1. Immunology and Inflammation
  2. Microbiology and Infectious Disease

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

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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  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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Further reading

    1. Immunology and Inflammation
    2. Microbiology and Infectious Disease

    NAIP–NLRC4-deficient mice are susceptible to shigellosis

    Patrick S Mitchell, Justin L Roncaioli ... Russell E Vance
    Research Article Updated

    Bacteria of the genus Shigella cause shigellosis, a severe gastrointestinal disease that is a major cause of diarrhea-associated mortality in humans. Mice are highly resistant to Shigella and the lack of a tractable physiological model of shigellosis has impeded our understanding of this important human disease. Here, we propose that the differential susceptibility of mice and humans to Shigella is due to mouse-specific activation of the NAIP–NLRC4 inflammasome. We find that NAIP–NLRC4-deficient mice are highly susceptible to oral Shigella infection and recapitulate the clinical features of human shigellosis. Although inflammasomes are generally thought to promote Shigella pathogenesis, we instead demonstrate that intestinal epithelial cell (IEC)-specific NAIP–NLRC4 activity is sufficient to protect mice from shigellosis. In addition to describing a new mouse model of shigellosis, our results suggest that the lack of an inflammasome response in IECs may help explain the susceptibility of humans to shigellosis.

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    Inflammasomes: A tale of two caspases

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    Soluble immune mediators orchestrate protective in vitro granulomatous responses across Mycobacterium tuberculosis complex lineages

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    The members of the Mycobacterium tuberculosis complex (MTBC) causing human tuberculosis comprise 10 phylogenetic lineages that differ in their geographical distribution. The human consequences of this phylogenetic diversity remain poorly understood. Here, we assessed the phenotypic properties at the host-pathogen interface of 14 clinical strains representing five major MTBC lineages. Using a human in vitro granuloma model combined with bacterial load assessment, microscopy, flow cytometry, and multiplexed-bead arrays, we observed considerable intra-lineage diversity. Yet, modern lineages were overall associated with increased growth rate and more pronounced granulomatous responses. MTBC lineages exhibited distinct propensities to accumulate triglyceride lipid droplets—a phenotype associated with dormancy—that was particularly pronounced in lineage 2 and reduced in lineage 3 strains. The most favorable granuloma responses were associated with strong CD4 and CD8 T cell activation as well as inflammatory responses mediated by CXCL9, granzyme B, and TNF. Both of which showed consistent negative correlation with bacterial proliferation across genetically distant MTBC strains of different lineages. Taken together, our data indicate that different virulence strategies and protective immune traits associate with MTBC genetic diversity at lineage and strain level.