Due to the frequent mutations, influenza A virus (IAV) becomes resistant to anti‐viral drugs targeting influenza viral proteins. There are increasing interests in anti‐viral agents that target host cellular proteins required for virus replication. Tankyrase (TNKS) has poly (ADP‐ribose) polymerase activity and is a negative regulator of many host proteins. The objectives of this study are to study the role of TNKS2 in IAV infection, identify the microRNAs targeting TNKS2, and to understand the mechanisms involved. We found that TNKS2 expression was elevated in human lung epithelial cells and mouse lungs during IAV infection. Knock‐down of TNKS2 by RNA interference reduced viral replication. Using a computation approach and 3′‐untranslation regions (3′‐UTR) reporter assay, we identified miR‐206 as the microRNA that targeted TNKS2. Overexpression of miR‐206 reduced viral protein levels and virus production in cell culture. The effect of miR‐206 on IAV replication was strain‐independent. miR‐206 activated JNK/c‐Jun signalling, induced type I interferon expression and enhanced Stat signalling. Finally, the delivery of an adenovirus expressing miR‐206 into the lung of mice challenged with IAV increased type I interferon response, suppressed viral load in the lungs and increased survival. Our results indicate that miR‐206 has anti‐influenza activity by targeting TNKS2 and subsequently activating the anti‐viral state.

中文翻译：

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MicroRNA-206 通过靶向 tankyrase 2 抑制甲型流感病毒复制

由于频繁的突变，甲型流感病毒 (IAV) 对针对流感病毒蛋白的抗病毒药物产生耐药性。人们对靶向病毒复制所需的宿主细胞蛋白的抗病毒药物越来越感兴趣。Tankyrase (TNKS) 具有聚 (ADP-核糖) 聚合酶活性，是许多宿主蛋白的负调节剂。本研究的目的是研究 TNKS2 在 IAV 感染中的作用，确定靶向 TNKS2 的 microRNA，并了解所涉及的机制。我们发现在 IAV 感染期间，人肺上皮细胞和小鼠肺中的 TNKS2 表达升高。通过 RNA 干扰敲低 TNKS2 可减少病毒复制。使用计算方法和 3'-非翻译区 (3'-UTR) 报告基因分析，我们将 miR-206 鉴定为靶向 TNKS2 的 microRNA。miR-206 的过表达降低了细胞培养物中的病毒蛋白水平和病毒产量。miR-206 对 IAV 复制的影响与菌株无关。miR-206 激活 JNK/c-Jun 信号，诱导 I 型干扰素表达并增强 Stat 信号。最后，将表达 miR-206 的腺病毒输送到受到 IAV 攻击的小鼠的肺部会增加 I 型干扰素反应，抑制肺部的病毒载量并提高存活率。我们的结果表明，miR-206 通过靶向 TNKS2 并随后激活抗病毒状态而具有抗流感活性。将表达 miR-206 的腺病毒输送到受到 IAV 攻击的小鼠的肺部会增加 I 型干扰素反应，抑制肺部病毒载量并提高存活率。我们的结果表明，miR-206 通过靶向 TNKS2 并随后激活抗病毒状态而具有抗流感活性。将表达 miR-206 的腺病毒输送到受到 IAV 攻击的小鼠的肺部会增加 I 型干扰素反应，抑制肺部病毒载量并提高存活率。我们的结果表明，miR-206 通过靶向 TNKS2 并随后激活抗病毒状态而具有抗流感活性。