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

  1. Justin L Roncaioli
  2. Janet P Babirye
  3. Roberto A Chavez
  4. Fitty L Liu
  5. Elizabeth A Turcotte
  6. Angus Y Lee
  7. Cammie F Lesser
  8. Russell E Vance  Is a corresponding author
  1. University of California, Berkeley, United States
  2. 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.

The following data sets were generated

Article and author information

Author details

  1. Justin L Roncaioli

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  2. Janet P Babirye

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  3. Roberto A Chavez

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  4. Fitty L Liu

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  5. Elizabeth A Turcotte

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  6. Angus Y Lee

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  7. Cammie F Lesser

    Department of Microbiology, Massachusetts General Hospital, Cambridge, United States
    Competing interests
    No competing interests declared.
  8. Russell E Vance

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    For correspondence
    rvance@berkeley.edu
    Competing interests
    Russell E Vance, Reviewing editor, eLife.Scientific Advisory Board member, Tempest Therapeutics..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6686-3912

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.

Reviewing Editor

  1. Arturo Casadevall, Johns Hopkins Bloomberg School of Public Health, United States

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.

Version history

  1. Preprint posted: September 21, 2022 (view preprint)
  2. Received: September 27, 2022
  3. Accepted: January 15, 2023
  4. Accepted Manuscript published: January 16, 2023 (version 1)
  5. Version of Record published: January 25, 2023 (version 2)

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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  1. Justin L Roncaioli
  2. Janet P Babirye
  3. Roberto A Chavez
  4. Fitty L Liu
  5. Elizabeth A Turcotte
  6. Angus Y Lee
  7. Cammie F Lesser
  8. Russell E Vance
(2023)
A hierarchy of cell death pathways confers layered resistance to shigellosis in mice
eLife 12:e83639.
https://doi.org/10.7554/eLife.83639

Share this article

https://doi.org/10.7554/eLife.83639

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