Distinct cell death pathways induced by granzymes collectively protect against intestinal Salmonella infection
Intestinal intraepithelial T lymphocytes (IEL) constitutively express high amounts of the cytotoxic proteases Granzymes (Gzm) A and B and are therefore thought to protect the intestinal epithelium against infection by killing infected epithelial cells. However, the role of IEL granzymes in a protective immune response has yet to be demonstrated. We show that GzmA and GzmB are required to protect mice against oral, but not intravenous, infection with Salmonella enterica serovar Typhimurium, consistent with an intestine-specific role. IEL-intrinsic granzymes mediate the protective effects by controlling intracellular bacterial growth and aiding in cell-intrinsic pyroptotic cell death of epithelial cells. Surprisingly, we found that both granzymes play non-redundant roles. GzmB<sup>-/-</sup> mice carried significantly lower burdens of Salmonella, as predominant GzmA-mediated cell death effectively reduced bacterial translocation across the intestinal barrier. Conversely, in GzmA<sup>-/-</sup> mice, GzmB-driven apoptosis favored luminal Salmonella growth by providing nutrients, while still reducing translocation across the epithelial barrier. Together, the concerted actions of both GzmA and GzmB balance cell death mechanisms at the intestinal epithelium to provide optimal control that Salmonella cannot subvert.
Authors
- Marcela Garzón-Tituaña (ORCID: https://orcid.org/0000-0001-6778-0636)
- Christopher J. Anderson (ORCID: https://orcid.org/0000-0003-2600-0968)
- Julián Pardo
- Jay C. D. Hinton (ORCID: https://orcid.org/0000-0003-2671-6026)
- Karen L. Edelblum (ORCID: https://orcid.org/0000-0001-8288-4898)
- Megan Bergkessel (ORCID: https://orcid.org/0000-0002-4530-1224)
- Amanpreet Singh Chawla (ORCID: https://orcid.org/0000-0001-5265-3431)
- Dina Dikovskaya (ORCID: https://orcid.org/0000-0003-3161-3072)
- Natasha B. Golovchenko (ORCID: https://orcid.org/0000-0001-8323-4643)
- Edna Ondari (ORCID: https://orcid.org/0000-0002-4073-2973)
- Nicolas Wenner (ORCID: https://orcid.org/0000-0001-6257-9423)
- Llipsy Santiago (ORCID: https://orcid.org/0000-0002-1861-5981)
- Mahima Swamy (ORCID: https://orcid.org/0000-0003-3977-3425)
- Maud Vandereyken (ORCID: https://orcid.org/0000-0002-6169-7396)
- Neema Skariah
- Chi Nguyen
- Sarah J. Thomson
- Maykel Arias
Institutions
- University of Liverpool (GB)
- University of Dundee (GB)
- University of Basel (CH)
- Universidad de Zaragoza (ES)
- MRC Protein Phosphorylation and Ubiquitylation Unit (GB)
- Instituto de Investigación Sanitaria Aragón (ES)
- Centre for Inflammation Research (GB)
- University of Edinburgh (GB)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Mucosal Immunology
- Published
- 2024-08-11
- DOI
- https://doi.org/10.1016/j.mucimm.2024.08.006
- Citations
- 8
- Primary Topic
- IL-33, ST2, and ILC Pathways
- Type
- article
- Field-Weighted Citation Impact
- 1.92
Funders
- Wellcome Trust
- Fundación Agencia Aragonesa para la Investigación y el Desarrollo
- Gobierno de Aragón
- National Institutes of Health