Differential role of TLR- and RLR-signaling in the immune responses to influenza A virus infection and vaccination.
The innate immune system recognizes influenza A virus via TLR 7 or retinoic acid-inducible gene I in a cell-type specific manner in vitro, however, physiological function(s) of the MyD88- or interferon-beta promoter stimulator 1 (IPS-1)-dependent signaling pathways in antiviral responses in vivo remain unclear. In this study, we show that although either MyD88- or IPS-1-signaling pathway was sufficient to control initial antiviral responses to intranasal influenza A virus infection, mice lacking both pathways failed to show antiviral responses, resulting in increased viral load in the lung. By contrast, induction of B cells or CD4 T cells specific to the dominant hemagglutinin or nuclear protein Ags respectively, was strictly dependent on MyD88 signaling, but not IPS-1 signaling, whereas induction of nuclear protein Ag-specific CD8 T cells was not impaired in the absence of either MyD88 or IPS-1. Moreover, vaccination of TLR7- and MyD88-deficient mice with inactivated virus failed to confer protection against a lethal live virus challenge. These results strongly suggest that either the MyD88 or IPS-1 signaling pathway is sufficient for initial antiviral responses, whereas the protective adaptive immune responses to influenza A virus are governed by the TLR7-MyD88 pathway.
Koyama
Shohei
S
Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Yamadaoka, Suita, Osaka, Japan.
Ishii
Ken J
KJ
Kumar
Himanshu
H
Tanimoto
Takeshi
T
Coban
Cevayir
C
Uematsu
Satoshi
S
Kawai
Taro
T
Akira
Shizuo
S
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D000941:Antigens / Q000276:immunology; D002478:Cells, Cultured; D007113:Immunity, Innate / Q000276:immunology; D009980:Influenza A virus / Q000276:immunology*; D007370:Interferon Type I / Q000096:biosynthesis; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000378:metabolism; D011956:Receptors, Cell Surface; D015398:Signal Transduction / Q000276:immunology*; D051193:Toll-Like Receptors / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014611:Vaccination; D000097905:Roundabout Proteins
D048868:Adaptor Proteins, Signal Transducing; D000941:Antigens; D007370:Interferon Type I; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface; D051193:Toll-Like Receptors; C118348:Robo3 protein, mouse; D000097905:Roundabout Proteins