[go: up one dir, main page]
More Web Proxy on the site http://driver.im/
Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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

Nature Microbiology volume 4, pages 362–374 (2019)Cite this article

Subjects

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.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: A secreted factor of B. cereus activates the NLRP3 inflammasome.
Fig. 2: The inflammasome-activating factor is highly prevalent in B. cereus isolates and is associated with isolates expressing HBL.
Fig. 3: HBL triggers activation of the NLRP3 inflammasome.
Fig. 4: Recombinant HBL components assemble sequentially to induce activation of the NLRP3 inflammasome.
Fig. 5: HBL induces pores on the host cell membrane.
Fig. 6: The NLRP3 inflammasome mediates lethality induced by B. cereus infection in vivo.

Similar content being viewed by others

Data availability

The data that support the findings of this study are included in this published article along with its Supplementary Information files, and are available from the corresponding author upon request.

References

  1. Schroder, K. & Tschopp, J. The inflammasomes. Cell 140, 821–832 (2010).

    Article  CAS  PubMed  Google Scholar 

  2. Lamkanfi, M. & Dixit, V. M. Mechanisms and functions of inflammasomes. Cell 157, 1013–1022 (2014).

    Article  CAS  PubMed  Google Scholar 

  3. Rathinam, V. A. & Fitzgerald, K. A. Inflammasome complexes: emerging mechanisms and effector functions. Cell 165, 792–800 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Latz, E., Xiao, T. S. & Stutz, A. Activation and regulation of the inflammasomes. Nat. Rev. Immunol. 13, 397–411 (2013).

    Article  CAS  PubMed  Google Scholar 

  5. Man, S. M. & Kanneganti, T. D. Converging roles of caspases in inflammasome activation, cell death and innate immunity. Nat. Rev. Immunol. 16, 7–21 (2016).

    Article  CAS  PubMed  Google Scholar 

  6. Man, S. M. et al. IRGB10 liberates bacterial ligands for sensing by the AIM2 and caspase-11–NLRP3 Inflammasomes. Cell 167, 382–396.e317 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Man, S. M. et al. The transcription factor IRF1 and guanylate-binding proteins target activation of the AIM2 inflammasome by Francisella infection. Nat. Immunol. 16, 467–475 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Meunier, E. et al. Caspase-11 activation requires lysis of pathogen-containing vacuoles by IFN-induced GTPases. Nature 509, 366–370 (2014).

    Article  CAS  PubMed  Google Scholar 

  9. Meunier, E. et al. Guanylate-binding proteins promote activation of the AIM2 inflammasome during infection with Francisella novicida. Nat. Immunol. 16, 476–484 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Mariathasan, S. et al. Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature 430, 213–218 (2004).

    Article  CAS  PubMed  Google Scholar 

  11. Kofoed, E. M. & Vance, R. E. Innate immune recognition of bacterial ligands by NAIPs determines inflammasome specificity. Nature 477, 592–595 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Zhao, Y. et al. The NLRC4 inflammasome receptors for bacterial flagellin and type III secretion apparatus. Nature 477, 596–600 (2011).

    Article  CAS  PubMed  Google Scholar 

  13. Miao, E. A. et al. Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1β via Ipaf. Nat. Immunol. 7, 569–575 (2006).

    Article  CAS  PubMed  Google Scholar 

  14. Franchi, L. et al. Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1β in Salmonella-infected macrophages. Nat. Immunol. 7, 576–582 (2006).

    Article  CAS  PubMed  Google Scholar 

  15. Amer, A. et al. Regulation of Legionella phagosome maturation and infection through flagellin and host Ipaf. J. Biol. Chem. 281, 35217–35223 (2006).

    Article  CAS  PubMed  Google Scholar 

  16. Liu, S., Moayeri, M. & Leppla, S. H. Anthrax lethal and edema toxins in anthrax pathogenesis. Trends Microbiol. 22, 317–325 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Dal Peraro, M. & van der Goot, F. G. Pore-forming toxins: ancient, but never really out of fashion. Nat. Rev. Microbiol. 14, 77–92 (2016).

