Spotted fever rickettsiosis

Infectious Disease MONDO:0001195 Pathograph 8 Show in embeddings browser Rickettsiaceae infectious disease Vector-borne disease Rickettsial disease

Spotted fever rickettsiosis is the group of acute febrile illnesses caused by the spotted fever group (SFG) of the genus Rickettsia — obligately intracytosolic, Gram-negative bacteria acquired from a feeding tick (or, for rickettsialpox, a mite). Whatever the species, the mechanism is the same: the organism is inoculated at the arthropod attachment site, disseminates haematogenously, and replicates inside microvascular endothelial cells, producing a disseminated small-vessel vasculitis with increased vascular permeability. That single lesion accounts for the group's shared clinical signature — fever, headache and myalgia, a centrifugally or centripetally spreading rash, and (in most members, though notably not in Rocky Mountain spotted fever) an inoculation eschar at the bite site — and, at the severe end, for non-cardiogenic pulmonary oedema and encephalitis. Members differ enormously in severity, from the self-limiting African tick-bite fever to the frequently fatal Rocky Mountain spotted fever, and that gradient tracks the species-specific inflammatory response the organism provokes in endothelium rather than any difference in the route of infection. This root entry is deliberately thin. It carries only what is defined over the group as a whole: the SFG taxon itself and the species-versus-geography naming problem, the shared eschar/fever/rash triad and how eschar frequency varies by species, the group-level serologic cross-reactivity that makes species-level diagnosis hard, the shared doxycycline-first-line logic including its paediatric arm, and the SFG-versus-typhus-group boundary. Per-member pathophysiology, epidemiology, phenotype frequencies and treatment detail live in the individual entries — `Rocky_Mountain_Spotted_Fever.yaml` and `Boutonneuse_Fever.yaml` are curated in full — and the antimicrobial mechanism is held once in `kb/modules/bacterial_protein_synthesis_inhibition.yaml` and `kb/modules/intracellular_pathogen_persistence.yaml`.

Ask OpenScientist

Ask a research question about Spotted fever rickettsiosis. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

7
Pathophys.
5
Phenotypes
4
Gaps
8
Pathograph
1
Medical Actions
6
Subtypes
21
References
🏷

Classifications

Harrison's Part
INFECTIOUS DISEASES
◆

Subtypes

6
Rocky Mountain spotted fever (Rickettsia rickettsii) MONDO:0019359
Caused by Rickettsia rickettsii and transmitted by Dermacentor and Rhipicephalus ticks. The most severe member of the group and the one in which an inoculation eschar is characteristically absent. Its range demonstrates that the species axis and the geographic axis do not coincide: the same organism causes Rocky Mountain spotted fever in North America and Brazilian spotted fever / febre maculosa in South America. Curated in full in `Rocky_Mountain_Spotted_Fever.yaml`.
Show evidence (2 references)
PMID:17961858 SUPPORT Other
"Rocky Mountain spotted fever (RMSF) is a life-threatening disease caused by Rickettsia rickettsii, an obligately intracellular bacterium that is spread to human beings by ticks."
Names the causative species and the tick route for this member. Evidence source is OTHER as this is a review article.
PMID:28169507 SUPPORT Human Clinical
"In Brazil, two pathogenic Rickettsia species have been identified causing tick-borne spotted fever (SF)."
Establishes that R. rickettsii spotted fever is a South American as well as a North American disease — the concrete case in which the species and geographic axes come apart.
Mediterranean spotted fever / boutonneuse fever (Rickettsia conorii) MONDO:0024472
Caused by Rickettsia conorii and transmitted by the brown dog tick Rhipicephalus sanguineus; the inoculation eschar is the classic tache noire. This member is the clearest illustration of why the primary axis is the species and not the place: one species carries four geographically named diseases — Mediterranean spotted fever (subsp. conorii), Indian tick typhus (subsp. indica), Israeli spotted fever (subsp. israelensis) and Astrakhan fever (subsp. caspia). Curated in full in `Boutonneuse_Fever.yaml`.
Show evidence (2 references)
PMID:23168048 SUPPORT Human Clinical
"Mediterranean spotted fever (MSF) is caused by a tick-borne pathogen, Rickettsia conorii subsp. conorii, belonging to the spotted fever group (SFG) rickettsiae."
Names the causative subspecies and states its membership of the spotted fever group.
PMID:15766388 SUPPORT Other
"Rickettsiae closely related to the Malish strain, the reference Rickettsia conorii strain, include Indian tick typhus rickettsia (ITTR), Israeli spotted fever rickettsia (ISFR), and Astrakhan fever rickettsia (AFR)."
Enumerates the four geographically named diseases that a single species accounts for, which is the evidence behind treating species as the primary subtype axis.
African tick-bite fever (Rickettsia africae) MONDO:0000227
Caused by Rickettsia africae and transmitted by Amblyomma ticks. The mildest commonly encountered member: a self-limiting flu-like illness in which fever, headache and myalgia are near-universal but the specific features — inoculation eschars (often multiple), lymphadenitis and rash — are present in only about half of patients. The commonest tick-borne rickettsiosis in returning travellers. No standalone dismech entry yet.
Show evidence (2 references)
PMID:12766836 SUPPORT Human Clinical
"More than 80% of the patients had fever, headache, and/or myalgia, whereas specific clinical features such as inoculation eschars, lymphadenitis, cutaneous rash, and aphthous stomatitis were seen in < or = 50% of patients."
A prospective cohort of 940 travellers quantifying the ATBF presentation, and showing that the eschar is not a constant feature even in a member of the group in which it is characteristic.
PMID:19091423 SUPPORT Human Clinical
"Mediterranean spotted fever (MSF) caused by Rickettsia conorii (R. conorii) is a potential lethal disease while African tick bite fever (ATBF) caused by Rickettsia africae is a self-limiting flu-like illness."
States the severity contrast between two members of the same group, which is what makes species rather than geography the discriminating axis.
Rickettsialpox (Rickettsia akari) MONDO:0019360
Caused by Rickettsia akari, and the one member of this list that is not tick-borne: it is transmitted by the house mouse mite Liponyssoides sanguineus in an urban rodent cycle. An eschar at the mite bite is followed by a papulovesicular rash. Its inclusion is deliberate and is what fixes the group's unifying criterion as the rickettsial clade rather than the arthropod vector; see the `sfr_group_boundary_and_naming_traps` discussion, which also records that R. akari has since been reassigned to the transitional group. No standalone dismech entry yet.
Show evidence (2 references)
PMID:12860597 SUPPORT Human Clinical
"IHC staining of biopsy specimens of eschars and papular lesions were positive for spotted fever group rickettsiae for 32 patients."
Confirmed rickettsialpox cases staining positive for spotted fever group rickettsiae — the serologic and immunohistochemical basis on which the disease is classified with this group.
PMID:28846279 SUPPORT Other
"R. akari is transmitted by the house mouse mite, Liponyssoides sanguineus."
States the mite (not tick) vector, the fact that prevents the group from being defined by its arthropod. Evidence source is OTHER as this is a reference-text chapter rather than a primary study.
Queensland tick typhus (Rickettsia australis) MONDO:0001118
Caused by Rickettsia australis and transmitted by Ixodes holocyclus and Ixodes tasmani. Despite the word "typhus" in its name this is a spotted fever group infection, not a typhus group one — see the `sfr_group_boundary_and_naming_traps` discussion. No standalone dismech entry yet.
Show evidence (1 reference)
PMID:28719297 SUPPORT Other
"Rickettsia australis, the etiologic agent of Queensland tick typhus (QTT), is increasingly being recognized as a cause of community-acquired acute febrile illness in eastern Australia."
Names the causative species and the geographic range, and — in a review whose title states the point explicitly — places a disease called "tick typhus" in the spotted fever group. Evidence source is OTHER as this is a review article.
North Asian (Siberian) tick typhus (Rickettsia sibirica subsp. sibirica) MONDO:0001154
Caused by Rickettsia sibirica subsp. sibirica and transmitted by Dermacentor and Haemaphysalis ticks. The second "tick typhus" in this list that is in fact a spotted fever group disease. Note that the sibling subspecies R. sibirica subsp. mongolitimonae causes a separate Mediterranean-spotted-fever-like illness in Europe and Africa, so even within one species the geographic label is not a reliable identifier. No standalone dismech entry yet.
Show evidence (1 reference)
PMID:22493192 SUPPORT Other
"Rickettsia sibirica sibirica is the causative agent of Siberian or North Asian tick typhus, a tick-borne rickettsiosis known to exist in Siberia and eastern China."
Establishes the subspecies-to-disease mapping and the geographic range, and confirms that the entity called North Asian tick typhus is a rickettsiosis of this group. Evidence source is OTHER as this is a genome announcement.
?

Discussions and Knowledge Gaps

4
Should spotted fever (MONDO:0001195) be modelled as a root `Disease` with `has_subtypes`, or as a `Grouping` over the member entries in `kb/groupings/`?
INTERPRETATION RESOLVED sfr_root_disease_vs_grouping
Resolved in favour of a root `Disease` with `has_subtypes`, on three grounds, the second of which is decisive on its own. First, tooling: `build_coverage_index()` in `src/dismech/compare/mondo_priority.py` calls `iter_disease_files()`, which globs `*.yaml` under the `--kb-dir` default of `kb/disorders` and never reads `kb/groupings/`. A `Grouping` alone would leave MONDO:0001195 permanently on the MONDO curation queue no matter how well curated it was. This was verified by reading `mondo_priority.py`, `compare/support.py` and the `--kb-dir` default in `priority_dashboard.py`, not assumed from the thanatophoric-dysplasia precedent. Second, and specific to this case: `tests/test_data.py::test_grouping_member_foreign_keys` requires every `members[].member` of a Grouping to resolve to a real `Disease.name`, module stem or grouping name. Only two of the six members curated here — Rocky Mountain spotted fever and boutonneuse fever — have standalone `kb/disorders/` entries; African tick-bite fever, rickettsialpox, Queensland tick typhus and North Asian tick typhus do not. A Grouping could therefore not list four of its six members at all, whereas `has_subtypes` carries them with their MONDO bindings and their evidence today and loses nothing when they are later promoted to standalone entries. Third, substance: several claims here are defined over the union and have no home on any member — the SFG taxon itself (NCBITaxon:114277), the group-versus-species resolution limit of rickettsial serology (PMID:27172113, PMID:10497980), the species-graded severity gradient (PMID:19091423, PMID:26394396), and the single all-ages doxycycline rule that is applied before the species is known (PMID:27172113). Note this differs from the thanatophoric-dysplasia case in one respect worth recording: there, a pre-existing grouping (`FGFR_Related_Skeletal_Dysplasias`) already unioned the members, so a second grouping would have been redundant. Here there is no rickettsial grouping at all, so the redundancy argument does not apply — the case rests on the coverage-index and foreign-key arguments instead. The counter-argument, that a Disease root duplicates content already held in the two curated member entries, is addressed by keeping this root deliberately thin: seven pathophysiology nodes, two of which are module `conforms_to` anchors, and explicit "not re-derived here" pointers on the nodes that the member entries carry in depth.
Posed by dismech curation (issue Posed 2026-08-19T00:00:00Z Resolved 2026-08-19T00:00:00Z
Resolution: Curated as a root `Disease` (this entry). No grouping was created. If African tick-bite fever, rickettsialpox, Queensland tick typhus and North Asian tick typhus are later curated as standalone entries, a `Grouping` over the six becomes viable and could be added alongside this root — it would then carry the auditable membership criteria that `has_subtypes` cannot express — but it would still not retire MONDO:0001195 from the priority queue, so this entry would remain.
Should the subtypes of this group be organised by causative Rickettsia species or by geography? The two largely co-vary, and MONDO's own children mix both conventions (Japanese spotted fever and African tick-bite fever are geographic labels; Rickettsia parkeri spotted fever is a species label).
INTERPRETATION RESOLVED sfr_subtype_axis_species_not_geography
Attached to
pathophysiology#Species-Graded Endothelial Inflammatory Response
Resolved in favour of the species. Geography is a downstream label set by the range of the vector tick, and it fails as an identity criterion in both directions. It is not one-to-one downward: a single species, R. conorii, carries four distinct geographically named diseases — Mediterranean spotted fever, Indian tick typhus, Israeli spotted fever and Astrakhan fever — which are genotypically homogeneous but serotypically and epidemio-clinically distinct (PMID:15766388). And it is not one-to-one upward: a single species, R. rickettsii, causes Rocky Mountain spotted fever in North America and Brazilian spotted fever in South America (PMID:28169507), so the geographic name changes while the organism does not. The species axis also tracks the thing that actually matters clinically. Severity across this group spans from self-limiting to frequently fatal, and that gradient follows the species-specific endothelial inflammatory response (PMID:19091423, PMID:26394396) rather than the latitude at which the tick bit. Geography is retained, but as the secondary descriptor it is: each `has_subtypes` entry carries a `geography` list alongside its species-named `display_name`.
Posed by dismech curation (issue Posed 2026-08-19T00:00:00Z Resolved 2026-08-19T00:00:00Z
Resolution: Subtypes are keyed on the causative species, with `geography` recorded per subtype. The list is explicitly non-exhaustive — MONDO:0001195 has seventeen descendants and new SFG species of undetermined pathogenicity continue to be described (PMID:24092850). The six curated here were chosen to span the severity range (RMSF to ATBF), both continents on which one species operates, both vector classes (tick and mite), and both naming traps ("tick typhus" that is SFG). Japanese spotted fever, Flinders Island spotted fever, Astrakhan spotted fever, Israeli tick typhus, Indian tick typhus, Far Eastern spotted fever, R. parkeri spotted fever and R. helvetica spotted fever all have MONDO terms and are candidates for a later tranche.
What exactly is the unifying criterion for membership of this group, given that the disease grouping, the arthropod vector and the current rickettsial phylogeny do not coincide?
OPEN QUESTION OPEN sfr_group_boundary_and_naming_traps
Three boundary problems sit under this entry, and they are recorded rather than resolved because resolving them is an ontology question, not a curation one. First, the vector is not the criterion. MONDO defines MONDO:0001195 as "a type of tick-borne disease", yet places rickettsialpox (MONDO:0019360) under it, and rickettsialpox is mite-borne (PMID:28846279). Either the definition is too narrow or rickettsialpox is misplaced. This entry takes the first reading and treats the rickettsial clade, not the arthropod, as the unifying criterion — which is the reading that matches how the diseases are diagnosed, since rickettsialpox eschars stain positive for spotted fever group rickettsiae (PMID:12860597). Second, the clade itself has moved. Gillespie et al. proposed a fourth rickettsial lineage, the transitional group, distinct from both the spotted fever and typhus groups (PMID:17342200), and both R. akari and R. australis have since been assigned to it (PMID:28846279). Two of the six members curated here are therefore, on current genomic classification, not spotted fever group organisms — while remaining spotted fever group DISEASES clinically, serologically and therapeutically. This entry keeps them, on the grounds that a dismech disease entry groups diseases by shared pathophysiology and management rather than by the current state of bacterial systematics, but a reviewer should know the tension exists and that MONDO has not tracked the reclassification. Third, the names lie in both directions. Queensland tick typhus and North Asian (Siberian) tick typhus are spotted fever group diseases despite the word "typhus" (PMID:28719297, PMID:22493192), whereas murine typhus and epidemic typhus are typhus group and scrub typhus is not even a Rickettsia (Orientia tsutsugamushi). This is a live Named Entity Confusion hazard for anyone curating from a deep-research report: a search on "tick typhus" will return both groups. `kb/disorders/Murine_Typhus.yaml` is deliberately NOT a member of this group and must not be added to it.
Posed by dismech curation (issue Posed 2026-08-19T00:00:00Z
What determines the severity gradient across spotted fever group species — from self-limiting African tick-bite fever to frequently fatal Rocky Mountain spotted fever — given that all members share the same endothelial target cell and the same intracytosolic lifestyle?
KNOWLEDGE GAP OPEN sfr_root_severity_gradient_mechanism
Attached to
pathophysiology#Species-Graded Endothelial Inflammatory Response
The evidence curated here establishes that the gradient exists and correlates with the strength of the endothelial inflammatory and barrier response the species provokes (PMID:19091423, PMID:26394396). It does not establish what makes one species provoke that response more strongly than another. The two studies cited compare only two species pairs (R. conorii versus R. africae; R. conorii ISF versus R. massiliae), both use immortalised or primary human endothelial monolayers rather than intact microvasculature, and neither identifies the bacterial determinant responsible. Host factors known to worsen individual members — G6PD deficiency in RMSF, age and comorbidity in MSF — are curated on the member entries and are a separate axis from the species difference modelled here.
Proposed experiments
Matched multi-species endothelial infection panel across the severity range
exp_sfr_multispecies_endothelial_panel
Infect a single human microvascular endothelial preparation with a panel of SFG species spanning the clinical severity range (R. rickettsii, R. conorii subsp. conorii, R. africae, R. akari, R. australis, R. parkeri) at matched multiplicity, and measure a common readout set — transendothelial electrical resistance, IL-8 and adhesion-molecule induction, and cell death — so that severity rank can be regressed against endothelial response rather than inferred from separate pairwise studies. Pair with comparative genomics across the same panel to nominate the bacterial determinants.
Posed by dismech curation (issue Posed 2026-08-19T00:00:00Z
⚙

