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Reassessing the role of the NLRP3 inflammasome during pathogenic influenza A
virus infection via temporal inhibition
#MMPMID27283237
Tate MD
; Ong JDH
; Dowling JK
; McAuley JL
; Robertson AB
; Latz E
; Drummond GR
; Cooper MA
; Hertzog PJ
; Mansell A
Sci Rep
2016[Jun]; 6
(?): 27912
PMID27283237
show ga
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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