RT Journal Article
SR Electronic
T1 A hierarchy of cell death pathways confers layered resistance to shigellosis in mice
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.09.21.508939
DO 10.1101/2022.09.21.508939
A1 Justin L Roncaioli
A1 Janet Peace Babirye
A1 Roberto A Chavez
A1 Fitty L Liu
A1 Elizabeth A Turcotte
A1 Angus Y Lee
A1 Cammie F Lesser
A1 Russell E Vance
YR 2022
UL http://biorxiv.org/content/early/2022/09/21/2022.09.21.508939.abstract
AB 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.Competing Interest StatementThe authors have declared no competing interest.