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...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2023-01-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/83639 |
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| author | Justin L Roncaioli Janet Peace Babirye Roberto A Chavez Fitty L Liu Elizabeth A Turcotte Angus Y Lee Cammie F Lesser Russell E Vance |
| author_facet | Justin L Roncaioli Janet Peace Babirye Roberto A Chavez Fitty L Liu Elizabeth A Turcotte Angus Y Lee Cammie F Lesser Russell E Vance |
| author_sort | Justin L Roncaioli |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-10T20:22:20Z |
| format | Article |
| id | doaj.art-aaf98aa5e32244a883032ca3f3475318 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-10T20:22:20Z |
| publishDate | 2023-01-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-aaf98aa5e32244a883032ca3f34753182023-01-25T15:45:29ZengeLife Sciences Publications LtdeLife2050-084X2023-01-011210.7554/eLife.83639A hierarchy of cell death pathways confers layered resistance to shigellosis in miceJustin L Roncaioli0Janet Peace Babirye1Roberto A Chavez2Fitty L Liu3Elizabeth A Turcotte4Angus Y Lee5Cammie F Lesser6Russell E Vance7https://orcid.org/0000-0002-6686-3912Division of Immunology & Molecular Medicine, Department of Molecular & Cell Biology, University of California, Berkeley, Berkeley, United StatesDivision of Immunology & Molecular Medicine, Department of Molecular & Cell Biology, University of California, Berkeley, Berkeley, United StatesDivision of Immunology & Molecular Medicine, Department of Molecular & Cell Biology, University of California, Berkeley, Berkeley, United StatesDivision of Immunology & Molecular Medicine, Department of Molecular & Cell Biology, University of California, Berkeley, Berkeley, United StatesDivision of Immunology & Molecular Medicine, Department of Molecular & Cell Biology, University of California, Berkeley, Berkeley, United StatesCancer Research Laboratory, University of California, Berkeley, Berkeley, United StatesDepartment of Microbiology, Harvard Medical School, Boston, United States; Broad Institute of Harvard and MIT, Cambridge, United States; Department of Medicine, Division of Infectious Diseases, Massachusetts General Hospital, Boston, United StatesDivision of Immunology & Molecular Medicine, Department of Molecular & Cell Biology, University of California, Berkeley, Berkeley, United States; Cancer Research Laboratory, University of California, Berkeley, Berkeley, United States; Immunotherapeutics and Vaccine Research Initiative, University of California, Berkeley, Berkeley, United States; Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United StatesBacteria 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.https://elifesciences.org/articles/83639pathogenesisShigellaintestine |
| spellingShingle | Justin L Roncaioli Janet Peace Babirye Roberto A Chavez Fitty L Liu Elizabeth A Turcotte Angus Y Lee Cammie F Lesser Russell E Vance A hierarchy of cell death pathways confers layered resistance to shigellosis in mice eLife pathogenesis Shigella intestine |
| 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 | pathogenesis Shigella intestine |
| url | https://elifesciences.org/articles/83639 |
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