NAIP-NLRC4-deficient mice are susceptible to shigellosis.

Abstract

Bacteria of the genus <i>Shigella</i> cause shigellosis, a severe gastrointestinal disease that is a major cause of diarrhea-associated mortality in humans. Mice are highly resistant to <i>Shigella</i> and the lack of a tractable physiological model of shigellosis has impeded our understanding of this important human disease. Here, we propose that the differential susceptibility of mice and humans to <i>Shigella</i> is due to mouse-specific activation of the NAIP-NLRC4 inflammasome. We find that NAIP-NLRC4-deficient mice are highly susceptible to oral <i>Shigella</i> infection and recapitulate the clinical features of human shigellosis. Although inflammasomes are generally thought to promote <i>Shigella</i> pathogenesis, we instead demonstrate that intestinal epithelial cell (IEC)-specific NAIP-NLRC4 activity is sufficient to protect mice from shigellosis. In addition to describing a new mouse model of shigellosis, our results suggest that the lack of an inflammasome response in IECs may help explain the susceptibility of humans to shigellosis.