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首页> 外文OA文献 >Lethal Dissemination of H5N1 Influenza Virus Is Associated with Dysregulation of Inflammation and Lipoxin Signaling in a Mouse Model of Infection▿ †
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Lethal Dissemination of H5N1 Influenza Virus Is Associated with Dysregulation of Inflammation and Lipoxin Signaling in a Mouse Model of Infection▿ †

机译：H5N1流感病毒的致死性传播与感染小鼠模型中的炎症反应失调和脂氧还蛋白信号有关▿†

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Periodic outbreaks of highly pathogenic avian H5N1 influenza viruses and the current H1N1 pandemic highlight the need for a more detailed understanding of influenza virus pathogenesis. To investigate the host transcriptional response induced by pathogenic influenza viruses, we used a functional-genomics approach to compare gene expression profiles in lungs from 129S6/SvEv mice infected with either the fully reconstructed H1N1 1918 pandemic virus (1918) or the highly pathogenic avian H5N1 virus Vietnam/1203/04 (VN/1203). Although the viruses reached similar titers in the lung and caused lethal infections, the mean time of death was 6 days for VN/1203-infected animals and 9 days for mice infected with the 1918 virus. VN/1203-infected animals also exhibited an earlier and more potent inflammatory response. This response included induction of genes encoding components of the inflammasome. VN/1203 was also able to disseminate to multiple organs, including the brain, which correlated with changes in the expression of genes associated with hematological functions and lipoxin biogenesis and signaling. Both viruses elicited expression of type I interferon (IFN)-regulated genes in wild-type mice and to a lesser extent in mice lacking the type I IFN receptor, suggesting alternative or redundant pathways for IFN signaling. Our findings suggest that VN/1203 is more pathogenic in mice as a consequence of several factors, including the early and sustained induction of the inflammatory response, the additive or synergistic effects of upregulated components of the immune response, and inhibition of lipoxin-mediated anti-inflammatory responses, which correlated with the ability of VN/1203 to disseminate to extrapulmonary organs.
机译：高致病性禽流感H5N1流感病毒的周期性爆发和当前的H1N1大流行凸显了对流感病毒发病机理的更详细了解的需求。为了研究由致病性流感病毒诱导的宿主转录应答，我们使用功能基因组学方法比较了感染了完全重建的H1N1 1918大流行病毒（1918）或高致病性禽类H5N1的129S6 / SvEv小鼠肺中的基因表达谱越南/ 1203/04（VN / 1203）病毒。尽管病毒在肺中达到相似的滴度并引起致命感染，但被VN / 1203感染的动物的平均死亡时间为6天，而感染1918病毒的小鼠的平均死亡时间为9天。受VN / 1203感染的动物还表现出更早，更有效的炎症反应。该反应包括诱导编码炎性体成分的基因。 VN / 1203还能够传播到包括大脑在内的多个器官，这些器官与血液功能，脂蛋白的生物发生和信号转导相关的基因表达变化有关。两种病毒均引起野生型小鼠中I型干扰素（IFN）调控基因的表达，而在缺乏I型IFN受体的小鼠中表达程度较低，提示IFN信号传导具有替代或冗余途径。我们的发现表明，由于多种因素，VN / 1203在小鼠中的致病性更高，包括炎症反应的早期和持续诱导，免疫应答上调成分的累加或协同作用以及脂蛋白介导的抗氧化剂的抑制作用。 -炎症反应，与VN / 1203扩散到肺外器官的能力有关。

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