Clostridium septicum α-toxin activates the NLRP3 inflammasome by engaging GPI-anchored proteins

Weidong Jing, Jordan Lo Pilato, Callum Kay, Shouya Feng, Daniel Enosi Tuipulotu, Anukriti Mathur, Cheng Shen, Chinh Ngo, Anyang Zhao, Lisa A. Miosge, Sidra A. Ali, Elizabeth E. Gardiner, Milena M. Awad, Dena Lyras, Avril A.B. Robertson, Nadeem O. Kaakoush, Si Ming Man

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8 Citations (Scopus)


Clostridium species are a group of Gram-positive bacteria that cause diseases in humans, such as food poisoning, botulism, and tetanus. Here, we analyzed 10 different Clostridium species and identified that Clostridium septicum, a pathogen that causes sepsis and gas gangrene, activates the mammalian cytosolic inflammasome complex in mice and humans. Mechanistically, we demonstrate that α-toxin secreted by C. septicum binds to glycosylphosphatidylinositol (GPI)-anchored proteins on the host plasma membrane, oligomerizing and forming a membrane pore that is permissive to efflux of magnesium and potassium ions. Efflux of these cytosolic ions triggers the activation of the innate immune sensor NLRP3, inducing activation of caspase-1 and gasdermin D, secretion of the proinflammatory cytokines interleukin-1β and interleukin-18, pyroptosis, and plasma membrane rupture via ninjurin-1. Furthermore, α-toxin of C. septicum induces rapid inflammasome-mediated lethality in mice and pharmacological inhibition of the NLRP3 inflammasome using MCC950 prevents C. septicum-induced lethality. Overall, our results reveal that cytosolic innate sensing of α-toxin is central to the recognition of C. septicum infection and that therapeutic blockade of the inflammasome pathway may prevent sepsis and death caused by toxin-producing pathogens.

Original languageEnglish
Article numbereabm1803
Number of pages17
JournalScience Immunology
Issue number71
Publication statusPublished - May 2022

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