Inflammasome-mediated antagonism of type I interferon enhancesRickettsiapathogenesis

Abstract

SummaryInflammasomes and interferons constitute two critical arms of innate immunity. Most facultative bacterial pathogens that inhabit the host cell cytosol avoid activating inflammasomes and are often resistant to killing by type I interferon (IFN-I). We report that the human pathogenRickettsia parkeri,an obligate intracellular pathogen that resides in the cytosol, is sensitive to IFN-I. The mechanism of IFN-I-dependent restriction requires the transcription factor IRF5, which upregulates anti-rickettsial factors including guanylate-binding proteins and iNOS. However,R. parkericurtails cGAS-dependent IFN-I production by causing caspase-11-dependent pyroptosis.In vivo, inflammasome activation antagonizes IFN-I production, enhancingR. parkeriabundance in the spleen. Mice lacking either IFN-I or IFN-γ signaling are resistant to infection, but mice lacking both rapidly succumb, revealing that both interferons are required to controlR. parkeri. This study illuminates how an obligate cytosolic pathogen exploits the intrinsic trade-off between cell death and cytokine production to escape killing by innate immunity.HighlightsRickettsiakilled by GBPs activates caspase-11 and GSDMD, promoting pyroptosisRickettsiaexploits pyroptosis to avoid cGAS-dependent type I interferonIRF5, GBPs, and iNOS contribute to controllingR. parkeriinfectionIfnar-/-Ifngr-/-mice succumb to infection, uncovering a mouse model to studyR. parkeri