PB1-F2 Peptide Derived from Avian Influenza A Virus H7N9 Induces Inflammation via Activation of the NLRP3 Inflammasome*

  1. Ashley Mansell‡,§14
  1. From the ‡Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia,
  2. the Departments of §Molecular and Translational Sciences and
  3. ¶¶Pharmacology, Monash University, Clayton, Victoria 3168, Australia,
  4. the Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4702, Australia,
  5. the ‖Institute of Innate Immunity, University Hospital, University of Bonn, Bonn 53127, Germany,
  6. the **Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts 01655,
  7. the ‡‡German Center for Neurodegenerative Diseases, Bonn 53175, Germany,
  8. the §§Commonwealth Scientific and Industrial Research Organization, Health and Biosecurity, Australian Animal Health Laboratory, Geelong, Victoria 3220, Australia,
  9. the ‖‖Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010, Australia
  1. ↵4 To whom correspondence should be addressed: Hudson Institute of Medical Research, 27–31 Wright St., Clayton, VIC 3168, Australia. Tel.: 61-3-8572-2741; E-mail: ashley.mansell{at}hudson.org.au.

  1. ↵1 These authors contributed equally to this work.

  2. Edited by Luke O'Neill

Abstract

The emergence of avian H7N9 influenza A virus in humans with associated high mortality has highlighted the threat of a potential pandemic. Fatal H7N9 infections are characterized by hyperinflammation and increased cellular infiltrates in the lung. Currently there are limited therapies to address the pathologies associated with H7N9 infection and the virulence factors that contribute to these pathologies. We have found that PB1-F2 derived from H7N9 activates the NLRP3 inflammasome and induces lung inflammation and cellular recruitment that is NLRP3-dependent. We have also shown that H7N9 and A/Puerto Rico/H1N1 (PR8)PB1-F2 peptide treatment induces significant mitochondrial reactive oxygen production, which contributes to NLRP3 activation. Importantly, treatment of cells or mice with the specific NLRP3 inhibitor MCC950 significantly reduces IL-1β maturation, lung cellular recruitment, and cytokine production. Together, these results suggest that PB1-F2 from H7N9 avian influenza A virus may be a major contributory factor to disease pathophysiology and excessive inflammation characteristic of clinical infections and that targeting the NLRP3 inflammasome may be an effective means to reduce the inflammatory burden associated with H7N9 infections.

Footnotes

  • ↵2 Supported by National Health and Medical Research Council Australia Fellowship 511105.

  • ↵3 Supported by National Health and Medical Research Council Early Career Fellowship 1035733.

  • ↵* This work was supported by the Victorian State Government Operational Infrastructure Scheme and by National Health and Medical Research Council of Australia Project Grants GNT1079924, GNT1062721, and GNT1062977 (to A. M., J. L. M., and G. D., respectively). The authors declare that they have no conflicts of interest with the contents of this article.

  • ↵Graphic This article contains supplemental Figs. S1–S4 and Movies 1–8.

  • Received August 30, 2016.
  • Revision received November 29, 2016.
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  1. First Published on December 2, 2016 doi: 10.1074/jbc.M116.756379 The Journal of Biological Chemistry 292, 826-836.
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