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

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.

• Authors: 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
• Journal: Science immunology (Sci Immunol) Vol. 7 Issue 71 Pg. eabm1803 (05 20 2022) ISSN: 2470-9468 [Electronic] United States
• PMID: 35594341 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Bacterial Toxins
• GPI-Linked Proteins
• Glycosylphosphatidylinositols
• Inflammasomes
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse
• hemolytic toxin, Clostridium septicum

Topics

• Animals
• Bacterial Toxins (metabolism)
• Clostridium septicum (chemistry)
• GPI-Linked Proteins (metabolism)
• Glycosylphosphatidylinositols (metabolism)
• Inflammasomes (metabolism)
• Mammals (metabolism)
• Mice
• NLR Family, Pyrin Domain-Containing 3 Protein
• Sepsis