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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\u2013NLRC4 inflammasome, is sufficient to convert mice from resistant to susceptible to oral\n                    <jats:italic>Shigella flexneri<\/jats:italic>\n                    challenge (Mitchell et al., 2020). Here, we investigate the protective role of additional cell death pathways during oral mouse\n                    <jats:italic>Shigella<\/jats:italic>\n                    infection. We find that the Caspase-11 inflammasome, which senses\n                    <jats:italic>Shigella<\/jats:italic>\n                    LPS, restricts\n                    <jats:italic>Shigella<\/jats:italic>\n                    colonization of the intestinal epithelium in the absence of NAIP\u2013NLRC4. However, this protection is limited when\n                    <jats:italic>Shigella<\/jats:italic>\n                    expresses OspC3, an effector that antagonizes Caspase-11 activity. TNF\u03b1, a cytokine that activates Caspase-8-dependent apoptosis, also provides potent protection from\n                    <jats:italic>Shigella<\/jats:italic>\n                    colonization of the intestinal epithelium when mice lack both NAIP\u2013NLRC4 and Caspase-11. The combined genetic removal of Caspases-1, -11, and -8 renders mice hyper-susceptible to oral\n                    <jats:italic>Shigella<\/jats:italic>\n                    infection. Our findings uncover a layered hierarchy of cell death pathways that limit the ability of an invasive gastrointestinal pathogen to cause disease.\n                  <\/jats:p>","DOI":"10.7554\/elife.83639","type":"journal-article","created":{"date-parts":[[2023,1,16]],"date-time":"2023-01-16T10:00:25Z","timestamp":1673863225000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.83639","source":"Crossref","is-referenced-by-count":35,"title":["A hierarchy of cell death pathways confers layered resistance to shigellosis in mice"],"prefix":"10.7554","volume":"12","author":[{"given":"Justin L","family":"Roncaioli","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01an7q238","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Immunology & Molecular Medicine, Department of Molecular & Cell Biology, University of California, Berkeley","place":["Berkeley, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janet 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