McCaskill Jana L, Ressel Sarah, Alber Andreas, Redford Jane, Power Ultan F, Schwarze Jürgen, Dutia Bernadette M, Buck Amy H
Institute of Immunology and Infection Research and Centre for Immunity, Infection and Evolution, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3FL, UK.
The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Edinburgh EH25 9RG, UK.
Mol Ther Nucleic Acids. 2017 Jun 16;7:256-266. doi: 10.1016/j.omtn.2017.03.008. Epub 2017 Apr 6.
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.
大多数抗病毒治疗药物靶向保守的病毒蛋白，然而，这种方法会给病毒带来选择性压力，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，从而将逃避药物活性的病毒突变机会降至最低。微小RNA（miRNA）是小的非编码RNA，在正常生物学和疾病生物学中发挥多种作用，它们通常通过对mRNA靶标的转录后调控发挥作用。我们之前已经鉴定出对多种疱疹病毒感染具有抗病毒活性的细胞miRNA，在此我们扩展了其中一些miRNA对流感病毒和呼吸道合胞病毒的抗病毒谱。通过这些筛选实验，我们鉴定出了在所有测试毒株中均能导致>75%病毒抑制的广谱抗病毒miRNA，并使用反相蛋白质阵列分析研究了它们的作用机制。在p38丝裂原活化蛋白激酶（MAPK）信号通路中鉴定出了主要候选miR-124、miR-24和miR-744的靶标，这项研究确定丝裂原活化蛋白激酶激活的蛋白激酶2是流感病毒和呼吸道合胞病毒（RSV）感染所需的广谱抗病毒靶标。
