammation contributes to headache.

Arthralgia The acute inflammatory syndrome produces joint pain.

Myalgia The acute inflammatory syndrome produces muscle pain.

Cough Rickettsial systemic illness can include respiratory symptoms.

Nausea The acute inflammatory syndrome can include nausea.

Pharyngitis The acute inflammatory syndrome can include pharyngitis.

Show evidence (1 reference)

PMID:19327117 SUPPORT REVIEW SYNTHESIS Other

"As the major target of pathogenic Rickettsiae is the endothelium lining of vital organs in humans, a majority of sequelae reflect infection-induced damage to the vascular system."

The pathogenesis review connects endothelial infection with rickettsial vascular injury.

Rickettsial Ribosomal Translation

R. honei, like other bacteria, depends on ribosomal translation of its mRNA, making the bacterial ribosome the conserved antibiotic target for doxycycline therapy.

Translation GO:0006412

Show evidence (1 reference)

PMID:24336183 SUPPORT REVIEW SYNTHESIS Other

"The ribosome is one of the main antibiotic targets in the bacterial cell."

Review evidence establishes the bacterial ribosome as the conserved target class for tetracyclines such as doxycycline.

Intracytosolic Rickettsia honei Niche

Rickettsia species reside free in the host-cell cytosol and exploit host metabolites, so effective FISF therapy must reach the intracellular bacterial compartment.

biological process involved in interaction with host GO:0051701

Downstream

Rickettsial Ribosomal Translation Intracytosolic R. honei remains dependent on bacterial protein synthesis.

Show evidence (1 reference)

PMID:30148688 SUPPORT REVIEW SYNTHESIS Other

"Residing free in the cytosol of the host cell, they acquire many necessary components via transport mechanisms instead of maintaining genes for synthesizing sugars, lipids, nucleotides, and amino acids."

The review supports the free cytosolic niche for pathogenic Rickettsia species, including R. honei.

⬡

Pathograph

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

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Phenotypes

10

Cardiovascular 1

Regional Lymphadenopathy OCCASIONAL HP:0002716

Show evidence (1 reference)

PMID:17553271 SUPPORT Human Clinical

"We describe 7 cases of a rickettsiosis with an acute onset and symptoms of fever (100%), headache (71%), arthralgia (43%), myalgia (43%), cough (43%), maculopapular/petechial rash (43%), nausea (29%), pharyngitis (29%), lymphadenopathy (29%), and eschar (29%)."

Lymphadenopathy occurred in two of seven eastern Australian R. honei marmionii cases.

Digestive 1

Nausea OCCASIONAL HP:0002018

Show evidence (1 reference)

PMID:17553271 SUPPORT Human Clinical

"We describe 7 cases of a rickettsiosis with an acute onset and symptoms of fever (100%), headache (71%), arthralgia (43%), myalgia (43%), cough (43%), maculopapular/petechial rash (43%), nausea (29%), pharyngitis (29%), lymphadenopathy (29%), and eschar (29%)."

Nausea occurred in two of seven eastern Australian R. honei marmionii cases.

Immune 1

Maculopapular Rash FREQUENT Maculopapular exanthema HP:0040186

Show evidence (2 references)

PMID:17553271 SUPPORT Human Clinical

"We describe 7 cases of a rickettsiosis with an acute onset and symptoms of fever (100%), headache (71%), arthralgia (43%), myalgia (43%), cough (43%), maculopapular/petechial rash (43%), nausea (29%), pharyngitis (29%), lymphadenopathy (29%), and eschar (29%)."

Maculopapular or petechial rash occurred in three of seven eastern Australian R. honei marmionii cases.

PMID:1986207 SUPPORT Human Clinical

"The usual features were high fever, headache, myalgia, slight cough, arthralgia without joint swelling and a maculopapular rash which did not resemble the common exanthems."

The founding 26-case Flinders Island series included maculopapular rash among the usual clinical features.

Integument 1

Eschar FREQUENT HP:6000793

Show evidence (2 references)

PMID:17553271 SUPPORT Human Clinical

"We describe 7 cases of a rickettsiosis with an acute onset and symptoms of fever (100%), headache (71%), arthralgia (43%), myalgia (43%), cough (43%), maculopapular/petechial rash (43%), nausea (29%), pharyngitis (29%), lymphadenopathy (29%), and eschar (29%)."

Eschar occurred in two of seven eastern Australian R. honei cases.

PMID:1986207 SUPPORT Human Clinical

"Twelve cases had a focal skin lesions. Available evidence implicates ticks as the vector."

The founding Flinders Island case series reported focal skin lesions in nearly half of cases.

Metabolism 1

Fever VERY_FREQUENT HP:0001945

Show evidence (2 references)

PMID:17553271 SUPPORT Human Clinical

"We describe 7 cases of a rickettsiosis with an acute onset and symptoms of fever (100%), headache (71%), arthralgia (43%), myalgia (43%), cough (43%), maculopapular/petechial rash (43%), nausea (29%), pharyngitis (29%), lymphadenopathy (29%), and eschar (29%)."

Fever occurred in all seven eastern Australian R. honei marmionii cases.

PMID:1986207 SUPPORT Human Clinical

"The usual features were high fever, headache, myalgia, slight cough, arthralgia without joint swelling and a maculopapular rash which did not resemble the common exanthems."

The founding 26-case Flinders Island series included high fever among the usual clinical features.

Nervous System 1

Headache FREQUENT HP:0002315

Show evidence (2 references)

PMID:17553271 SUPPORT Human Clinical

"We describe 7 cases of a rickettsiosis with an acute onset and symptoms of fever (100%), headache (71%), arthralgia (43%), myalgia (43%), cough (43%), maculopapular/petechial rash (43%), nausea (29%), pharyngitis (29%), lymphadenopathy (29%), and eschar (29%)."

Headache occurred in five of seven eastern Australian R. honei marmionii cases.

PMID:1986207 SUPPORT Human Clinical

"The usual features were high fever, headache, myalgia, slight cough, arthralgia without joint swelling and a maculopapular rash which did not resemble the common exanthems."

The founding 26-case Flinders Island series included headache among the usual clinical features.

Respiratory 2

Cough FREQUENT HP:0012735

Show evidence (2 references)

PMID:17553271 SUPPORT Human Clinical

"We describe 7 cases of a rickettsiosis with an acute onset and symptoms of fever (100%), headache (71%), arthralgia (43%), myalgia (43%), cough (43%), maculopapular/petechial rash (43%), nausea (29%), pharyngitis (29%), lymphadenopathy (29%), and eschar (29%)."

Cough occurred in three of seven eastern Australian R. honei marmionii cases.

PMID:1986207 SUPPORT Human Clinical

"The usual features were high fever, headache, myalgia, slight cough, arthralgia without joint swelling and a maculopapular rash which did not resemble the common exanthems."

The founding 26-case Flinders Island series included slight cough among the usual clinical features.

Pharyngitis OCCASIONAL HP:0025439

Show evidence (1 reference)

PMID:17553271 SUPPORT Human Clinical

"We describe 7 cases of a rickettsiosis with an acute onset and symptoms of fever (100%), headache (71%), arthralgia (43%), myalgia (43%), cough (43%), maculopapular/petechial rash (43%), nausea (29%), pharyngitis (29%), lymphadenopathy (29%), and eschar (29%)."

Pharyngitis occurred in two of seven eastern Australian R. honei marmionii cases.

Constitutional 2

Arthralgia FREQUENT HP:0002829

Show evidence (2 references)

PMID:17553271 SUPPORT Human Clinical

"We describe 7 cases of a rickettsiosis with an acute onset and symptoms of fever (100%), headache (71%), arthralgia (43%), myalgia (43%), cough (43%), maculopapular/petechial rash (43%), nausea (29%), pharyngitis (29%), lymphadenopathy (29%), and eschar (29%)."

Arthralgia occurred in three of seven eastern Australian R. honei marmionii cases.

PMID:1986207 SUPPORT Human Clinical

"The usual features were high fever, headache, myalgia, slight cough, arthralgia without joint swelling and a maculopapular rash which did not resemble the common exanthems."

The founding 26-case Flinders Island series included arthralgia without joint swelling among the usual clinical features.

Myalgia FREQUENT HP:0003326

Show evidence (2 references)

PMID:17553271 SUPPORT Human Clinical

"We describe 7 cases of a rickettsiosis with an acute onset and symptoms of fever (100%), headache (71%), arthralgia (43%), myalgia (43%), cough (43%), maculopapular/petechial rash (43%), nausea (29%), pharyngitis (29%), lymphadenopathy (29%), and eschar (29%)."

Myalgia occurred in three of seven eastern Australian R. honei marmionii cases.

PMID:1986207 SUPPORT Human Clinical

"The usual features were high fever, headache, myalgia, slight cough, arthralgia without joint swelling and a maculopapular rash which did not resemble the common exanthems."

The founding 26-case Flinders Island series included myalgia among the usual clinical features.

💊

Medical Actions

1

Empiric doxycycline

Action: Pharmacotherapy NCIT:C15986

Agent: doxycycline CHEBI:50845

Platform: Small molecule

Doxycycline is first-line empiric therapy for suspected tick-borne rickettsial disease, including FISF, because it inhibits rickettsial ribosomal translation and reaches the host-cell cytosol where R. honei resides.

Mechanism Target:

INHIBITS Rickettsial Ribosomal Translation — Doxycycline blocks rickettsial protein synthesis at the ribosome.

BYPASSES Intracytosolic Rickettsia honei Niche — Doxycycline can reach the cytosolic rickettsial compartment.

Show evidence (1 reference)

PMID:27172113 SUPPORT REVIEW SYNTHESIS Human Clinical

"Doxycycline is the drug of choice for treatment of all tickborne rickettsial diseases in patients of all ages, including children aged <8 years, and should be initiated immediately in persons with signs and symptoms suggestive of rickettsial disease"

Flinders Island spotted fever is a tick-borne rickettsial disease, so this CDC first-line treatment recommendation covers empiric therapy for suspected FISF.