Pathophysiology

7
Arthropod Inoculation of a Spotted Fever Group Rickettsia
A feeding tick — or, for rickettsialpox, a mite — deposits SFG rickettsiae in the dermis at the attachment site. In most members of the group this produces a local dermal lesion that necroses into an inoculation eschar; the resulting fever, rash and eschar triad is what makes the group clinically recognisable. The vector genus and the incubation period are member-specific and are curated on the member entries.
Downstream
Obligate Intracytosolic Infection of Microvascular Endothelium Inoculated organisms disseminate haematogenously and enter endothelial cells, the group's shared target cell.
Show evidence (2 references)
PMID:15109588 SUPPORT Other
"Most patients present with a mild-to-moderately severe flu-like illness typically accompanied by a cutaneous rash and an inoculation eschar at the site of the tick bite, but potentially life-threatening disease with disseminated vaculitis is occasionally seen."
States the shared presentation of the group in one sentence — the triad plus the severe vasculitic tail — and locates the eschar at the inoculation site. Evidence source is OTHER as this is a literature-based review.
PMID:27172113 SUPPORT Other
"Unlike some SFG rickettsioses, an inoculation eschar is rarely present with RMSF"
Bounds the triad claim: the eschar is characteristic of the group but is conspicuously absent in its most dangerous member, so its absence cannot be used to exclude the diagnosis. Evidence source is OTHER as this is a national recommendations report.
Obligate Intracytosolic Infection of Microvascular Endothelium
The mechanistic core shared by every member of the group. SFG rickettsiae adhere to and induce their own uptake by microvascular endothelial cells, escape the phagosome into the cytosol, and replicate free in the cytoplasm, exploiting host actin for both entry and intracellular movement. This node is the group-level statement of endothelial tropism only; the receptor-ligand detail, the actin-based motility machinery and the VE-cadherin biology are not re-derived here and are curated in `Rocky_Mountain_Spotted_Fever.yaml`.
microvascular endothelial cell CL:2000008 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves microvascular endothelial cell (CL:2000008). CL:2000008 is a cell type from the Cell Ontology. blood vessel endothelial cell CL:0000071 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves blood vessel endothelial cell (CL:0000071). CL:0000071 is a cell type from the Cell Ontology.
symbiont entry into host GO:0044409 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased symbiont entry into host (GO:0044409). GO:0044409 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Species-Graded Endothelial Inflammatory Response Infected endothelium mounts a cytokine, chemokine and adhesion-molecule response whose magnitude differs sharply between SFG species.
Disseminated Small-Vessel Vasculitis and Increased Vascular Permeability Multifocal infection of the microvasculature produces a disseminated vasculitis with barrier failure.
Show evidence (3 references)
PMID:30148688 SUPPORT Other
"Obligately intracytosolic rickettsiae that cycle between arthropod and vertebrate hosts cause human diseases with a spectrum of severity, primarily by targeting microvascular endothelial cells, resulting in endothelial dysfunction."
The definitive statement of the group-level mechanism: intracytosolic lifestyle, microvascular endothelial target, endothelial dysfunction as the outcome — and explicitly across a spectrum of severity. Evidence source is OTHER as this is a review article.
PMID:30148688 SUPPORT Other
"Rickettsiae interact with host cell actin to effect both cellular entry and intracellular actin-based mobility."
Supports the entry-and-spread step of this node. Evidence source is OTHER as this is a review article.
PMID:26394396 SUPPORT In Vitro
"Rickettsiae primarily target microvascular endothelial cells."
Independent confirmation of the target cell type from an experimental study comparing two SFG species in human endothelial monolayers.
Species-Graded Endothelial Inflammatory Response
The node that only a root entry can carry, because it is a statement about the differences between members rather than about any one of them. Members of the group share a target cell and a route of infection but differ by orders of magnitude in severity, from self-limiting African tick-bite fever to frequently fatal Rocky Mountain spotted fever. That gradient tracks how strongly the particular species drives interleukin-8 and adhesion-molecule expression in endothelium and how much endothelial barrier failure and cell death follow: R. conorii elicits a markedly stronger response in vitro and in patients than R. africae does, and the Israeli spotted fever strain of R. conorii collapses endothelial monolayer resistance where the mild pathogen R. massiliae does not.
microvascular endothelial cell CL:2000008 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves microvascular endothelial cell (CL:2000008). CL:2000008 is a cell type from the Cell Ontology.
interleukin-8 production GO:0032637 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased interleukin-8 production (GO:0032637). GO:0032637 is a biological process from the Gene Ontology. ↑ INCREASED leukocyte adhesion to vascular endothelial cell GO:0061756 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased leukocyte adhesion to vascular endothelial cell (GO:0061756). GO:0061756 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Disseminated Small-Vessel Vasculitis and Increased Vascular Permeability The strength of the endothelial inflammatory and barrier response sets how far the vasculitic lesion progresses in a given member of the group.
Show evidence (3 references)
PMID:19091423 SUPPORT Human Clinical
"Our findings suggest a superior inflammatory potential of R. conorii as compared to R. africae in endothelial cells, potentially related to the more severe inflammation in MSF comparing ATBF."
Directly links a species difference in endothelial inflammatory potential to the clinical severity difference between two members of the group, using paired in vitro and patient-serum measurements.
PMID:19091423 SUPPORT In Vitro
"R. conorii induced a marked increase in MCP-1, IL-8, and adhesion molecules in endothelial cells, involving toll-like receptor 4 activation."
Gives the specific mediators behind this node, supporting the IL-8 and leukocyte-adhesion process annotations.
PMID:26394396 SUPPORT In Vitro
"Monolayers of endothelial cells infected with R. conorii (ISF) showed a statistically significant decrease in electrical resistance across the monolayer compared to both R. massiliae-infected and uninfected cells at 72 HPI, suggesting increased endothelial permeability."
A second, independent species pair showing the same pattern — a virulent SFG species disrupts the endothelial barrier where a mild one does not — measured as transendothelial electrical resistance.
Disseminated Small-Vessel Vasculitis and Increased Vascular Permeability
Multifocal endothelial infection and injury produce a disseminated small-vessel vasculitis with perivascular mononuclear infiltration and loss of endothelial barrier integrity. This is the single lesion that explains the group's rash, and at its severe end the oedema of the lungs and brain. The downstream haemostatic detail — platelet consumption, fibrin thrombi, disseminated intravascular coagulation — is member-specific and is curated in `Rocky_Mountain_Spotted_Fever.yaml` rather than repeated here.
blood vessel endothelial cell CL:0000071 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves blood vessel endothelial cell (CL:0000071). CL:0000071 is a cell type from the Cell Ontology.
inflammatory response GO:0006954 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased inflammatory response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology. ↑ INCREASED positive regulation of vascular permeability GO:0043117 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased positive regulation of vascular permeability (GO:0043117). GO:0043117 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Severe End-Organ Involvement of the Lung and Brain Where permeability failure is extensive, plasma leaks into the pulmonary interstitium and the brain.
Show evidence (2 references)
PMID:15109588 SUPPORT Other
"Most patients present with a mild-to-moderately severe flu-like illness typically accompanied by a cutaneous rash and an inoculation eschar at the site of the tick bite, but potentially life-threatening disease with disseminated vaculitis is occasionally seen."
Names disseminated vasculitis as the lesion of severe disease across the group. Evidence source is OTHER as this is a literature-based review.
PMID:30148688 SUPPORT Other
"Obligately intracytosolic rickettsiae that cycle between arthropod and vertebrate hosts cause human diseases with a spectrum of severity, primarily by targeting microvascular endothelial cells, resulting in endothelial dysfunction."
Endothelial dysfunction is stated as the common outcome of infection across the group, which is the barrier-failure half of this node. Evidence source is OTHER as this is a review article.
Severe End-Organ Involvement of the Lung and Brain
The severe tail of the group. Vascular leak in the pulmonary microcirculation produces non-cardiogenic pulmonary oedema and respiratory failure; in the central nervous system it produces meningoencephalitis with seizures and coma. These two are the proximate causes of death across the group, and in a large Brazilian case-control series seizures and coma were the strongest predictors of a fatal outcome. Which members reach this node, and how often, differs by species — that dependency is the point of the `Species-Graded Endothelial Inflammatory Response` node above.
positive regulation of vascular permeability GO:0043117 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased positive regulation of vascular permeability (GO:0043117). GO:0043117 is a biological process from the Gene Ontology. ↑ INCREASED
lung UBERON:0002048 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in lung (UBERON:0002048). UBERON:0002048 is an anatomical location from the Uberon multi-species anatomy ontology. brain UBERON:0000955 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in brain (UBERON:0000955). UBERON:0000955 is an anatomical location from the Uberon multi-species anatomy ontology.
Show evidence (2 references)
PMID:28169507 SUPPORT Human Clinical
"seizures (OR, 11.24; 95% CI, 6.49-19.45) and coma (OR of 15.16; 95% CI, 8.51-27.02)"
Quantifies the neurological arm of this node as the strongest predictor of death in a 386-case, 415-control series of tick-borne spotted fever.
PMID:15109588 SUPPORT Other
"Most patients present with a mild-to-moderately severe flu-like illness typically accompanied by a cutaneous rash and an inoculation eschar at the site of the tick bite, but potentially life-threatening disease with disseminated vaculitis is occasionally seen."
Establishes that a life-threatening vasculitic course occurs across the group but is the exception rather than the rule. Recorded as PARTIAL because it does not name the specific pulmonary and neurological end-organs. Evidence source is OTHER as this is a literature-based review.
Rickettsial Ribosomal Translation (Doxycycline Target)
Every member of the group depends on its own 70S ribosome for protein synthesis, and that ribosome — not a cell-wall target — is what doxycycline inhibits. The molecular mechanism is held once in the `bacterial_protein_synthesis_inhibition` module and is not re-derived here; this node exists so the group-level doxycycline recommendation has a mechanism node to point at.
translation GO:0006412 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves translation (GO:0006412). GO:0006412 is a biological process from the Gene Ontology.
Show evidence (2 references)
PMID:24336183 SUPPORT Other
"The ribosome is one of the main antibiotic targets in the bacterial cell."
Establishes the bacterial ribosome as the target of the tetracyclines and the other protein-synthesis inhibitors — the molecular step this node represents. The same reference anchors the equivalent node in `Rocky_Mountain_Spotted_Fever.yaml` and `Murine_Typhus.yaml`. Evidence source is OTHER as this is a review article.
PMID:15109588 SUPPORT Other
"Doxycycline is the recommended treatment for tick-borne rickettsioses and prevention is based on personal protective measures against tick bites when travelling in endemic areas."
Establishes at group level that a tetracycline — a ribosome-targeting agent — is the recommended therapy, which is the clinical fact this target node underwrites. Evidence source is OTHER as this is a literature-based review.
Obligate Intracytosolic Niche (Cell-Penetrant Drug Requirement)
Because SFG rickettsiae replicate free in the host cell cytosol, effective therapy is restricted to agents that accumulate intracellularly. Doxycycline does; beta-lactams do not reach the organism whatever their in vitro activity. This is the pharmacokinetic gate that, together with the ribosomal target above, makes doxycycline first-line for every member of the group regardless of species or geography. The gating principle itself is held once in the `intracellular_pathogen_persistence` module.
response to antibiotic GO:0046677 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves response to antibiotic (GO:0046677). GO:0046677 is a biological process from the Gene Ontology.
Show evidence (4 references)
PMID:30148688 SUPPORT Other
"Obligately intracytosolic rickettsiae that cycle between arthropod and vertebrate hosts cause human diseases with a spectrum of severity, primarily by targeting microvascular endothelial cells, resulting in endothelial dysfunction."
Establishes the obligately intracytosolic lifestyle that creates the penetration constraint this node represents. Evidence source is OTHER as this is a review article.
PMID:18611821 SUPPORT Other
"The intracellular location of some microorganisms allow them to resist antibiotics with poor ability to penetrate eukaryotic cell membranes, such as the beta-lactam compounds."
The exclusion half of the gating principle: the intracellular niche confers resistance to poorly cell-penetrant agents such as the beta-lactams. This is the same anchor the `intracellular_pathogen_persistence` module uses. Evidence source is OTHER as this is a review article.
PMID:28639230 SUPPORT Other
"Therapeutic efficacy against intracellular pathogens has been correlated mainly with the intracellular concentrations achieved by the different antimicrobial agents."
The requirement half of the gating principle, and the evidence the module node this entry conforms to is itself built on: efficacy tracks the intracellular concentration achieved, not the in vitro MIC. Evidence source is OTHER as this is a review article.
+ 1 more reference
⬡

