MicroRNA Expression and Virulence in Pandemic Influenza Virus-Infected Mice
MicroRNA Expression and Virulence in Pandemic Influenza Virus-Infected Mice
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DOI：
10.1128/jvi.02203-09
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发表时间：
2010-03-01
影响因子：
5.4
通讯作者：
Katze, Michael G.
中科院分区：
文献类型：
--
作者：
Li, Yu;Chan, Eric Y.;Katze, Michael G.
历史上已知的最严重的H1N1流感大流行在1918年和1919年导致2000多万人死亡。虽然导致1918年流感病毒极端毒力的潜在机制仍然不清楚，但我们先前的功能基因组学分析揭示了重建的1918年流感病毒（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的相关性。最近，microRNA已经成为一类重要的基因表达调控因子。为了确定细胞microRNA的差异表达是否在宿主对r1918感染的反应中起作用，我们比较了感染r1918病毒的小鼠的肺细胞“microRNAome”与感染非致死性季节性流感病毒A/Texas/36/91的小鼠的肺细胞“microRNAome”。我们发现一组microRNA，包括miR-200 a和miR-223，在流感病毒感染时表达差异，r1918和A/Texas/36/91感染诱导不同的microRNA表达谱。此外，我们观察到预测的细胞靶mRNA的数量显著富集，其表达与这些microRNA的表达呈负相关。有趣的是，基因本体分析显示，这些mRNA中的许多在免疫应答和细胞死亡途径中发挥作用，已知这与r1918的极端毒力有关。这是首次证明流感病毒感染小鼠的细胞基因表达模式可能部分归因于microRNA调控，并且这种调控可能是r1918极端毒力的一个促成因素。
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.