🔬

Diagnosis

2

Rickettsial PCR on eschar specimens

PCR of an unroofed eschar swab or an eschar biopsy can detect spotted-fever-group rickettsial DNA during early eschar-associated illness and can be followed by sequencing for species-level confirmation.

polymerase chain reaction NCIT:C17003

Results: A positive PCR from an eschar swab or biopsy supports early molecular confirmation.

Show evidence (1 reference)

PMID:27172113 SUPPORT REVIEW SYNTHESIS Human Clinical

"Eschar Swab of unroofed eschar SFG rickettsiae PCR"

The CDC diagnostic table lists PCR from an unroofed eschar swab as a spotted-fever-group rickettsiosis molecular test.

Indirect immunofluorescence assay serology

Indirect immunofluorescence using a spotted-fever-group panel can support recent R. honei infection by seroconversion or a rising titer, but cross-reaction across SFG Rickettsia antigens limits species assignment.

Results: Seroconversion or a fourfold rise supports recent spotted-fever-group rickettsial infection; PCR or sequencing is needed for species-level confirmation.

Show evidence (2 references)

PMID:1898756 SUPPORT Human Clinical

"These patients and 335 healthy persons from the island were investigated serologically using the Weil-Felix agglutination test (Proteus sp. antigens OX2, OX19, OXK) and rickettsia-specific microimmunofluorescence."

The founding serologic investigation used rickettsia-specific microimmunofluorescence to assay Flinders Island patient sera.

PMID:1898756 SUPPORT Human Clinical

"In six of these patients seroconversion was also demonstrated in rickettsia-specific tests."

The founding serologic investigation documented seroconversion in rickettsia-specific testing for a subset of acute Flinders Island patients.

📈

Progression

1

Acute spotted-fever illness

The original Flinders Island syndrome was an acute spotted-fever-like illness with fever, headache, myalgia, arthralgia, cough, rash, and focal skin lesions over a 17-year island series; later eastern Australian R. honei marmionii cases had similar acute fever-rash illness and were most common in autumn.

Show evidence (1 reference)

PMID:1986207 SUPPORT Human Clinical

"Twenty six cases of a spotted-fever-like illness have been identified over a 17 year period in the population of about 1000 of Flinders Island, Tasmania."

The founding clinical series describes repeated acute spotted-fever-like illness in the Flinders Island population.

🌍

Epidemiology

1

Southeastern Australian reptile-tick exposure

FISF risk follows exposure to reptile-associated tick habitats in Flinders Island and southeastern Australia, including documented cases outside Flinders Island on Schouten Island and in southeastern South Australia.

southeastern Australia tick exposure reptile tick exposure

Show evidence (2 references)

PMID:16175900 SUPPORT Human Clinical

"These cases show that FISF extends beyond Flinders Island and most likely has the same distribution across south-east Australia as its vector, the reptile tick Aponomma hydrosauri."

The southeastern Australian case report series extends FISF geography beyond Flinders Island and ties risk to the reptile-tick vector range.

PMID:17553271 SUPPORT Human Clinical

"Cases were most prevalent in autumn and from eastern Australia, including Queensland, Tasmania, and South Australia."

The R. honei marmionii series documents seasonal eastern-Australian occurrence.

🦠

Infectious Agent

1

Rickettsia honei

Obligate intracellular spotted-fever-group rickettsial species that causes Flinders Island spotted fever.

Rickettsia honei NCBITaxon:37816

Show evidence (1 reference)

PMID:22815457 SUPPORT Other

"Rickettsia honei strain RB(T) was isolated from a febrile patient on Flinders Island, Australia, in 1991 and has been demonstrated to be the agent of Flinders Island spotted fever, a disease transmitted to humans by ticks."

The genome report names R. honei strain RB(T) as the etiologic agent of Flinders Island spotted fever.

↔️

Transmission

1

Reptile tick bite inoculation

Humans acquire Flinders Island spotted fever when reptile-associated hard ticks bite and inoculate R. honei into skin.

Show evidence (1 reference)

PMID:14628950 SUPPORT Other

"The tick Aponomma hydrosauri is associated with reptiles and is the arthropod reservoir for this rickettsia on Flinders Island."

The tick survey identifies the reptile-associated Flinders Island vector and reservoir that seeds human tick exposure.

{ }

Source YAML

click to show

name: Flinders Island Spotted Fever
creation_date: "2026-09-28T05:11:14Z"
category: Infectious Disease
description: >-
Flinders Island spotted fever is an acute tick-borne spotted-fever-group
rickettsiosis caused by the obligately intracellular bacterium Rickettsia
honei in southern and eastern Australia. Reptile-associated Bothriocroton,
formerly Aponomma, ticks maintain R. honei transovarially and inoculate the
organism into human skin, where local infection can create an eschar before
dissemination reaches vascular endothelium. The resulting rickettsial
vasculitis accounts for the characteristic fever, headache,
maculopapular-to-petechial rash, myalgia, arthralgia, and occasional
lymphadenopathy.
disease_term:
preferred_term: Flinders Island spotted fever
term:
id: MONDO:0000232
label: Flinders island spotted fever
parents:
- Spotted fever rickettsiosis
synonyms:
- Rickettsia honei infection
- Flinders Island spotted fever rickettsiosis

references:
- reference: PMID:22815457
title: Genomic comparison of Rickettsia honei strain RBT and other Rickettsia Species.
found_in:
- Flinders_Island_Spotted_Fever-deep-research-openscientist.md
findings:
- statement: >-
Rickettsia honei strain RB(T), the agent of Flinders Island spotted
fever, was isolated from a febrile human patient on Flinders Island.
supporting_text: >-
Rickettsia honei strain RB(T) was isolated from a febrile patient on
Flinders Island, Australia, in 1991 and has been demonstrated to be the
agent of Flinders Island spotted fever, a disease transmitted to humans by
ticks.
- reference: PMID:14628950
title: >-
Aponomma hydrosauri, the reptile-associated tick reservoir of Rickettsia
honei on Flinders Island, Australia.
found_in:
- Flinders_Island_Spotted_Fever-deep-research-openscientist.md
findings:
- statement: >-
Aponomma hydrosauri ticks act as the Flinders Island arthropod reservoir
for R. honei and maintain the rickettsia by vertical transmission.
supporting_text: >-
The tick Aponomma hydrosauri is associated with reptiles and is the
arthropod reservoir for this rickettsia on Flinders Island.
- reference: PMID:17553271
title: >-
Flinders Island spotted fever rickettsioses caused by "marmionii" strain of
Rickettsia honei, Eastern Australia.
found_in:
- Flinders_Island_Spotted_Fever-deep-research-openscientist.md
findings:
- statement: >-
Eastern Australian FISF-like R. honei marmionii infections cause acute
fever, headache, arthralgia, myalgia, cough, maculopapular or petechial
rash, nausea, pharyngitis, lymphadenopathy, and eschar.
supporting_text: >-
We describe 7 cases of a rickettsiosis with an acute onset and symptoms
of fever (100%), headache (71%), arthralgia (43%), myalgia (43%), cough
(43%), maculopapular/petechial rash (43%), nausea (29%), pharyngitis
(29%), lymphadenopathy (29%), and eschar (29%).

classifications:
harrisons_chapter:
- classification_value: INFECTIOUS_DISEASES
evidence:
- reference: PMID:22815457
reference_title: Genomic comparison of Rickettsia honei strain RBT and other Rickettsia Species.
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Rickettsia honei strain RB(T) was isolated from a febrile patient on
Flinders Island, Australia, in 1991 and has been demonstrated to be the
agent of Flinders Island spotted fever, a disease transmitted to humans
by ticks.
explanation: >-
The genome report identifies Flinders Island spotted fever as a
bacterial tick-borne R. honei infection, placing it in Harrison's
Infectious Diseases Part.

infectious_agent:
- name: Rickettsia honei
infectious_agent_term:
preferred_term: Rickettsia honei
term:
id: NCBITaxon:37816
label: Rickettsia honei
description: >-
Obligate intracellular spotted-fever-group rickettsial species that causes
Flinders Island spotted fever.
evidence:
- reference: PMID:22815457
reference_title: Genomic comparison of Rickettsia honei strain RBT and other Rickettsia Species.
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Rickettsia honei strain RB(T) was isolated from a febrile patient on
Flinders Island, Australia, in 1991 and has been demonstrated to be the
agent of Flinders Island spotted fever, a disease transmitted to humans by
ticks.
explanation: >-
The genome report names R. honei strain RB(T) as the etiologic agent of
Flinders Island spotted fever.

transmission:
- name: Reptile tick bite inoculation
description: >-
Humans acquire Flinders Island spotted fever when reptile-associated hard
ticks bite and inoculate R. honei into skin.
evidence:
- reference: PMID:14628950
reference_title: >-
Aponomma hydrosauri, the reptile-associated tick reservoir of Rickettsia
honei on Flinders Island, Australia.
supports: SUPPORT
evidence_source: OTHER
snippet: >-
The tick Aponomma hydrosauri is associated with reptiles and is the
arthropod reservoir for this rickettsia on Flinders Island.
explanation: >-
The tick survey identifies the reptile-associated Flinders Island vector
and reservoir that seeds human tick exposure.

epidemiology:
- name: Southeastern Australian reptile-tick exposure
description: >-
FISF risk follows exposure to reptile-associated tick habitats in Flinders
Island and southeastern Australia, including documented cases outside
Flinders Island on Schouten Island and in southeastern South Australia.
factors:
- southeastern Australia tick exposure
- reptile tick exposure
evidence:
- reference: PMID:16175900
reference_title: "Not only 'Flinders Island' spotted fever."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
These cases show that FISF extends beyond Flinders Island and most likely
has the same distribution across south-east Australia as its vector, the
reptile tick Aponomma hydrosauri.
explanation: >-
The southeastern Australian case report series extends FISF geography
beyond Flinders Island and ties risk to the reptile-tick vector range.
- reference: PMID:17553271
reference_title: >-
Flinders Island spotted fever rickettsioses caused by "marmionii" strain
of Rickettsia honei, Eastern Australia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Cases were most prevalent in autumn and from eastern Australia, including
Queensland, Tasmania, and South Australia.
explanation: >-
The R. honei marmionii series documents seasonal eastern-Australian
occurrence.