Pathograph

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

Phenotypes

5
Immune 1
Skin rash HP:0000988 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Skin rash (HP:0000988). HP:0000988 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:15109588 SUPPORT Other
"Most patients present with a mild-to-moderately severe flu-like illness typically accompanied by a cutaneous rash and an inoculation eschar at the site of the tick bite, but potentially life-threatening disease with disseminated vaculitis is occasionally seen."
States the rash as a typical accompaniment across the group. `frequency` is deliberately omitted: "typically accompanied by" does not license a band, and the one quantitative cohort cited here reports rash in half or fewer of ATBF patients, so no single band holds across the group. Evidence source is OTHER as this is a literature-based review.
Metabolism 1
Fever HP:0001945 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fever (HP:0001945). HP:0001945 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:12766836 SUPPORT Human Clinical
"More than 80% of the patients had fever, headache, and/or myalgia, whereas specific clinical features such as inoculation eschars, lymphadenitis, cutaneous rash, and aphthous stomatitis were seen in < or = 50% of patients."
Establishes that fever belongs to the dominant early symptom complex, but supports the phenotype only PARTIALLY and supports no frequency band. The reported ">80%" is a disjunction — it counts patients with fever, headache and/or myalgia, so it cannot be distributed across its three disjuncts to give a rate for fever alone. The denominator is also a single member (n=38 African tick-bite fever patients, the mildest member of the group) rather than the group. `frequency` is therefore omitted, on the same grounds as for rash and eschar below, which are bounded by the second half of this same sentence.
Nervous System 1
Headache HP:0002315 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Headache (HP:0002315). HP:0002315 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:12766836 SUPPORT Human Clinical
"More than 80% of the patients had fever, headache, and/or myalgia, whereas specific clinical features such as inoculation eschars, lymphadenitis, cutaneous rash, and aphthous stomatitis were seen in < or = 50% of patients."
Places headache in the dominant early symptom complex. Recorded as PARTIAL and with no frequency band: the cohort reports the three symptoms as an "and/or" disjunction, so the ">80%" figure applies to the complex as a whole and cannot be read as a rate for headache.
Constitutional 1
Myalgia HP:0003326 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myalgia (HP:0003326). HP:0003326 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:12766836 SUPPORT Human Clinical
"More than 80% of the patients had fever, headache, and/or myalgia, whereas specific clinical features such as inoculation eschars, lymphadenitis, cutaneous rash, and aphthous stomatitis were seen in < or = 50% of patients."
Places myalgia in the dominant early symptom complex. Recorded as PARTIAL and with no frequency band, for the same reason as fever and headache above — the ">80%" figure is reported over an "and/or" disjunction of the three symptoms and is not divisible among them.
Other 1
Inoculation eschar HP:6000793 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Eschar (HP:6000793). HP:6000793 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:15109588 SUPPORT Other
"Most patients present with a mild-to-moderately severe flu-like illness typically accompanied by a cutaneous rash and an inoculation eschar at the site of the tick bite, but potentially life-threatening disease with disseminated vaculitis is occasionally seen."
States the inoculation eschar as a typical group-level feature and locates it at the bite site. Evidence source is OTHER as this is a literature-based review.
PMID:27172113 SUPPORT Other
"Unlike some SFG rickettsioses, an inoculation eschar is rarely present with RMSF"
Recorded as PARTIAL because it supports the phenotype's presence in the group only by contrast, while refuting its presence in one member. That is exactly the bound the description records, and it is why `frequency` is omitted. Evidence source is OTHER as this is a national recommendations report.
💊

Medical Actions

1
Empiric doxycycline for all patients of all ages
Category: Therapeutic Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: doxycycline CHEBI:50845 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses doxycycline (CHEBI:50845). CHEBI:50845 is a therapeutic agent from Chemical Entities of Biological Interest.
One recommendation covers the entire group: doxycycline, started immediately on clinical suspicion, in patients of every age including children under eight. This is a genuinely group-level rule — it does not depend on which SFG species is involved, and it is made before the species (or often even the group) is known, which is what makes it a root-level claim rather than a per-member one. Its two mechanistic legs are the shared rickettsial ribosome and the shared cytosolic niche, both modelled above. The historical reluctance to give doxycycline to young children has been overturned: the concern derived from older tetracyclines that bind calcium more readily, and a CDC cohort of 58 children given short courses before age eight showed no dental staining, no enamel hypoplasia and no difference in tooth shade against 213 unexposed controls. Per-member specifics — the day-5 mortality window in RMSF, the sulfonamide contraindication, macrolide alternatives in pregnancy — are curated on the member entries.
Mechanism Target:
INHIBITS Rickettsial Ribosomal Translation (Doxycycline Target) — Doxycycline binds the bacterial 30S ribosomal subunit and arrests rickettsial protein synthesis. The molecular detail is held in the `bacterial_protein_synthesis_inhibition` module.
Show evidence (1 reference)
PMID:15109588 SUPPORT Other
"Doxycycline is the recommended treatment for tick-borne rickettsioses and prevention is based on personal protective measures against tick bites when travelling in endemic areas."
Establishes that the recommended agent for the group is a tetracycline, that is, a ribosome-targeting drug acting on this node. Evidence source is OTHER as this is a literature-based review.
BYPASSES Obligate Intracytosolic Niche (Cell-Penetrant Drug Requirement) — Doxycycline accumulates within host cells and so reaches the cytosolic organism that poorly penetrant agents such as the beta-lactams cannot.
Show evidence (1 reference)
PMID:27172113 SUPPORT Other
"Doxycycline is the drug of choice for treatment of all tickborne rickettsial diseases in patients of all ages, including children aged <8 years"
A single cell-penetrant agent is recommended across the whole group, which is the clinical expression of this pharmacokinetic gate. Evidence source is OTHER as this is a national recommendations report.
Show evidence (5 references)
PMID:27172113 SUPPORT Other
"Doxycycline is the drug of choice for treatment of all tickborne rickettsial diseases in patients of all ages, including children aged <8 years"
The group-level recommendation in the CDC's own words, covering all members and all ages. Evidence source is OTHER as this is a national recommendations report.
PMID:27172113 SUPPORT Other
"The American Academy of Pediatrics and CDC recommend doxycycline as the treatment of choice for children of all ages with suspected tickborne rickettsial disease"
The paediatric arm of the recommendation, endorsed jointly by AAP and CDC. Evidence source is OTHER as this is a national recommendations report.
PMID:27172113 SUPPORT Other
"Previous concerns about tooth staining in children aged <8 years stem from experience with older tetracycline-class drugs that bind more readily to calcium than newer members of the drug class, such as doxycycline"
Explains why the old paediatric contraindication was wrong for doxycycline specifically — it was inherited from drugs with different calcium binding. Evidence source is OTHER as this is a national recommendations report.
+ 2 more references
🔬

Diagnosis

2
Empiric clinical and epidemiologic diagnosis
Across the whole group, the diagnosis is made clinically and epidemiologically and treatment is started on suspicion. Confirmatory testing is retrospective in practice, an absent tick-bite history is common and does not argue against the diagnosis, and waiting for a laboratory result costs lives.
clinical evaluation NCIT:C124351 NCI Thesaurus (NCIT)
`diagnosis_term` is bound to `NCIT:C124351` (Clinical Evaluation) rather than the broader laboratory-procedure term used for the same node in `Rocky_Mountain_Spotted_Fever.yaml`. The divergence is deliberate: this node's claim is that treatment starts on clinical and epidemiologic grounds *without* laboratory confirmation, so a laboratory-procedure term would contradict the claim it annotates. The specific confirmatory modalities (paired-serum IFA, whole-blood PCR, eschar-swab PCR, immunohistochemistry on skin biopsy) are curated with their own terms on the member entries.
Show evidence (2 references)
PMID:15109588 SUPPORT Other
"Definite microbiological confirmation of tick-borne rickettsioses by isolation or antigen detection is only available at reference laboratories and diagnosis must in most cases rely on clinical and epidemiological data supported by serology."
States the group-level diagnostic reality: clinical and epidemiological assessment, with serology as support rather than as the primary test. Evidence source is OTHER as this is a literature-based review.
PMID:15109588 SUPPORT Other
"Only a minority of infected travellers can recall a preceding tick bite."
Supports the specific caution that an absent exposure history does not exclude the diagnosis. Evidence source is OTHER as this is a literature-based review.
Group-specific serology and the species-level limit
Serology is the mainstay of confirmation for the whole group, and it is group-specific rather than species-specific. The immunodominant response is against spotted fever group lipopolysaccharide, which is shared, rather than against the OmpA and OmpB outer-membrane proteins that carry the species-specific epitopes. A reactive R. rickettsii titre therefore establishes infection with an SFG rickettsia, not with R. rickettsii — which is why species assignment needs cross-adsorption, Western blot, PCR or culture, and why the individual member diseases are so often reported as an undifferentiated "spotted fever group rickettsiosis". This is a claim about the group as a whole and has no home on any member entry.
serologic testing NCIT:C25294 NCI Thesaurus (NCIT)
Show evidence (3 references)
PMID:27172113 SUPPORT Other
"Cross-reactive immune responses to rickettsial antigens result in antibodies that are typically group-specific, although perhaps not species-specific, for tickborne rickettsial pathogens"
The direct statement of the group-versus-species resolution limit of rickettsial serology. Evidence source is OTHER as this is a national recommendations report.
PMID:27172113 SUPPORT Other
"antibodies reactive with R. rickettsii detected by a serologic test could result from infection with other SFG rickettsiae"
The worked consequence: a positive R. rickettsii serology does not identify the species. Evidence source is OTHER as this is a national recommendations report.
PMID:10497980 SUPPORT Human Clinical
"Immunoblotting with antigens of R. akari identified antibodies against antigens of spotted fever group lipopolysaccharides and not against rickettsial outer membrane proteins A and B, which contain the species-specific epitopes."
Gives the molecular reason for the cross-reactivity: the dominant response is against shared group lipopolysaccharide rather than the species-specific OmpA and OmpB epitopes.
🦠

Infectious Agent

7
Spotted fever group Rickettsia
The taxon that defines this disease group. SFG rickettsiae are obligately intracytosolic Gram-negative bacteria that cycle between an arthropod vector and a vertebrate host and that share an endothelial tropism in humans. Membership of this clade — not the identity of the arthropod, and not the geography of the disease name — is the unifying criterion for the entries grouped here.
spotted fever group NCBITaxon:114277 NCBI Taxonomy (NCBITaxon)
Show evidence (2 references)
PMID:24092850 SUPPORT Other
"Tick-borne rickettsioses are caused by obligate intracellular bacteria belonging to the spotted fever group of the genus Rickettsia."
Defines the group by its taxon and by the obligate intracellular lifestyle. Evidence source is OTHER as this is a review article.
PMID:24092850 SUPPORT Other
"Several species of tick-borne rickettsiae that were considered nonpathogenic for decades are now associated with human infections, and novel Rickettsia species of undetermined pathogenicity continue to be detected in or isolated from ticks around the world."
Establishes that the membership of this group is open and still growing, which is why the subtype list below is explicitly non-exhaustive.
Rickettsia rickettsii
Agent of Rocky Mountain spotted fever in North America and of Brazilian spotted fever in South America; the most virulent member of the group.
Rickettsia rickettsii NCBITaxon:783 NCBI Taxonomy (NCBITaxon)
Show evidence (1 reference)
PMID:17961858 SUPPORT Other
"Rocky Mountain spotted fever (RMSF) is a life-threatening disease caused by Rickettsia rickettsii, an obligately intracellular bacterium that is spread to human beings by ticks."
Assigns the species to its disease. Evidence source is OTHER as this is a review article.
Rickettsia conorii
Agent of Mediterranean spotted fever (boutonneuse fever) and, through its subspecies indica, israelensis and caspia, of Indian tick typhus, Israeli spotted fever and Astrakhan fever.
Rickettsia conorii NCBITaxon:781 NCBI Taxonomy (NCBITaxon)
Show evidence (1 reference)
PMID:15766388 SUPPORT Other
"Although homogeneous genotypically, strains within the R. conorii species show MST genotypic, serotypic, and epidemio-clinical dissimilarities."
Establishes that one genotypically homogeneous species underlies several epidemiologically and clinically distinct named diseases. Evidence source is OTHER as this is a bacterial taxonomy proposal.
Rickettsia africae
Agent of African tick-bite fever; a mild, self-limiting member of the group that provokes a markedly weaker endothelial inflammatory response than R. conorii.
Rickettsia africae NCBITaxon:35788 NCBI Taxonomy (NCBITaxon)
Show evidence (1 reference)
PMID:19091423 SUPPORT Human Clinical
"Mediterranean spotted fever (MSF) caused by Rickettsia conorii (R. conorii) is a potential lethal disease while African tick bite fever (ATBF) caused by Rickettsia africae is a self-limiting flu-like illness."
Assigns the species to its disease and states its comparative severity.
Rickettsia akari
Agent of rickettsialpox, transmitted by the house mouse mite rather than a tick. Historically classified within the spotted fever group and still grouped with it clinically and serologically, but reassigned to the transitional group on genomic grounds.
Rickettsia akari NCBITaxon:786 NCBI Taxonomy (NCBITaxon)
Show evidence (1 reference)
PMID:28846279 SUPPORT Other
"R. akari was initially classified as a member of the spotted fever group (SFG) of rickettsia, but it is now placed in the transitional group, which has features of both the spotted fever group and the typhus group (TG) of rickettsiae."
States both the historical SFG placement that underlies the disease grouping and the later genomic reassignment. Evidence source is OTHER as this is a reference-text chapter.
Rickettsia australis
Agent of Queensland tick typhus in eastern Australia. Like R. akari it has been assigned to the transitional group on genomic grounds while remaining a spotted fever group infection clinically.
Rickettsia australis NCBITaxon:787 NCBI Taxonomy (NCBITaxon)
Show evidence (1 reference)
PMID:28719297 SUPPORT Other
"Rickettsia australis, the etiologic agent of Queensland tick typhus (QTT), is increasingly being recognized as a cause of community-acquired acute febrile illness in eastern Australia."
Assigns the species to its disease. Evidence source is OTHER as this is a review article.
Rickettsia sibirica subsp. sibirica
Agent of North Asian (Siberian) tick typhus across Siberia, Mongolia, Kazakhstan and eastern China.
Rickettsia sibirica subsp. sibirica NCBITaxon:1144281 NCBI Taxonomy (NCBITaxon)
Show evidence (1 reference)
PMID:22493192 SUPPORT Other
"Rickettsia sibirica sibirica is the causative agent of Siberian or North Asian tick typhus, a tick-borne rickettsiosis known to exist in Siberia and eastern China."
Assigns the subspecies to its disease. Evidence source is OTHER as this is a genome announcement.
↔️

