Rickettsia are arthropod-borne pathogens that cause severe human disease worldwide. The spotted fever group (SFG) pathogen Rickettsia parkeri elicits skin lesion (eschar) formation in humans after tick bite. However, intradermal inoculation of inbred mice with millions of bacteria fails to elicit eschar formation or disseminated disease, hindering investigations into understanding eschar-associated rickettsiosis. Here, we report that intradermal infection of mice deficient for both interferon receptors ( Ifnar -/- Ifngr -/- ) with R. parkeri causes eschar formation, recapitulating the hallmark clinical feature of human disease. Intradermal infection with doses that recapitulate tick infestation caused eschar formation and lethality, including with as few as 10 bacteria. Using this model, we found that the actin-based motility protein Sca2 is required for R. parkeri dissemination from the skin to internal organs and for causing lethal disease, and that the abundant R. parkeri outer membrane protein OmpB contributes to eschar formation. We also found that immunizing mice with sca2 and ompB mutant R. parkeri protects against subsequent rechallenge with wild-type bacteria, revealing live-attenuated vaccine candidates. Thus, interferon receptor-deficient mice are a tractable model to investigate rickettsiosis, bacterial virulence factors, and immunity. Our results suggest that differences in interferon signaling in the skin between mice and humans may explain the discrepancy in susceptibility to SFG Rickettsia . ### Competing Interest Statement The authors have declared no competing interest.
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