A hierarchy of cell death pathways confers layered resistance to shigellosis in mice

Bacteria of the genus cause shigellosis, a severe gastrointestinal disease driven by bacterial colonization of colonic intestinal epithelial cells. Vertebrates have evolved programmed cell death pathways that sense invasive enteric pathogens and eliminate their intracellular niche. Previously we reported that genetic removal of one such pathway, the NAIP-NLRC4 inflammasome, is sufficient to convert mice from resistant to susceptible to oral challenge (Mitchell et al., 2020). Here, we investigate the protective role of additional cell death pathways during oral mouse infection. We find that the Caspase-11 inflammasome, which senses LPS, restricts colonization of the intestinal epithelium in the absence of NAIP-NLRC4. However, this protection is limited when expresses OspC3, an effector that antagonizes Caspase-11 activity. TNFα, a cytokine that activates Caspase-8-dependent apoptosis, also provides potent protection from colonization of the intestinal epithelium when mice lack both NAIP-NLRC4 and Caspase-11. The combined genetic removal of Caspases-1, -11, and -8 renders mice hyper-susceptible to oral infection. Our findings uncover a layered hierarchy of cell death pathways that limit the ability of an invasive gastrointestinal pathogen to cause disease.