Gsdma, a member of the gasdermin family, is a key executor of inflammatory cell death (pyroptosis) [1,2]. Gasdermins are pore-forming proteins, and Gsdma is predominantly expressed in the skin, mucosa, and immune sentinel cells. Pyroptosis is crucial for recruiting immune cells to infection sites and promoting protective immunity [1].

Research has shown that the cysteine protease SpeB of Streptococcus pyogenes (Group A Streptococcus, GAS) can trigger keratinocyte pyroptosis by cleaving Gsdma, releasing an active N-terminal fragment [1]. Gsdma1 genetic deficiency in mice blunts the immune responses to GAS, leading to uncontrolled bacterial dissemination and death [1]. Also, triple-knockout mice of the three mouse homologues of human Gsdma are more susceptible to invasive infection by a pandemic hypervirulent M1T1 clone of GAS, indicating Gsdma's critical role in the immune defence against invasive skin infections by GAS [2].

In conclusion, Gsdma is essential in the pyroptosis process and immune defence against GAS-related invasive skin infections. The gene knockout mouse models have significantly contributed to revealing Gsdma's role in this specific disease area, enhancing our understanding of the host-pathogen interaction mechanism and providing potential targets for treating related infectious diseases.

References:

1. Deng, Wanyan, Bai, Yang, Deng, Fan, Lieberman, Judy, Liu, Xing. 2022. Streptococcal pyrogenic exotoxin B cleaves GSDMA and triggers pyroptosis. In Nature, 602, 496-502. doi:10.1038/s41586-021-04384-4. https://pubmed.ncbi.nlm.nih.gov/35110732/

2. LaRock, Doris L, Johnson, Anders F, Wilde, Shyra, Monteiro, Marcos P, LaRock, Christopher N. 2022. Group A Streptococcus induces GSDMA-dependent pyroptosis in keratinocytes. In Nature, 605, 527-531. doi:10.1038/s41586-022-04717-x. https://pubmed.ncbi.nlm.nih.gov/35545676/