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* Department of Host Defense,
Department of Molecular Protozoology,
The 21st Century Center of Excellence, Combined Program on Microbiology and Immunology, Research Institute for Microbial Diseases, Osaka University, Yamadaoka, Suita, Osaka, Japan;
Exploratory Research for Advanced Technology, Japan Science and Technology Agency, Yamadaoka, Suita, Osaka, Japan;
¶ The Research Foundation for Microbial Diseases of Osaka University, Yahata-cho, Kan-on-ji, Kagawa, Japan; and
|| Respiratory Oncology and Molecular Medicine, Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Miyagi, Japan
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-
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 Address correspondence and reprint requests to Dr. Shizuo Akira, Department of Host Defense or Dr. Ken J. Ishii, Department of Molecular Protozoology, Research Institute for Microbial Diseases, Osaka University Yamadaoka, Suita City, Osaka, Japan. E-mail addresses: sakira{at}biken.osaka-u.ac.jp or kenishii{at}biken.osaka-u.ac.jp
2 Abbreviations used in this paper: DC, dendritic cell; MEF, mouse embryonic fibroblasts; IPS-1, interferon- promoter stimulator 1; TBK1, Tank-binding kinase1; MOI, multiplicity of infection; RIG-I, retinoic acid-inducible gene I; TRIF, Toll/IL-1 receptor domain-containing adaptor inducing IFN-; HA, hemagglutinin; NP, nuclear protein; IRF3, interferon regulatory factor 3; WT, wild type; NC, New Caledonia; PR, Puerto Rico; KO, knockout; RLR, RIG-like receptor.
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