title: PB1-F2 Peptide Derived from Avian Influenza A Virus H7N9 Induces Inflammation via Activation of the NLRP3 Inflammasome.
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.
authors.affiliation: From the Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia.|the Departments of Molecular and Translational Sciences and.
authors.forename: Anita
authors.initials: A
authors.lastname: Pinar
authors.affiliation: From the Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia.|the Departments of Molecular and Translational Sciences and.
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Dowling
authors.affiliation: From the Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia.|the Departments of Molecular and Translational Sciences and.
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Bitto
authors.affiliation: the Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4702, Australia.
authors.forename: Avril A B
authors.initials: AA
authors.lastname: Robertson
authors.affiliation: the Institute of Innate Immunity, University Hospital, University of Bonn, Bonn 53127, Germany.|the Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts 01655.|the German Center for Neurodegenerative Diseases, Bonn 53175, Germany.
authors.forename: Eicke
authors.initials: E
authors.lastname: Latz
authors.affiliation: the Commonwealth Scientific and Industrial Research Organization, Health and Biosecurity, Australian Animal Health Laboratory, Geelong, Victoria 3220, Australia.
authors.forename: Cameron R
authors.initials: CR
authors.lastname: Stewart
authors.affiliation: Pharmacology, Monash University, Clayton, Victoria 3168, Australia.
authors.forename: Grant R
authors.initials: GR
authors.lastname: Drummond
authors.affiliation: the Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4702, Australia.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Cooper
authors.affiliation: the Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Julie L
authors.initials: JL
authors.lastname: McAuley
authors.affiliation: From the Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia.|the Departments of Molecular and Translational Sciences and.
authors.forename: Michelle D
authors.initials: MD
authors.lastname: Tate
authors.affiliation: From the Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia, ashley.mansell@hudson.org.au.|the Departments of Molecular and Translational Sciences and.
authors.forename: Ashley
authors.initials: A
authors.lastname: Mansell
mesh_terms: D000818:Animals; D002461:Cell Line, Transformed; D005663:Furans; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D007192:Indenes; D007249:Inflammation / Q000276:immunology; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology; D064766:Influenza A Virus, H7N9 Subtype / Q000276:immunology*; D051379:Mice; D008928:Mitochondria / Q000276:immunology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000037:antagonists & inhibitors / Q000276:immunology*; D009976:Orthomyxoviridae Infections / Q000276:immunology*; D010455:Peptides / Q000276:immunology*; D017382:Reactive Oxygen Species / Q000276:immunology; D013449:Sulfonamides; D013450:Sulfones / Q000494:pharmacology; D014764:Viral Proteins / Q000276:immunology*
chemical_list: D005663:Furans; D006576:Heterocyclic Compounds, 4 or More Rings; D007192:Indenes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D010455:Peptides; D017382:Reactive Oxygen Species; D013449:Sulfonamides; D013450:Sulfones; D014764:Viral Proteins; C000597426:N-(1,2,3,5,6,7-hexahydro-S-indacen-4-ylcarbamoyl)-4-(2-hydroxy-2-propanyl)-2-furansulfonamide
keywords: IL-1; NLRP3; inflammasome; inflammation; influenza