Gsdma is one of the five pore-forming proteins in the gasdermin family, predominantly expressed in the skin, mucosa, and immune sentinel cells. It is a key executioner in the inflammatory cell death process of pyroptosis, which recruits immune cells to infection sites and promotes protective immunity [1,2].

Group A Streptococcus (GAS) secretes the protease virulence factor SpeB, which cleaves Gsdma after Gln246. This releases an active N-terminal fragment that triggers pyroptosis in keratinocytes [1,2]. Gsdma1 genetic deficiency in mice blunts the immune responses to GAS, leading to uncontrolled bacterial dissemination and death [1]. 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 is critical in the immune defence against invasive skin infections by GAS [2].

In conclusion, Gsdma plays a crucial role in the host immune response against GAS infections, especially in the skin. The use of gene-knockout mouse models has revealed its significance in preventing invasive skin infections, providing insights into the mechanisms of host-pathogen interactions and potential therapeutic targets for treating GAS-related 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/