ASC inflammasome mediates host protection against rickettsiae via a NLRP3-independent signaling pathway (INC7P.403)

Abstract

Abstract Rickettsiae escape from the vacuole into the cytosol, where they replicate and inflammasomes recognize the cytosolic infectious pathogens via Nod-like receptors leading to secretion of IL-1β and IL-18. However, the interaction of rickettsiae with inflammasomes has never been investigated. In this study, we found that secretion of mature IL-1β and IL-18 from Rickettsia australis-infected macrophages is caspase-1 and ASC-dependent, suggesting that Rickettsia activates ASC inflammasome. All R. australis-infected ASC-/- mice succumbed to infection (100% mortality) while all infected wild type (WT) mice survived (0% mortality). Rickettsial loads in liver in infected ASC-/- mice were significantly increased with less cellular infiltration compared to infected WT mice. In vivo production of IL-18 was completely dependent on ASC in R. australis-infected mice as evidenced by abolished IL-18 production in infected ASC-/- mice compared to infected WT mice. R. australis-induced-IL-1β and IL-18 concentrations were only reduced, but not abolished in macrophages from NLRP3-/- mice compared to WT controls. Host survival and rickettsial loads in lung and liver of NLRP3-/- mice were comparable with those of WT mice, suggesting a negligible role of NLRP3 in host defense. Taken together, our results suggest that R. australis are recognized by ASC inflammasome in vitro and in vivo via a NLRP3-independent pathway. ASC inflammasome mediates host protection against this intracellular bacterium.