IFI204-STING drives protective innate immunity against gangrenous Clostridium perfringens infection via regulation of NLRP3 signaling.

Inflammasomes are an essential component of the innate immune response against pathogen infections. However, the molecular mechanism regulating the inflammasome signaling in response to gangrenous Clostridium perfringens (C. perfringens) infection remains elusive. We herein report the unexpected discovery that IFI204 (the murine homolog of human IFI16)-dependent STING protects against C. perfringens gas gangrene via enhancing NLRP3 inflammasome signaling. In the C. perfringens gas gangrene model, compared with wild-type (WT) mice, Sting deficiency (Sting(-/-) ) mice displayed an increased susceptibility to C. perfringens soft tissue infection, with more bacterial colonization, severe muscle damage, and higher mortality rates. Obviously, Sting deficiency leads to the defect of inflammasome signaling activation and bacterial killing and clearance. STING promotes inflammasome signaling activation in an IFI204-dependent manner. Crucially, the IFI204-STING axis enhances NLRP3 inflammasome signaling activation, which, in turn, facilitates pathogen elimination and host defense. Our findings highlight STING acts as a positive regulator in defense of C. perfringens infection and present it as a potential target for anti-infection drug development.