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

  • Sci Immunol. 2022 May 20;7(71):eabm1803. doi: 10.1126/sciimmunol.abm1803.
Weidong Jing  1 ,  Jordan Lo Pilato  1 ,  Callum Kay  1 ,  Shouya Feng  1 ,  Daniel Enosi Tuipulotu  1 ,  Anukriti Mathur  1 ,  Cheng Shen  1 ,  Chinh Ngo  1 ,  Anyang Zhao  1 ,  Lisa A Miosge  1 ,  Sidra A Ali  2 ,  Elizabeth E Gardiner  2 ,  Milena M Awad  3 ,  Dena Lyras  3 ,  Avril A B Robertson  4 ,  Nadeem O Kaakoush  5 ,  Si Ming Man  1
Affiliations
  • 1. Division of Immunity, Inflammation and Infection, The John Curtin School of Medical Research, The Australian National University, Canberra, Australia.
  • 2. Division of Genome Science and Cancer, The John Curtin School of Medical Research, The Australian National University, Canberra, Australia.
  • 3. Infection and Immunity Program and Department of Microbiology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Australia.
  • 4. School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia.
  • 5. School of Medical Sciences, UNSW Sydney, Sydney, Australia.
PMID: 35594341 DOI: 10.1126/sciimmunol.abm1803
Abstract

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.