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.

Clostridium perfringens virulence factors are nonredundant activators of the NLRP3 inflammasome

“…The majority of bacterial toxins that activate the NLRP3 inflammasome are pore‐forming toxins; however, several enzymatic toxins which do not induce pore‐formation, such as Mycoplasma pneumoniae CARDS toxin and Shiga toxin, have been reported to activate the NLRP3 inflammasome (Bose et al , 2014 ; Lee et al , 2016 ). Unlike pore‐forming toxins that emanate a signal from the plasma membrane to trigger K + efflux and subsequent NLRP3 activation (Jing et al , 2022 ), lecithinase accesses the lysosome to trigger NLRP3 activation. Several exogenous activators of NLRP3, such as asbestos and silica crystals (Dostert et al , 2008 ; Hornung et al , 2008 ), and endogenous aggregates, including circulating ASC specks, neuronal amyloid‐β fibrils and multiple myeloma‐associated β 2 ‐microglobulin fibrils (Halle et al , 2008 ; Franklin et al , 2014 ; Hofbauer et al , 2021 ), have been described to undergo a pathway of internalization, endo‐lysosomal trafficking and lysosomal membrane destabilization.…”

ASC/inflammasome-independent pyroptosis in ovarian cancer cells through translational augmentation of caspase-1

“… 3 Targeting various inflammasome subunits including ASC and NLRP3 through inhibitors or depletion can effectively abolish pyroptosis. 32 , 33 Our initial hypothesis was that DHA initiated ovarian cancer cell pyroptosis in a similar manner. Quite in the contrary, we found that depletion of ASC or inhibiting NLRP3 with MCC950 exhibited little effect on DHA-induced caspase-1 activation and cell death, indicating that DHA-led caspase-1 activation and pyroptosis occur in a mechanism not involving in ASC or NLRP3.…”

RACK1 mediates NLRP3 inflammasome activation during Pasteurella multocida infection

“…It is well known that NLRP3 inflammasome assembly and activation lead to the secretion of proinflammatory cytokines, including IL-1β and IL-18. It has been reported that NLRP3 is activated by different pathogens, such as Mycobacterium tuberculosis (M.tb) [ 8 ], Staphylococcus aureus [ 9 ], and Clostridium septicum [ 10 ], and NLRP3 plays an important role in protecting the host against infection. Similarly, our previous study showed that P. multocida activates the NLRP3 inflammasome, leading to caspase-1 activation and subsequent IL-1β secretion in vivo and in vitro, and this NLRP3 inflammasome activation depends on macrophage phagocytosis [ 11 ].…”