MicroRNA Expression Profile of Mouse Lung Infected with 2009 Pandemic H1N1 Influenza Virus

MicroRNAs have been implicated in the regulation of gene expression of various biological processes in a post-transcriptional manner under physiological and pathological conditions including host responses to viral infections. The 2009 pandemic H1N1 influenza virus is an emerging reassortant strain of swine, human and bird influenza virus that can cause mild to severe illness and even death. To further understand the molecular pathogenesis of the 2009 pandemic H1N1 influenza virus, we profiled cellular microRNAs of lungs from BALB/c mice infected with wild-type 2009 pandemic influenza virus A/Beijing/501/2009 (H1N1) (hereafter referred to as BJ501) and mouse-adapted influenza virus A/Puerto Rico/8/1934 (H1N1) (hereafter referred to as PR8) for comparison. Microarray analysis showed both the influenza virus BJ501 and PR8 infection induced strain- and temporal-specific microRNA expression patterns and that their infection caused a group of common and distinct differentially expressed microRNAs. Characteristically, more differentially expressed microRNAs were aroused on day 5 post infection than on day 2 and more up-regulated differentially expressed microRNAs were provoked than the down-regulated for both strains of influenza virus. Finally, 47 differentially expressed microRNAs were obtained for the infection of both strains of H1N1 influenza virus with 29 for influenza virus BJ501 and 43 for PR8. Among them, 15 microRNAs had no reported function, while 32 including miR-155 and miR-233 are known to play important roles in cancer, immunity and antiviral activity. Pathway enrichment analyses of the predicted targets revealed that the transforming growth factor-β (TGF-β) signaling pathway was the key cellular pathway associated with the differentially expressed miRNAs during influenza virus PR8 or BJ501 infection. To our knowledge, this is the first report of microRNA expression profiles of the 2009 pandemic H1N1 influenza virus in a mouse model, and our findings might offer novel therapy targets for influenza virus infection.

微小核糖核酸（microRNAs）可在生理与病理状态下，通过转录后调控方式参与多种生物学过程的基因表达调控，其中包括宿主对病毒感染的免疫应答。2009年甲型H1N1流感大流行病毒是一种由猪、人流感病毒与禽流感病毒重组产生的新型毒株，可引发轻症至重症疾病，甚至导致宿主死亡。为进一步阐明2009年甲型H1N1流感大流行病毒的分子致病机制，本研究对感染野生型2009年大流行流感病毒A/Beijing/501/2009（H1N1，下文简称BJ501）以及鼠适应性流感病毒A/Puerto Rico/8/1934（H1N1，下文简称PR8）的BALB/c小鼠肺部细胞内的微小核糖核酸进行了表达谱分析，以开展对比研究。基因芯片分析结果显示，BJ501与PR8两种毒株的感染均可诱导出毒株特异性与时间特异性的微小核糖核酸表达模式，且二者感染均会引发一组共有及特异的差异表达微小核糖核酸。值得注意的是，相较于感染后第2天，感染后第5天诱导产生的差异表达微小核糖核酸数量更多；且两种流感毒株感染后，上调表达的差异微小核糖核酸数量均多于下调表达者。最终，针对两种H1N1流感毒株的感染，共获得47个差异表达微小核糖核酸，其中BJ501感染组对应29个，PR8感染组对应43个。其中15个微小核糖核酸尚未见功能报道，剩余32个（包括miR-155与miR-233）已被证实可在癌症发生、免疫调控以及抗病毒活动中发挥重要作用。对预测靶基因进行通路富集分析后发现，转化生长因子-β（transforming growth factor-β, TGF-β）信号通路是PR8或BJ501流感病毒感染过程中，与差异表达微小核糖核酸密切相关的核心细胞通路。据我们所知，本研究是首个在小鼠模型中报道2009年甲型H1N1流感大流行病毒微小核糖核酸表达谱的研究，本研究结果可为流感病毒感染的新型治疗靶点开发提供新思路。