Endogenous Cellular MicroRNAs Mediate Antiviral Defense against Influenza A Virus.
Endogenous Cellular MicroRNAs Mediate Antiviral Defense against Influenza A Virus.
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内源性细胞 microRNA 介导针对甲型流感病毒的抗病毒防御
DOI：
10.1016/j.omtn.2017.12.016
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发表时间：
2018-03-02
期刊：
影响因子：
--
通讯作者：
Meng S
中科院分区：
文献类型：
--
作者：
Peng S;Wang J;Wei S;Li C;Zhou K;Hu J;Ye X;Yan J;Liu W;Gao GF;Fang M;Meng S
流感病毒与宿主microRNAs(MiRNAs)之间的相互作用参与了病毒复制和宿主趋向性的调节。然而，细胞miRNA谱系的全球作用和miRNA介导的抗病毒防御机制有待进一步阐明。在本研究中，我们系统地从人和小鼠上皮细胞中筛选出297个细胞miRNAs，并鉴定出5个在体外和体内有效抑制流感病毒复制的抑制性miRNAs。在这些miRNA中，hsa-mir-127-3p、hsa-mir-486-5p、hsa-mir-593-5p和MMU-mir-487b-5p至少针对人季节性流感H3N2和减毒PR8(H1N1)病毒的一个病毒基因片段，而hsa-miR-1-3p通过靶向支持性宿主因子ATP6V1a而抑制病毒复制。此外，病毒RNA片段中miRNA结合位点的数量与宿主miRNA诱导的抗病毒防御活性呈正相关。通过Agomir递送的五种miRNAs的组合治疗明显抑制了病毒的复制，并有效地提高了对PR8对小鼠致命攻击的保护。这些数据表明，呼吸道上皮细胞中高表达的miRNAs能够有效地对抗甲型流感病毒，并将有助于设计基于miRNA的治疗方法。
The reciprocal interaction between influenza virus and host microRNAs (miRNAs) has been implicated in the regulation of viral replication and host tropism. However, the global roles of the cellular miRNA repertoire and the mechanisms of miRNA-mediated antiviral defense await further elucidation. In this study, we systematically screened 297 cellular miRNAs from human and mouse epithelial cells and identified five inhibitory miRNAs that efficiently inhibited influenza virus replication in vitro and in vivo. Among these miRNAs, hsa-mir-127-3p, hsa-mir-486-5p, hsa-mir-593-5p, and mmu-mir-487b-5p were found to target at least one viral gene segment of both the human seasonal influenza H3N2 and the attenuated PR8 (H1N1) virus, whereas hsa-miR-1-3p inhibited viral replication by targeting the supportive host factor ATP6V1A. Moreover, the number of miRNA binding sites in viral RNA segments was positively associated with the activity of host miRNA-induced antiviral defense. Treatment with a combination of the five miRNAs through agomir delivery pronouncedly suppressed viral replication and effectively improved protection against lethal challenge with PR8 in mice. These data suggest that the highly expressed miRNAs in respiratory epithelial cells elicit effective antiviral defenses against influenza A viruses and will be useful for designing miRNA-based therapies against viral infection.
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