Inflammasome recognition of influenza virus is essential for adaptive immune responses.
Influenza virus infection is recognized by the innate immune system through Toll like receptor (TLR) 7 and retinoic acid inducible gene I. These two recognition pathways lead to the activation of type I interferons and resistance to infection. In addition, TLR signals are required for the CD4 T cell and IgG2a, but not cytotoxic T lymphocyte, responses to influenza virus infection. In contrast, the role of NOD-like receptors (NLRs) in viral recognition and induction of adaptive immunity to influenza virus is unknown. We demonstrate that respiratory infection with influenza virus results in the activation of NLR inflammasomes in the lung. Although NLRP3 was required for inflammasome activation in certain cell types, CD4 and CD8 T cell responses, as well as mucosal IgA secretion and systemic IgG responses, required ASC and caspase-1 but not NLRP3. Consequently, ASC, caspase-1, and IL-1R, but not NLRP3, were required for protective immunity against flu challenge. Furthermore, we show that caspase-1 inflammasome activation in the hematopoietic, but not stromal, compartment was required to induce protective antiviral immunity. These results demonstrate that in addition to the TLR pathways, ASC inflammasomes play a central role in adaptive immunity to influenza virus.
Ichinohe
Takeshi
T
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Lee
Heung Kyu
HK
Ogura
Yasunori
Y
Flavell
Richard
R
Iwasaki
Akiko
A
D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D053468:CARD Signaling Adaptor Proteins; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D002135:Calcium-Binding Proteins / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D020170:Caspase 1 / Q000235:genetics; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D003598:Cytoskeletal Proteins / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology; D007111:Immunity, Cellular / Q000235:genetics / Q000276:immunology*; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology*; D007132:Immunoglobulin Isotypes / Q000097:blood / Q000276:immunology; D053583:Interleukin-1beta / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000821:virology; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000276:immunology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D017817:Nasal Lavage Fluid / Q000276:immunology; D009975:Orthomyxoviridae / Q000276:immunology*; D009976:Orthomyxoviridae Infections / Q000235:genetics / Q000276:immunology* / Q000821:virology; D017472:Receptors, Interleukin-1 / Q000235:genetics; D016019:Survival Analysis
D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D007132:Immunoglobulin Isotypes; D053583:Interleukin-1beta; C512299:Ipaf protein, mouse; D046912:Multiprotein Complexes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C498534:Pycard protein, mouse; D017472:Receptors, Interleukin-1; D020170:Caspase 1