Original Article

Cell Research (2015) 25:39–49. doi:10.1038/cr.2014.130; published online 7 October 2014

Honeysuckle-encoded atypical microRNA2911 directly targets influenza A viruses
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Zhen Zhou1,*, Xihan Li1,*, Jinxiong Liu2,*, Lei Dong1,*, Qun Chen1, Jialing Liu1, Huihui Kong2, Qianyi Zhang2, Xian Qi3, Dongxia Hou1, Lin Zhang1, Guoquan Zhang2, Yuchen Liu1, Yujing Zhang1, Jing Li1, Jin Wang1, Xi Chen1, Hua Wang3, Junfeng Zhang1, Hualan Chen2, Ke Zen1 and Chen-Yu Zhang1

  1. 1Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210093, China
  2. 2State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, Heilongjiang 150001, China
  3. 3Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, Jiangsu 210090, China

Correspondence: Chen-Yu Zhang, E-mail: cyzhang@nju.edu.cn; Ke Zen, E-mail: kzen@nju.edu.cn; Hualan Chen, E-mail: chenhualan@caas.cn; Junfeng Zhang, E-mail: jfzhang@nju.edu.cn; Hua Wang, E-mail: hua@jscdc.cn

*These four authors contributed equally to this work.

Received 18 June 2014; Revised 28 August 2014; Accepted 1 September 2014
Advance online publication 7 October 2014

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Abstract

Influenza A viruses (IAVs), particularly H1N1, H5N1 and H7N9, pose a substantial threat to public health worldwide. Here, we report that MIR2911, a honeysuckle (HS)-encoded atypical microRNA, directly targets IAVs with a broad spectrum. MIR2911 is highly stable in HS decoction, and continuous drinking or gavage feeding of HS decoction leads to a significant elevation of the MIR2911 level in mouse peripheral blood and lung. Bioinformatics prediction and a luciferase reporter assay showed that MIR2911 could target various IAVs, including H1N1, H5N1 and H7N9. Synthetic MIR2911 significantly inhibited H1N1-encoded PB2 and NS1 protein expression, but did not affect mutants in which the MIR2911-binding nucleotide sequences were altered. Synthetic MIR2911, extracted RNA from HS decoction and HS decoction all significantly inhibited H1N1 viral replication and rescued viral infection-induced mouse weight loss, but did not affect infection with a mutant virus in which the MIR2911-binding nucleotide sequences of PB2 and NS1 were altered. Importantly, the inhibitory effect of HS decoction on viral replication was abolished by an anti-MIR2911 antagomir, indicating that the physiological concentration of MIR2911 in HS decoction could directly and sufficiently suppress H1N1 viral replication. MIR2911 also inhibited H5N1 and H7N9 viral replication in vitro and in vivo. Strikingly, administration of MIR2911 or HS decoction dramatically reduced mouse mortality caused by H5N1 infection. Our results demonstrate that MIR2911 is the first active component identified in Traditional Chinese Medicine to directly target various IAVs and may represent a novel type of natural product that effectively suppresses viral infection.

Keywords:

microRNA; influenza A virus; H1N1; H5N1; H7N9; honeysuckle; MIR2911