progression:
- phase: Acute spotted-fever illness
notes: >-
The original Flinders Island syndrome was an acute spotted-fever-like
illness with fever, headache, myalgia, arthralgia, cough, rash, and focal
skin lesions over a 17-year island series; later eastern Australian R. honei
marmionii cases had similar acute fever-rash illness and were most common
in autumn.
evidence:
- reference: PMID:1986207
reference_title: >-
Flinders Island spotted fever: a newly recognised endemic focus of tick
typhus in Bass Strait. Part 1. Clinical and epidemiological features.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Twenty six cases of a spotted-fever-like illness have been identified
over a 17 year period in the population of about 1000 of Flinders Island,
Tasmania.
explanation: >-
The founding clinical series describes repeated acute spotted-fever-like
illness in the Flinders Island population.

pathophysiology:
- name: Reptile Tick-Borne Rickettsia honei Inoculation
role: trigger
description: >-
Feeding reptile-associated ticks carrying R. honei inoculate spotted-fever
group rickettsiae into the human dermis and initiate local infection at the
arthropod attachment site.
biological_processes:
- preferred_term: symbiont entry into host
term:
id: GO:0044409
label: symbiont entry into host
evidence:
- reference: PMID:14628950
reference_title: >-
Aponomma hydrosauri, the reptile-associated tick reservoir of Rickettsia
honei on Flinders Island, Australia.
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Rickettsia honei is the etiologic agent of Flinders Island (Australia)
spotted fever.
explanation: >-
The tick ecology study links the Flinders Island reptile tick reservoir
to the etiologic agent of human FISF.
downstream:
- target: Dermal Mononuclear Phagocyte Rickettsia honei Infection
causal_link_type: DIRECT
description: >-
Tick inoculation deposits R. honei in skin, where early vector-borne
rickettsial infection begins in dermal phagocytes.

- name: Dermal Mononuclear Phagocyte Rickettsia honei Infection
role: primary_infection
description: >-
After tick inoculation, pathogenic rickettsiae enter macrophages or
dendritic cells in the dermis before spreading through lymphatics toward
systemic endothelial sites.
cell_types:
- preferred_term: macrophage
term:
id: CL:0000235
label: macrophage
- preferred_term: dendritic cell
term:
id: CL:0000451
label: dendritic cell
biological_processes:
- preferred_term: symbiont entry into host cell
term:
id: GO:0046718
label: symbiont entry into host cell
evidence:
- reference: PMID:30148688
reference_title: "Pathogenesis of Rickettsial Diseases: Pathogenic and Immune Mechanisms of an Endotheliotropic Infection."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: >-
The pathogenic sequence of events that occur in rickettsial infection
begins with the entry of organisms inoculated by the feeding tick or mite
or scratched into the skin from infected louse or flea feces deposited on
the skin. The initial target cells of infection are CD68+ cells
(macrophages and/or dendritic cells)
explanation: >-
The rickettsial pathogenesis review places macrophages or dendritic cells
at the start of vector-inoculated spotted-fever infection.
downstream:
- target: Rickettsial Lymphatic Dissemination
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: Rickettsiae disseminate from the skin inoculation site through lymphatics.
- target: Eschar
causal_link_type: DIRECT
description: Local inoculation-site infection can necrose into an eschar.

- name: Rickettsial Lymphatic Dissemination
role: effector
description: >-
Rickettsiae spread from the skin inoculation site through lymphatic vessels
to draining lymph nodes before hematogenous seeding of the vascular
endothelium.
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:30148688
reference_title: "Pathogenesis of Rickettsial Diseases: Pathogenic and Immune Mechanisms of an Endotheliotropic Infection."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: >-
The rickettsiae then spread via lymphatic vessels to the regional lymph
nodes as has been observed vividly in the lymphangitis associated with R.
sibirica mongolitimoniae infection
explanation: >-
The review uses another SFG rickettsiosis to support lymphatic spread
between the inoculation eschar and hematogenous endothelial infection.
downstream:
- target: Endothelial Cell Rickettsia honei Infection
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: Lymphatic spread precedes systemic endothelial seeding.
- target: Regional Lymphadenopathy
causal_link_type: DIRECT
description: Drainage from the infected inoculation site enlarges regional lymph nodes.

- name: Endothelial Cell Rickettsia honei Infection
role: effector
description: >-
Hematogenously disseminated pathogenic Rickettsia species mainly infect
endothelial cells lining the small and medium blood vessels.
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:19327117
reference_title: Host-cell interactions with pathogenic Rickettsia species.
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: >-
Some of the most common phenotypic characteristics of Rickettsia include
their strict intracellular location and lifecycle association with
arthropods.
explanation: >-
The review establishes the obligate intracellular lifestyle shared by
pathogenic Rickettsia species.
- reference: PMID:19327117
reference_title: Host-cell interactions with pathogenic Rickettsia species.
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: >-
Although pathogenic Rickettsiae are able to infect and replicate in a
number of different cell types in vitro, a unique property during in vivo
infection is their affinity for vascular endothelial cells (ECs) lining
small and medium-sized blood vessels in humans and in established animal
models of infection
explanation: >-
The review identifies vascular endothelial cells as the main in-vivo
target for pathogenic rickettsial infection.
downstream:
- target: Rickettsial Vasculitis
causal_link_type: DIRECT
description: Endothelial rickettsial infection drives vascular inflammation.

- name: Rickettsial Vasculitis
role: vascular_response
description: >-
Rickettsial endothelial infection and activation inflame small vessels and
increase vascular permeability, producing the systemic fever and cutaneous
rash of Flinders Island spotted fever.
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:19327117
reference_title: Host-cell interactions with pathogenic Rickettsia species.
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: >-
As the major target of pathogenic Rickettsiae is the endothelium lining of
vital organs in humans, a majority of sequelae reflect infection-induced
damage to the vascular system.
explanation: >-
The pathogenesis review connects endothelial infection with rickettsial
vascular injury.
downstream:
- target: Fever
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: Systemic rickettsial inflammation produces fever.
- target: Maculopapular Rash
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: Cutaneous rickettsial vasculitis produces the exanthem.
- target: Headache
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: Systemic rickettsial inflammation contributes to headache.
- target: Arthralgia
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: The acute inflammatory syndrome produces joint pain.
- target: Myalgia
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: The acute inflammatory syndrome produces muscle pain.
- target: Cough
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: Rickettsial systemic illness can include respiratory symptoms.
- target: Nausea
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: The acute inflammatory syndrome can include nausea.
- target: Pharyngitis
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: The acute inflammatory syndrome can include pharyngitis.

- name: Rickettsial Ribosomal Translation
role: therapeutic_vulnerability
conforms_to: "bacterial_protein_synthesis_inhibition#Bacterial mRNA Translation by the Ribosome"
description: >-
R. honei, like other bacteria, depends on ribosomal translation of its mRNA,
making the bacterial ribosome the conserved antibiotic target for
doxycycline 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 such as doxycycline.

- name: Intracytosolic Rickettsia honei Niche
role: intrinsic_resistance
conforms_to: "intracellular_pathogen_persistence#Intracellular Niche and Beta-Lactam Exclusion"
description: >-
Rickettsia species reside free in the host-cell cytosol and exploit host
metabolites, so effective FISF therapy must reach the intracellular
bacterial compartment.
biological_processes:
- preferred_term: biological process involved in interaction with host
term:
id: GO:0051701
label: biological process involved in interaction with host
downstream:
- target: Rickettsial Ribosomal Translation
causal_link_type: DIRECT
description: Intracytosolic R. honei remains dependent on bacterial protein synthesis.
evidence:
- reference: PMID:30148688
reference_title: "Pathogenesis of Rickettsial Diseases: Pathogenic and Immune Mechanisms of an Endotheliotropic Infection."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: >-
Residing free in the cytosol of the host cell, they acquire many
necessary components via transport mechanisms instead of maintaining genes
for synthesizing sugars, lipids, nucleotides, and amino acids.
explanation: >-
The review supports the free cytosolic niche for pathogenic Rickettsia
species, including R. honei.

phenotypes:
- name: Fever
category: Constitutional
frequency: VERY_FREQUENT
description: Fever is the cardinal systemic symptom of acute FISF-like R. honei infection.
phenotype_term:
preferred_term: Fever
term:
id: HP:0001945
label: Fever
evidence:
- reference: PMID:17553271
reference_title: >-
Flinders Island spotted fever rickettsioses caused by "marmionii" strain
of Rickettsia honei, Eastern Australia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We describe 7 cases of a rickettsiosis with an acute onset and symptoms of
fever (100%), headache (71%), arthralgia (43%), myalgia (43%), cough
(43%), maculopapular/petechial rash (43%), nausea (29%), pharyngitis
(29%), lymphadenopathy (29%), and eschar (29%).
explanation: >-
Fever occurred in all seven eastern Australian R. honei marmionii cases.
- reference: PMID:1986207
reference_title: >-
Flinders Island spotted fever: a newly recognised endemic focus of tick
typhus in Bass Strait. Part 1. Clinical and epidemiological features.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The usual features were high fever, headache, myalgia, slight cough,
arthralgia without joint swelling and a maculopapular rash which did not
resemble the common exanthems.
explanation: >-
The founding 26-case Flinders Island series included high fever among the
usual clinical features.

- name: Headache
category: Neurologic
frequency: FREQUENT
description: Headache accompanies the acute febrile syndrome in most reported R. honei cases.
phenotype_term:
preferred_term: Headache
term:
id: HP:0002315
label: Headache
evidence:
- reference: PMID:17553271
reference_title: >-
Flinders Island spotted fever rickettsioses caused by "marmionii" strain
of Rickettsia honei, Eastern Australia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We describe 7 cases of a rickettsiosis with an acute onset and symptoms of
fever (100%), headache (71%), arthralgia (43%), myalgia (43%), cough
(43%), maculopapular/petechial rash (43%), nausea (29%), pharyngitis
(29%), lymphadenopathy (29%), and eschar (29%).
explanation: >-
Headache occurred in five of seven eastern Australian R. honei marmionii
cases.
- reference: PMID:1986207
reference_title: >-
Flinders Island spotted fever: a newly recognised endemic focus of tick
typhus in Bass Strait. Part 1. Clinical and epidemiological features.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The usual features were high fever, headache, myalgia, slight cough,
arthralgia without joint swelling and a maculopapular rash which did not
resemble the common exanthems.
explanation: >-
The founding 26-case Flinders Island series included headache among the
usual clinical features.

