LIU Xing’s Group Reveals New Immune Protection Mechanism against Streptococcus pyogenes Infection


Streptococcus pyogenes (a.k.a. group A Streptococcus, GAS) causes a wide variety of acute infections ranging from local suppurative infections to severe, sometimes fatal, invasive diseases, including necrotizing fasciitis and streptococcal toxic shock-like syndrome. Systemic dissemination is generally initiated by bacterial penetration of the epithelial barrier of the pharynx or damaged skin, leading to invasion in the bloodstream and soft tissues if not well controlled. Superficial colonization and invasive infection of GAS rely on secreted GAS virulence factors, among which the cysteine protease streptococcal pyrogenic exotoxin B (SpeB) is a key one. SpeB was reported to contribute to GAS localization in the epidermis and systemic dissemination, while the underlying mechanism remains unknown. In a study published online in Nature, Prof. LIU Xing’s group at Institut Pasteur of Shanghai, Chinese Academy of Sciences revealed that gasdermin A (GSDMA) could be cleaved directly by SpeB and triggers pyroptotic cell death of epithelial cells to control systemic dissemination of GAS.

In this study, the researchers firstly showed that in contrast to SpeB-sufficient GAS, SpeB-deficient GAS failed to induce severe pyogenic and necrotic lesions at skin infection site. Tissue damage and neutrophil infiltration were dramatically reduced after infection with SpeB-deficient GAS. SpeB-sufficient GAS caused massive cell death of primary mouse keratinocytes (KCs), with typical pyroptotic ballooning morphology and lactate dehydrogenase release, whereas SpeB-deficient GAS failed to do so. Subsequent whole-genome CRISPR screen identified GSDMA, a member of pore-forming protein family, as the key executioner of SpeB-triggered lytic cell death. The researchers further dissected the underlying mechanisms of SpeB-mediated GSDMA activation and pyroptosis induction. Immune sensing of GAS is realized through direct binding and proteolytic cleavage of GSDMA by SpeB in the linker region after Gln246, resulting in release of active GSDMA-NT which possesses membrane pore-forming and pyroptosis-inducing activity. In vivo functional study using a mouse model revealed that Gsdma1 genetic deficiency blunts mouse immune responses to GAS, resulting in uncontrolled bacterial dissemination and death.

In summary, this study identified GSDMA as both a sensor for GAS SpeB and an effector for pyroptosis induction, adding a new paradigm of host immune recognition and response to microbial pathogens. This single molecule alarm system initiates inflammatory responses that mobilizes host immune defenses to the infection site and orchestrates protection against potentially lethal systemic infection. The host pyroptotic response turns the SpeB virulence factor, which is known to promote bacterial invasion and adhesion, into an agent that guards against the more dangerous consequences of systemic dissemination. Future studies can leverage these insights to explore more mechanistic details of GSDM activation, as well as to manipulate this process for therapeutic benefits.