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

Bacteria of the genus Shigella 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 Shigella flexneri challenge (Mitchell et al., 2020). Here, we investigate the protective role of additional cell death pathways during oral mouse Shigella infection. We find that the Caspase-11 inflammasome, which senses Shigella LPS, restricts Shigella colonization of the intestinal epithelium in the absence of NAIP-NLRC4. However, this protection is limited when Shigella expresses OspC3, an effector that antagonizes Caspase-11 activity. TNF alpha, a cytokine that activates Caspase-8-dependent apoptosis, also provides potent protection from Shigella 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 Shigella infection. Our findings uncover a layered hierarchy of cell death pathways that limit the ability of an invasive gastrointestinal pathogen to cause disease.

Automated summary

Bacteria of the genus Shigella, which cause shigellosis, can colonize colonic intestinal epithelial cells and result in severe gastrointestinal disease. In this study, the researchers investigate the protective role of cell death pathways during oral Shigella infection in mice. They find that the Caspase-11 inflammasome and TNF alpha, a cytokine that activates Caspase-8-dependent apoptosis, provide protection against Shigella colonization in the absence of the NAIP-NLRC4 pathway. However, the protection is limited when Shigella expresses OspC3, which antagonizes Caspase-11 activity. Overall, the study reveals a layered hierarchy of cell death pathways that limit the ability of Shigella to cause disease.