Differential Role of TLR- and RLR-Signaling in the Immune Responses to Influenza A Virus Infection and Vaccination

• Published in: Journal of Immunology Vol. 179; no. 7; pp. 4711 - 4720
• Main Authors: Koyama, Shohei, Ishii, Ken J, Kumar, Himanshu, Tanimoto, Takeshi, Coban, Cevayir, Uematsu, Satoshi, Kawai, Taro, Akira, Shizuo
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 01.10.2007
• Subjects: Adaptor Proteins, Signal Transducing - deficiency; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - immunology; Adaptor Proteins, Signal Transducing - metabolism; Animals; Antigens - immunology; Cells, Cultured; Immunity, Innate - immunology; Influenza A virus; Influenza A virus - immunology; Interferon Type I - biosynthesis; Membrane Proteins - metabolism; Mice; Mice, Knockout; Nerve Tissue Proteins - metabolism; Orthomyxoviridae Infections - immunology; Orthomyxoviridae Infections - metabolism; Signal Transduction - immunology; Toll-Like Receptors - deficiency; Toll-Like Receptors - genetics; Toll-Like Receptors - immunology; Toll-Like Receptors - metabolism; Vaccination
• ISSN: 0022-1767; 1550-6606; 1365-2567
• DOI: 10.4049/jimmunol.179.7.4711

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.