Distinct cell death pathways induced by granzymes collectively protect against intestinal Salmonella infection.

Autor:	Chawla AS; MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee DD1 5EH, United Kingdom., Vandereyken M; MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee DD1 5EH, United Kingdom., Arias M; Fundación Instituto de Investigación Sanitaria Aragón (IIS Aragón), Biomedical Research Centre of Aragón (CIBA), 50009, Zaragoza, and CIBER en Enfermedades Infecciosas, Madrid, Spain; Departamento de Microbiología y Medicina Preventiva, Facultad de Medicina, Universidad de Zaragoza, Spain., Santiago L; Fundación Instituto de Investigación Sanitaria Aragón (IIS Aragón), Biomedical Research Centre of Aragón (CIBA), 50009, Zaragoza, and CIBER en Enfermedades Infecciosas, Madrid, Spain; Departamento de Microbiología y Medicina Preventiva, Facultad de Medicina, Universidad de Zaragoza, Spain., Dikovskaya D; MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee DD1 5EH, United Kingdom., Nguyen C; MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee DD1 5EH, United Kingdom., Skariah N; MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee DD1 5EH, United Kingdom., Wenner N; Department of Clinical Infection Microbiology & Immunology, Institute of Infection, Veterinary & Ecological Sciences, University of Liverpool, Liverpool, United Kingdom; Current address: Biozentrum, University of Basel, Basel, Switzerland., Golovchenko NB; Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Thomson SJ; Biological Services, School of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom., Ondari E; Molecular Microbiology, School of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom., Garzón-Tituaña M; Fundación Instituto de Investigación Sanitaria Aragón (IIS Aragón), Biomedical Research Centre of Aragón (CIBA), 50009, Zaragoza, and CIBER en Enfermedades Infecciosas, Madrid, Spain., Anderson CJ; Centre for Inflammation Research, Institute for Regeneration & Repair, University of Edinburgh, Edinburgh, United Kingdom., Bergkessel M; Molecular Microbiology, School of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom., C D Hinton J; Department of Clinical Infection Microbiology & Immunology, Institute of Infection, Veterinary & Ecological Sciences, University of Liverpool, Liverpool, United Kingdom., Edelblum KL; Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Pardo J; Fundación Instituto de Investigación Sanitaria Aragón (IIS Aragón), Biomedical Research Centre of Aragón (CIBA), 50009, Zaragoza, and CIBER en Enfermedades Infecciosas, Madrid, Spain; Departamento de Microbiología y Medicina Preventiva, Facultad de Medicina, Universidad de Zaragoza, Spain., Swamy M; MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee DD1 5EH, United Kingdom. Electronic address: m.swamy@dundee.ac.uk.
Jazyk:	angličtina
Zdroj:	Mucosal immunology [Mucosal Immunol] 2024 Dec; Vol. 17 (6), pp. 1242-1255. Date of Electronic Publication: 2024 Aug 11.
DOI:	10.1016/j.mucimm.2024.08.006
Abstrakt:	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 -/- mice carried significantly lower burdens of Salmonella, as predominant GzmA-mediated cell death effectively reduced bacterial translocation across the intestinal barrier. Conversely, in GzmA -/- 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. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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