@article{32b68faec7e842d4a25e57c3f06f1107,
title = "A multi-component toxin from Bacillus cereus incites inflammation and shapes host outcome via the NLRP3 inflammasome",
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.",
keywords = "bacterial pathogenesis, infection, infectious diseases, innate immunity, pattern recognition receptors",
author = "Anukriti Mathur and Shouya Feng and Jenni Hayward and Chinh Ngo and Daniel Fox and Ines Atmosukarto and Jason Price and Kristina Schauer and Erwin Martlbauer and Avril Robertson and Gaetan Burgio and Edward Fox and Stephen Leppla and Nadeem Kaakoush and Man, {Si Ming}",
note = "Funding Information: The authors would like to thank V. M. Dixit (Genentech, USA), K. Schroder (Institute of Molecular Bioscience, Australia), P. Broz (University of Lausanne, Switzerland), J. Ng (Westmead Hospital, Australia), A. Rice (The Canberra Hospital, Australia) and J. Bates (Department of Health Queensland, Australia) for reagents. They also thank B. Quah (ANU, Australia), C. Gillespie (ANU, Australia), I. Sastalla (National Institutes of Health, USA), M. Rug (Centre for Advanced Microscopy, ANU, Australia), J. Lee (Centre for Advanced Microscopy, ANU, Australia), C. O{\textquoteright}Brien (The Canberra Hospital, Australia) and D. Gordon (ANU, Australia) for assistance. A.M. is supported by a John Curtin School of Medical Research International Ph.D. scholarship. S.H.L. is supported, in part, by the Intramural Program of the National Institute of Allergy and Infectious Diseases, NIH, USA. N.O.K. is supported by a Career Development Fellowship from the Cancer Institute NSW (15/CDF/1-11). S.M.M. is supported by the Australian National University, The Gretel and Gordon Bootes Medical Research Foundation, and the National Health and Medical Research Council of Australia (under Project Grants APP1141504 and APP1146864) and the R.G. Menzies Early Career Fellowship (APP1091544). Publisher Copyright: {\textcopyright} 2018, The Author(s), under exclusive licence to Springer Nature Limited. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.",
year = "2019",
month = feb,
day = "1",
doi = "10.1038/s41564-018-0318-0",
language = "English",
volume = "4",
pages = "362--374",
journal = "Nature Microbiology",
issn = "2058-5276",
publisher = "Nature Publishing Group",
number = "2",
}