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

被引:0
|
作者
Fattinger, Stefan A. [1 ,2 ,3 ]
Maurer, Luca [1 ]
Geiser, Petra [2 ]
Bernard, Elliott M. [4 ]
Enz, Ursina [1 ]
Ganguillet, Suwannee [1 ]
Gul, Ersin [1 ]
Kroon, Sanne [1 ]
Demarco, Benjamin [4 ]
Mack, Vanessa [4 ]
Furter, Markus [1 ]
Barthel, Manja [1 ]
Pelczar, Pawel [5 ]
Shao, Feng [6 ]
Broz, Petr [4 ]
Sellin, Mikael E. [2 ]
Hardt, Wolf-Dietrich [1 ]
机构
[1] Swiss Fed Inst Technol, Inst Microbiol, Dept Biol, CH-8093 Zurich, Switzerland
[2] Uppsala Univ, Sci Life Lab, Dept Med Biochem & Microbiol, S-75123 Uppsala, Sweden
[3] Univ Calif Berkeley, Dept Mol & Cell Biol, Div Immunol & Mol Med, Berkeley, CA 94720 USA
[4] Univ Lausanne, Dept Immunobiol, CH-1066 Epalinges, Switzerland
[5] Univ Basel, Ctr Transgen Models, CH-4002 Basel, Switzerland
[6] Natl Inst Biol Sci, Beijing 102206, Peoples R China
基金
瑞典研究理事会; 瑞士国家科学基金会;
关键词
SEROVAR TYPHIMURIUM; INFLAMMASOME; GSDMD; PYROPTOSIS; ACTIVATION; MUCOSAL; MOUSE; EXPRESSION; CASPASE-11; IL-1-BETA;
D O I
10.1073/pnas.2315503120
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 1 ss (IL1 ss) 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.
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页数:11
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