Transmission

2
Tick bite inoculation
For every member of the group except rickettsialpox, the organism is inoculated by a feeding ixodid tick. Which tick genus is involved varies by rickettsial species and therefore by geography — Dermacentor and Rhipicephalus for R. rickettsii, Rhipicephalus sanguineus for R. conorii, Amblyomma for R. africae, Ixodes for R. australis — but the route is common to the group, and most patients cannot recall the bite.
Show evidence (2 references)
PMID:24092850 SUPPORT Other
"Tick-borne rickettsioses are caused by obligate intracellular bacteria belonging to the spotted fever group of the genus Rickettsia."
Establishes the tick route as definitional for the group. Evidence source is OTHER as this is a review article.
PMID:15109588 SUPPORT Other
"Only a minority of infected travellers can recall a preceding tick bite."
A group-level observation with direct diagnostic consequence: an absent bite history does not argue against the diagnosis. Evidence source is OTHER as this is a literature-based review.
Mite bite inoculation (rickettsialpox)
Rickettsialpox is the exception to the tick route: R. akari is transmitted by the house mouse mite Liponyssoides sanguineus in an urban rodent cycle. This is the reason the group cannot be defined by its arthropod vector.
Show evidence (1 reference)
PMID:28846279 SUPPORT Other
"R. akari is transmitted by the house mouse mite, Liponyssoides sanguineus."
Names the mite vector for the one non-tick-borne member listed here. Evidence source is OTHER as this is a reference-text chapter.
{ }

Source YAML

click to show 
name: Spotted fever rickettsiosis
creation_date: '2026-08-19T00:00:00Z'
category: Infectious Disease
description: >
  Spotted fever rickettsiosis is the group of acute febrile illnesses caused by the
  spotted fever group (SFG) of the genus Rickettsia — obligately intracytosolic,
  Gram-negative bacteria acquired from a feeding tick (or, for rickettsialpox, a
  mite). Whatever the species, the mechanism is the same: the organism is inoculated
  at the arthropod attachment site, disseminates haematogenously, and replicates
  inside microvascular endothelial cells, producing a disseminated small-vessel
  vasculitis with increased vascular permeability. That single lesion accounts for
  the group's shared clinical signature — fever, headache and myalgia, a
  centrifugally or centripetally spreading rash, and (in most members, though
  notably not in Rocky Mountain spotted fever) an inoculation eschar at the bite
  site — and, at the severe end, for non-cardiogenic pulmonary oedema and
  encephalitis. Members differ enormously in severity, from the self-limiting
  African tick-bite fever to the frequently fatal Rocky Mountain spotted fever, and
  that gradient tracks the species-specific inflammatory response the organism
  provokes in endothelium rather than any difference in the route of infection.

  This root entry is deliberately thin. It carries only what is defined over the
  group as a whole: the SFG taxon itself and the species-versus-geography naming
  problem, the shared eschar/fever/rash triad and how eschar frequency varies by
  species, the group-level serologic cross-reactivity that makes species-level
  diagnosis hard, the shared doxycycline-first-line logic including its paediatric
  arm, and the SFG-versus-typhus-group boundary. Per-member pathophysiology,
  epidemiology, phenotype frequencies and treatment detail live in the individual
  entries — `Rocky_Mountain_Spotted_Fever.yaml` and `Boutonneuse_Fever.yaml` are
  curated in full — and the antimicrobial mechanism is held once in
  `kb/modules/bacterial_protein_synthesis_inhibition.yaml` and
  `kb/modules/intracellular_pathogen_persistence.yaml`.
disease_term:
  preferred_term: spotted fever
  term:
    id: MONDO:0001195
    label: spotted fever
synonyms:
- Spotted fever
- Spotted fever group rickettsiosis
- SFG rickettsioses
- Spotted fever rickettsiae disease
- Tick-borne rickettsiosis
parents:
- Rickettsiaceae infectious disease
- Vector-borne disease
- Rickettsial disease
classifications:
  harrisons_chapter:
  - classification_value: INFECTIOUS_DISEASES
    evidence:
    - reference: PMID:24092850
      reference_title: "Update on tick-borne rickettsioses around the world: a geographic approach."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Tick-borne rickettsioses are caused by obligate intracellular bacteria
        belonging to the spotted fever group of the genus Rickettsia.
      explanation: >-
        The spotted fever group rickettsioses are acute bacterial infections acquired
        from an arthropod vector, placing the group in Harrison's Infectious Diseases
        Part. Evidence source is OTHER as this is a review article.

has_subtypes:
- name: RMSF
  display_name: Rocky Mountain spotted fever (Rickettsia rickettsii)
  classification: etiologic_species
  geography:
  - United States
  - Mexico
  - Central America
  - Brazil
  - Argentina
  description: >-
    Caused by Rickettsia rickettsii and transmitted by Dermacentor and Rhipicephalus
    ticks. The most severe member of the group and the one in which an inoculation
    eschar is characteristically absent. Its range demonstrates that the species axis
    and the geographic axis do not coincide: the same organism causes Rocky Mountain
    spotted fever in North America and Brazilian spotted fever / febre maculosa in
    South America. Curated in full in `Rocky_Mountain_Spotted_Fever.yaml`.
  subtype_term:
    preferred_term: Rocky mountain spotted fever
    term:
      id: MONDO:0019359
      label: Rocky mountain spotted fever
  evidence:
  - reference: PMID:17961858
    reference_title: Rocky Mountain spotted fever.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Rocky Mountain spotted fever (RMSF) is a life-threatening disease caused by
      Rickettsia rickettsii, an obligately intracellular bacterium that is spread to
      human beings by ticks.
    explanation: >-
      Names the causative species and the tick route for this member. Evidence source
      is OTHER as this is a review article.
  - reference: PMID:28169507
    reference_title: Predictive Factors for Fatal Tick-Borne Spotted Fever in Brazil.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In Brazil, two pathogenic Rickettsia species have been identified causing
      tick-borne spotted fever (SF).
    explanation: >-
      Establishes that R. rickettsii spotted fever is a South American as well as a
      North American disease — the concrete case in which the species and geographic
      axes come apart.
- name: MSF
  display_name: Mediterranean spotted fever / boutonneuse fever (Rickettsia conorii)
  classification: etiologic_species
  geography:
  - Mediterranean basin
  - Southern Europe
  - North Africa
  - Sub-Saharan Africa
  - Middle East
  - India
  description: >-
    Caused by Rickettsia conorii and transmitted by the brown dog tick Rhipicephalus
    sanguineus; the inoculation eschar is the classic tache noire. This member is the
    clearest illustration of why the primary axis is the species and not the place:
    one species carries four geographically named diseases — Mediterranean spotted
    fever (subsp. conorii), Indian tick typhus (subsp. indica), Israeli spotted fever
    (subsp. israelensis) and Astrakhan fever (subsp. caspia). Curated in full in
    `Boutonneuse_Fever.yaml`.
  subtype_term:
    preferred_term: boutonneuse fever
    term:
      id: MONDO:0024472
      label: boutonneuse fever
  evidence:
  - reference: PMID:23168048
    reference_title: Mediterranean spotted fever in the Trakya region of Turkey.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mediterranean spotted fever (MSF) is caused by a tick-borne pathogen, Rickettsia
      conorii subsp. conorii, belonging to the spotted fever group (SFG) rickettsiae.
    explanation: >-
      Names the causative subspecies and states its membership of the spotted fever
      group.
  - reference: PMID:15766388
    reference_title: >-
      Proposal to create subspecies of Rickettsia conorii based on multi-locus sequence
      typing and an emended description of Rickettsia conorii.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Rickettsiae closely related to the Malish strain, the reference Rickettsia conorii
      strain, include Indian tick typhus rickettsia (ITTR), Israeli spotted fever
      rickettsia (ISFR), and Astrakhan fever rickettsia (AFR).
    explanation: >-
      Enumerates the four geographically named diseases that a single species accounts
      for, which is the evidence behind treating species as the primary subtype axis.
- name: ATBF
  display_name: African tick-bite fever (Rickettsia africae)
  classification: etiologic_species
  geography:
  - Sub-Saharan Africa
  - Eastern Caribbean
  description: >-
    Caused by Rickettsia africae and transmitted by Amblyomma ticks. The mildest
    commonly encountered member: a self-limiting flu-like illness in which fever,
    headache and myalgia are near-universal but the specific features — inoculation
    eschars (often multiple), lymphadenitis and rash — are present in only about half
    of patients. The commonest tick-borne rickettsiosis in returning travellers. No
    standalone dismech entry yet.
  subtype_term:
    preferred_term: African tick-bite fever
    term:
      id: MONDO:0000227
      label: African tick-bite fever
  evidence:
  - reference: PMID:12766836
    reference_title: African tick bite fever in travelers to rural sub-Equatorial Africa.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      More than 80% of the patients had fever, headache, and/or myalgia, whereas
      specific clinical features such as inoculation eschars, lymphadenitis, cutaneous
      rash, and aphthous stomatitis were seen in < or = 50% of patients.
    explanation: >-
      A prospective cohort of 940 travellers quantifying the ATBF presentation, and
      showing that the eschar is not a constant feature even in a member of the group
      in which it is characteristic.
  - reference: PMID:19091423
    reference_title: >-
      Relative chemokine and adhesion molecule expression in Mediterranean spotted
      fever and African tick bite fever.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mediterranean spotted fever (MSF) caused by Rickettsia conorii (R. conorii) is a
      potential lethal disease while African tick bite fever (ATBF) caused by
      Rickettsia africae is a self-limiting flu-like illness.
    explanation: >-
      States the severity contrast between two members of the same group, which is what
      makes species rather than geography the discriminating axis.
- name: Rickettsialpox
  display_name: Rickettsialpox (Rickettsia akari)
  classification: etiologic_species
  geography:
  - United States
  - Ukraine
  - Croatia
  - Turkey
  - Republic of Korea
  description: >-
    Caused by Rickettsia akari, and the one member of this list that is not
    tick-borne: it is transmitted by the house mouse mite Liponyssoides sanguineus in
    an urban rodent cycle. An eschar at the mite bite is followed by a papulovesicular
    rash. Its inclusion is deliberate and is what fixes the group's unifying criterion
    as the rickettsial clade rather than the arthropod vector; see the
    `sfr_group_boundary_and_naming_traps` discussion, which also records that R. akari
    has since been reassigned to the transitional group. No standalone dismech entry
    yet.
  subtype_term:
    preferred_term: rickettsialpox
    term:
      id: MONDO:0019360
      label: rickettsialpox
  evidence:
  - reference: PMID:12860597
    reference_title: "Rickettsialpox in New York City: a persistent urban zoonosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      IHC staining of biopsy specimens of eschars and papular lesions were positive for
      spotted fever group rickettsiae for 32 patients.
    explanation: >-
      Confirmed rickettsialpox cases staining positive for spotted fever group
      rickettsiae — the serologic and immunohistochemical basis on which the disease is
      classified with this group.
  - reference: PMID:28846279
    reference_title: Rickettsia akari (Rickettsialpox).
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      R. akari is transmitted by the house mouse mite, Liponyssoides sanguineus.
    explanation: >-
      States the mite (not tick) vector, the fact that prevents the group from being
      defined by its arthropod. Evidence source is OTHER as this is a reference-text
      chapter rather than a primary study.
- name: QTT
  display_name: Queensland tick typhus (Rickettsia australis)
  classification: etiologic_species
  geography:
  - Eastern Australia
  description: >-
    Caused by Rickettsia australis and transmitted by Ixodes holocyclus and Ixodes
    tasmani. Despite the word "typhus" in its name this is a spotted fever group
    infection, not a typhus group one — see the `sfr_group_boundary_and_naming_traps`
    discussion. No standalone dismech entry yet.
  subtype_term:
    preferred_term: Queensland tick typhus
    term:
      id: MONDO:0001118
      label: Queensland tick typhus
  evidence:
  - reference: PMID:28719297
    reference_title: >-
      Rickettsia australis and Queensland Tick Typhus: A Rickettsial Spotted Fever
      Group Infection in Australia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Rickettsia australis, the etiologic agent of Queensland tick typhus (QTT), is
      increasingly being recognized as a cause of community-acquired acute febrile
      illness in eastern Australia.
    explanation: >-
      Names the causative species and the geographic range, and — in a review whose
      title states the point explicitly — places a disease called "tick typhus" in the
      spotted fever group. Evidence source is OTHER as this is a review article.
- name: NATT
  display_name: North Asian (Siberian) tick typhus (Rickettsia sibirica subsp. sibirica)
  classification: etiologic_species
  geography:
  - Siberia
  - Eastern China
  - Mongolia
  - Kazakhstan
  description: >-
    Caused by Rickettsia sibirica subsp. sibirica and transmitted by Dermacentor and
    Haemaphysalis ticks. The second "tick typhus" in this list that is in fact a
    spotted fever group disease. Note that the sibling subspecies R. sibirica subsp.
    mongolitimonae causes a separate Mediterranean-spotted-fever-like illness in Europe
    and Africa, so even within one species the geographic label is not a reliable
    identifier. No standalone dismech entry yet.
  subtype_term:
    preferred_term: Siberian tick typhus
    term:
      id: MONDO:0001154
      label: Siberian tick typhus
  evidence:
  - reference: PMID:22493192
    reference_title: Sequence and annotation of Rickettsia sibirica sibirica genome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Rickettsia sibirica sibirica is the causative agent of Siberian or North Asian
      tick typhus, a tick-borne rickettsiosis known to exist in Siberia and eastern
      China.
    explanation: >-
      Establishes the subspecies-to-disease mapping and the geographic range, and
      confirms that the entity called North Asian tick typhus is a rickettsiosis of
      this group. Evidence source is OTHER as this is a genome announcement.

