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

Abstract

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, Roncaioli 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. TNFα, a cytokine that activates Caspase-8-dependent apoptosis, also provides protection from Shigella colonization of the intestinal epithelium, but only in the absence of 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.

YersiniaType III-Secreted Effectors Evade the Caspase-4 Inflammasome in Human Cells

“…2, 4C-D, 5A-B). Caspase-4 is more highly expressed in human IECs than other inflammasome components (56), and a broad range of intracellular enteric pathogens engage or inhibit caspase-4/11 in human and murine IECs, respectively (49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59). In myeloid cells, activated caspase-4/11 directly executes cell death, but requires NLRP3 and caspase-1 for downstream IL-18 maturation and secretion (24).…”

“…However, inflammasomes are expressed in multiple cell types, including intestinal epithelial cells (IECs) (48), which are the first colonization barrier and the primary site of infection of many gastrointestinal pathogens, including Y. enterocolitica and Y. pseudotuberculosis. In mice, intestinal epithelial-intrinsic NAIP/NLRC4 and caspase-11 inflammasome responses restrict intraepithelial bacterial burdens during infection with enteric pathogens, including Salmonella, Shigella, enteropathogenic Escherichia coli (EPEC), and Citrobacter rodentium (49)(50)(51)(52)(53)(54)(55). The NAIP/NLRC4 inflammasome is not present in human IECs, wherein the human homolog of caspase-11, caspase-4, instead plays a critical role in controlling bacterial burdens and driving expulsion of infected cells (49,56,57), highlighting speciesspecific differences as well as cell type-specific differences in inflammasome responses.…”