NAIP–NLRC4-deficient mice are susceptible to shigellosis

AbstractBacteria of the genusShigellacause shigellosis, a severe gastrointestinal disease that is a major cause of diarrhea-associated mortality in humans. Shigellosis develops upon oral ingestion of as few as 100 bacteria, but million-fold higher doses fail to cause disease in mice. The lack of a physiologically relevant mouse model of shigellosis has impeded our understanding of this important human disease, but why mice are resistant is unknown. Here we show that in human cells, but not in mice,Shigellaevades detection by the NAIP–NLRC4 inflammasome, an immune sensor present in intestinal epithelial cells (IECs). We find that NAIP–NLRC4-deficient mice are highly susceptible to oralShigellainfection and recapitulate the clinical features of human shigellosis, including bacterial replication in IECs and neutrophilic inflammation of the colon. Confirming a role for bacterial replication in IECs in our new model, aShigellamutant lacking IcsA, a factor required for cell-to-cell spread among IECs, is attenuated in otherwise susceptible NAIP–NLRC4-deficient mice. Although inflammasome-mediated cell death is widely held to promoteShigellainfection and pathogenesis, we instead demonstrate that IEC-specific NAIP–NLRC4-induced cell death is sufficient to protect the host from shigellosis. Thus, NAIP–NLRC4-deficient mice are a physiologically relevant and experimentally tractable model for shigellosis. More broadly, our results suggest that the lack of an inflammasome response in IECs may help explain the extreme susceptibility of humans to shigellosis.