Abstract
Inflammasomes are important for host defence against pathogens and homeostasis with commensal microbes. Here, we show non-haemolytic enterotoxin (NHE) from the neglected human foodborne pathogen Bacillus cereus is an activator of the NLRP3 inflammasome and pyroptosis. NHE is a non-redundant toxin to haemolysin BL (HBL) despite having a similar mechanism of action. Via a putative transmembrane region, subunit C of NHE initiates binding to the plasma membrane, leading to the recruitment of subunit B and subunit A, thus forming a tripartite lytic pore that is permissive to efflux of potassium. NHE mediates killing of cells from multiple lineages and hosts, highlighting a versatile functional repertoire in different host species. These data indicate that NHE and HBL operate synergistically to induce inflammation and show that multiple virulence factors from the same pathogen with conserved function and mechanism of action can be exploited for sensing by a single inflammasome.
Highlights
Inflammasomes are important for host defence against pathogens and homeostasis with commensal microbes
We have previously demonstrated that innate immune recognition of Bacillus cereus infection requires inflammasome-mediated sensing of a toxin known as HBL31
Stimulation of primary wildtype (WT) bone marrow-derived macrophages (BMDMs) with the supernatant of WT B. cereus led to activation of caspase-1, cleavage of gasdermin D (GSDMD), secretion of IL-1β and IL-18, and pyroptosis within 3 h, whereas stimulation of WT BMDMs with the supernatant of an isogenic mutant of B. cereus lacking haemolysin BL (HBL) (ΔHbl B. cereus) did not (Fig. 1a–d), consistent with our previous findings[31]
Summary
Inflammasomes are important for host defence against pathogens and homeostasis with commensal microbes. We show non-haemolytic enterotoxin (NHE) from the neglected human foodborne pathogen Bacillus cereus is an activator of the NLRP3 inflammasome and pyroptosis. NHE mediates killing of cells from multiple lineages and hosts, highlighting a versatile functional repertoire in different host species These data indicate that NHE and HBL operate synergistically to induce inflammation and show that multiple virulence factors from the same pathogen with conserved function and mechanism of action can be exploited for sensing by a single inflammasome. Bacterial toxins are key virulence factors that represent a class of PAMPs, which are potent activators of inflammasome sensors, leading to inflammation and cell death in the host[14,16]. The lethal factor from the anthrax-causing pathogen Bacillus anthracis can enter the host cell cytoplasm and induce cleavage of the inflammasome sensor NLRP1b17–23.
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