Downregulation of miR-218 by porcine reproductive and respiratory syndrome virus facilitates viral replication via inhibition of type I interferon responses.

Abstract

Porcine reproductive and respiratory syndrome virus (PRRSV) is a devastating pathogen in the swine industry worldwide. miRNAs are reported to be involved in virus-host interaction. Here, we used high-throughput sequencing and miRNA inhibitors to screen possible miRNAs 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 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.

• Authors: Lin Zhang, Lu Zhang, Yu Pan, Junxin Gao, Yunfei Xu, Xi Li, Zhijun Tian, Hongyan Chen, Yue Wang
• Journal: The Journal of biological chemistry (J Biol Chem) 2021 Jan-Jun Vol. 296 Pg. 100683 ISSN: 1083-351X [Electronic] United States
• PMID: 33887325 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Interferon Type I
• MicroRNAs
• Suppressor of Cytokine Signaling 3 Protein

Topics

• Animals
• Cell Line
• Down-Regulation
• Interferon Type I (metabolism)
• Macrophages, Alveolar (metabolism, virology)
• MicroRNAs (genetics)
• Porcine respiratory and reproductive syndrome virus (physiology)
• Suppressor of Cytokine Signaling 3 Protein (metabolism)
• Virus Replication