Koyama Shohei, Ishii Ken J, Kumar Himanshu, Tanimoto Takeshi, Coban Cevayir, Uematsu Satoshi, Kawai Taro, Akira Shizuo
Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Yamadaoka, Suita, Osaka, Japan.
J Immunol. 2007 Oct 1;179(7):4711-20. 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.
在体外，天然免疫系统以细胞类型特异性方式通过Toll样受体7（TLR 7）或维甲酸诱导基因I识别甲型流感病毒，然而，髓样分化因子88（MyD88）或β干扰素启动子刺激因子1（IPS-1）依赖性信号通路在体内抗病毒反应中的生理功能仍不清楚。在本研究中，我们发现，虽然MyD88或IPS-1信号通路足以控制对鼻内甲型流感病毒感染的初始抗病毒反应，但缺乏这两种通路的小鼠未能表现出抗病毒反应，导致肺部病毒载量增加。相比之下，分别针对优势血凝素或核蛋白抗原的B细胞或CD4 T细胞的诱导严格依赖于MyD88信号通路，而不依赖于IPS-1信号通路，而在缺乏MyD88或IPS-1的情况下，核蛋白抗原特异性CD8 T细胞的诱导并未受损。此外，用灭活病毒对TLR7和MyD88缺陷小鼠进行疫苗接种，未能使其免受致死性活病毒攻击。这些结果强烈表明，MyD88或IPS-1信号通路中的任何一条对于初始抗病毒反应都是足够的，而对甲型流感病毒的保护性适应性免疫反应则由TLR7-MyD88通路控制。
