Porcine Reproductive and Respiratory Syndrome Virus Antagonizes PCSK9's Antiviral Effect via Nsp11 Endoribonuclease Activity.

Yujiao Zhang,Liwei Li,Shan Jiang,Guangzhi Tong,Lingxue Yu,Changlong Liu,Yifeng Jiang,Kuan Zhao,Yanjun Zhou,Fei Gao

doi:10.3390/v12060655

Abstract

Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most important pathogens in the swine industry worldwide. Our previous study had indicated that proprotein convertase subtilisin/kexin type 9 (PCSK9) was a responsive gene in porcine alveolar macrophages (PAMs) upon PRRSV infection. However, whether PCSK9 impacts the PRRSV replication and how the PRRSV modulates host PCSK9 remains elusive. Here, we demonstrated that PCSK9 protein suppressed the replication of both type-1 and type-2 PRRSV species. More specifically, the C-terminal domain of PCSK9 was responsible for the antiviral activity. Besides, we showed that PCSK9 inhibited PRRSV replication by targeting the virus receptor CD163 for degradation through the lysosome. In turn, PRRSV could down-regulate the expression of PCSK9 in both PAMs and MARC-145 cells. By screening the nonstructural proteins (nsps) of PRRSV, we showed that nsp11 could antagonize PCSK9’s antiviral activity. Furthermore, mutagenic analyses of PRRSV nsp11 revealed that the endoribonuclease activity of nsp11 was critical for antagonizing the antiviral effect of PCSK9. Collectively, our data provide further insights into the interaction between PRRSV and the cell host and offer a new potential target for the antiviral therapy of PRRSV.

Highlights

Porcine reproductive and respiratory syndrome (PRRS) has been a major disease affecting the swine industry worldwide since it was first reported in the USA in the late 1980s [1,2]
The cell hosts are responsive to viral infection and cells have been extensively studied [2], more research on host changes upon PRRS virus (PRRSV) infection is and fight viruses through a variety of anti-viral approaches
The interactions between needed, because the knowledge of these factors is essential for understanding viral infection and can PRRSV and cells have been extensively studied [2], more research on host changes upon PRRSV

Summary

Introduction

Porcine reproductive and respiratory syndrome (PRRS) has been a major disease affecting the swine industry worldwide since it was first reported in the USA in the late 1980s [1,2]. The causative agent PRRS virus (PRRSV) strains—which were isolated from two continents, Western Europe (type-1). North America (type-2)—are tremendously different, with merely 55–70% nucleotide identity [2–5]. PRRSV is an enveloped, positive-sense, single-stranded RNA virus classified in the Arteriviridae family within the Nidovirales order [6–8]. The PRRSV genome is approximate 15 kb in length and encodes. During PRRSV infection, the replicase-associated polyproteins pp1a and pp1ab encoded by the ORF1a and ORF1b are cleaved by its papain-like protease nsp (nonstructural protein 2) and 3C-like protease nsp into more than 14 nonstructural proteins [12,13]. Eight structural proteins including glycoprotein 2 (GP2), envelope protein (E), GP3, Viruses 2020, 12, 655; doi:10.3390/v12060655 www.mdpi.com/journal/viruses

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