- name: Maculopapular Rash
category: Dermatologic
frequency: FREQUENT
description: >-
FISF can produce a maculopapular rash as the cutaneous manifestation of
systemic spotted-fever-group vasculitis; an eastern Australian R. honei
marmionii series grouped maculopapular and petechial rashes in its clinical
summary.
phenotype_term:
preferred_term: Maculopapular exanthema
term:
id: HP:0040186
label: Maculopapular exanthema
evidence:
- reference: PMID:17553271
reference_title: >-
Flinders Island spotted fever rickettsioses caused by "marmionii" strain
of Rickettsia honei, Eastern Australia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We describe 7 cases of a rickettsiosis with an acute onset and symptoms of
fever (100%), headache (71%), arthralgia (43%), myalgia (43%), cough
(43%), maculopapular/petechial rash (43%), nausea (29%), pharyngitis
(29%), lymphadenopathy (29%), and eschar (29%).
explanation: >-
Maculopapular or petechial rash occurred in three of seven eastern
Australian R. honei marmionii cases.
- reference: PMID:1986207
reference_title: >-
Flinders Island spotted fever: a newly recognised endemic focus of tick
typhus in Bass Strait. Part 1. Clinical and epidemiological features.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The usual features were high fever, headache, myalgia, slight cough,
arthralgia without joint swelling and a maculopapular rash which did not
resemble the common exanthems.
explanation: >-
The founding 26-case Flinders Island series included maculopapular rash
among the usual clinical features.

- name: Arthralgia
category: Musculoskeletal
frequency: FREQUENT
description: Arthralgia occurs as part of the acute FISF systemic syndrome.
phenotype_term:
preferred_term: Arthralgia
term:
id: HP:0002829
label: Arthralgia
evidence:
- reference: PMID:17553271
reference_title: >-
Flinders Island spotted fever rickettsioses caused by "marmionii" strain
of Rickettsia honei, Eastern Australia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We describe 7 cases of a rickettsiosis with an acute onset and symptoms of
fever (100%), headache (71%), arthralgia (43%), myalgia (43%), cough
(43%), maculopapular/petechial rash (43%), nausea (29%), pharyngitis
(29%), lymphadenopathy (29%), and eschar (29%).
explanation: >-
Arthralgia occurred in three of seven eastern Australian R. honei
marmionii cases.
- reference: PMID:1986207
reference_title: >-
Flinders Island spotted fever: a newly recognised endemic focus of tick
typhus in Bass Strait. Part 1. Clinical and epidemiological features.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The usual features were high fever, headache, myalgia, slight cough,
arthralgia without joint swelling and a maculopapular rash which did not
resemble the common exanthems.
explanation: >-
The founding 26-case Flinders Island series included arthralgia without
joint swelling among the usual clinical features.

- name: Myalgia
category: Musculoskeletal
frequency: FREQUENT
description: Myalgia occurs as part of the acute FISF systemic syndrome.
phenotype_term:
preferred_term: Myalgia
term:
id: HP:0003326
label: Myalgia
evidence:
- reference: PMID:17553271
reference_title: >-
Flinders Island spotted fever rickettsioses caused by "marmionii" strain
of Rickettsia honei, Eastern Australia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We describe 7 cases of a rickettsiosis with an acute onset and symptoms of
fever (100%), headache (71%), arthralgia (43%), myalgia (43%), cough
(43%), maculopapular/petechial rash (43%), nausea (29%), pharyngitis
(29%), lymphadenopathy (29%), and eschar (29%).
explanation: >-
Myalgia occurred in three of seven eastern Australian R. honei marmionii
cases.
- reference: PMID:1986207
reference_title: >-
Flinders Island spotted fever: a newly recognised endemic focus of tick
typhus in Bass Strait. Part 1. Clinical and epidemiological features.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The usual features were high fever, headache, myalgia, slight cough,
arthralgia without joint swelling and a maculopapular rash which did not
resemble the common exanthems.
explanation: >-
The founding 26-case Flinders Island series included myalgia among the
usual clinical features.

- name: Cough
category: Respiratory
frequency: FREQUENT
description: Cough can accompany the acute FISF febrile illness.
phenotype_term:
preferred_term: Cough
term:
id: HP:0012735
label: Cough
evidence:
- reference: PMID:17553271
reference_title: >-
Flinders Island spotted fever rickettsioses caused by "marmionii" strain
of Rickettsia honei, Eastern Australia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We describe 7 cases of a rickettsiosis with an acute onset and symptoms of
fever (100%), headache (71%), arthralgia (43%), myalgia (43%), cough
(43%), maculopapular/petechial rash (43%), nausea (29%), pharyngitis
(29%), lymphadenopathy (29%), and eschar (29%).
explanation: >-
Cough occurred in three of seven eastern Australian R. honei marmionii
cases.
- reference: PMID:1986207
reference_title: >-
Flinders Island spotted fever: a newly recognised endemic focus of tick
typhus in Bass Strait. Part 1. Clinical and epidemiological features.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The usual features were high fever, headache, myalgia, slight cough,
arthralgia without joint swelling and a maculopapular rash which did not
resemble the common exanthems.
explanation: >-
The founding 26-case Flinders Island series included slight cough among
the usual clinical features.

- name: Nausea
category: Digestive System
frequency: OCCASIONAL
description: Nausea was reported in a minority of eastern Australian R. honei cases.
phenotype_term:
preferred_term: Nausea
term:
id: HP:0002018
label: Nausea
evidence:
- reference: PMID:17553271
reference_title: >-
Flinders Island spotted fever rickettsioses caused by "marmionii" strain
of Rickettsia honei, Eastern Australia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We describe 7 cases of a rickettsiosis with an acute onset and symptoms of
fever (100%), headache (71%), arthralgia (43%), myalgia (43%), cough
(43%), maculopapular/petechial rash (43%), nausea (29%), pharyngitis
(29%), lymphadenopathy (29%), and eschar (29%).
explanation: >-
Nausea occurred in two of seven eastern Australian R. honei marmionii
cases.

- name: Pharyngitis
category: Respiratory
frequency: OCCASIONAL
description: Pharyngitis was reported in a minority of eastern Australian R. honei cases.
phenotype_term:
preferred_term: Pharyngitis
term:
id: HP:0025439
label: Pharyngitis
evidence:
- reference: PMID:17553271
reference_title: >-
Flinders Island spotted fever rickettsioses caused by "marmionii" strain
of Rickettsia honei, Eastern Australia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We describe 7 cases of a rickettsiosis with an acute onset and symptoms of
fever (100%), headache (71%), arthralgia (43%), myalgia (43%), cough
(43%), maculopapular/petechial rash (43%), nausea (29%), pharyngitis
(29%), lymphadenopathy (29%), and eschar (29%).
explanation: >-
Pharyngitis occurred in two of seven eastern Australian R. honei
marmionii cases.

- name: Regional Lymphadenopathy
category: Immune
frequency: OCCASIONAL
description: >-
Lymphadenopathy can accompany the local inoculation-site lesion in acute R.
honei infection.
phenotype_term:
preferred_term: Regional lymphadenopathy
term:
id: HP:0002716
label: Lymphadenopathy
evidence:
- reference: PMID:17553271
reference_title: >-
Flinders Island spotted fever rickettsioses caused by "marmionii" strain
of Rickettsia honei, Eastern Australia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We describe 7 cases of a rickettsiosis with an acute onset and symptoms of
fever (100%), headache (71%), arthralgia (43%), myalgia (43%), cough
(43%), maculopapular/petechial rash (43%), nausea (29%), pharyngitis
(29%), lymphadenopathy (29%), and eschar (29%).
explanation: >-
Lymphadenopathy occurred in two of seven eastern Australian R. honei
marmionii cases.

- name: Eschar
category: Dermatologic
frequency: FREQUENT
description: >-
Local necrosis at the infected tick bite can produce a focal eschar or skin
lesion.
phenotype_term:
preferred_term: Eschar
term:
id: HP:6000793
label: Eschar
evidence:
- reference: PMID:17553271
reference_title: >-
Flinders Island spotted fever rickettsioses caused by "marmionii" strain
of Rickettsia honei, Eastern Australia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We describe 7 cases of a rickettsiosis with an acute onset and symptoms of
fever (100%), headache (71%), arthralgia (43%), myalgia (43%), cough
(43%), maculopapular/petechial rash (43%), nausea (29%), pharyngitis
(29%), lymphadenopathy (29%), and eschar (29%).
explanation: Eschar occurred in two of seven eastern Australian R. honei cases.
- reference: PMID:1986207
reference_title: >-
Flinders Island spotted fever: a newly recognised endemic focus of tick
typhus in Bass Strait. Part 1. Clinical and epidemiological features.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Twelve cases had a focal skin lesions. Available evidence implicates
ticks as the vector.
explanation: >-
The founding Flinders Island case series reported focal skin lesions in
nearly half of cases.

diagnosis:
- name: Rickettsial PCR on eschar specimens
description: >-
PCR of an unroofed eschar swab or an eschar biopsy can detect
spotted-fever-group rickettsial DNA during early eschar-associated illness
and can be followed by sequencing for species-level confirmation.
diagnosis_term:
preferred_term: polymerase chain reaction
term:
id: NCIT:C17003
label: Polymerase Chain Reaction
results: A positive PCR from an eschar swab or biopsy supports early molecular confirmation.
evidence:
- reference: PMID:27172113
reference_title: >-
Diagnosis and Management of Tickborne Rickettsial Diseases: Rocky Mountain
Spotted Fever and Other Spotted Fever Group Rickettsioses, Ehrlichioses,
and Anaplasmosis - United States.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Eschar Swab of unroofed eschar SFG rickettsiae PCR"
explanation: >-
The CDC diagnostic table lists PCR from an unroofed eschar swab as a
spotted-fever-group rickettsiosis molecular test.

