Lin Zhang, Lu Zhang, Yu Pan, Junxin Gao, Yunfei Xu, Xi Li, Zhijun Tian, Hongyan Chen, Yue Wang

J Biol Chem.2021 Apr 19;100683. doi: 10.1016/j.jbc.2021.100683. Online ahead of print.

Abstract

Porcine reproductive and respiratory syndrome virus (PRRSV) is a devastating pathogen in the swine industry worldwide. MicroRNAs are reported to be involved in virus-host interaction. Here, we used high-throughput sequencing and microRNAs inhibitors to screen possible microRNAs that can inhibit PRRSV infection on its target cell, porcine alveolar macrophages. We observed that miR-218 was downregulated upon virus infection, and knockdown of miR-218 significantly enhanced PRRSV replication. Overexpression of miR-218 resulted in a decrease in PRRSV replication, and this overexpression did not alter viral genomic RNA levels, but rather increased antiviral interferon signaling. Further analysis revealed that that miR-218 regulated PRRSV replication by directly targeting porcine suppressor of cytokine signaling 3 (SOCS3), a JAK2 kinase inhibitor. Knockdown of the endogenous SOCS3 expression led to augmentation of type I interferon genes and resulted in decreased PRRSV replication, and vice versa. During PRRSV infection in vivo and in vitro, cellular miR-218 expression was downregulated and SOCS3 expression was upregulated, further supporting the inverse correlation between miR-218 and SOCS3 expression. The data on SOCS3 depletion in combination with miR-218 inhibition suggested that the antiviral activity of miR-218 required the SOCS3-mediated signaling pathway. Similarly, miR-218 negatively regulated PRRSV replication in Marc-145 cells, as well as the replication of porcine epidemic diarrhea virus and transmissible gastroenteritis virus in Vero and ST cells respectively. Taken together, these results demonstrate that PRRSV-induced miR-218 downregulation serves to inhibit the type I interferon response, and may provide a novel therapeutic target for treatment of PRRSV and other viral infections.

Keywords: host-virus interaction; miR-218; porcine reproductive and respiratory syndrome virus; suppressor of cytokine signaling 3 (SOCS3); type I interferon response.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.