    Article  PubMed  Google Scholar 

  18. Mariathasan, S. et al. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 440, 228–232 (2006).

    Article  CAS  PubMed  Google Scholar 

  19. Muñoz-Planillo, R., Franchi, L., Miller, L. S. & Núñez, G. A critical role for hemolysins and bacterial lipoproteins in Staphylococcus aureus-induced activation of the Nlrp3 inflammasome. J. Immunol. 183, 3942–3948 (2009).

    Article  PubMed  Google Scholar 

  20. Craven, R. R. et al. Staphylococcus aureus alpha-hemolysin activates the NLRP3-inflammasome in human and mouse monocytic cells. PLoS ONE 4, e7446 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Kebaier, C. et al. Staphylococcus aureus alpha-hemolysin mediates virulence in a murine model of severe pneumonia through activation of the NLRP3 inflammasome. J. Infect. Dis. 205, 807–817 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zhang, X. et al. Enterohemorrhagic Escherichia coli specific enterohemolysin induced IL-1beta in human macrophages and EHEC-induced IL-1beta required activation of NLRP3 inflammasome. PLoS ONE 7, e50288 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Schaale, K. et al. Strain- and host species-specific inflammasome activation, IL-1β release, and cell death in macrophages infected with uropathogenic Escherichia coli. Mucosal Immunol. 9, 124 (2015).

    Article  PubMed  Google Scholar 

  24. Costa, A. et al. Activation of the NLRP3 inflammasome by group B streptococci. J. Immunol. 188, 1953–1960 (2012).

    Article  CAS  PubMed  Google Scholar 

  25. Whidbey, C. et al. A streptococcal lipid toxin induces membrane permeabilization and pyroptosis leading to fetal injury. EMBO Mol. Med. 7, 488–505 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Gupta, R. et al. RNA and beta-hemolysin of group B Streptococcus induce interleukin-1beta (IL-1beta) by activating NLRP3 inflammasomes in mouse macrophages. J. Biol. Chem. 289, 13701–13705 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Harder, J. et al. Activation of the Nlrp3 inflammasome by Streptococcus pyogenes requires streptolysin O and NF-kappa B activation but proceeds independently of TLR signaling and P2X7 receptor. J. Immunol. 183, 5823–5829 (2009).

    Article  CAS  PubMed  Google Scholar 

  28. Keyel, P. A., Roth, R., Yokoyama, W. M., Heuser, J. E. & Salter, R. D. Reduction of streptolysin O (SLO) pore-forming activity enhances inflammasome activation. Toxins 5, 1105–1118 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ozoren, N. et al. Distinct roles of TLR2 and the adaptor ASC in IL-1β/IL-18 secretion in response to Listeria monocytogenes. J. Immunol. 176, 4337–4342 (2006).

    Article  PubMed  Google Scholar 

  30. Hamon, M. A. & Cossart, P. K+ efflux is required for histone H3 dephosphorylation by Listeria monocytogenes listeriolysin O and other pore-forming toxins. Infect. Immun. 79, 2839–2846 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Toma, C. et al. Pathogenic Vibrio activate NLRP3 inflammasome via cytotoxins and TLR/nucleotide-binding oligomerization domain-mediated NF-kappa B signaling. J. Immunol. 184, 5287–5297 (2010).

    Article  CAS  PubMed  Google Scholar 

  32. Higa, N. et al. Vibrio parahaemolyticus effector proteins suppress inflammasome activation by interfering with host autophagy signaling. PLoS Pathog. 9, e1003142 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Song, L. et al. A critical role for hemolysin in Vibrio fluvialis-induced IL-1beta secretion mediated by the NLRP3 inflammasome in macrophages. Front. Microbiol. 6, 510 (2015).

