Increasing Expression of MicroRNA 181 Inhibits Porcine Reproductive and Respiratory Syndrome Virus Replication and Has Implications for Controlling Virus Infection

Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most important viral pathogens in the swine industry. Emerging evidence indicates that the host microRNAs (miRNAs) are involved in host-pathogen interactions. However, whether host miRNAs can target PRRSV and be used to inhibit PRRSV infection has not been reported. Recently, microRNA 181 (miR-181) has been identified as a positive regulator of immune response, and here we report that miR-181 can directly impair PRRSV infection. Our results showed that delivered miR-181 mimics can strongly inhibit PRRSV replication in vitro through specifically binding to a highly (over 96%) conserved region in the downstream of open reading frame 4 (ORF4) of the viral genomic RNA. The inhibition of PRRSV replication was specific and dose dependent. In PRRSV-infected Marc-145 cells, the viral mRNAs could compete with miR-181-targeted sequence in luciferase vector to interact with miR-181 and result in less inhibition of luciferase activity, further demonstrating the specific interactions between miR-181 and PRRSV RNAs. As expected, miR-181 and other potential PRRSV-targeting miRNAs (such as miR-206) are expressed much more abundantly in minimally permissive cells or tissues than in highly permissive cells or tissues. Importantly, highly pathogenic PRRSV (HP-PRRSV) strain-infected pigs treated with miR-181 mimics showed substantially decreased viral loads in blood and relief from PRRSV-induced fever compared to negative-control (NC)-treated controls. These results indicate the important role of host miRNAs in modulating PRRSV infection and viral pathogenesis and also support the idea that host miRNAs could be useful for RNA interference (RNAi)-mediated antiviral therapeutic strategies.