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Abstract
The nucleotide-binding domain and leucine-rich-repeat-containing (NLR) family of pattern-recognition
molecules mediate host immunity to various pathogenic stimuli. However, in vivo evidence
for the involvement of NLR proteins in viral sensing has not been widely investigated
and remains controversial. As a test of the physiologic role of the NLR molecule NLRP3
during RNA viral infection, we explored the in vivo role of NLRP3 inflammasome components
during influenza virus infection. Mice lacking Nlrp3, Pycard, or caspase-1, but not
Nlrc4, exhibited dramatically increased mortality and a reduced immune response after
exposure to the influenza virus. Utilizing analogs of dsRNA (poly(I:C)) and ssRNA
(ssRNA40), we demonstrated that an NLRP3-mediated response could be activated by RNA
species. Mechanistically, NLRP3 inflammasome activation by the influenza virus was
dependent on lysosomal maturation and reactive oxygen species (ROS). Inhibition of
ROS induction eliminated IL-1beta production in animals during influenza infection.
Together, these data place the NLRP3 inflammasome as an essential component in host
defense against influenza infection through the sensing of viral RNA.