    PubMed  PubMed Central  Google Scholar 

  34. Coll, R. C. et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat. Med. 21, 248–255 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Man, S. M. & Kanneganti, T. D. Regulation of inflammasome activation. Immunol. Rev. 265, 6–21 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Bottone, E. J. Bacillus cereus, a volatile human pathogen. Clin. Microbiol. Rev. 23, 382–398 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Beecher, D. J. & Wong, A. C. Improved purification and characterization of hemolysin BL, a hemolytic dermonecrotic vascular permeability factor from Bacillus cereus. Infect. Immun. 62, 980–986 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Heinrichs, J. H., Beecher, D. J., MacMillan, J. D. & Zilinskas, B. A. Molecular cloning and characterization of the hblA gene encoding the B component of hemolysin BL from Bacillus cereus. J. Bacteriol. 175, 6760–6766 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Ryan, P. A., Macmillan, J. D. & Zilinskas, B. A. Molecular cloning and characterization of the genes encoding the L1 and L2 components of hemolysin BL from Bacillus cereus. J. Bacteriol. 179, 2551–2556 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Sastalla, I. et al. The Bacillus cereus Hbl and Nhe tripartite enterotoxin components assemble sequentially on the surface of target cells and are not interchangeable. PLoS ONE 8, e76955 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Lund, T., De Buyser, M. L. & Granum, P. E. A new cytotoxin from Bacillus cereus that may cause necrotic enteritis. Mol. Microbiol. 38, 254–261 (2000).

    Article  CAS  PubMed  Google Scholar 

  42. Beecher, D. J. & Wong, A. C. Tripartite hemolysin BL from Bacillus cereus. Hemolytic analysis of component interactions and a model for its characteristic paradoxical zone phenomenon. J. Biol. Chem. 272, 233–239 (1997).

    Article  CAS  PubMed  Google Scholar 

  43. Levinsohn, J. L. et al. Anthrax lethal factor cleavage of Nlrp1 is required for activation of the inflammasome. PLoS Pathog. 8, e1002638 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Hellmich, K. A. et al. Anthrax lethal factor cleaves mouse nlrp1b in both toxin-sensitive and toxin-resistant macrophages. PLoS ONE 7, e49741 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Moayeri, M. et al. Inflammasome sensor Nlrp1b-dependent resistance to anthrax is mediated by caspase-1, IL-1 signaling and neutrophil recruitment. PLoS Pathog. 6, e1001222 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Man, S. M. et al. Actin polymerization as a key innate immune effector mechanism to control Salmonella infection. Proc. Natl Acad. Sci. USA 111, 17588–17593 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Madegowda, M., Eswaramoorthy, S., Burley, S. K. & Swaminathan, S. X-ray crystal structure of the B component of hemolysin BL from Bacillus cereus. Proteins 71, 534–540 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Yohannan, S., Faham, S., Yang, D., Whitelegge, J. P. & Bowie, J. U. The evolution of transmembrane helix kinks and the structural diversity of G protein-coupled receptors. Proc. Natl Acad. Sci. USA 101, 959–963 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Cordes, F. S., Bright, J. N. & Sansom, M. S. Proline-induced distortions of transmembrane helices. J. Mol. Biol. 323, 951–960 (2002).

    Article  CAS  PubMed  Google Scholar 

  50. Jin, T. et al. The (beta)gamma subunits of G proteins gate a K(+) channel by pivoted bending of a transmembrane segment. Mol. Cell 10, 469–481 (2002).

    Article  CAS  PubMed  Google Scholar 

  51. Tieleman, D. P., Shrivastava, I. H., Ulmschneider, M. R. & Sansom, M. S. Proline-induced hinges in transmembrane helices: possible roles in ion channel gating. Proteins 44, 63–72 (2001).

    Article  CAS  PubMed  Google Scholar 

  52. Miao, E. A. et al. Caspase-1-induced pyroptosis is an innate immune effector mechanism against intracellular bacteria. Nat. Immunol. 11, 1136–1142 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Jorgensen, I., Zhang, Y., Krantz, B. A. & Miao, E. A. Pyroptosis triggers pore-induced intracellular traps (PITs) that capture bacteria and lead to their clearance by efferocytosis. J. Exp. Med. 213, 2113–2128 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Hayward, J. A., Mathur, A., Ngo, C. & Man, S. M. Cytosolic recognition of microbes and pathogens: inflammasomes in action. Microbiol. Mol. Biol. Rev. 82, e00015-18 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Perregaux, D. & Gabel, C. A. Interleukin-1 beta maturation and release in response to ATP and nigericin. Evidence that potassium depletion mediated by these agents is a necessary and common feature of their activity. J. Biol. Chem. 269, 15195–15203 (1994).

