The NLRP3 inflammasome mediates in vivo innate immunity to influenza A virus through recognition of viral RNA.
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.
Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Irving C
IC
Allen
Margaret A
MA
Scull
Chris B
CB
Moore
Eda K
EK
Holl
Erin
E
McElvania-TeKippe
Debra J
DJ
Taxman
Elizabeth H
EH
Guthrie
Raymond J
RJ
Pickles
Jenny P-Y
JP
Ting
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D055354:Exosomes / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D053118:Influenza A Virus, H1N1 Subtype; D053122:Influenza A Virus, H3N2 Subtype; D009980:Influenza A virus / Q000276:immunology*; D007251:Influenza, Human / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009976:Orthomyxoviridae Infections / Q000276:immunology*; D012367:RNA, Viral; D014777:Virus Diseases / Q000276:immunology*
D002352:Carrier Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D012367:RNA, Viral