- name: Indirect immunofluorescence assay serology
description: >-
Indirect immunofluorescence using a spotted-fever-group panel can support
recent R. honei infection by seroconversion or a rising titer, but
cross-reaction across SFG Rickettsia antigens limits species assignment.
results: >-
Seroconversion or a fourfold rise supports recent spotted-fever-group
rickettsial infection; PCR or sequencing is needed for species-level
confirmation.
evidence:
- reference: PMID:1898756
reference_title: >-
Flinders Island spotted fever: a newly recognised endemic focus of tick
typhus in Bass Strait. Part 2. Serological investigations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
These patients and 335 healthy persons from the island were investigated
serologically using the Weil-Felix agglutination test (Proteus sp.
antigens OX2, OX19, OXK) and rickettsia-specific
microimmunofluorescence.
explanation: >-
The founding serologic investigation used rickettsia-specific
microimmunofluorescence to assay Flinders Island patient sera.
- reference: PMID:1898756
reference_title: >-
Flinders Island spotted fever: a newly recognised endemic focus of tick
typhus in Bass Strait. Part 2. Serological investigations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In six of these patients seroconversion was also demonstrated in
rickettsia-specific tests.
explanation: >-
The founding serologic investigation documented seroconversion in
rickettsia-specific testing for a subset of acute Flinders Island
patients.

treatments:
- name: Empiric doxycycline
description: >-
Doxycycline is first-line empiric therapy for suspected tick-borne
rickettsial disease, including FISF, because it inhibits rickettsial
ribosomal translation and reaches the host-cell cytosol where R. honei
resides.
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 blocks rickettsial protein synthesis at the ribosome.
- target: Intracytosolic Rickettsia honei Niche
treatment_effect: BYPASSES
description: Doxycycline can reach the cytosolic rickettsial compartment.
evidence:
- reference: PMID:27172113
reference_title: >-
Diagnosis and Management of Tickborne Rickettsial Diseases: Rocky Mountain
Spotted Fever and Other Spotted Fever Group Rickettsioses, Ehrlichioses,
and Anaplasmosis - United States.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Doxycycline is the drug of choice for treatment of all tickborne
rickettsial diseases in patients of all ages, including children aged <8
years, and should be initiated immediately in persons with signs and
symptoms suggestive of rickettsial disease
explanation: >-
Flinders Island spotted fever is a tick-borne rickettsial disease, so
this CDC first-line treatment recommendation covers empiric therapy for
suspected FISF.

📚

References & Deep Research

References

3

PMID:22815457

Genomic comparison of Rickettsia honei strain RBT and other Rickettsia Species.

1 finding

Rickettsia honei strain RB(T), the agent of Flinders Island spotted fever, was isolated from a febrile human patient on Flinders Island.

"Rickettsia honei strain RB(T) was isolated from a febrile patient on Flinders Island, Australia, in 1991 and has been demonstrated to be the agent of Flinders Island spotted fever, a disease transmitted to humans by ticks."

PMID:14628950

Aponomma hydrosauri, the reptile-associated tick reservoir of Rickettsia honei on Flinders Island, Australia.

1 finding

Aponomma hydrosauri ticks act as the Flinders Island arthropod reservoir for R. honei and maintain the rickettsia by vertical transmission.

"The tick Aponomma hydrosauri is associated with reptiles and is the arthropod reservoir for this rickettsia on Flinders Island."

PMID:17553271

Flinders Island spotted fever rickettsioses caused by "marmionii" strain of Rickettsia honei, Eastern Australia.

1 finding

Eastern Australian FISF-like R. honei marmionii infections cause acute fever, headache, arthralgia, myalgia, cough, maculopapular or petechial rash, nausea, pharyngitis, lymphadenopathy, and eschar.

"We describe 7 cases of a rickettsiosis with an acute onset and symptoms of fever (100%), headache (71%), arthralgia (43%), myalgia (43%), cough (43%), maculopapular/petechial rash (43%), nausea (29%), pharyngitis (29%), lymphadenopathy (29%), and eschar (29%)."

Deep Research

1

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.

Evaluations and curation notes (1)

Create Flinders Island spotted fever · 2026-09-28T05:54:53Z · View source

Created a de novo Flinders Island spotted fever entry from the OpenScientist deep-research report, with infectious-agent, transmission, epidemiology, pathophysiology, phenotype, diagnosis, and doxycycline treatment curation. Follow-up review tightened IFA serology evidence, frequency and source coverage for the founding Flinders Island phenotypes, and graph connectivity for minor phenotypes.

OpenScientist ▸

Flinders Island Spotted Fever (MONDO:0000232): Comprehensive Disease Characterization Report

openscientist-autonomous 18 citations 2026-09-27T22:27:43.498890

Flinders Island Spotted Fever (MONDO:0000232): Comprehensive Disease Characterization Report

A tick-borne spotted fever group rickettsiosis of south-east Australia caused by Rickettsia honei

Summary

Flinders Island Spotted Fever (FISF) is a rare, acute, self-limited, tick-borne infectious disease caused by the obligate intracellular Gram-negative bacterium Rickettsia honei (spotted fever group, SFG). It is not a genetic disease — there are no human causal genes, no inheritance pattern, and no pathogenic germline variants. It is an infectious/zoonotic rickettsiosis, and every section of the standard disease-characteristics template must be read through that lens: the "genetic/molecular" and "inheritance" sections properly describe the pathogen's biology and ecology rather than host heritability.

FISF was first defined clinically by Stewart in 1991 as a spotted-fever-like illness affecting a small Bass Strait island community (~1000 people), with 26 cases identified over a 17-year period. The causal organism was isolated from a febrile patient's blood in 1991/1993 and formally described as the new species Rickettsia honei strain RB(T) in 1998. The bacterium is maintained transovarially (vertically) in reptile-associated ticks — chiefly Bothriocroton (formerly Aponomma) hydrosauri — whose vertebrate hosts are reptiles (blue-tongued lizards, tiger and copperhead snakes) rather than mammals, an ecologically unusual feature. Humans are incidental hosts infected by tick bite.

Clinically, FISF presents as an acute febrile illness with headache, maculopapular/petechial rash, arthralgia/myalgia, and frequently an inoculation eschar. Pathophysiologically, R. honei infects the vascular endothelium, using surface cell antigen autotransporters (Sca2, OmpB) to adhere and invade, actin-based motility (RickA/Arp2/3 early phase; Sca2/formin-mimic late phase) to spread cell-to-cell, and triggering NF-κB– and p38-MAPK–driven chemokine release (IL-8, MCP-1) that recruits leukocytes and produces rickettsial vasculitis. The disease responds rapidly to doxycycline and is generally self-limited with prompt treatment. Prevention rests on tick-bite avoidance; there is no vaccine.

Disease Identity and Classification

Attribute	Value
Disease name	Flinders Island Spotted Fever (FISF)
MONDO ID	MONDO:0000232
Category	Infectious disease (zoonotic, tick-borne rickettsiosis)
Causal organism	Rickettsia honei strain RB(T) (= Thai tick typhus strain TT-118)
Pathogen taxonomy	Bacteria; Proteobacteria; Alphaproteobacteria; Rickettsiales; Rickettsiaceae; Rickettsia; spotted fever group
Genome size	~1.27 Mb
Synonyms	Flinders Island spotted fever rickettsiosis; Australian tick typhus (Bass Strait focus); "marmionii" strain rickettsiosis (eastern Australian variant)
Vector / reservoir	Bothriocroton (Aponomma) hydrosauri reptile tick
Vertebrate hosts	Reptiles (lizards, snakes); humans are incidental
Geography	South-east Australia (Flinders Island, Tasmania, South Australia, Queensland/Torres Strait, Western Australia); related strain in Thailand and Texas
Data source type	Aggregated disease-level resources (case series, serosurveys, vector surveillance) — not EHR/individual-patient omics

FISF is best understood as one of Australia's four recognised rickettsioses: murine typhus (R. typhi), Queensland tick typhus (R. australis), Flinders Island spotted fever (R. honei), and scrub typhus (Orientia tsutsugamushi) (PMID: 17553271).

Key Findings

Finding 1 — The causal agent is Rickettsia honei, a distinct spotted fever group species (F001)

FISF is caused by Rickettsia honei, a genetically distinct member of the spotted fever group. Strain RB(T) was isolated from a febrile patient on Flinders Island in 1991/1993 and formally described as a new species in 1998. Phylogenetic comparison of the 16S rRNA, rompA (ompA), gltA (citrate synthase) and 17-kDa antigen genes confirmed its distinctness from other SFG rickettsiae; its genome is ~1.27 Mb. Its closest genetic relative is Thai tick typhus strain TT-118, now regarded as a strain of R. honei, establishing an intercontinental species identity.

"The name Rickettsia honei, strain RBT, has been proposed for a unique spotted fever group (SFG) agent which is pathogenic for humans." — PMID: 9828442

"Rickettsia honei strain RB(T) was isolated from a febrile patient on Flinders Island, Australia, in 1991 and has been demonstrated to be the agent of Flinders Island spotted fever, a disease transmitted to humans by ticks." — PMID: 22815457

This finding anchors Sections 1 (Disease Information), 2 (Etiology), and 5 (Infectious Agents) of the template. The primary cause is infectious; there is no genetic host etiology.

Finding 2 — Reptile-tick reservoir with transovarial maintenance (F002)

R. honei is maintained in nature within the reptile-associated tick Aponomma (Bothriocroton) hydrosauri, which is the arthropod reservoir on Flinders Island. In a survey, 29 of 46 (63%) ticks were PCR-positive for SFG rickettsiae, with sequences 100% homologous to R. honei. Electron microscopy localised rickettsiae in tick salivary glands, malpighian tubules, and midgut epithelium, and — critically — within oocytes and immature eggs, indicating transovarial (vertical) transmission. The vertebrate hosts are reptiles (blue-tongued lizards, tiger and copperhead snakes) rather than mammals, an ecologically unusual arrangement.

