CSIRO Australian Animal Health Laboratory, Geelong, Victoria, Australia.
J Virol. 2013 Apr;87(7):3782-91. doi: 10.1128/JVI.01342-12. Epub 2013 Jan 23.
Hendra virus is a highly pathogenic zoonotic paramyxovirus in the genus Henipavirus. Thirty-nine outbreaks of Hendra virus have been reported since its initial identification in Queensland, Australia, resulting in seven human infections and four fatalities. Little is known about cellular host factors impacting Hendra virus replication. In this work, we demonstrate that Hendra virus makes use of a microRNA (miRNA) designated miR-146a, an NF-κB-responsive miRNA upregulated by several innate immune ligands, to favor its replication. miR-146a is elevated in the blood of ferrets and horses infected with Hendra virus and is upregulated by Hendra virus in human cells in vitro. Blocking miR-146a reduces Hendra virus replication in vitro, suggesting a role for this miRNA in Hendra virus replication. In silico analysis of miR-146a targets identified ring finger protein (RNF)11, a member of the A20 ubiquitin editing complex that negatively regulates NF-κB activity, as a novel component of Hendra virus replication. RNA interference-mediated silencing of RNF11 promotes Hendra virus replication in vitro, suggesting that increased NF-κB activity aids Hendra virus replication. Furthermore, overexpression of the IκB superrepressor inhibits Hendra virus replication. These studies are the first to demonstrate a host miRNA response to Hendra virus infection and suggest an important role for host miRNAs in Hendra virus disease.
亨德拉病毒是一种高致病性人畜共患副粘病毒，属于亨德拉病毒属。自最初在澳大利亚昆士兰州被鉴定以来，已经报告了 39 次亨德拉病毒爆发，导致 7 人感染，4 人死亡。人们对影响亨德拉病毒复制的细胞宿主因素知之甚少。在这项工作中，我们证明亨德拉病毒利用了一种 microRNA（miRNA），称为 miR-146a，这是一种由几种先天免疫配体上调的 NF-κB 反应性 miRNA，有利于其复制。感染亨德拉病毒的雪貂和马的血液中 miR-146a 升高，并且亨德拉病毒在体外人细胞中上调 miR-146a。阻断 miR-146a 可减少体外的亨德拉病毒复制，表明该 miRNA 在亨德拉病毒复制中起作用。miR-146a 靶标的计算机分析鉴定了 RING 指蛋白 (RNF)11，它是 A20 泛素编辑复合物的成员，可负调节 NF-κB 活性，是亨德拉病毒复制的新组成部分。RNA 干扰介导的 RNF11 沉默促进了体外的亨德拉病毒复制，表明 NF-κB 活性的增加有助于亨德拉病毒复制。此外，IκB 超级阻遏物的过表达抑制了亨德拉病毒的复制。这些研究首次证明了宿主对亨德拉病毒感染的 miRNA 反应，并表明宿主 miRNAs 在亨德拉病毒病中起着重要作用。
