TY - JOUR
T1 - The NLRP3 Inflammasome Mediates In Vivo Innate Immunity to Influenza A Virus through Recognition of Viral RNA
AU - Allen, Irving C.
AU - Scull, Margaret A.
AU - Moore, Chris B.
AU - Holl, Eda K.
AU - McElvania-TeKippe, Erin
AU - Taxman, Debra J.
AU - Guthrie, Elizabeth H.
AU - Pickles, Raymond J.
AU - Ting, Jenny P Y
N1 - Funding Information:
The authors thank the Carolina Vaccine Institute for supplying aliquots of the mouse-adapted influenza A/PR/8/34 virus. We acknowledge Wendy Barclay for critical review and advice on viral propagation and Rob Tarran for providing the JME cell line. We thank Richard Flavell (Yale University), Vishva M. Dixit (Genentech, Inc), Fayyaz Sutterwala (the University of Iowa), and Millenium Pharmaceuticals for supplying the Nlrp3 −/− , Pycard −/− , Nlrc4 −/− and Casp1 −/− mice. We also thank Willie June Brickey and Sushmita Jha for maintaining mouse colonies and providing histology scoring assistance. This work is supported by 3-U54-AI057157-06S1, AI067798, 05-0064, and 1U19-AI077437-01 (J.P.Y.T.). I.C.A. is supported by a National Institutes of Health training grant. M.A.S. is a recipient of the George H. Hitchings Fund for Health Research and Science Education of the Triangle Community Foundation.
PY - 2009/4/17
Y1 - 2009/4/17
N2 - 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-1β 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.
AB - 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-1β 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.
KW - MOLIMMUNO
UR - http://www.scopus.com/inward/record.url?scp=64049111768&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=64049111768&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2009.02.005
DO - 10.1016/j.immuni.2009.02.005
M3 - Article
C2 - 19362020
AN - SCOPUS:64049111768
SN - 1074-7613
VL - 30
SP - 556
EP - 565
JO - Immunity
JF - Immunity
IS - 4
ER -