Type I IFN regulates non-canonical inflammasome activation and impairs protective immunity during fatal ehrlichia-induced toxic shock (MPF1P.762)

Abstract

Abstract Inflammasome complexes such as NLRP3 play a major role in antimicrobial defense to infection. Canonical and non-canonical pathways activate caspase 1 and caspase 11 to secrete IL-1β and induce inflammatory cell death. Ehrlichia, obligate intracellular bacteria that cause fatal toxic shock in humans and mice, activate inflammasomes and induce expression of type 1 interferon (IFN1). The contribution of the NLRP3 and IFN1 to Ehrlichia-induced toxic shock is not known. We show that NLRP3-/- and Caspase 1-/- mice succumb to lethal Ehrlichia infection similar to wild type (WT) mice. Unlike caspase 1-/- and WT, NLRP3-/- mice have lower bacterial burdens with higher IFNγ, suggesting that NLRP3 impairs bacterial clearance in a caspase 1-independent manner. Unexpectedly, infected IFNαR-/- mice were protected against a normally lethal dose of Ehrlichia with effective bacterial clearance, altered pathology with less apoptosis, increased IFNγ, decreased IL-10 and IL-10 producing Treg cells, and increased number of protective CD4+ Th1 and NKT cells. Lack of IFN1 signaling abrogated caspase 11 activation and IL-1β secretion, suggesting that IFN1 activates the non-canonical inflammasome. Our data also show that WT, but not IFNαR-/-, cells exhibit defective autophagy. Together, these data demonstrate that IFN 1 signaling suppresses autophagy and activates the non-canonical inflammasome pathway contributing to impaired protective immunity and development of fatal Ehrlichia-induced toxic shock.