"The tick Aponomma hydrosauri is associated with reptiles and is the arthropod reservoir for this rickettsia on Flinders Island. The rickettsia appears to be maintained in the tick via vertical transmission. Of 46 ticks examined, 29 (63%) were positive for spotted fever group rickettsiae" — PMID: 14628950

"The ecology of R. honei in this location is unusual in that reptiles, rather than mammals, are the vertebrate hosts." — PMID: 12860601

This underpins Sections 9 (population/reservoir ecology), 13 (Prevention — vector control), and 14 (Other Species / zoonotic transmission). Transovarial maintenance means the tick is both vector and reservoir, so the pathogen persists independent of amplifying mammalian hosts.

Finding 3 — Clinical phenotype: acute febrile illness with rash, arthralgia/myalgia, and eschar (F003)

Across a case series of the eastern-Australian "marmionii" strain (n = 7), the symptom frequencies were: fever 100%, headache 71%, arthralgia 43%, myalgia 43%, cough 43%, maculopapular/petechial rash 43%, nausea 29%, pharyngitis 29%, lymphadenopathy 29%, and eschar 29%. Onset is acute, most cases occur in autumn, and cases cluster in eastern Australia (Queensland, Tasmania, South Australia). A severe imported case in Nepal displayed clinical features typical of FISF, confirming the phenotype outside Australia.

"symptoms of fever (100%), headache (71%), arthralgia (43%), myalgia (43%), cough (43%), maculopapular/petechial rash (43%), nausea (29%), pharyngitis (29%), lymphadenopathy (29%), and eschar (29%)" — PMID: 17553271

"The patient had severe illness and many clinical features typical of Flinders Island spotted fever." — PMID: 22000356

Suggested HPO terms: Fever (HP:0001945); Headache (HP:0002315); Skin rash (HP:0000988) / Maculopapular exanthema; Arthralgia (HP:0002829); Myalgia (HP:0003326); Cough (HP:0012735); Nausea (HP:0002018); Pharyngitis (HP:0025439); Lymphadenopathy (HP:0002716); Skin ulcer / eschar (HP:0200042). This supports Section 3 (Phenotypes).

Finding 4 — Pathophysiology: endothelial tropism causing rickettsial vasculitis (F004)

Pathogenic Rickettsia are Gram-negative obligate intracellular bacteria with an affinity for the endothelium lining blood vessels. Infection causes vascular inflammation, insult to vascular integrity, and increased vascular permeability — collectively termed "rickettsial vasculitis." SFG rickettsiae activate host-cell transcriptional signalling upon adhesion and invasion. Related SFG rickettsioses (e.g., Mediterranean spotted fever) show leucocytoclastic vasculitis on skin biopsy and can involve multiple organs, providing histologic correlates for the FISF mechanism.

"a majority of sequelae associated with human rickettsioses are the outcome of the pathogen's affinity for endothelium lining the blood vessels, the consequences of which are vascular inflammation, insult to vascular integrity and compromised vascular permeability, collectively termed 'Rickettsial vasculitis'" — PMID: 19327117

"Skin biopsy of the purpura confirmed leucocytoclastic vasculitis" — PMID: 33622746

This establishes the core of Section 6 (Mechanism) and Section 7 (Anatomical Structures — vascular endothelium).

Finding 5 — Geographic distribution across three continents (F005)

R. honei (= strain TT-118) has been detected on three continents: Thailand (isolated 1962, confirmed 2001; Ixodes/Rhipicephalus, including I. granulatus from Rattus rattus), Australia (Flinders Island 1993; also Tasmania, South Australia, Queensland/Torres Strait, and Western Australia), and Texas, USA (1998, Amblyomma cajennense). Within Australia, FISF extends across south-east Australia, matching the range of its reptile-tick vector; a human case reached Nepal in 2009.

"Rickettsia honei (also known as strain TT-118) has been detected on three continents. Originally isolated in Thailand in 1962 (and confirmed in 2001), it has also been detected on Flinders Island (Australia) in 1993 and in Texas (USA) in 1998." — PMID: 12860601

"These cases show that FISF extends beyond Flinders Island and most likely has the same distribution across south-east Australia as its vector, the reptile tick Aponomma hydrosauri." — PMID: 16175900

This informs Section 9 (geographic distribution).

Finding 6 — Co-circulation with other rickettsioses; serologic cross-reactivity complicates diagnosis (F006)

On Darnley Island (Torres Strait), FISF (R. honei "marmionii") was found alongside Queensland tick typhus (R. australis) and scrub typhus (a unique Orientia tsutsugamushi strain), demonstrating overlapping endemic ranges and a broad differential diagnosis. Serosurveys rely on indirect immunofluorescence assay (IFA) panels that cross-react across SFG antigens (R. honei, R. conorii, R. sibirica, R. rickettsii, R. australis, R. akari), so species-level confirmation requires PCR/sequencing (e.g., eschar swab or biopsy PCR).

"In addition to previously described cases of Flinders Island spotted fever (Rickettsia honei strain 'marmionii'), we describe 1 case of Queensland tick typhus (R. australis) and 2 cases of scrub typhus caused by a unique strain (Orientia tsutsugamushi)." — PMID: 18214193

"Australia has 4 rickettsial diseases: murine typhus, Queensland tick typhus, Flinders Island spotted fever, and scrub typhus." — PMID: 17553271

This is central to Section 10 (Diagnostics — differential diagnosis and serology/PCR).

Finding 7 — Emerging/expanding geography and multi-species tick carriage (F007)

The first reported case of SFG rickettsiosis in Western Australia included R. honei among identified agents, expanding the known Australian range beyond the south-east. Ongoing molecular surveillance of reptile ticks continues to detect Rickettsia spp. (e.g., in Bothriocroton hydrosauri and Amblyomma moreliae from reptiles in NSW/SA), refining vector/reservoir maps. Importantly, not all B. hydrosauri-borne Rickettsia are R. honei — multiple SFG species can share the same vector, complicating vector-based risk mapping.

"We describe the first reported case of spotted fever group rickettsiosis in Western Australia" — PMID: 30270856

"although we discovered Rickettsia in all tick samples, it was not Rickettsia honei" — PMID: 27338482

This informs Sections 9 and 13 (surveillance, emerging foci).

Finding 8 — Molecular mechanism: Sca2/OmpB invasion, actin-based motility, and NF-κB/p38 chemokine response (F008)

SFG rickettsiae adhere to and invade endothelium via surface cell antigen (Sca) autotransporters. In R. conorii, Sca2 alone is sufficient to mediate both adherence and invasion of human endothelial cells and to drive intracellular actin-based motility, with separable mammalian-association and actin-nucleation domains. Intracellular motility occurs in two phases: an early RickA/Arp2/3-dependent phase (slow, curved actin tails) and a late Sca2/formin-mimic-dependent phase (fast, straight tails), enabling cell-to-cell spread. Endothelial infection activates NF-κB (biphasic for R. conorii; RelA p65–p50 dimers) and p38 MAPK, inducing the chemokines IL-8 and MCP-1 (5–28-fold), which recruit neutrophils and monocytes. NF-κB inhibition abrogates the chemokine response, and p38 inhibition reduces IL-8/MCP-1 secretion.

"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

"Early motility requires RickA and Arp2/3 complex... Late motility is independent of Arp2/3 complex and RickA and requires Sca2" — PMID: 24361066

"Infection of endothelial cells (ECs) lining vessel walls, and the resultant vascular inflammation and haemostatic alterations are salient pathogenetic features of both of these rickettsial diseases" — PMID: 17577053

"increased mRNA expression of IL-8 and MCP-1 in R. rickettsii-infected EC was evident as early as 3 h ... synthetic peptide SN-50 to inhibit the nuclear translocation of nuclear factor-kappa B (NF-kappaB) resulted in significant inhibition of the chemokine response" — PMID: 16128401

Note: the detailed molecular mechanism is derived from closely related SFG species (R. conorii, R. rickettsii) and Orientia, and is inferred for R. honei by phylogenetic conservation rather than demonstrated directly in R. honei. This forms the mechanistic backbone of Section 6.

Finding 9 — Original 1991 clinical/epidemiologic and serologic description (F009)

Stewart (1991) identified 26 cases of a spotted-fever-like illness over a 17-year period in the ~1000-person Flinders Island population. Usual features were high fever, headache, myalgia, slight cough, arthralgia without joint swelling, and a maculopapular rash unlike common exanthems; 12 of 26 (~46%) had a focal skin lesion (eschar); ticks were implicated as vector. The companion serologic study (Graves et al., 1991) showed patients had higher seroprevalence than 335 healthy islanders to Weil-Felix OX2 (36% vs <1%) and OX19 (36% vs <1%), and to SFG microimmunofluorescence antigens R. rickettsii (42% vs 1%), R. australis (46% vs 1%), and R. conorii (42% vs 1%) but not R. typhi (4% vs 4%). Seroconversion was demonstrated in 7 of 26 patients (27%), confirming recent SFG rickettsial infection (the agent had not yet been isolated at that time).

"Twenty six cases of a spotted-fever-like illness have been identified over a 17 year period in the population of about 1000 of Flinders Island, Tasmania. The usual features were high fever, headache, myalgia, slight cough, arthralgia without joint swelling and a maculopapular rash which did not resemble the common exanthems. Twelve cases had a focal skin lesions. Available evidence implicates ticks as the vector." — PMID: 1986207

"In seven of the 26 patients (27%) seroconversion was demonstrated by means of Weil-Felix tests, confirming recent infection." — PMID: 1898756

This is the founding evidence for Sections 1, 3, 9, and 10.

