Reassessing the role of the NLRP3 inflammasome during pathogenic influenza A virus infection via temporal inhibition.
The inflammasome NLRP3 is activated by pathogen associated molecular patterns (PAMPs) during infection, including RNA and proteins from influenza A virus (IAV). However, chronic activation by danger associated molecular patterns (DAMPs) can be deleterious to the host. We show that blocking NLRP3 activation can be either protective or detrimental at different stages of lethal influenza A virus (IAV). Administration of the specific NLRP3 inhibitor MCC950 to mice from one day following IAV challenge resulted in hypersusceptibility to lethality. In contrast, delaying treatment with MCC950 until the height of disease (a more likely clinical scenario) significantly protected mice from severe and highly virulent IAV-induced disease. These findings identify for the first time that NLRP3 plays a detrimental role later in infection, contributing to IAV pathogenesis through increased cytokine production and lung cellular infiltrates. These studies also provide the first evidence identifying NLRP3 inhibition as a novel therapeutic target to reduce IAV disease severity.
Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.|Department of Molecular and Translational Sciences, Monash University, Clayton, Victoria, Australia.
Michelle D
MD
Tate
Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.|Department of Molecular and Translational Sciences, Monash University, Clayton, Victoria, Australia.
James D H
JDH
Ong
Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.|Department of Molecular and Translational Sciences, Monash University, Clayton, Victoria, Australia.
Jennifer K
JK
Dowling
Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria, Australia.
Julie L
JL
McAuley
Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia.
Avril B
AB
Robertson
Institute of Innate Immunity, University Hospital, University of Bonn, Bonn, Germany.|Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.|German Center for Neurodegenerative Diseases, Bonn, Germany.
Eicke
E
Latz
Department of Pharmacology, Monash University, Clayton, Victoria, Australia.
Grant R
GR
Drummond
Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia.
Matthew A
MA
Cooper
Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.|Department of Molecular and Translational Sciences, Monash University, Clayton, Victoria, Australia.
Paul J
PJ
Hertzog
Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.|Department of Molecular and Translational Sciences, Monash University, Clayton, Victoria, Australia.
Ashley
A
Mansell
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D016207:Cytokines / Q000032:analysis; D004797:Enzyme-Linked Immunosorbent Assay; D058847:Inflammasomes / Q000037:antagonists & inhibitors / Q000378:metabolism; D007249:Inflammation / Q000517:prevention & control; D053122:Influenza A Virus, H3N2 Subtype / Q000472:pathogenicity*; D007962:Leukocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009976:Orthomyxoviridae Infections / Q000401:mortality / Q000473:pathology; D013453:Sulfonylurea Compounds / Q000494:pharmacology*; D015996:Survival Rate
D016207:Cytokines; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D013453:Sulfonylurea Compounds