Department of Microbiology, University of Washington, Seattle, WA 98195-8070, USA.
J Virol. 2010 Mar;84(6):3023-32. doi: 10.1128/JVI.02203-09. Epub 2010 Jan 13.
The worst known H1N1 influenza pandemic in history resulted in more than 20 million deaths in 1918 and 1919. Although the underlying mechanism causing the extreme virulence of the 1918 influenza virus is still obscure, our previous functional genomics analyses revealed a correlation between the lethality of the reconstructed 1918 influenza virus (r1918) in mice and a unique gene expression pattern associated with severe immune responses in the lungs. Lately, microRNAs have emerged as a class of crucial regulators for gene expression. To determine whether differential expression of cellular microRNAs plays a role in the host response to r1918 infection, we compared the lung cellular "microRNAome" of mice infected by r1918 virus with that of mice infected by a nonlethal seasonal influenza virus, A/Texas/36/91. We found that a group of microRNAs, including miR-200a and miR-223, were differentially expressed in response to influenza virus infection and that r1918 and A/Texas/36/91 infection induced distinct microRNA expression profiles. Moreover, we observed significant enrichment in the number of predicted cellular target mRNAs whose expression was inversely correlated with the expression of these microRNAs. Intriguingly, gene ontology analysis revealed that many of these mRNAs play roles in immune response and cell death pathways, which are known to be associated with the extreme virulence of r1918. This is the first demonstration that cellular gene expression patterns in influenza virus-infected mice may be attributed in part to microRNA regulation and that such regulation may be a contributing factor to the extreme virulence of the r1918.
历史上最著名的 H1N1 流感大流行在 1918 年和 1919 年导致了超过 2000 万人死亡。尽管导致 1918 年流感病毒极度致命的潜在机制仍然不清楚，但我们之前的功能基因组学分析揭示了重建的 1918 流感病毒（r1918）在小鼠中的致死性与肺部严重免疫反应相关的独特基因表达模式之间存在相关性。最近，microRNAs 已成为一类关键的基因表达调控因子。为了确定细胞 microRNAs 的差异表达是否在宿主对 r1918 感染的反应中发挥作用，我们比较了 r1918 病毒感染和非致死性季节性流感病毒 A/Texas/36/91 感染的小鼠肺部细胞“microRNAome”。我们发现，一组 microRNAs，包括 miR-200a 和 miR-223，在流感病毒感染时表现出差异表达，并且 r1918 和 A/Texas/36/91 感染诱导了不同的 microRNA 表达谱。此外，我们观察到预测的细胞靶 mRNA 的数量显著增加，这些 mRNA 的表达与这些 microRNAs 的表达呈负相关。有趣的是，基因本体分析表明，这些 mRNA 中的许多在免疫反应和细胞死亡途径中发挥作用，这些途径与 r1918 的极端致命性有关。这是首次证明感染流感病毒的小鼠中的细胞基因表达模式部分归因于 microRNA 调节，并且这种调节可能是 r1918 极度致命的一个因素。
