Gasdermin D is the only Gasdermin that provides non-redundant protection against acuteSalmonellagut infection

Abstract

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 have performed littermate-controlled oral S.Tm infections 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 72h of the infection. Full protection requires GSDMD expression by both bone-marrow-derived lamina propria cells and intestinal epithelial cells (IECs). In vivo experiments, 3D- and 2D-enteroid infections further show that infected IEC extrusion proceeds also without GSDMD, but that GSDMD controls the permeabilization and morphology of the extruding cells and affects extrusion kinetics. As such, this work identifies a non-redundant multipronged role of GSDMD in mucosal tissue defence against a common enteric pathogen.

The Role of Gasdermin-D-Mediated Pyroptosis in Organ Injury and Its Therapeutic Implications

“… 84 , 85 GSDMD also plays a role in metabolic diseases, systemic endotoxemia, and gut dysbiosis. 86 Mice fed with high fat diet (HFD) have activated GSDMD-NT in mouse liver, kidney, and adipose tissue, and prevents systemic endotoxemia by killing endogenous bacteria (Proteobacteria) produced from LPS in HFD-mice. 86 Interestingly, GSDMD is the only GSDM protein that can protect against Salmonella typhimurium gut infection.…”

“… 86 Interestingly, GSDMD is the only GSDM protein that can protect against Salmonella typhimurium gut infection. 86 …”

Intraluminal neutrophils limit epithelium damage by reducing pathogen assault on intestinal epithelial cells duringSalmonellagut infection

“…Similarly, excessive assault on epithelial cells and increased pathogen tissue loads due to the lack of one or more of the mucosal defenses can also drive pathological cell loss and destruction of the epithelium. This was shown in the examples of NAIP/NLRC4 or GSDMD (downstream of NLRC4 inflammasome; executer of pyroptotic cell death [19]) deficiency, where failure to initiate timely epithelial immune responses resulted in increased pathogen loads and disruption of the epithelium at later stages of the infection [20, 21]. These reports highlight the importance of a balanced and timely mucosal immune response to maintain epithelium integrity during enteric infections.…”

Intraluminal neutrophils limit epithelium damage by reducing pathogen assault on intestinal epithelial cells during Salmonella gut infection

“…Similarly, excessive assault on epithelial cells and increased pathogen tissue loads due to the lack of one or more of the mucosal defenses can also drive pathological cell loss and destruction of the epithelium. This was shown in the examples of NAIP/NLRC4 or GSDMD (downstream of NLRC4 inflammasome; executer of pyroptotic cell death [ 20 ]) deficiency, where failure to initiate timely epithelial immune responses resulted in increased pathogen loads and disruption of the epithelium at later stages of the infection [ 21 , 22 ]. These reports highlight the importance of a balanced and timely mucosal immune response to maintain epithelium integrity during enteric infections.…”