    CAS  PubMed  Google Scholar 

  56. Petrilli, V. et al. Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration. Cell Death Differ. 14, 1583–1589 (2007).

    Article  CAS  PubMed  Google Scholar 

  57. Munoz-Planillo, R. et al. K(+) efflux is the common trigger of NLRP3 inflammasome activation by bacterial toxins and particulate matter. Immunity 38, 1142–1153 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Henry, T., Brotcke, A., Weiss, D. S., Thompson, L. J. & Monack, D. M. Type I interferon signaling is required for activation of the inflammasome during Francisella infection. J. Exp. Med. 204, 987–994 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Hara, H. et al. Dependency of caspase-1 activation induced in macrophages by Listeria monocytogenes on cytolysin, listeriolysin O, after evasion from phagosome into the cytoplasm. J. Immunol. 180, 7859–7868 (2008).

    Article  CAS  PubMed  Google Scholar 

  60. Ehling-Schulz, M., Fricker, M. & Scherer, S. Bacillus cereus, the causative agent of an emetic type of food-borne illness. Mol. Nutr. Food. Res. 48, 479–487 (2004).

    Article  PubMed  Google Scholar 

  61. Man, S. M. et al. Differential roles of caspase-1 and caspase-11 in infection and inflammation. Sci. Rep. 7, 45126 (2017).

    Article  CAS  PubMed  Google Scholar 

  62. Tate, M. D. et al. Reassessing the role of the NLRP3 inflammasome during pathogenic influenza A virus infection via temporal inhibition. Sci. Rep. 6, 27912 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Primiano, M. J. et al. Efficacy and pharmacology of the NLRP3 inflammasome inhibitor CP-456,773 (CRID3) in murine models of dermal and pulmonary inflammation. J. Immunol. 197, 2421–2433 (2016).

    Article  CAS  PubMed  Google Scholar 

  64. Mridha, A. R. et al. NLRP3 inflammasome blockade reduces liver inflammation and fibrosis in experimental NASH in mice. J. Hepatol. 66, 1037–1046 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Chen, W. et al. Specific inhibition of NLRP3 in chikungunya disease reveals a role for inflammasomes in alphavirus-induced inflammation. Nat. Microbiol. 2, 1435–1445 (2017).

    Article  CAS  PubMed  Google Scholar 

  66. Moayeri, M. et al. Small-molecule inhibitors of lethal factor protease activity protect against anthrax infection. Antimicrob. Agents Chemother. 57, 4139–4145 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Leysath, C. E. et al. Mouse monoclonal antibodies to anthrax edema factor protect against infection. Infect. Immun. 79, 4609–4616 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Lund, T. & Granum, P. E. Characterisation of a non-haemolytic enterotoxin complex from Bacillus cereus isolated after a foodborne outbreak. FEMS Microbiol. Lett. 141, 151–156 (1996).

    Article  CAS  PubMed  Google Scholar 

  69. Ganash, M. et al. Structure of the NheA component of the Nhe toxin from Bacillus cereus: implications for function. PLoS ONE 8, e74748 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Haug, T. M. et al. Formation of very large conductance channels by Bacillus cereus Nhe in Vero and GH(4) cells identifies NheA + B as the inherent pore-forming structure. J. Membr. Biol. 237, 1–11 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Jones, J. W. et al. Absent in melanoma 2 is required for innate immune recognition of Francisella tularensis. Proc. Natl Acad. Sci. USA 107, 9771–9776 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Kuida, K. et al. Altered cytokine export and apoptosis in mice deficient in interleukin-1 beta converting enzyme. Science 267, 2000–2003 (1995).

