A hierarchy of cell death pathways confers layered resistance to shigellosis in mice
- University of California, Berkeley, United States
- Massachusetts General Hospital, United States
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 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. TNFa, 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.
Data availability
All data generated or analysed during this study are included in the manuscript or have been deposited with Dryad at https://doi.org/10.6078/D1S13W.
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Data from: A hierarchy of cell death pathways confers layered resistance to shigellosis in miceDryad Digital Repository, doi:10.6078/D1S13W.
Article and author information
Author details
Funding
Howard Hughes Medical Institute
- Russell E Vance
National Institutes of Health (AI075039)
- Russell E Vance
National Institutes of Health (AI063302)
- Russell E Vance
National Institutes of Health (AI155634)
- Russell E Vance
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (AUP-2014-09-6665-1) of the University of California Berkeley.
Copyright
© 2023, Roncaioli et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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A hierarchy of cell death pathways confers layered resistance to shigellosis in mice
eLife 12:e83639.
https://doi.org/10.7554/eLife.83639
