A multicomponent toxin from Bacillus cereus incites inflammation and shapes host outcome via the NLRP3 inflammasome

Mathur, Anukriti, Feng, Shouya, Hayward, Jenni A., Ngo, Chinh, Fox, Daniel, Atmosukarto, Ines I., Price, Jason D., Schauer, Kristina, Märtlbauer, Erwin, Robertson, Avril A. B., Burgio, Gaetan, Fox, Edward M., Leppla, Stephen H., Kaakoush, Nadeem O. and Man, Si Ming (2019) A multicomponent toxin from Bacillus cereus incites inflammation and shapes host outcome via the NLRP3 inflammasome. Nature Microbiology, 4 (2). pp. 362-374. ISSN 2058-5276

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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.

Item Type:	Article
Uncontrolled Keywords:	bacterial pathogenesis, infection, infectious diseases, innate immunity, pattern recognition receptors
Subjects:	C500 Microbiology
Department:	Faculties > Health and Life Sciences > Applied Sciences
Depositing User:	Paul Burns
Date Deposited:	22 Feb 2019 17:09
Last Modified:	10 Oct 2019 16:46
URI:	http://nrl.northumbria.ac.uk/id/eprint/38207

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