infectious_agent:
- name: Spotted fever group Rickettsia
  infectious_agent_term:
    preferred_term: spotted fever group
    term:
      id: NCBITaxon:114277
      label: spotted fever group
  description: >-
    The taxon that defines this disease group. SFG rickettsiae are obligately
    intracytosolic Gram-negative bacteria that cycle between an arthropod vector and a
    vertebrate host and that share an endothelial tropism in humans. Membership of this
    clade — not the identity of the arthropod, and not the geography of the disease
    name — is the unifying criterion for the entries grouped here.
  evidence:
  - reference: PMID:24092850
    reference_title: "Update on tick-borne rickettsioses around the world: a geographic approach."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Tick-borne rickettsioses are caused by obligate intracellular bacteria belonging
      to the spotted fever group of the genus Rickettsia.
    explanation: >-
      Defines the group by its taxon and by the obligate intracellular lifestyle.
      Evidence source is OTHER as this is a review article.
  - reference: PMID:24092850
    reference_title: "Update on tick-borne rickettsioses around the world: a geographic approach."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Several species of tick-borne rickettsiae that were considered nonpathogenic for
      decades are now associated with human infections, and novel Rickettsia species of
      undetermined pathogenicity continue to be detected in or isolated from ticks
      around the world.
    explanation: >-
      Establishes that the membership of this group is open and still growing, which is
      why the subtype list below is explicitly non-exhaustive.
- name: Rickettsia rickettsii
  infectious_agent_term:
    preferred_term: Rickettsia rickettsii
    term:
      id: NCBITaxon:783
      label: Rickettsia rickettsii
  description: >-
    Agent of Rocky Mountain spotted fever in North America and of Brazilian spotted
    fever in South America; the most virulent member of the group.
  evidence:
  - reference: PMID:17961858
    reference_title: Rocky Mountain spotted fever.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Rocky Mountain spotted fever (RMSF) is a life-threatening disease caused by
      Rickettsia rickettsii, an obligately intracellular bacterium that is spread to
      human beings by ticks.
    explanation: >-
      Assigns the species to its disease. Evidence source is OTHER as this is a review
      article.
- name: Rickettsia conorii
  infectious_agent_term:
    preferred_term: Rickettsia conorii
    term:
      id: NCBITaxon:781
      label: Rickettsia conorii
  description: >-
    Agent of Mediterranean spotted fever (boutonneuse fever) and, through its
    subspecies indica, israelensis and caspia, of Indian tick typhus, Israeli spotted
    fever and Astrakhan fever.
  evidence:
  - reference: PMID:15766388
    reference_title: >-
      Proposal to create subspecies of Rickettsia conorii based on multi-locus sequence
      typing and an emended description of Rickettsia conorii.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Although homogeneous genotypically, strains within the R. conorii species show
      MST genotypic, serotypic, and epidemio-clinical dissimilarities.
    explanation: >-
      Establishes that one genotypically homogeneous species underlies several
      epidemiologically and clinically distinct named diseases. Evidence source is
      OTHER as this is a bacterial taxonomy proposal.
- name: Rickettsia africae
  infectious_agent_term:
    preferred_term: Rickettsia africae
    term:
      id: NCBITaxon:35788
      label: Rickettsia africae
  description: >-
    Agent of African tick-bite fever; a mild, self-limiting member of the group that
    provokes a markedly weaker endothelial inflammatory response than R. conorii.
  evidence:
  - reference: PMID:19091423
    reference_title: >-
      Relative chemokine and adhesion molecule expression in Mediterranean spotted
      fever and African tick bite fever.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mediterranean spotted fever (MSF) caused by Rickettsia conorii (R. conorii) is a
      potential lethal disease while African tick bite fever (ATBF) caused by
      Rickettsia africae is a self-limiting flu-like illness.
    explanation: Assigns the species to its disease and states its comparative severity.
- name: Rickettsia akari
  infectious_agent_term:
    preferred_term: Rickettsia akari
    term:
      id: NCBITaxon:786
      label: Rickettsia akari
  description: >-
    Agent of rickettsialpox, transmitted by the house mouse mite rather than a tick.
    Historically classified within the spotted fever group and still grouped with it
    clinically and serologically, but reassigned to the transitional group on genomic
    grounds.
  evidence:
  - reference: PMID:28846279
    reference_title: Rickettsia akari (Rickettsialpox).
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      R. akari was initially classified as a member of the spotted fever group (SFG) of
      rickettsia, but it is now placed in the transitional group, which has features of
      both the spotted fever group and the typhus group (TG) of rickettsiae.
    explanation: >-
      States both the historical SFG placement that underlies the disease grouping and
      the later genomic reassignment. Evidence source is OTHER as this is a
      reference-text chapter.
- name: Rickettsia australis
  infectious_agent_term:
    preferred_term: Rickettsia australis
    term:
      id: NCBITaxon:787
      label: Rickettsia australis
  description: >-
    Agent of Queensland tick typhus in eastern Australia. Like R. akari it has been
    assigned to the transitional group on genomic grounds while remaining a spotted
    fever group infection clinically.
  evidence:
  - reference: PMID:28719297
    reference_title: >-
      Rickettsia australis and Queensland Tick Typhus: A Rickettsial Spotted Fever
      Group Infection in Australia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Rickettsia australis, the etiologic agent of Queensland tick typhus (QTT), is
      increasingly being recognized as a cause of community-acquired acute febrile
      illness in eastern Australia.
    explanation: >-
      Assigns the species to its disease. Evidence source is OTHER as this is a review
      article.
- name: Rickettsia sibirica subsp. sibirica
  infectious_agent_term:
    preferred_term: Rickettsia sibirica subsp. sibirica
    term:
      id: NCBITaxon:1144281
      label: Rickettsia sibirica subsp. sibirica
  description: >-
    Agent of North Asian (Siberian) tick typhus across Siberia, Mongolia, Kazakhstan
    and eastern China.
  evidence:
  - reference: PMID:22493192
    reference_title: Sequence and annotation of Rickettsia sibirica sibirica genome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Rickettsia sibirica sibirica is the causative agent of Siberian or North Asian
      tick typhus, a tick-borne rickettsiosis known to exist in Siberia and eastern
      China.
    explanation: >-
      Assigns the subspecies to its disease. Evidence source is OTHER as this is a
      genome announcement.

transmission:
- name: Tick bite inoculation
  description: >-
    For every member of the group except rickettsialpox, the organism is inoculated by
    a feeding ixodid tick. Which tick genus is involved varies by rickettsial species
    and therefore by geography — Dermacentor and Rhipicephalus for R. rickettsii,
    Rhipicephalus sanguineus for R. conorii, Amblyomma for R. africae, Ixodes for R.
    australis — but the route is common to the group, and most patients cannot recall
    the bite.
  evidence:
  - reference: PMID:24092850
    reference_title: "Update on tick-borne rickettsioses around the world: a geographic approach."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Tick-borne rickettsioses are caused by obligate intracellular bacteria belonging
      to the spotted fever group of the genus Rickettsia.
    explanation: >-
      Establishes the tick route as definitional for the group. Evidence source is
      OTHER as this is a review article.
  - reference: PMID:15109588
    reference_title: Tick-borne rickettsioses in international travellers.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Only a minority of infected travellers can recall a preceding tick bite.
    explanation: >-
      A group-level observation with direct diagnostic consequence: an absent bite
      history does not argue against the diagnosis. Evidence source is OTHER as this is
      a literature-based review.
- name: Mite bite inoculation (rickettsialpox)
  description: >-
    Rickettsialpox is the exception to the tick route: R. akari is transmitted by the
    house mouse mite Liponyssoides sanguineus in an urban rodent cycle. This is the
    reason the group cannot be defined by its arthropod vector.
  evidence:
  - reference: PMID:28846279
    reference_title: Rickettsia akari (Rickettsialpox).
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      R. akari is transmitted by the house mouse mite, Liponyssoides sanguineus.
    explanation: >-
      Names the mite vector for the one non-tick-borne member listed here. Evidence
      source is OTHER as this is a reference-text chapter.

pathophysiology:
- name: Arthropod Inoculation of a Spotted Fever Group Rickettsia
  biological_scale: ORGANISM
  role: trigger
  description: >-
    A feeding tick — or, for rickettsialpox, a mite — deposits SFG rickettsiae in the
    dermis at the attachment site. In most members of the group this produces a local
    dermal lesion that necroses into an inoculation eschar; the resulting fever, rash
    and eschar triad is what makes the group clinically recognisable. The vector genus
    and the incubation period are member-specific and are curated on the member
    entries.
  evidence:
  - reference: PMID:15109588
    reference_title: Tick-borne rickettsioses in international travellers.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Most patients present with a mild-to-moderately severe flu-like illness typically
      accompanied by a cutaneous rash and an inoculation eschar at the site of the tick
      bite, but potentially life-threatening disease with disseminated vaculitis is
      occasionally seen.
    explanation: >-
      States the shared presentation of the group in one sentence — the triad plus the
      severe vasculitic tail — and locates the eschar at the inoculation site. Evidence
      source is OTHER as this is a literature-based review.
  - 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: OTHER
    snippet: >-
      Unlike some SFG rickettsioses, an inoculation eschar is rarely present with RMSF
    explanation: >-
      Bounds the triad claim: the eschar is characteristic of the group but is
      conspicuously absent in its most dangerous member, so its absence cannot be used
      to exclude the diagnosis. Evidence source is OTHER as this is a national
      recommendations report.
  downstream:
  - target: Obligate Intracytosolic Infection of Microvascular Endothelium
    description: >-
      Inoculated organisms disseminate haematogenously and enter endothelial cells,
      the group's shared target cell.
    causal_link_type: DIRECT

- name: Obligate Intracytosolic Infection of Microvascular Endothelium
  biological_scale: CELLULAR
  role: effector
  description: >-
    The mechanistic core shared by every member of the group. SFG rickettsiae adhere
    to and induce their own uptake by microvascular endothelial cells, escape the
    phagosome into the cytosol, and replicate free in the cytoplasm, exploiting host
    actin for both entry and intracellular movement. This node is the group-level
    statement of endothelial tropism only; the receptor-ligand detail, the
    actin-based motility machinery and the VE-cadherin biology are not re-derived here
    and are curated in `Rocky_Mountain_Spotted_Fever.yaml`.
  cell_types:
  - preferred_term: microvascular endothelial cell
    term:
      id: CL:2000008
      label: microvascular endothelial cell
  - preferred_term: blood vessel endothelial cell
    term:
      id: CL:0000071
      label: blood vessel endothelial cell
  biological_processes:
  - preferred_term: symbiont entry into host
    term:
      id: GO:0044409
      label: symbiont entry into host
    modifier: INCREASED
  evidence:
  - reference: PMID:30148688
    reference_title: >-
      Pathogenesis of Rickettsial Diseases: Pathogenic and Immune Mechanisms of an
      Endotheliotropic Infection.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Obligately intracytosolic rickettsiae that cycle between arthropod and vertebrate
      hosts cause human diseases with a spectrum of severity, primarily by targeting
      microvascular endothelial cells, resulting in endothelial dysfunction.
    explanation: >-
      The definitive statement of the group-level mechanism: intracytosolic lifestyle,
      microvascular endothelial target, endothelial dysfunction as the outcome — and
      explicitly across a spectrum of severity. Evidence source is OTHER as this is a
      review article.
  - reference: PMID:30148688
    reference_title: >-
      Pathogenesis of Rickettsial Diseases: Pathogenic and Immune Mechanisms of an
      Endotheliotropic Infection.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Rickettsiae interact with host cell actin to effect both cellular entry and
      intracellular actin-based mobility.
    explanation: >-
      Supports the entry-and-spread step of this node. Evidence source is OTHER as this
      is a review article.
  - reference: PMID:26394396
    reference_title: >-
      Rickettsia massiliae and Rickettsia conorii Israeli Spotted Fever Strain
      Differentially Regulate Endothelial Cell Responses.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Rickettsiae primarily target microvascular endothelial cells.
    explanation: >-
      Independent confirmation of the target cell type from an experimental study
      comparing two SFG species in human endothelial monolayers.
  downstream:
  - target: Species-Graded Endothelial Inflammatory Response
    description: >-
      Infected endothelium mounts a cytokine, chemokine and adhesion-molecule response
      whose magnitude differs sharply between SFG species.
    causal_link_type: DIRECT
  - target: Disseminated Small-Vessel Vasculitis and Increased Vascular Permeability
    description: >-
      Multifocal infection of the microvasculature produces a disseminated vasculitis
      with barrier failure.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES

- name: Species-Graded Endothelial Inflammatory Response
  biological_scale: CELLULAR
  role: modifier
  description: >-
    The node that only a root entry can carry, because it is a statement about the
    differences between members rather than about any one of them. Members of the
    group share a target cell and a route of infection but differ by orders of
    magnitude in severity, from self-limiting African tick-bite fever to frequently
    fatal Rocky Mountain spotted fever. That gradient tracks how strongly the
    particular species drives interleukin-8 and adhesion-molecule expression in
    endothelium and how much endothelial barrier failure and cell death follow: R.
    conorii elicits a markedly stronger response in vitro and in patients than R.
    africae does, and the Israeli spotted fever strain of R. conorii collapses
    endothelial monolayer resistance where the mild pathogen R. massiliae does not.
  cell_types:
  - preferred_term: microvascular endothelial cell
    term:
      id: CL:2000008
      label: microvascular endothelial cell
  biological_processes:
  - preferred_term: interleukin-8 production
    term:
      id: GO:0032637
      label: interleukin-8 production
    modifier: INCREASED
  - preferred_term: leukocyte adhesion to vascular endothelial cell
    term:
      id: GO:0061756
      label: leukocyte adhesion to vascular endothelial cell
    modifier: INCREASED
  evidence:
  - reference: PMID:19091423
    reference_title: >-
      Relative chemokine and adhesion molecule expression in Mediterranean spotted
      fever and African tick bite fever.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings suggest a superior inflammatory potential of R. conorii as compared
      to R. africae in endothelial cells, potentially related to the more severe
      inflammation in MSF comparing ATBF.
    explanation: >-
      Directly links a species difference in endothelial inflammatory potential to the
      clinical severity difference between two members of the group, using paired in
      vitro and patient-serum measurements.
  - reference: PMID:19091423
    reference_title: >-
      Relative chemokine and adhesion molecule expression in Mediterranean spotted
      fever and African tick bite fever.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      R. conorii induced a marked increase in MCP-1, IL-8, and adhesion molecules in
      endothelial cells, involving toll-like receptor 4 activation.
    explanation: >-
      Gives the specific mediators behind this node, supporting the IL-8 and
      leukocyte-adhesion process annotations.
  - reference: PMID:26394396
    reference_title: >-
      Rickettsia massiliae and Rickettsia conorii Israeli Spotted Fever Strain
      Differentially Regulate Endothelial Cell Responses.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Monolayers of endothelial cells infected with R. conorii (ISF) showed a
      statistically significant decrease in electrical resistance across the monolayer
      compared to both R. massiliae-infected and uninfected cells at 72 HPI, suggesting
      increased endothelial permeability.
    explanation: >-
      A second, independent species pair showing the same pattern — a virulent SFG
      species disrupts the endothelial barrier where a mild one does not — measured as
      transendothelial electrical resistance.
  downstream:
  - target: Disseminated Small-Vessel Vasculitis and Increased Vascular Permeability
    description: >-
      The strength of the endothelial inflammatory and barrier response sets how far
      the vasculitic lesion progresses in a given member of the group.
    causal_link_type: DIRECT

