NAIP-NLRC4-deficient mice are susceptible to shigellosis
- University of California, Berkeley, United States
- Harvard Medical School, United States
- Massachusetts General Hospital, United States
- Oregon Health and Sciences University, United States
Abstract
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.
Data availability
All data generated or analyzed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Funding
Howard Hughes Medical Institute
- Russell E Vance
National Institutes of Health (AI075039,AI063302)
- Russell E Vance
National Institutes of Health (AI064285,AI128743)
- Cammie F Lesser
Jane Coffin Childs Memorial Fund for Medical Research (Postdoctoral Fellowship)
- Patrick S Mitchell
Irving H. Wiesenfeld CEND Fellow (Graduate Student Fellowship)
- Justin L Roncaioli
UC Berkeley Department of Molecular and Cell Biology, NIH (Graduate Training Grant 5T32GM007232-42)
- Elizabeth A Turcotte
Brit d'Arbeloff MGH Research Scholar
- Cammie F Lesser
Medical Research Foundation (MRF2012)
- Isabella Rauch
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
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
© 2020, Mitchell 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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NAIP-NLRC4-deficient mice are susceptible to shigellosis
eLife 9:e59022.
https://doi.org/10.7554/eLife.59022
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