Section-by-Section Characterization

1. Disease Information

FISF is an acute, tick-borne SFG rickettsiosis of south-east Australia caused by R. honei. Identifiers: MONDO:0000232. OMIM is not applicable (infectious, non-Mendelian). Orphanet does not maintain a dedicated FISF entry as a rare genetic disease; it is catalogued under rickettsioses/spotted fevers. ICD-10: A77.8 (Other spotted fevers) / ICD-11: 1C30.2 (Spotted fever due to other/unspecified Rickettsia). MeSH: the disease maps under "Rickettsia Infections" / "Spotted Fever Group Rickettsiosis"; organism MeSH term Rickettsia honei. Synonyms: Flinders Island spotted fever rickettsiosis; the eastern-Australian variant is the "marmionii" strain. Information source: aggregated disease-level literature (case series, serosurveys, vector surveys), not individual EHR/omics.

2. Etiology

Primary cause: infectious — the obligate intracellular bacterium R. honei transmitted by tick bite (F001, F002). Risk factors: environmental/occupational and recreational exposure to reptile-tick habitat in endemic south-east Australia; seasonality (autumn predominance, F003); outdoor activity. Genetic host risk factors: none identified — this is not a heritable disease. Protective factors: tick-bite avoidance (clothing, repellents, tick checks); prompt doxycycline. Gene-environment interactions: not applicable to the human host; the key "interaction" is ecological — the pathogen–tick–reptile cycle.

3. Phenotypes

See Finding 3 and Finding 9 for symptom frequencies. Phenotype type: predominantly symptoms/clinical signs (fever, rash, eschar, lymphadenopathy) with associated laboratory abnormalities typical of SFG rickettsioses (mild thrombocytopenia, mild transaminitis, elevated CRP — inferred from the SFG class; not specifically quantified for FISF in the reviewed literature). Onset: adult and pediatric; acute. Severity: mild-to-moderate and generally self-limited; severe illness is documented (Nepal case). Progression: acute, self-limited with treatment. Frequency among affected: fever ~100%, rash ~43%, eschar ~29–46%. QoL impact: acute febrile disability lasting days-to-weeks; excellent recovery with doxycycline; no documented chronic sequelae.

4. Genetic/Molecular Information

Not applicable to the human host. FISF has no causal human genes, no pathogenic germline/somatic variants, no modifier genes, no host epigenetic changes, and no chromosomal abnormalities. The relevant molecular biology is that of the pathogen: R. honei genome ~1.27 Mb; key genetic/antigenic loci used for identification and phylogeny include gltA (citrate synthase), ompA/rompA, ompB, 16S rRNA, and the 17-kDa antigen gene (F001). Pathogen virulence loci include the Sca autotransporters (Sca2, OmpB/Sca5) and the actin-nucleator RickA (F008). Suggested gene/protein annotations pertain to the bacterium, not the host.

5. Environmental Information

Infectious agent: Rickettsia honei (NCBI Taxonomy: Rickettsia honei). Vector: Bothriocroton (Aponomma) hydrosauri (reptile tick); also implicated/related ticks include Amblyomma spp. and Haemaphysalis spp. in different foci. Environmental/lifestyle factors: exposure to tick habitat; outdoor/rural activity; contact with reptiles or their tick-laden environments. No toxin, radiation, or pollution etiology.

6. Mechanism / Pathophysiology — Causal Chain

1. Infected reptile tick (B. hydrosauri) bites human
│  (rickettsiae in tick salivary glands, F002)
▼
2. R. honei is inoculated into dermis → local replication → ESCHAR forms
│
▼
3. Bacteria adhere to & invade vascular ENDOTHELIAL CELLS
│  via Sca2 / OmpB(Sca5) autotransporters (F008, inferred from R. conorii)
▼
4. Intracellular replication + ACTIN-BASED MOTILITY
│  early: RickA/Arp2/3 (curved tails); late: Sca2/formin-mimic (straight tails)
▼  → cell-to-cell spread through the endothelium
5. Endothelial signalling activated: NF-κB (RelA p65-p50) + p38 MAPK
│
▼
6. Chemokine induction: IL-8 & MCP-1 (5–28×) → recruit neutrophils & monocytes
│
├──▼ 7a. Perivascular leukocyte infiltration → VASCULITIS
│        (leucocytoclastic vasculitis histologically, F004)
│
└──▼ 7b. Increased vascular permeability + haemostatic alterations
         → RASH (maculopapular/petechial), local edema
▼
8. Systemic inflammatory response → FEVER, HEADACHE, MYALGIA/ARTHRALGIA,
   LYMPHADENOPATHY (clinical manifestation, F003/F009)
▼
9. Doxycycline halts bacterial replication → rapid resolution (self-limited)

Upstream vs downstream: the initiating lesion is tick inoculation and endothelial invasion (upstream); NF-κB/p38 chemokine signalling and leukocyte recruitment are intermediate; vasculitis, increased permeability, rash, and systemic febrile illness are downstream. Cell types: vascular endothelial cells (CL:0000115), neutrophils (CL:0000775), monocytes/macrophages (CL:0000576/CL:0000235). GO biological processes: response to bacterium (GO:0009617); actin-based movement / actin nucleation (GO:0006928, GO:0045010); NF-κB signaling (GO:0038061 / GO:0007249); chemokine production (GO:0032602); inflammatory response (GO:0006954). GO cellular components: host cell cytoplasm/cytoskeleton (GO:0005856); bacterial cell surface. Metabolic/immune notes: disease is driven by innate immune activation and chemokine-mediated leukocyte recruitment rather than autoimmunity or immunodeficiency. No omics profiling (transcriptomics/proteomics/metabolomics) specific to FISF is available in the reviewed literature.

7. Anatomical Structures Affected

Primary: vascular endothelium of small and medium blood vessels (systemic) — UBERON:0001981 (blood vessel), UBERON:0001986 (endothelium); cell type CL:0000115 (endothelial cell).
Skin (rash, eschar) — UBERON:0002097; lymph nodes (lymphadenopathy) — UBERON:0000029.
Body systems: cardiovascular (vasculature), integumentary (skin), lymphatic/immune, musculoskeletal (arthralgia/myalgia), respiratory (cough), and potentially multi-organ in severe SFG disease (by analogy to Mediterranean spotted fever, F004).
Subcellular: host cell cytosol/cytoskeleton (site of replication and actin-based motility) — GO:0005829 (cytosol), GO:0015629 (actin cytoskeleton).
Lateralization: rash is typically generalized/bilateral; eschar is focal at the bite site.

8. Temporal Development

Onset: acute, following an incubation period of ~days after tick bite; adult and pediatric.
Progression: self-limited acute course over days to ~2 weeks; rapid defervescence after doxycycline.
Course pattern: monophasic acute illness; not relapsing or chronic.
Critical period: early antibiotic initiation (empiric doxycycline before serologic confirmation) is the key therapeutic window; delay risks more severe SFG disease.
Remission: treatment-induced; spontaneous resolution possible but treatment shortens illness and prevents complications.
Seasonality: autumn predominance in eastern Australia (F003).

9. Inheritance and Population

Inheritance: not applicable (infectious, non-heritable). No penetrance/expressivity/anticipation/founder-effect/carrier-frequency concepts apply to the human host. (These concepts apply, if at all, only to the pathogen's clonal population genetics.)
Epidemiology: rare. Founding series: 26 cases over 17 years in a ~1000-person island population (F009), implying a locally appreciable but numerically small burden; broader Australian incidence is not precisely quantified. FISF is likely underdiagnosed due to serologic cross-reactivity (F006).
Geographic distribution: south-east Australia (Flinders Island, Tasmania, South Australia, Queensland/Torres Strait, Western Australia), with related R. honei/TT-118 in Thailand and Texas (F005, F007). Distribution tracks the reptile-tick vector.
Sex ratio / age: not robustly quantified for FISF; SFG rickettsioses generally affect outdoor-exposed individuals across ages.

10. Diagnostics

Serology: indirect immunofluorescence assay (IFA) is the mainstay; a ≥4-fold rise between acute and convalescent titres to R. honei (and cross-reacting SFG antigens) confirms infection. Weil-Felix (OX2/OX19) was used historically (F009). Cross-reactivity across SFG antigens is substantial (F006), so serology confirms SFG infection but not species.
Molecular: PCR and sequencing (targeting gltA, ompA, ompB, 17-kDa) from eschar swab/biopsy or blood provides species-level confirmation and is the preferred definitive test.
Culture: R. honei can be isolated (as in the index case) but requires specialized biosafety facilities; not routine.
Laboratory abnormalities: typical SFG findings (mild thrombocytopenia, mild transaminase elevation, elevated inflammatory markers) — inferred for FISF from the SFG class.
Differential diagnosis: Queensland tick typhus (R. australis), scrub typhus (Orientia tsutsugamushi), murine typhus (R. typhi), and other SFG rickettsioses; also dengue and other acute febrile illnesses in the region (F006).
Genetic testing / omics diagnostics: not applicable to the host.

11. Outcome / Prognosis

Prognosis: excellent with prompt doxycycline; FISF is generally self-limited and non-fatal. No FISF-specific mortality rate is established in the reviewed literature; severe illness is documented (Nepal, F003) but recovery is the norm.
Complications: by analogy to other SFG rickettsioses, untreated or severe cases can have multi-organ involvement and vasculitic complications (F004); these appear uncommon in FISF.
Recovery: full recovery expected; no documented chronic sequelae.
Prognostic factors: timeliness of antibiotic therapy; host age/comorbidity.

12. Treatment

First-line pharmacotherapy: doxycycline (tetracycline-class antibiotic; inhibits bacterial 30S ribosomal protein synthesis). Empiric therapy is recommended for suspected SFG rickettsiosis before confirmation. Rapid clinical response is characteristic (NCIT: Doxycycline C561; Tetracycline Antibiotic C1364).
Alternatives: other tetracyclines; macrolides (e.g., clarithromycin/azithromycin) have been used for SFG rickettsioses, particularly in young children and pregnancy (by analogy to Mediterranean spotted fever); chloramphenicol is a historical alternative.
Advanced/experimental/targeted/immuno/gene/cell therapies: not applicable.
Supportive care: antipyretics, hydration, symptom management.
Pharmacogenomics: none established for FISF.
Treatment outcome: high response rate; adverse events are those of doxycycline (GI upset, photosensitivity, dental staining in young children — the reason macrolides are considered in that group).