- name: Disseminated Small-Vessel Vasculitis and Increased Vascular Permeability
  biological_scale: TISSUE
  role: effector
  description: >-
    Multifocal endothelial infection and injury produce a disseminated small-vessel
    vasculitis with perivascular mononuclear infiltration and loss of endothelial
    barrier integrity. This is the single lesion that explains the group's rash, and
    at its severe end the oedema of the lungs and brain. The downstream haemostatic
    detail — platelet consumption, fibrin thrombi, disseminated intravascular
    coagulation — is member-specific and is curated in
    `Rocky_Mountain_Spotted_Fever.yaml` rather than repeated here.
  cell_types:
  - preferred_term: blood vessel endothelial cell
    term:
      id: CL:0000071
      label: blood vessel endothelial cell
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  - preferred_term: positive regulation of vascular permeability
    term:
      id: GO:0043117
      label: positive regulation of vascular permeability
    modifier: INCREASED
  evidence:
  - reference: PMID:15109588
    reference_title: Tick-borne rickettsioses in international travellers.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Most patients present with a mild-to-moderately severe flu-like illness typically
      accompanied by a cutaneous rash and an inoculation eschar at the site of the tick
      bite, but potentially life-threatening disease with disseminated vaculitis is
      occasionally seen.
    explanation: >-
      Names disseminated vasculitis as the lesion of severe disease across the group.
      Evidence source is OTHER as this is a literature-based review.
  - reference: PMID:30148688
    reference_title: >-
      Pathogenesis of Rickettsial Diseases: Pathogenic and Immune Mechanisms of an
      Endotheliotropic Infection.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Obligately intracytosolic rickettsiae that cycle between arthropod and vertebrate
      hosts cause human diseases with a spectrum of severity, primarily by targeting
      microvascular endothelial cells, resulting in endothelial dysfunction.
    explanation: >-
      Endothelial dysfunction is stated as the common outcome of infection across the
      group, which is the barrier-failure half of this node. Evidence source is OTHER
      as this is a review article.
  downstream:
  - target: Severe End-Organ Involvement of the Lung and Brain
    description: >-
      Where permeability failure is extensive, plasma leaks into the pulmonary
      interstitium and the brain.
    causal_link_type: DIRECT

- name: Severe End-Organ Involvement of the Lung and Brain
  biological_scale: ORGANISM
  role: consequence
  description: >-
    The severe tail of the group. Vascular leak in the pulmonary microcirculation
    produces non-cardiogenic pulmonary oedema and respiratory failure; in the central
    nervous system it produces meningoencephalitis with seizures and coma. These two
    are the proximate causes of death across the group, and in a large Brazilian
    case-control series seizures and coma were the strongest predictors of a fatal
    outcome. Which members reach this node, and how often, differs by species — that
    dependency is the point of the `Species-Graded Endothelial Inflammatory Response`
    node above.
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  biological_processes:
  - preferred_term: positive regulation of vascular permeability
    term:
      id: GO:0043117
      label: positive regulation of vascular permeability
    modifier: INCREASED
  evidence:
  - reference: PMID:28169507
    reference_title: Predictive Factors for Fatal Tick-Borne Spotted Fever in Brazil.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      seizures (OR, 11.24; 95% CI, 6.49-19.45) and coma (OR of 15.16; 95% CI,
      8.51-27.02)
    explanation: >-
      Quantifies the neurological arm of this node as the strongest predictor of death
      in a 386-case, 415-control series of tick-borne spotted fever.
  - reference: PMID:15109588
    reference_title: Tick-borne rickettsioses in international travellers.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Most patients present with a mild-to-moderately severe flu-like illness typically
      accompanied by a cutaneous rash and an inoculation eschar at the site of the tick
      bite, but potentially life-threatening disease with disseminated vaculitis is
      occasionally seen.
    explanation: >-
      Establishes that a life-threatening vasculitic course occurs across the group but
      is the exception rather than the rule. Recorded as PARTIAL because it does not
      name the specific pulmonary and neurological end-organs. Evidence source is OTHER
      as this is a literature-based review.
  notes: >-
    Non-cardiogenic pulmonary oedema is named in the description because it is the
    standard characterisation of the severe pulmonary lesion in this group, but no
    cited abstract in this entry states it in those words, so no evidence item claims
    it. The evidenced content of this node is the neurological arm plus the
    group-level statement that a life-threatening vasculitic course occurs. The
    pulmonary arm is curated with its own evidence on
    `Rocky_Mountain_Spotted_Fever.yaml`.

- name: Rickettsial Ribosomal Translation (Doxycycline Target)
  biological_scale: MOLECULAR
  role: therapeutic_vulnerability
  conforms_to: "bacterial_protein_synthesis_inhibition#Bacterial mRNA Translation by the Ribosome"
  description: >-
    Every member of the group depends on its own 70S ribosome for protein synthesis,
    and that ribosome — not a cell-wall target — is what doxycycline inhibits. The
    molecular mechanism is held once in the
    `bacterial_protein_synthesis_inhibition` module and is not re-derived here; this
    node exists so the group-level doxycycline recommendation has a mechanism node to
    point at.
  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
    snippet: >-
      The ribosome is one of the main antibiotic targets in the bacterial cell.
    explanation: >-
      Establishes the bacterial ribosome as the target of the tetracyclines and the
      other protein-synthesis inhibitors — the molecular step this node represents. The
      same reference anchors the equivalent node in `Rocky_Mountain_Spotted_Fever.yaml`
      and `Murine_Typhus.yaml`. Evidence source is OTHER as this is a review article.
  - reference: PMID:15109588
    reference_title: Tick-borne rickettsioses in international travellers.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Doxycycline is the recommended treatment for tick-borne rickettsioses and
      prevention is based on personal protective measures against tick bites when
      travelling in endemic areas.
    explanation: >-
      Establishes at group level that a tetracycline — a ribosome-targeting agent — is
      the recommended therapy, which is the clinical fact this target node underwrites.
      Evidence source is OTHER as this is a literature-based review.

- name: Obligate Intracytosolic Niche (Cell-Penetrant Drug Requirement)
  biological_scale: CELLULAR
  role: intrinsic_resistance
  conforms_to: "intracellular_pathogen_persistence#Requirement for Cell-Penetrant Antimicrobials"
  description: >-
    Because SFG rickettsiae replicate free in the host cell cytosol, effective therapy
    is restricted to agents that accumulate intracellularly. Doxycycline does;
    beta-lactams do not reach the organism whatever their in vitro activity. This is
    the pharmacokinetic gate that, together with the ribosomal target above, makes
    doxycycline first-line for every member of the group regardless of species or
    geography. The gating principle itself is held once in the
    `intracellular_pathogen_persistence` module.
  biological_processes:
  - preferred_term: response to antibiotic
    term:
      id: GO:0046677
      label: response to antibiotic
  evidence:
  - reference: PMID:30148688
    reference_title: >-
      Pathogenesis of Rickettsial Diseases: Pathogenic and Immune Mechanisms of an
      Endotheliotropic Infection.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Obligately intracytosolic rickettsiae that cycle between arthropod and vertebrate
      hosts cause human diseases with a spectrum of severity, primarily by targeting
      microvascular endothelial cells, resulting in endothelial dysfunction.
    explanation: >-
      Establishes the obligately intracytosolic lifestyle that creates the penetration
      constraint this node represents. Evidence source is OTHER as this is a review
      article.
  - reference: PMID:18611821
    reference_title: Intracellular organisms.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The intracellular location of some microorganisms allow them to resist antibiotics
      with poor ability to penetrate eukaryotic cell membranes, such as the beta-lactam
      compounds.
    explanation: >-
      The exclusion half of the gating principle: the intracellular niche confers
      resistance to poorly cell-penetrant agents such as the beta-lactams. This is the
      same anchor the `intracellular_pathogen_persistence` module uses. Evidence source
      is OTHER as this is a review article.
  - reference: PMID:28639230
    reference_title: >-
      Intracellular Pharmacokinetics of Antibacterials and Their Clinical Implications.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Therapeutic efficacy against intracellular pathogens has been correlated mainly
      with the intracellular concentrations achieved by the different antimicrobial
      agents.
    explanation: >-
      The requirement half of the gating principle, and the evidence the module node
      this entry conforms to is itself built on: efficacy tracks the intracellular
      concentration achieved, not the in vitro MIC. Evidence source is OTHER as this is
      a review article.
  - 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: OTHER
    snippet: >-
      Doxycycline is the drug of choice for treatment of all tickborne rickettsial
      diseases in patients of all ages, including children aged <8 years
    explanation: >-
      The clinical corollary of the penetration constraint: one cell-penetrant agent is
      recommended across the whole group. Evidence source is OTHER as this is a
      national recommendations report.

phenotypes:
- category: Infectious
  name: Fever
  description: >-
    Fever is present in essentially every member of the group and is the presenting
    complaint. Per-member frequency figures are curated on the member entries.
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
  evidence:
  - reference: PMID:12766836
    reference_title: African tick bite fever in travelers to rural sub-Equatorial Africa.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      More than 80% of the patients had fever, headache, and/or myalgia, whereas
      specific clinical features such as inoculation eschars, lymphadenitis, cutaneous
      rash, and aphthous stomatitis were seen in < or = 50% of patients.
    explanation: >-
      Establishes that fever belongs to the dominant early symptom complex, but supports
      the phenotype only PARTIALLY and supports no frequency band. The reported ">80%"
      is a disjunction — it counts patients with fever, headache and/or myalgia, so it
      cannot be distributed across its three disjuncts to give a rate for fever alone.
      The denominator is also a single member (n=38 African tick-bite fever patients,
      the mildest member of the group) rather than the group. `frequency` is therefore
      omitted, on the same grounds as for rash and eschar below, which are bounded by
      the second half of this same sentence.

- category: Dermatological
  name: Skin rash
  description: >-
    A cutaneous eruption — usually maculopapular, sometimes petechial or (in
    rickettsialpox) papulovesicular — is the feature that gives the group its name. Its
    distribution, timing and morphology are member-specific.
  phenotype_term:
    preferred_term: Skin rash
    term:
      id: HP:0000988
      label: Skin rash
  evidence:
  - reference: PMID:15109588
    reference_title: Tick-borne rickettsioses in international travellers.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Most patients present with a mild-to-moderately severe flu-like illness typically
      accompanied by a cutaneous rash and an inoculation eschar at the site of the tick
      bite, but potentially life-threatening disease with disseminated vaculitis is
      occasionally seen.
    explanation: >-
      States the rash as a typical accompaniment across the group. `frequency` is
      deliberately omitted: "typically accompanied by" does not license a band, and the
      one quantitative cohort cited here reports rash in half or fewer of ATBF patients,
      so no single band holds across the group. Evidence source is OTHER as this is a
      literature-based review.

- category: Dermatological
  name: Inoculation eschar
  description: >-
    A necrotic, dark-scabbed lesion at the arthropod attachment site (the tache noire
    of Mediterranean spotted fever), which in most members of the group precedes the
    fever. It is a group-level diagnostic asset with a group-level trap attached: it is
    characteristically ABSENT in Rocky Mountain spotted fever, the member in which
    missing the diagnosis is most dangerous.
  phenotype_term:
    preferred_term: Eschar
    term:
      id: HP:6000793
      label: Eschar
  diagnostic: true
  evidence:
  - reference: PMID:15109588
    reference_title: Tick-borne rickettsioses in international travellers.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Most patients present with a mild-to-moderately severe flu-like illness typically
      accompanied by a cutaneous rash and an inoculation eschar at the site of the tick
      bite, but potentially life-threatening disease with disseminated vaculitis is
      occasionally seen.
    explanation: >-
      States the inoculation eschar as a typical group-level feature and locates it at
      the bite site. Evidence source is OTHER as this is a literature-based review.
  - 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: OTHER
    snippet: >-
      Unlike some SFG rickettsioses, an inoculation eschar is rarely present with RMSF
    explanation: >-
      Recorded as PARTIAL because it supports the phenotype's presence in the group only
      by contrast, while refuting its presence in one member. That is exactly the bound
      the description records, and it is why `frequency` is omitted. Evidence source is
      OTHER as this is a national recommendations report.

- category: Neurological
  name: Headache
  description: Headache is part of the near-universal early triad with fever and myalgia.
  phenotype_term:
    preferred_term: Headache
    term:
      id: HP:0002315
      label: Headache
  evidence:
  - reference: PMID:12766836
    reference_title: African tick bite fever in travelers to rural sub-Equatorial Africa.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      More than 80% of the patients had fever, headache, and/or myalgia, whereas
      specific clinical features such as inoculation eschars, lymphadenitis, cutaneous
      rash, and aphthous stomatitis were seen in < or = 50% of patients.
    explanation: >-
      Places headache in the dominant early symptom complex. Recorded as PARTIAL and
      with no frequency band: the cohort reports the three symptoms as an "and/or"
      disjunction, so the ">80%" figure applies to the complex as a whole and cannot be
      read as a rate for headache.

- category: Constitutional
  name: Myalgia
  description: Myalgia completes the nonspecific early triad.
  phenotype_term:
    preferred_term: Myalgia
    term:
      id: HP:0003326
      label: Myalgia
  evidence:
  - reference: PMID:12766836
    reference_title: African tick bite fever in travelers to rural sub-Equatorial Africa.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      More than 80% of the patients had fever, headache, and/or myalgia, whereas
      specific clinical features such as inoculation eschars, lymphadenitis, cutaneous
      rash, and aphthous stomatitis were seen in < or = 50% of patients.
    explanation: >-
      Places myalgia in the dominant early symptom complex. Recorded as PARTIAL and with
      no frequency band, for the same reason as fever and headache above — the ">80%"
      figure is reported over an "and/or" disjunction of the three symptoms and is not
      divisible among them.

diagnosis:
- name: Empiric clinical and epidemiologic diagnosis
  description: >-
    Across the whole group, the diagnosis is made clinically and epidemiologically and
    treatment is started on suspicion. Confirmatory testing is retrospective in
    practice, an absent tick-bite history is common and does not argue against the
    diagnosis, and waiting for a laboratory result costs lives.
  diagnosis_term:
    preferred_term: clinical evaluation
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  evidence:
  - reference: PMID:15109588
    reference_title: Tick-borne rickettsioses in international travellers.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Definite microbiological confirmation of tick-borne rickettsioses by isolation or
      antigen detection is only available at reference laboratories and diagnosis must
      in most cases rely on clinical and epidemiological data supported by serology.
    explanation: >-
      States the group-level diagnostic reality: clinical and epidemiological
      assessment, with serology as support rather than as the primary test. Evidence
      source is OTHER as this is a literature-based review.
  - reference: PMID:15109588
    reference_title: Tick-borne rickettsioses in international travellers.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Only a minority of infected travellers can recall a preceding tick bite.
    explanation: >-
      Supports the specific caution that an absent exposure history does not exclude the
      diagnosis. Evidence source is OTHER as this is a literature-based review.
  notes: >-
    `diagnosis_term` is bound to `NCIT:C124351` (Clinical Evaluation) rather than the
    broader laboratory-procedure term used for the same node in
    `Rocky_Mountain_Spotted_Fever.yaml`. The divergence is deliberate: this node's claim
    is that treatment starts on clinical and epidemiologic grounds *without* laboratory
    confirmation, so a laboratory-procedure term would contradict the claim it annotates.
    The specific confirmatory modalities (paired-serum IFA, whole-blood PCR, eschar-swab
    PCR, immunohistochemistry on skin biopsy) are curated with their own terms on the
    member entries.

