Broad-spectrum inhibition of respiratory virus infection by microRNA mimics targeting p38 MAPK signalling

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 minimising 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 generally operate through the post-transcriptional regulation of messenger RNA 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 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 MAPK signalling pathway and this work identified MAPK activated protein kinase 2 as a broad-spectrum antiviral target required for both Influenza and RSV infection.