A multi-component toxin from Bacillus cereus incites inflammation and shapes host outcome via the NLRP3 inflammasome

Anukriti Mathur, Shouya Feng, Jenni Hayward, Chinh Ngo, Daniel Fox, Ines Atmosukarto, Jason Price, Kristina Schauer, Erwin Martlbauer, Avril Robertson, Gaetan Burgio, Edward Fox, Stephen Leppla, Nadeem Kaakoush, Si Ming Man

Research output: Contribution to journalArticlepeer-review

30 Citations (Scopus)

Abstract

Host recognition of microbial components is essential in mediating an effective immune response. Cytosolic bacteria must secure entry into the host cytoplasm to facilitate replication and, in doing so, liberate microbial ligands that activate cytosolic innate immune sensors and the inflammasome. Here, we identified a multicomponent enterotoxin, haemolysin BL (HBL), that engages activation of the inflammasome. This toxin is highly conserved among the human pathogen Bacillus cereus. The three subunits of HBL bind to the cell membrane in a linear order, forming a lytic pore and inducing activation of the NLRP3 inflammasome, secretion of interleukin-1β and interleukin-18, and pyroptosis. Mechanistically, the HBL-induced pore results in the efflux of potassium and triggers the activation of the NLRP3 inflammasome. Furthermore, HBL-producing B. cereus induces rapid inflammasome-mediated mortality. Pharmacological inhibition of the NLRP3 inflammasome using MCC950 prevents B. cereus-induced lethality. Overall, our results reveal that cytosolic sensing of a toxin is central to the innate immune recognition of infection. Therapeutic modulation of this pathway enhances host protection against deadly bacterial infections.
Original languageEnglish
Pages (from-to)362-374
Number of pages13
JournalNature Microbiology
Volume4
Issue number2
Early online date10 Dec 2018
DOIs
Publication statusPublished - 1 Feb 2019

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