Gasdermin D is the only Gasdermin that provides protection against acute Salmonella gut infection in mice.

Autor:	Fattinger SA; Department of Biology, Institute of Microbiology, ETH Zurich, Zurich 8093, Switzerland.; Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Uppsala 75123, Sweden.; Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720., Maurer L; Department of Biology, Institute of Microbiology, ETH Zurich, Zurich 8093, Switzerland., Geiser P; Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Uppsala 75123, Sweden., Bernard EM; Department of Immunobiology, University of Lausanne, Epalinges 1066, Switzerland., Enz U; Department of Biology, Institute of Microbiology, ETH Zurich, Zurich 8093, Switzerland., Ganguillet S; Department of Biology, Institute of Microbiology, ETH Zurich, Zurich 8093, Switzerland., Gül E; Department of Biology, Institute of Microbiology, ETH Zurich, Zurich 8093, Switzerland., Kroon S; Department of Biology, Institute of Microbiology, ETH Zurich, Zurich 8093, Switzerland., Demarco B; Department of Immunobiology, University of Lausanne, Epalinges 1066, Switzerland., Mack V; Department of Immunobiology, University of Lausanne, Epalinges 1066, Switzerland., Furter M; Department of Biology, Institute of Microbiology, ETH Zurich, Zurich 8093, Switzerland., Barthel M; Department of Biology, Institute of Microbiology, ETH Zurich, Zurich 8093, Switzerland., Pelczar P; Center for Transgenic Models, University of Basel, Basel 4002, Switzerland., Shao F; National Institute of Biological Sciences, Beijing 102206, China., Broz P; Department of Immunobiology, University of Lausanne, Epalinges 1066, Switzerland., Sellin ME; Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Uppsala 75123, Sweden., Hardt WD; Department of Biology, Institute of Microbiology, ETH Zurich, Zurich 8093, Switzerland.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2023 Nov 28; Vol. 120 (48), pp. e2315503120. Date of Electronic Publication: 2023 Nov 21.
DOI:	10.1073/pnas.2315503120
Abstrakt:	Gasdermins (GSDMs) share a common functional domain structure and are best known for their capacity to form membrane pores. These pores are hallmarks of a specific form of cell death called pyroptosis and mediate the secretion of pro-inflammatory cytokines such as interleukin 1β (IL1β) and interleukin 18 (IL18). Thereby, Gasdermins have been implicated in various immune responses against cancer and infectious diseases such as acute Salmonella Typhimurium ( S. Tm) gut infection. However, to date, we lack a comprehensive functional assessment of the different Gasdermins (GSDMA-E) during S .Tm infection in vivo. Here, we used epithelium-specific ablation, bone marrow chimeras, and mouse lines lacking individual Gasdermins, combinations of Gasdermins or even all Gasdermins (GSDMA1-3C1-4DE) at once and performed littermate-controlled oral S .Tm infections in streptomycin-pretreated mice to investigate the impact of all murine Gasdermins. While GSDMA, C, and E appear dispensable, we show that GSDMD i) restricts S .Tm loads in the gut tissue and systemic organs, ii) controls gut inflammation kinetics, and iii) prevents epithelium disruption by 72 h of the infection. Full protection requires GSDMD expression by both bone-marrow-derived lamina propria cells and intestinal epithelial cells (IECs). In vivo experiments as well as 3D-, 2D-, and chimeric enteroid infections further show that infected IEC extrusion proceeds also without GSDMD, but that GSDMD controls the permeabilization and morphology of the extruding IECs, affects extrusion kinetics, and promotes overall mucosal barrier capacity. As such, this work identifies a unique multipronged role of GSDMD among the Gasdermins for mucosal tissue defense against a common enteric pathogen. Competing Interests: Competing interests statement:The authors declare no competing interest.
Databáze:	MEDLINE
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