Broad-Spectrum Inhibition of Respiratory Virus Infection by MicroRNA Mimics Targeting p38 MAPK Signaling.
Broad-Spectrum Inhibition of Respiratory Virus Infection by MicroRNA Mimics Targeting p38 MAPK Signaling.
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DOI：
10.1016/j.omtn.2017.03.008
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发表时间：
2017-06-16
期刊：
影响因子：
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通讯作者：
Buck AH
中科院分区：
文献类型：
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作者：
McCaskill JL;Ressel S;Alber A;Redford J;Power UF;Schwarze J;Dutia BM;Buck AH
大多数抗病毒疗法靶向保守的病毒蛋白，然而，这种方法赋予病毒选择性压力并增加抗病毒药物耐药性的可能性。另一种治疗策略是靶向病毒感染所需的宿主编码因子，从而最大限度地减少逃避药物活性的病毒突变的机会。microRNAs（miRNAs）是一类在正常和疾病生物学中发挥不同作用的小分子非编码RNA，它们通常通过mRNA靶点的转录后调节发挥作用。我们以前已经鉴定出对广泛的疱疹病毒感染具有抗病毒活性的细胞miRNA，在这里，我们扩展了许多这些miRNA对流感和呼吸道合胞病毒的抗病毒谱。从这些筛选实验中，我们鉴定了在所有测试菌株中引起>75%病毒抑制的广谱抗病毒miRNA，并且我们使用反相蛋白质阵列分析来检查它们的作用机制。在p38丝裂原活化蛋白激酶（MAPK）信号通路中鉴定了主要候选物miR-124、miR-24和miR-744的靶点，这项工作将MAPK活化蛋白激酶2鉴定为流感和呼吸道合胞病毒（RSV）感染所需的广谱抗病毒靶点。
The majority of antiviral therapeutics target conserved viral proteins, however, this approach confers selective pressure on the virus and increases the probability of antiviral drug resistance. An alternative therapeutic strategy is to target the host-encoded factors that are required for virus infection, thus minimizing the opportunity for viral mutations that escape drug activity. MicroRNAs (miRNAs) are small noncoding RNAs that play diverse roles in normal and disease biology, and they generally operate through the post-transcriptional regulation of mRNA targets. We have previously identified cellular miRNAs that have antiviral activity against a broad range of herpesvirus infections, and here we extend the antiviral profile of a number of these miRNAs against influenza and respiratory syncytial virus. From these screening experiments, we identified broad-spectrum antiviral miRNAs that caused >75% viral suppression in all strains tested, and we examined their mechanism of action using reverse-phase protein array analysis. Targets of lead candidates, miR-124, miR-24, and miR-744, were identified within the p38 mitogen-activated protein kinase (MAPK) signaling pathway, and this work identified MAPK-activated protein kinase 2 as a broad-spectrum antiviral target required for both influenza and respiratory syncytial virus (RSV) infection.