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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. Previous...

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Autores principales: Roncaioli, Justin L, Babirye, Janet Peace, Chavez, Roberto A, Liu, Fitty L, Turcotte, Elizabeth A, Lee, Angus Y, Lesser, Cammie F, Vance, Russell E
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9876568/
https://www.ncbi.nlm.nih.gov/pubmed/36645406
http://dx.doi.org/10.7554/eLife.83639
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author Roncaioli, Justin L
Babirye, Janet Peace
Chavez, Roberto A
Liu, Fitty L
Turcotte, Elizabeth A
Lee, Angus Y
Lesser, Cammie F
Vance, Russell E
author_facet Roncaioli, Justin L
Babirye, Janet Peace
Chavez, Roberto A
Liu, Fitty L
Turcotte, Elizabeth A
Lee, Angus Y
Lesser, Cammie F
Vance, Russell E
author_sort Roncaioli, Justin L
collection PubMed
description 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. TNFα, 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.
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spelling pubmed-98765682023-01-26 A hierarchy of cell death pathways confers layered resistance to shigellosis in mice Roncaioli, Justin L Babirye, Janet Peace Chavez, Roberto A Liu, Fitty L Turcotte, Elizabeth A Lee, Angus Y Lesser, Cammie F Vance, Russell E eLife Immunology and Inflammation 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. TNFα, 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. eLife Sciences Publications, Ltd 2023-01-16 /pmc/articles/PMC9876568/ /pubmed/36645406 http://dx.doi.org/10.7554/eLife.83639 Text en © 2023, Roncaioli et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Immunology and Inflammation
Roncaioli, Justin L
Babirye, Janet Peace
Chavez, Roberto A
Liu, Fitty L
Turcotte, Elizabeth A
Lee, Angus Y
Lesser, Cammie F
Vance, Russell E
A hierarchy of cell death pathways confers layered resistance to shigellosis in mice
title A hierarchy of cell death pathways confers layered resistance to shigellosis in mice
title_full A hierarchy of cell death pathways confers layered resistance to shigellosis in mice
title_fullStr A hierarchy of cell death pathways confers layered resistance to shigellosis in mice
title_full_unstemmed A hierarchy of cell death pathways confers layered resistance to shigellosis in mice
title_short A hierarchy of cell death pathways confers layered resistance to shigellosis in mice
title_sort hierarchy of cell death pathways confers layered resistance to shigellosis in mice
topic Immunology and Inflammation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9876568/
https://www.ncbi.nlm.nih.gov/pubmed/36645406
http://dx.doi.org/10.7554/eLife.83639
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