Reassessing the role of the NLRP3 inflammasome during pathogenic influenza A virus infection via temporal inhibition

Michelle D. Tate, James DH Ong, Jennifer K. Dowling, Julie L. McAuley, Avril B. Robertson, Eicke Latz, Grant R. Drummond, Matthew A. Cooper, Paul J. Hertzog, Ashley Mansell

Research output: Contribution to journalArticleResearchpeer-review

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Abstract

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.

Original languageEnglish
Article number27912
Number of pages8
JournalScientific Reports
Volume6
DOIs
Publication statusPublished - 10 Jun 2016

Cite this

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title = "Reassessing the role of the NLRP3 inflammasome during pathogenic influenza A virus infection via temporal inhibition",
abstract = "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.",
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Reassessing the role of the NLRP3 inflammasome during pathogenic influenza A virus infection via temporal inhibition. / Tate, Michelle D.; Ong, James DH; Dowling, Jennifer K.; McAuley, Julie L.; Robertson, Avril B.; Latz, Eicke; Drummond, Grant R.; Cooper, Matthew A.; Hertzog, Paul J.; Mansell, Ashley.

In: Scientific Reports, Vol. 6, 27912, 10.06.2016.

Research output: Contribution to journalArticleResearchpeer-review

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