PMID- 37988464
OWN - NLM
STAT- MEDLINE
DCOM- 20231127
LR  - 20231205
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 120
IP  - 48
DP  - 2023 Nov 28
TI  - Gasdermin D is the only Gasdermin that provides protection against acute 
      Salmonella gut infection in mice.
PG  - e2315503120
LID - 10.1073/pnas.2315503120 [doi]
LID - e2315503120
AB  - 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 1beta (IL1beta) 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.
FAU - Fattinger, Stefan A
AU  - Fattinger SA
AUID- ORCID: 0000-0003-4899-4414
AD  - Department of Biology, Institute of Microbiology, ETH Zurich, Zurich 8093, 
      Switzerland.
AD  - Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, 
      Uppsala University, Uppsala 75123, Sweden.
AD  - Division of Immunology and Molecular Medicine, Department of Molecular and Cell 
      Biology, University of California, Berkeley, CA 94720.
FAU - Maurer, Luca
AU  - Maurer L
AUID- ORCID: 0000-0002-9498-2775
AD  - Department of Biology, Institute of Microbiology, ETH Zurich, Zurich 8093, 
      Switzerland.
FAU - Geiser, Petra
AU  - Geiser P
AUID- ORCID: 0000-0003-2785-4201
AD  - Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, 
      Uppsala University, Uppsala 75123, Sweden.
FAU - Bernard, Elliott M
AU  - Bernard EM
AUID- ORCID: 0000-0003-2761-3790
AD  - Department of Immunobiology, University of Lausanne, Epalinges 1066, Switzerland.
FAU - Enz, Ursina
AU  - Enz U
AUID- ORCID: 0000-0002-4220-2650
AD  - Department of Biology, Institute of Microbiology, ETH Zurich, Zurich 8093, 
      Switzerland.
FAU - Ganguillet, Suwannee
AU  - Ganguillet S
AD  - Department of Biology, Institute of Microbiology, ETH Zurich, Zurich 8093, 
      Switzerland.
FAU - Gul, Ersin
AU  - Gul E
AUID- ORCID: 0000-0003-2873-8034
AD  - Department of Biology, Institute of Microbiology, ETH Zurich, Zurich 8093, 
      Switzerland.
FAU - Kroon, Sanne
AU  - Kroon S
AUID- ORCID: 0000-0002-5722-0763
AD  - Department of Biology, Institute of Microbiology, ETH Zurich, Zurich 8093, 
      Switzerland.
FAU - Demarco, Benjamin
AU  - Demarco B
AD  - Department of Immunobiology, University of Lausanne, Epalinges 1066, Switzerland.
FAU - Mack, Vanessa
AU  - Mack V
AD  - Department of Immunobiology, University of Lausanne, Epalinges 1066, Switzerland.
FAU - Furter, Markus
AU  - Furter M
AUID- ORCID: 0000-0003-4073-2268
AD  - Department of Biology, Institute of Microbiology, ETH Zurich, Zurich 8093, 
      Switzerland.
FAU - Barthel, Manja
AU  - Barthel M
AD  - Department of Biology, Institute of Microbiology, ETH Zurich, Zurich 8093, 
      Switzerland.
FAU - Pelczar, Pawel
AU  - Pelczar P
AD  - Center for Transgenic Models, University of Basel, Basel 4002, Switzerland.
FAU - Shao, Feng
AU  - Shao F
AUID- ORCID: 0000-0002-9562-7791
AD  - National Institute of Biological Sciences, Beijing 102206, China.
FAU - Broz, Petr
AU  - Broz P
AUID- ORCID: 0000-0002-2334-7790
AD  - Department of Immunobiology, University of Lausanne, Epalinges 1066, Switzerland.
FAU - Sellin, Mikael E
AU  - Sellin ME
AUID- ORCID: 0000-0002-8355-0803
AD  - Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, 
      Uppsala University, Uppsala 75123, Sweden.
FAU - Hardt, Wolf-Dietrich
AU  - Hardt WD
AUID- ORCID: 0000-0002-9892-6420
AD  - Department of Biology, Institute of Microbiology, ETH Zurich, Zurich 8093, 
      Switzerland.
LA  - eng
GR  - 310030_192567/Schweizerischer Nationalfonds zur Forderung der Wissenschaftlichen 
      Forschung (SNF)/
GR  - #21B079/Novartis Stiftung fur Medizinisch-Biologische Forschung (Novartis 
      Foundation for Medical-Biological Research)/
GR  - ERC-2017-CoG 770988/EC | European Research Council (ERC)/
GR  - 310030_198005/Schweizerischer Nationalfonds zur Forderung der Wissenschaftlichen 
      Forschung (SNF)/
GR  - 2018-02223/Vetenskapsradet (VR)/
GR  - ICA16-0031; FFL18-0165/Stiftelsen for Strategisk Forskning (SSF)/
GR  - ALTF 617- 2021/European Molecular Biology Organization (EMBO)/
GR  - P500PB_206801/Schweizerischer Nationalfonds zur Forderung der Wissenschaftlichen 
      Forschung (SNF)/
PT  - Journal Article
DEP - 20231121
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Gasdermins)
RN  - 0 (Inflammasomes)
SB  - IM
MH  - Animals
MH  - Mice
MH  - *Gasdermins
MH  - *Salmonella Infections/prevention & control
MH  - Salmonella typhimurium
MH  - Inflammation
MH  - Epithelial Cells
MH  - Inflammasomes
PMC - PMC10691232
OTO - NOTNLM
OT  - immunology
OT  - microbiology
OT  - pathogen
OT  - pyroptosis
COIS- Competing interests statement:The authors declare no competing interest.
EDAT- 2023/11/21 18:43
MHDA- 2023/11/27 12:44
PMCR- 2023/11/21
CRDT- 2023/11/21 14:06
PHST- 2023/11/27 12:44 [medline]
PHST- 2023/11/21 18:43 [pubmed]
PHST- 2023/11/21 14:06 [entrez]
PHST- 2023/11/21 00:00 [pmc-release]
AID - 202315503 [pii]
AID - 10.1073/pnas.2315503120 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2023 Nov 28;120(48):e2315503120. doi: 
      10.1073/pnas.2315503120. Epub 2023 Nov 21.