13. Prevention

Primary prevention: tick-bite avoidance — protective clothing, repellents (DEET/picaridin), avoiding reptile-tick habitat, prompt tick removal, and tick checks after outdoor exposure in endemic areas.
Vector control / public health: habitat awareness; surveillance of reptile ticks to map foci (F002, F007).
Secondary prevention: early recognition of the fever-rash-eschar syndrome and prompt empiric doxycycline.
Immunization: no vaccine exists.
Prophylaxis: routine post-tick-bite antibiotic prophylaxis is not standard; treat if symptomatic.
Counseling / genetic screening: not applicable.

14. Other Species / Natural Disease

Reservoir/host taxonomy: reptile tick Bothriocroton (Aponomma) hydrosauri; vertebrate hosts are reptiles — blue-tongued lizards (Tiliqua spp.), tiger and copperhead snakes; also Tiliqua rugosa (shingleback) carrying related Rickettsia (F002, F007).
Zoonotic transmission: humans are incidental hosts infected by tick bite; there is no human-to-human transmission. This is a zoonotic, vector-borne disease.
Comparative biology: related R. honei strain TT-118 circulates in Ixodes granulatus from Rattus rattus in Thailand and in Amblyomma cajennense in Texas (F005), indicating a broad host-tick range for the species. Multiple SFG Rickettsia can share reptile-tick vectors (F007).
Natural disease in companion/wildlife species: clinical rickettsiosis attributable to R. honei in animals is not documented; reptiles and ticks serve as asymptomatic reservoirs.

15. Model Organisms

No dedicated R. honei/FISF animal model is described in the reviewed literature. Mechanistic understanding derives from in vitro human endothelial cell infection models and cell-biology studies using related SFG species (R. conorii, R. rickettsii) and Orientia tsutsugamushi, plus tick-cell (Dermacentor variabilis) invasion models for R. montanensis (F008 and supporting literature). These systems recapitulate endothelial invasion, actin-based motility, and NF-κB/p38 chemokine responses but are surrogates, not FISF-specific models. Guinea pig and mouse models are standard for SFG rickettsiae generally but are not reported specifically for R. honei here.

Mechanistic Model / Interpretation

FISF is a paradigmatic vector-borne endothelial infection. The disease's clinical signature — fever, rash, and eschar — maps directly onto its cellular pathology. The eschar is the histologic footprint of local R. honei replication and vasculitis at the inoculation site; the rash reflects disseminated endothelial infection with increased vascular permeability; and the systemic febrile syndrome is the downstream consequence of NF-κB/p38-driven chemokine release and innate immune activation.

The molecular engine (Finding 8) is conserved across the SFG and is therefore confidently inferred for R. honei, though it has been demonstrated principally in R. conorii and R. rickettsii. The pathogen uses a two-tool strategy: Sca autotransporters for endothelial adhesion/invasion and actin-based motility (RickA/Arp2/3 early; Sca2/formin-mimic late) for intercellular spread without leaving the protected intracellular niche. Host endothelial signalling (NF-κB, p38 MAPK) then converts infection into the inflammatory chemokine milieu (IL-8, MCP-1) that recruits the neutrophils and monocytes responsible for vasculitis.

The ecology (Findings 2, 5, 7) is what makes FISF distinctive among rickettsioses: a reptile-based enzootic cycle with transovarial maintenance in the tick, so the tick is simultaneously vector and reservoir. This decouples pathogen persistence from mammalian amplifying hosts and ties human risk tightly to reptile-tick habitat. The observation that a single reptile-tick species can carry multiple Rickettsia species complicates simple vector-based risk mapping and argues for molecular (species-level) confirmation in both surveillance and diagnosis.

Evidence Base

PMID	Role in report	Supports finding
9828442	Formal species description of R. honei strain RBT	F001
22815457	Confirms etiologic agent, isolation history, 1.27-Mb genome	F001
14628950	Vector/reservoir identification; 63% tick positivity; vertical transmission	F002
12860601	Reptile vertebrate-host ecology; three-continent distribution	F002, F005
12860602	Ultrastructural/EM evidence of transovarial transmission in A. hydrosauri	F002
17553271	"marmionii" case series; symptom frequencies; Australia's 4 rickettsioses	F003, F006
22000356	Severe imported case, Nepal 2009	F003
19327117	Endothelial tropism → rickettsial vasculitis	F004
33622746	Leucocytoclastic vasculitis histology (SFG correlate)	F004
16175900	Geographic extension across south-east Australia	F005
18214193	Co-circulation with R. australis and scrub typhus	F006
30270856	First WA SFG rickettsiosis incl. R. honei	F007
27338482	B. hydrosauri carries non-honei Rickettsia	F007
22612237	Sca2 mediates adhesion/invasion/motility	F008
24361066	Two-phase actin-based motility (RickA/Arp2/3 → Sca2)	F008
17577053	Endothelial infection, NF-κB/p38, vascular inflammation	F008
16128401	NF-κB regulation of IL-8/MCP-1 in infected EC	F008
16153249	p38 activation drives chemokine response	F008
1986207	Founding clinical/epidemiologic description (26 cases/17 yr)	F009
1898756	Founding serologic confirmation (seroconversion 27%)	F009
11716110	Thai tick typhus TT-118 = R. honei in I. granulatus	F005
38194190	Reptile-tick Rickettsia surveillance (NSW)	F007

Evidence source types: F001, F003, F005, F006, F007, F009 rest on human clinical/epidemiologic and vector-surveillance data specific to R. honei/FISF. F002 combines field ecology, PCR, and EM. F004 and F008 rest largely on in vitro endothelial/cell-biology studies of related SFG species and are inferred for R. honei by phylogenetic conservation.

Limitations and Knowledge Gaps

Mechanism is inferred, not demonstrated in R. honei. The Sca2/OmpB invasion and NF-κB/p38 chemokine cascade come from R. conorii, R. rickettsii, and Orientia studies. Direct molecular studies of R. honei itself are lacking.
No FISF-specific animal model or omics data. There are no transcriptomic, proteomic, or metabolomic signatures reported for FISF, and no dedicated model organism.
Imprecise epidemiology. Incidence/prevalence beyond the original island series are not well quantified; underdiagnosis due to serologic cross-reactivity likely biases case counts.
Sparse quantitative clinical/laboratory data. Symptom frequencies come from small series (n = 7; n = 26). Laboratory abnormalities (thrombocytopenia, transaminitis) are inferred from the SFG class rather than measured in FISF cohorts.
Prognosis data are qualitative. No formal mortality/morbidity rates or quality-of-life instruments have been applied to FISF.
Template mismatch. Sections designed for genetic diseases (causal genes, inheritance, penetrance, model organisms, gene therapy) are largely not applicable; the report reinterprets these in terms of pathogen biology and ecology.

Proposed Follow-up Actions

Direct molecular validation in R. honei: infect primary human dermal microvascular endothelial cells with R. honei and confirm Sca2/OmpB-dependent invasion, two-phase actin motility, and NF-κB/p38-driven IL-8/MCP-1 induction — closing the inference gap for F008.
Prospective clinical cohort: assemble a multi-centre south-east Australian FISF cohort with standardized PCR confirmation to quantify symptom frequencies, laboratory abnormalities, severity distribution, and outcomes.
Seroepidemiology with species-specific assays: develop and deploy R. honei-specific serologic/molecular tools to overcome SFG cross-reactivity and produce true prevalence/incidence estimates.
Expanded vector/reservoir surveillance: systematically genotype Rickettsia in reptile ticks across the Australian range (and WA foci) to map R. honei vs. co-circulating SFG species and refine human-risk geography.
Comparative genomics: leverage the 1.27-Mb R. honei genome against R. conorii/R. rickettsii to identify virulence-locus conservation/divergence that may explain FISF's generally milder course.
Diagnostic algorithm formalization: validate eschar-swab PCR as a rapid, species-level point-of-care confirmatory test and integrate into Australian febrile-illness guidelines alongside empiric doxycycline.

Report compiled from 5 investigative iterations, 9 confirmed findings, and 42 reviewed papers. Evidence is drawn from primary literature; mechanistic claims specific to R. honei are flagged as inferred from closely related spotted fever group rickettsiae where direct data are unavailable.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0rc3.

Outcome	Count
References checked	22
Resolved	22
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	22
On topic	14
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	29
Resolved	28
Unresolved (possible confabulation)	0
Obsolete	1
Unverifiable	0
Terms whose name was checked	6
Terms named correctly	5
Terms named as a different term	1

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:

MONDO:0000232 (3 mentions) - the report calls it "MONDO ID"; MONDO calls it Flinders island spotted fever

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

GO:0006928 (obsolete movement of cell or subcellular component) (1 mention)

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Classifications

Pathophysiology

Pathograph

Phenotypes

Medical Actions

Diagnosis

Progression

Epidemiology

Infectious Agent

Transmission

Source YAML

References & Deep Research

References

Deep Research

Flinders Island Spotted Fever (MONDO:0000232): Comprehensive Disease Characterization Report

Summary

Disease Identity and Classification

Key Findings

Finding 1 — The causal agent is Rickettsia honei, a distinct spotted fever group species (F001)

Finding 2 — Reptile-tick reservoir with transovarial maintenance (F002)

Finding 3 — Clinical phenotype: acute febrile illness with rash, arthralgia/myalgia, and eschar (F003)

Finding 4 — Pathophysiology: endothelial tropism causing rickettsial vasculitis (F004)

Finding 5 — Geographic distribution across three continents (F005)

Finding 6 — Co-circulation with other rickettsioses; serologic cross-reactivity complicates diagnosis (F006)

Finding 7 — Emerging/expanding geography and multi-species tick carriage (F007)

Finding 8 — Molecular mechanism: Sca2/OmpB invasion, actin-based motility, and NF-κB/p38 chemokine response (F008)

Finding 9 — Original 1991 clinical/epidemiologic and serologic description (F009)

Section-by-Section Characterization

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology — Causal Chain

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Mechanistic Model / Interpretation

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Actions

Artifacts

Reference Validation

Term Validation

Terms the report names something else

Obsolete terms