- name: Group-specific serology and the species-level limit
  description: >-
    Serology is the mainstay of confirmation for the whole group, and it is
    group-specific rather than species-specific. The immunodominant response is against
    spotted fever group lipopolysaccharide, which is shared, rather than against the
    OmpA and OmpB outer-membrane proteins that carry the species-specific epitopes. A
    reactive R. rickettsii titre therefore establishes infection with an SFG rickettsia,
    not with R. rickettsii — which is why species assignment needs cross-adsorption,
    Western blot, PCR or culture, and why the individual member diseases are so often
    reported as an undifferentiated "spotted fever group rickettsiosis". This is a claim
    about the group as a whole and has no home on any member entry.
  diagnosis_term:
    preferred_term: serologic testing
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  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: OTHER
    snippet: >-
      Cross-reactive immune responses to rickettsial antigens result in antibodies that
      are typically group-specific, although perhaps not species-specific, for tickborne
      rickettsial pathogens
    explanation: >-
      The direct statement of the group-versus-species resolution limit of rickettsial
      serology. Evidence source is OTHER as this is a national recommendations report.
  - 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: OTHER
    snippet: >-
      antibodies reactive with R. rickettsii detected by a serologic test could result
      from infection with other SFG rickettsiae
    explanation: >-
      The worked consequence: a positive R. rickettsii serology does not identify the
      species. Evidence source is OTHER as this is a national recommendations report.
  - reference: PMID:10497980
    reference_title: >-
      Serologic study of the prevalence of rickettsiosis in Yucatán: evidence for a
      prevalent spotted fever group rickettsiosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Immunoblotting with antigens of R. akari identified antibodies against antigens of
      spotted fever group lipopolysaccharides and not against rickettsial outer membrane
      proteins A and B, which contain the species-specific epitopes.
    explanation: >-
      Gives the molecular reason for the cross-reactivity: the dominant response is
      against shared group lipopolysaccharide rather than the species-specific OmpA and
      OmpB epitopes.

treatments:
- name: Empiric doxycycline for all patients of all ages
  action_category: THERAPEUTIC
  description: >-
    One recommendation covers the entire group: doxycycline, started immediately on
    clinical suspicion, in patients of every age including children under eight. This
    is a genuinely group-level rule — it does not depend on which SFG species is
    involved, and it is made before the species (or often even the group) is known,
    which is what makes it a root-level claim rather than a per-member one. Its two
    mechanistic legs are the shared rickettsial ribosome and the shared cytosolic
    niche, both modelled above. The historical reluctance to give doxycycline to young
    children has been overturned: the concern derived from older tetracyclines that
    bind calcium more readily, and a CDC cohort of 58 children given short courses
    before age eight showed no dental staining, no enamel hypoplasia and no difference
    in tooth shade against 213 unexposed controls. Per-member specifics — the day-5
    mortality window in RMSF, the sulfonamide contraindication, macrolide alternatives
    in pregnancy — are curated on the member entries.
  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 (Doxycycline Target)
    treatment_effect: INHIBITS
    description: >-
      Doxycycline binds the bacterial 30S ribosomal subunit and arrests rickettsial
      protein synthesis. The molecular detail is held in the
      `bacterial_protein_synthesis_inhibition` module.
    evidence:
    - reference: PMID:15109588
      reference_title: Tick-borne rickettsioses in international travellers.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Doxycycline is the recommended treatment for tick-borne rickettsioses and
        prevention is based on personal protective measures against tick bites when
        travelling in endemic areas.
      explanation: >-
        Establishes that the recommended agent for the group is a tetracycline, that is,
        a ribosome-targeting drug acting on this node. Evidence source is OTHER as this
        is a literature-based review.
  - target: Obligate Intracytosolic Niche (Cell-Penetrant Drug Requirement)
    treatment_effect: BYPASSES
    description: >-
      Doxycycline accumulates within host cells and so reaches the cytosolic organism
      that poorly penetrant agents such as the beta-lactams cannot.
    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: OTHER
      snippet: >-
        Doxycycline is the drug of choice for treatment of all tickborne rickettsial
        diseases in patients of all ages, including children aged <8 years
      explanation: >-
        A single cell-penetrant agent is recommended across the whole group, which is
        the clinical expression of this pharmacokinetic gate. Evidence source is OTHER
        as this is a national recommendations report.
  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: OTHER
    snippet: >-
      Doxycycline is the drug of choice for treatment of all tickborne rickettsial
      diseases in patients of all ages, including children aged <8 years
    explanation: >-
      The group-level recommendation in the CDC's own words, covering all members and
      all ages. Evidence source is OTHER as this is a national recommendations report.
  - 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: OTHER
    snippet: >-
      The American Academy of Pediatrics and CDC recommend doxycycline as the treatment
      of choice for children of all ages with suspected tickborne rickettsial disease
    explanation: >-
      The paediatric arm of the recommendation, endorsed jointly by AAP and CDC.
      Evidence source is OTHER as this is a national recommendations report.
  - 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: OTHER
    snippet: >-
      Previous concerns about tooth staining in children aged <8 years stem from
      experience with older tetracycline-class drugs that bind more readily to calcium
      than newer members of the drug class, such as doxycycline
    explanation: >-
      Explains why the old paediatric contraindication was wrong for doxycycline
      specifically — it was inherited from drugs with different calcium binding.
      Evidence source is OTHER as this is a national recommendations report.
  - reference: PMID:25794784
    reference_title: >-
      No visible dental staining in children treated with doxycycline for suspected
      Rocky Mountain Spotted Fever.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      No tetracycline-like staining was observed in any of the exposed children's teeth
      (0/58, 95% CI 0%-5%), and no significant difference in tooth shade (P=.20) or
      hypoplasia (P=1.0) was found between the 2 groups.
    explanation: >-
      The primary cohort study that removed the age barrier: no staining, no hypoplasia
      and no shade difference in 58 exposed versus 213 unexposed children.
  - reference: PMID:15109588
    reference_title: Tick-borne rickettsioses in international travellers.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Doxycycline is the recommended treatment for tick-borne rickettsioses and
      prevention is based on personal protective measures against tick bites when
      travelling in endemic areas.
    explanation: >-
      Independent confirmation from the travel-medicine literature that the same agent
      is recommended for the group outside the United States, that is, that the rule is
      not a CDC-local one. Evidence source is OTHER as this is a literature-based
      review.

discussions:
- discussion_id: sfr_root_disease_vs_grouping
  kind: INTERPRETATION
  status: RESOLVED
  prompt: >-
    Should spotted fever (MONDO:0001195) be modelled as a root `Disease` with
    `has_subtypes`, or as a `Grouping` over the member entries in `kb/groupings/`?
  rationale: >-
    Resolved in favour of a root `Disease` with `has_subtypes`, on three grounds, the
    second of which is decisive on its own. First, tooling: `build_coverage_index()` in
    `src/dismech/compare/mondo_priority.py` calls `iter_disease_files()`, which globs
    `*.yaml` under the `--kb-dir` default of `kb/disorders` and never reads
    `kb/groupings/`. A `Grouping` alone would leave MONDO:0001195 permanently on the
    MONDO curation queue no matter how well curated it was. This was verified by reading
    `mondo_priority.py`, `compare/support.py` and the `--kb-dir` default in
    `priority_dashboard.py`, not assumed from the thanatophoric-dysplasia precedent.
    Second, and specific to this case:
    `tests/test_data.py::test_grouping_member_foreign_keys` requires every
    `members[].member` of a Grouping to resolve to a real `Disease.name`, module stem or
    grouping name. Only two of the six members curated here — Rocky Mountain spotted
    fever and boutonneuse fever — have standalone `kb/disorders/` entries; African
    tick-bite fever, rickettsialpox, Queensland tick typhus and North Asian tick typhus
    do not. A Grouping could therefore not list four of its six members at all, whereas
    `has_subtypes` carries them with their MONDO bindings and their evidence today and
    loses nothing when they are later promoted to standalone entries. Third, substance:
    several claims here are defined over the union and have no home on any member — the
    SFG taxon itself (NCBITaxon:114277), the group-versus-species resolution limit of
    rickettsial serology (PMID:27172113, PMID:10497980), the species-graded severity
    gradient (PMID:19091423, PMID:26394396), and the single all-ages doxycycline rule
    that is applied before the species is known (PMID:27172113). Note this differs from
    the thanatophoric-dysplasia case in one respect worth recording: there, a
    pre-existing grouping (`FGFR_Related_Skeletal_Dysplasias`) already unioned the
    members, so a second grouping would have been redundant. Here there is no rickettsial
    grouping at all, so the redundancy argument does not apply — the case rests on the
    coverage-index and foreign-key arguments instead. The counter-argument, that a
    Disease root duplicates content already held in the two curated member entries, is
    addressed by keeping this root deliberately thin: seven pathophysiology nodes, two of
    which are module `conforms_to` anchors, and explicit "not re-derived here" pointers
    on the nodes that the member entries carry in depth.
  resolution_note: >-
    Curated as a root `Disease` (this entry). No grouping was created. If African
    tick-bite fever, rickettsialpox, Queensland tick typhus and North Asian tick typhus
    are later curated as standalone entries, a `Grouping` over the six becomes viable
    and could be added alongside this root — it would then carry the auditable
    membership criteria that `has_subtypes` cannot express — but it would still not
    retire MONDO:0001195 from the priority queue, so this entry would remain.
  posed_by: dismech curation (issue #8890)
  posed_date: '2026-08-19T00:00:00Z'
  resolved_date: '2026-08-19T00:00:00Z'

- discussion_id: sfr_subtype_axis_species_not_geography
  kind: INTERPRETATION
  status: RESOLVED
  prompt: >-
    Should the subtypes of this group be organised by causative Rickettsia species or by
    geography? The two largely co-vary, and MONDO's own children mix both conventions
    (Japanese spotted fever and African tick-bite fever are geographic labels;
    Rickettsia parkeri spotted fever is a species label).
  attaches_to:
  - pathophysiology#Species-Graded Endothelial Inflammatory Response
  rationale: >-
    Resolved in favour of the species. Geography is a downstream label set by the range
    of the vector tick, and it fails as an identity criterion in both directions. It is
    not one-to-one downward: a single species, R. conorii, carries four distinct
    geographically named diseases — Mediterranean spotted fever, Indian tick typhus,
    Israeli spotted fever and Astrakhan fever — which are genotypically homogeneous but
    serotypically and epidemio-clinically distinct (PMID:15766388). And it is not
    one-to-one upward: a single species, R. rickettsii, causes Rocky Mountain spotted
    fever in North America and Brazilian spotted fever in South America (PMID:28169507),
    so the geographic name changes while the organism does not. The species axis also
    tracks the thing that actually matters clinically. Severity across this group spans
    from self-limiting to frequently fatal, and that gradient follows the
    species-specific endothelial inflammatory response (PMID:19091423, PMID:26394396)
    rather than the latitude at which the tick bit. Geography is retained, but as the
    secondary descriptor it is: each `has_subtypes` entry carries a `geography` list
    alongside its species-named `display_name`.
  resolution_note: >-
    Subtypes are keyed on the causative species, with `geography` recorded per subtype.
    The list is explicitly non-exhaustive — MONDO:0001195 has seventeen descendants and
    new SFG species of undetermined pathogenicity continue to be described
    (PMID:24092850). The six curated here were chosen to span the severity range (RMSF
    to ATBF), both continents on which one species operates, both vector classes (tick
    and mite), and both naming traps ("tick typhus" that is SFG). Japanese spotted
    fever, Flinders Island spotted fever, Astrakhan spotted fever, Israeli tick typhus,
    Indian tick typhus, Far Eastern spotted fever, R. parkeri spotted fever and R.
    helvetica spotted fever all have MONDO terms and are candidates for a later tranche.
  posed_by: dismech curation (issue #8890)
  posed_date: '2026-08-19T00:00:00Z'
  resolved_date: '2026-08-19T00:00:00Z'

- discussion_id: sfr_group_boundary_and_naming_traps
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    What exactly is the unifying criterion for membership of this group, given that the
    disease grouping, the arthropod vector and the current rickettsial phylogeny do not
    coincide?
  rationale: >-
    Three boundary problems sit under this entry, and they are recorded rather than
    resolved because resolving them is an ontology question, not a curation one.

    First, the vector is not the criterion. MONDO defines MONDO:0001195 as "a type of
    tick-borne disease", yet places rickettsialpox (MONDO:0019360) under it, and
    rickettsialpox is mite-borne (PMID:28846279). Either the definition is too narrow or
    rickettsialpox is misplaced. This entry takes the first reading and treats the
    rickettsial clade, not the arthropod, as the unifying criterion — which is the
    reading that matches how the diseases are diagnosed, since rickettsialpox eschars
    stain positive for spotted fever group rickettsiae (PMID:12860597).

    Second, the clade itself has moved. Gillespie et al. proposed a fourth rickettsial
    lineage, the transitional group, distinct from both the spotted fever and typhus
    groups (PMID:17342200), and both R. akari and R. australis have since been assigned
    to it (PMID:28846279). Two of the six members curated here are therefore, on current
    genomic classification, not spotted fever group organisms — while remaining spotted
    fever group DISEASES clinically, serologically and therapeutically. This entry keeps
    them, on the grounds that a dismech disease entry groups diseases by shared
    pathophysiology and management rather than by the current state of bacterial
    systematics, but a reviewer should know the tension exists and that MONDO has not
    tracked the reclassification.