    Article  CAS  PubMed  Google Scholar 

  73. Wang, S. et al. Murine caspase-11, an ICE-interacting protease, is essential for the activation of ICE. Cell 92, 501–509 (1998).

    Article  CAS  PubMed  Google Scholar 

  74. Kovarova, M. et al. NLRP1-dependent pyroptosis leads to acute lung injury and morbidity in mice. J. Immunol. 189, 2006–2016 (2012).

    Article  CAS  PubMed  Google Scholar 

  75. Dietrich, R., Moravek, M., Burk, C., Granum, P. E. & Martlbauer, E. Production and characterization of antibodies against each of the three subunits of the Bacillus cereus nonhemolytic enterotoxin complex. Appl. Environ. Microbiol. 71, 8214–8220 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. van Meer, G., Voelker, D. R. & Feigenson, G. W. Membrane lipids: where they are and how they behave. Nat. Rev. Mol. Cell Biol. 9, 112–124 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  77. Snider, C., Jayasinghe, S., Hristova, K. & White, S. H. MPEx: a tool for exploring membrane proteins. Protein Sci. 18, 2624–2628 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Gautier, R., Douguet, D., Antonny, B. & Drin, G. HELIQUEST: a web server to screen sequences with specific alpha-helical properties. Bioinformatics 24, 2101–2102 (2008).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

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’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).

Author information

Authors and Affiliations

  1. Department of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia

    Anukriti Mathur, Shouya Feng, Jenni A. Hayward, Chinh Ngo, Daniel Fox, Gaetan Burgio & Si Ming Man

  2. Lipotek Pty Ltd, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia

    Ines I. Atmosukarto & Jason D. Price

  3. Department of Veterinary Sciences, Faculty of Veterinary Medicine, Ludwig-Maximilians-Universität München, Oberschleißheim, Germany

    Kristina Schauer & Erwin Märtlbauer

  4. School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland, Australia

    Avril A. B. Robertson

  5. Commonwealth Scientific and Industrial Research Organisation (CSIRO) Agriculture and Food, Werribee, Victoria, Australia

    Edward M. Fox

  6. Microbial Pathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA

    Stephen H. Leppla

  7. School of Medical Sciences, UNSW Sydney, Sydney, New South Wales, Australia

    Nadeem O. Kaakoush

Authors
  1. Anukriti Mathur
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shouya Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jenni A. Hayward
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chinh Ngo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Daniel Fox
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ines I. Atmosukarto
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jason D. Price
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kristina Schauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Erwin Märtlbauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Avril A. B. Robertson
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Gaetan Burgio
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Edward M. Fox
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Stephen H. Leppla
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Nadeem O. Kaakoush
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Si Ming Man
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

A.M. and S.M.M. conceptualized the study. A.M., S.F., J.A.H., C.N., D.F., I.I.A., J.D.P. and N.O.K. performed the experiments. A.M., S.F., J.A.H., C.N., D.F. and N.O.K. conducted the analyses, and A.M. and S.M.M. wrote the manuscript. S.M.M. acquired the funding, and I.I.A., J.D.P., K.S., E.M., A.A.B.R., G.B., E.M.F. and S.H.L. provided resources and intellectual input. S.M.M. provided overall supervision, and all authors reviewed the manuscript.

Corresponding author

Correspondence to Si Ming Man.

Ethics declarations

Competing interests

I.I.A. is Director of Lipotek, a niche biotech company with a focus on liposome technology. I.I.A. and J.D.P. are shareholders of Lipotek. A.A.B.R. is a named inventor on inflammasome inhibitor patents (WO2017140778 and WO2016131098). All other authors have no competing interests.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Supplementary Figures 1–11, Supplementary Blots, Supplementary Tables 1 and 2, and Supplementary References.

Reporting Summary

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mathur, A., Feng, S., Hayward, J.A. et al. A multicomponent toxin from Bacillus cereus incites inflammation and shapes host outcome via the NLRP3 inflammasome. Nat Microbiol 4, 362–374 (2019). https://doi.org/10.1038/s41564-018-0318-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41564-018-0318-0

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing