Interferon receptor-deficient mice are susceptible to eschar-associated rickettsiosis.

Abstract

Arthropod-borne rickettsial pathogens cause mild and severe human disease worldwide. The tick-borne pathogen <i>Rickettsia parkeri</i> elicits skin lesions (eschars) and disseminated disease in humans; however, inbred mice are generally resistant to infection. We report that intradermal infection of mice lacking both interferon receptors (<i>Ifnar1^-/-;Ifngr1^-/-</i>) with as few as 10 <i>R</i>. <i>parkeri</i> elicits eschar formation and disseminated, lethal disease. Similar to human infection, eschars exhibited necrosis and inflammation, with bacteria primarily found in leukocytes. Using this model, we find that the actin-based motility factor Sca2 is required for dissemination from the skin to internal organs, and the outer membrane protein OmpB contributes to eschar formation. Immunizing <i>Ifnar1^-/-;Ifngr1^-/-</i> mice with <i>sca2</i> and <i>ompB</i> mutant <i>R. parkeri</i> protects against rechallenge, revealing live-attenuated vaccine candidates. Thus, <i>Ifnar1^-/-;Ifngr1^-/-</i> mice are a tractable model to investigate rickettsiosis, virulence factors, and immunity. Our results further suggest that discrepancies between mouse and human susceptibility may be due to differences in interferon signaling.