    Third, the names lie in both directions. Queensland tick typhus and North Asian
    (Siberian) tick typhus are spotted fever group diseases despite the word "typhus"
    (PMID:28719297, PMID:22493192), whereas murine typhus and epidemic typhus are typhus
    group and scrub typhus is not even a Rickettsia (Orientia tsutsugamushi). This is a
    live Named Entity Confusion hazard for anyone curating from a deep-research report:
    a search on "tick typhus" will return both groups. `kb/disorders/Murine_Typhus.yaml`
    is deliberately NOT a member of this group and must not be added to it.
  posed_by: dismech curation (issue #8890)
  posed_date: '2026-08-19T00:00:00Z'

- discussion_id: sfr_root_severity_gradient_mechanism
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What determines the severity gradient across spotted fever group species — from
    self-limiting African tick-bite fever to frequently fatal Rocky Mountain spotted
    fever — given that all members share the same endothelial target cell and the same
    intracytosolic lifestyle?
  attaches_to:
  - pathophysiology#Species-Graded Endothelial Inflammatory Response
  rationale: >-
    The evidence curated here establishes that the gradient exists and correlates with
    the strength of the endothelial inflammatory and barrier response the species
    provokes (PMID:19091423, PMID:26394396). It does not establish what makes one
    species provoke that response more strongly than another. The two studies cited
    compare only two species pairs (R. conorii versus R. africae; R. conorii ISF versus
    R. massiliae), both use immortalised or primary human endothelial monolayers rather
    than intact microvasculature, and neither identifies the bacterial determinant
    responsible. Host factors known to worsen individual members — G6PD deficiency in
    RMSF, age and comorbidity in MSF — are curated on the member entries and are a
    separate axis from the species difference modelled here.
  proposed_experiments:
  - experiment_id: exp_sfr_multispecies_endothelial_panel
    name: Matched multi-species endothelial infection panel across the severity range
    description: >-
      Infect a single human microvascular endothelial preparation with a panel of SFG
      species spanning the clinical severity range (R. rickettsii, R. conorii subsp.
      conorii, R. africae, R. akari, R. australis, R. parkeri) at matched multiplicity,
      and measure a common readout set — transendothelial electrical resistance, IL-8
      and adhesion-molecule induction, and cell death — so that severity rank can be
      regressed against endothelial response rather than inferred from separate
      pairwise studies. Pair with comparative genomics across the same panel to nominate
      the bacterial determinants.
  posed_by: dismech curation (issue #8890)
  posed_date: '2026-08-19T00:00:00Z'

notes: >
  Scope. This entry is deliberately thin, in the sense used by
  `kb/disorders/Thanatophoric_Dysplasia.yaml`. It carries only claims that are defined
  over the spotted fever group as a whole and that therefore have no home on any single
  member: the SFG taxon and the species-versus-geography naming problem, the shared
  eschar, fever and rash triad together with the RMSF exception that bounds it, the
  group-versus-species resolution limit of rickettsial serology, the single all-ages
  doxycycline rule and its paediatric arm, and the SFG-versus-typhus-group boundary.
  The endothelial pathophysiology is stated once, at group level, with explicit
  pointers to where it is curated in depth; the VE-cadherin and coagulation arms, the
  cytotoxic T cell clearance arm, the per-member epidemiology, phenotype frequencies,
  differential diagnoses, histopathology and second-line therapy are NOT re-derived
  here. `Rocky_Mountain_Spotted_Fever.yaml` (2,119 lines) and `Boutonneuse_Fever.yaml`
  (1,273 lines) carry those. `Murine_Typhus.yaml` is typhus group, not spotted fever
  group, and is deliberately out of scope; it is a useful contrast and shares the two
  antimicrobial modules, but it is not a member of this group.

  Deep research. No new deep-research provider pass was run for this entry, by
  instruction. `research/Rocky_Mountain_Spotted_Fever-deep-research-claude_code.md` and
  `research/Boutonneuse_Fever-deep-research-fallback.md` were available as leads for the
  two curated members; every claim here was built from primary literature fetched
  directly from PubMed and verified against `references_cache/`. Because no
  deep-research report drives any claim, `just preflight-dr` is not applicable. Named
  Entity Confusion discipline was applied manually and mattered more than usual for this
  family: every cited abstract was checked to confirm which Rickettsia species it
  concerns, no paper about rickettsiosis in general is cited for an SFG-specific claim,
  and the "tick typhus" versus "typhus group" versus "scrub typhus" trap is recorded
  explicitly in the `sfr_group_boundary_and_naming_traps` discussion rather than left
  implicit.

  Sources not usable at curation time. Orphanet ORPHA:102022, which MONDO:0001195 xrefs
  and which would supply a quotable group-level definition and an epidemiology table,
  could not be cached: `just refresh-orphadata` fails a sha256 check against the pinned
  `data/orphadata/MANIFEST.yaml` because upstream Orphadata has drifted, and re-pinning
  the manifest would rebuild every `references_cache/ORPHA_*.md` in the repository. Both
  curated member entries already cite their own ORPHA records from the existing cache.
  No prevalence block is curated here as a result: population occurrence for this group
  is reported per member and per country, not for the union, and inventing a
  group-level figure from the member figures would be a fabricated aggregate.

references:
- reference: PMID:24092850
  title: "Update on tick-borne rickettsioses around the world: a geographic approach."
  findings:
  - statement: >-
      Defines tick-borne rickettsioses as caused by obligate intracellular bacteria of
      the spotted fever group of the genus Rickettsia
  - statement: >-
      Records that the group's membership is open — species once thought nonpathogenic
      are now recognised as human pathogens and novel species continue to be found
- reference: PMID:27172113
  title: >-
    Diagnosis and Management of Tickborne Rickettsial Diseases: Rocky Mountain Spotted
    Fever and Other Spotted Fever Group Rickettsioses, Ehrlichioses, and Anaplasmosis -
    United States.
  findings:
  - statement: >-
      Doxycycline is the drug of choice for all tickborne rickettsial diseases in
      patients of all ages, including children under 8
  - statement: >-
      Rickettsial serology is group-specific but not species-specific; a reactive R.
      rickettsii titre can result from any SFG infection
  - statement: >-
      An inoculation eschar is rarely present in RMSF, unlike some other SFG
      rickettsioses
- reference: PMID:25794784
  title: >-
    No visible dental staining in children treated with doxycycline for suspected Rocky
    Mountain Spotted Fever.
  findings:
  - statement: >-
      No dental staining, enamel hypoplasia or tooth-shade difference in 58 children
      given short doxycycline courses before age 8 versus 213 unexposed controls
- reference: PMID:15109588
  title: Tick-borne rickettsioses in international travellers.
  findings:
  - statement: >-
      States the group-level presentation: flu-like illness with cutaneous rash and
      inoculation eschar, occasionally life-threatening disseminated vasculitis
  - statement: Only a minority of infected travellers recall a preceding tick bite
  - statement: Doxycycline is the recommended treatment for tick-borne rickettsioses
- reference: PMID:30148688
  title: >-
    Pathogenesis of Rickettsial Diseases: Pathogenic and Immune Mechanisms of an
    Endotheliotropic Infection.
  findings:
  - statement: >-
      Obligately intracytosolic rickettsiae target microvascular endothelial cells,
      producing endothelial dysfunction across a spectrum of disease severity
- reference: PMID:10497980
  title: >-
    Serologic study of the prevalence of rickettsiosis in Yucatán: evidence for a
    prevalent spotted fever group rickettsiosis.
  findings:
  - statement: >-
      The dominant antibody response is against shared SFG lipopolysaccharide rather
      than the OmpA and OmpB proteins carrying species-specific epitopes
- reference: PMID:17342200
  title: "Plasmids and rickettsial evolution: insight from Rickettsia felis."
  findings:
  - statement: >-
      Proposes the transitional group as a fourth rickettsial lineage distinct from the
      spotted fever and typhus groups
- reference: PMID:15766388
  title: >-
    Proposal to create subspecies of Rickettsia conorii based on multi-locus sequence
    typing and an emended description of Rickettsia conorii.
  findings:
  - statement: >-
      One genotypically homogeneous species, R. conorii, underlies four
      epidemio-clinically distinct geographically named diseases
- reference: PMID:26394396
  title: >-
    Rickettsia massiliae and Rickettsia conorii Israeli Spotted Fever Strain
    Differentially Regulate Endothelial Cell Responses.
  findings:
  - statement: >-
      A virulent SFG strain reduces endothelial monolayer electrical resistance while a
      mild one does not, at matched infection
- reference: PMID:19091423
  title: >-
    Relative chemokine and adhesion molecule expression in Mediterranean spotted fever
    and African tick bite fever.
  findings:
  - statement: >-
      R. conorii has a superior endothelial inflammatory potential to R. africae,
      matching the severity difference between MSF and ATBF
- reference: PMID:28169507
  title: Predictive Factors for Fatal Tick-Borne Spotted Fever in Brazil.
  findings:
  - statement: Seizures and coma are the strongest predictors of fatal spotted fever
  - statement: >-
      R. rickettsii causes tick-borne spotted fever in Brazil as well as North America
- reference: PMID:12766836
  title: African tick bite fever in travelers to rural sub-Equatorial Africa.
  findings:
  - statement: >-
      Over 80% of ATBF patients had fever, headache and/or myalgia; eschar, rash and
      lymphadenitis were present in half or fewer
- reference: PMID:12860597
  title: "Rickettsialpox in New York City: a persistent urban zoonosis."
  findings:
  - statement: >-
      Rickettsialpox eschars and papular lesions stain positive for spotted fever group
      rickettsiae
- reference: PMID:28846279
  title: Rickettsia akari (Rickettsialpox).
  findings:
  - statement: R. akari is transmitted by the house mouse mite, not a tick
  - statement: >-
      R. akari was initially classified in the spotted fever group but is now placed in
      the transitional group
- reference: PMID:28719297
  title: >-
    Rickettsia australis and Queensland Tick Typhus: A Rickettsial Spotted Fever Group
    Infection in Australia.
  findings:
  - statement: >-
      Queensland tick typhus, despite its name, is a spotted fever group infection
      caused by R. australis
- reference: PMID:22493192
  title: Sequence and annotation of Rickettsia sibirica sibirica genome.
  findings:
  - statement: >-
      R. sibirica subsp. sibirica is the agent of Siberian / North Asian tick typhus in
      Siberia and eastern China
- reference: PMID:17961858
  title: Rocky Mountain spotted fever.
  findings:
  - statement: >-
      RMSF is a life-threatening disease caused by the obligately intracellular R.
      rickettsii, spread by ticks
- reference: PMID:23168048
  title: Mediterranean spotted fever in the Trakya region of Turkey.
  findings:
  - statement: >-
      MSF is caused by R. conorii subsp. conorii, a member of the spotted fever group
- reference: PMID:24336183
  title: Ribosome-targeting antibiotics and mechanisms of bacterial resistance.
  findings:
  - statement: >-
      The bacterial ribosome is one of the main antibiotic targets, the molecular target
      of the tetracyclines used across this group
- reference: PMID:18611821
  title: Intracellular organisms.
  findings:
  - statement: >-
      The intracellular niche confers resistance to poorly cell-penetrant antibiotics
      such as the beta-lactams
- reference: PMID:28639230
  title: Intracellular Pharmacokinetics of Antibacterials and Their Clinical Implications.
  findings:
  - statement: >-
      Efficacy against intracellular pathogens tracks the intracellular concentration
      achieved rather than the in vitro MIC

clinical_trials: []
datasets: []
📚

References & Deep Research

References

21
PMID:24092850
Update on tick-borne rickettsioses around the world: a geographic approach.
2 findings
Defines tick-borne rickettsioses as caused by obligate intracellular bacteria of the spotted fever group of the genus Rickettsia
Records that the group's membership is open — species once thought nonpathogenic are now recognised as human pathogens and novel species continue to be found
PMID:27172113
Diagnosis and Management of Tickborne Rickettsial Diseases: Rocky Mountain Spotted Fever and Other Spotted Fever Group Rickettsioses, Ehrlichioses, and Anaplasmosis - United States.
3 findings
Doxycycline is the drug of choice for all tickborne rickettsial diseases in patients of all ages, including children under 8
Rickettsial serology is group-specific but not species-specific; a reactive R. rickettsii titre can result from any SFG infection
An inoculation eschar is rarely present in RMSF, unlike some other SFG rickettsioses
PMID:25794784
No visible dental staining in children treated with doxycycline for suspected Rocky Mountain Spotted Fever.
1 finding
No dental staining, enamel hypoplasia or tooth-shade difference in 58 children given short doxycycline courses before age 8 versus 213 unexposed controls
PMID:15109588
Tick-borne rickettsioses in international travellers.
3 findings
States the group-level presentation: flu-like illness with cutaneous rash and inoculation eschar, occasionally life-threatening disseminated vasculitis
Only a minority of infected travellers recall a preceding tick bite
Doxycycline is the recommended treatment for tick-borne rickettsioses
PMID:30148688
Pathogenesis of Rickettsial Diseases: Pathogenic and Immune Mechanisms of an Endotheliotropic Infection.
1 finding
Obligately intracytosolic rickettsiae target microvascular endothelial cells, producing endothelial dysfunction across a spectrum of disease severity
PMID:10497980
Serologic study of the prevalence of rickettsiosis in Yucatán: evidence for a prevalent spotted fever group rickettsiosis.
1 finding
The dominant antibody response is against shared SFG lipopolysaccharide rather than the OmpA and OmpB proteins carrying species-specific epitopes
PMID:17342200
Plasmids and rickettsial evolution: insight from Rickettsia felis.
1 finding
Proposes the transitional group as a fourth rickettsial lineage distinct from the spotted fever and typhus groups
PMID:15766388
Proposal to create subspecies of Rickettsia conorii based on multi-locus sequence typing and an emended description of Rickettsia conorii.
1 finding
One genotypically homogeneous species, R. conorii, underlies four epidemio-clinically distinct geographically named diseases
PMID:26394396
Rickettsia massiliae and Rickettsia conorii Israeli Spotted Fever Strain Differentially Regulate Endothelial Cell Responses.
1 finding
A virulent SFG strain reduces endothelial monolayer electrical resistance while a mild one does not, at matched infection
PMID:19091423
Relative chemokine and adhesion molecule expression in Mediterranean spotted fever and African tick bite fever.
1 finding
R. conorii has a superior endothelial inflammatory potential to R. africae, matching the severity difference between MSF and ATBF
PMID:28169507
Predictive Factors for Fatal Tick-Borne Spotted Fever in Brazil.
2 findings
Seizures and coma are the strongest predictors of fatal spotted fever
R. rickettsii causes tick-borne spotted fever in Brazil as well as North America
PMID:12766836
African tick bite fever in travelers to rural sub-Equatorial Africa.
1 finding
Over 80% of ATBF patients had fever, headache and/or myalgia; eschar, rash and lymphadenitis were present in half or fewer
PMID:12860597
Rickettsialpox in New York City: a persistent urban zoonosis.
1 finding
Rickettsialpox eschars and papular lesions stain positive for spotted fever group rickettsiae
PMID:28846279
Rickettsia akari (Rickettsialpox).
2 findings
R. akari is transmitted by the house mouse mite, not a tick
R. akari was initially classified in the spotted fever group but is now placed in the transitional group
PMID:28719297
Rickettsia australis and Queensland Tick Typhus: A Rickettsial Spotted Fever Group Infection in Australia.
1 finding
Queensland tick typhus, despite its name, is a spotted fever group infection caused by R. australis
PMID:22493192
Sequence and annotation of Rickettsia sibirica sibirica genome.
1 finding
R. sibirica subsp. sibirica is the agent of Siberian / North Asian tick typhus in Siberia and eastern China
PMID:17961858
Rocky Mountain spotted fever.
1 finding
RMSF is a life-threatening disease caused by the obligately intracellular R. rickettsii, spread by ticks
PMID:23168048
Mediterranean spotted fever in the Trakya region of Turkey.
1 finding
MSF is caused by R. conorii subsp. conorii, a member of the spotted fever group
PMID:24336183
Ribosome-targeting antibiotics and mechanisms of bacterial resistance.
1 finding
The bacterial ribosome is one of the main antibiotic targets, the molecular target of the tetracyclines used across this group
PMID:18611821
Intracellular organisms.
1 finding
The intracellular niche confers resistance to poorly cell-penetrant antibiotics such as the beta-lactams
PMID:28639230
Intracellular Pharmacokinetics of Antibacterials and Their Clinical Implications.
1 finding
Efficacy against intracellular pathogens tracks the intracellular concentration achieved rather than the in vitro MIC