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Research Progress on the NSP9 Protein of Porcine Reproductive and Respiratory Syndrome Virus.

ABSTRACT: Porcine reproductive and respiratory syndrome (PRRS) is a contagious disease caused by the porcine reproductive and respiratory syndrome virus (PRRSV). PRRS is also called "blue ear disease" because of the characteristic blue ear in infected sows and piglets. Its main clinical features are reproductive disorders of sows, breathing difficulties in piglets, and fattening in pigs, which cause considerable losses to the swine industry. NSP9, a non-structural protein of PRRSV, plays a vital role in PRRSV replication and virulence because of its RNA-dependent RNA polymerase (RdRp) structure. The NSP9 sequence is highly conserved and contains T cell epitopes, which are beneficial for the development of future vaccines. NSP9 acts as the protein interaction hub between virus and host during PRRSV infection, especially in RNA replication and transcription. Herein, we comprehensively review the application of NSP9 in terms of genetic evolution analysis, interaction with host proteins that affect virus replication, interaction with other viral proteins, pathogenicity, regulation of cellular immune response, antiviral drugs, vaccines, and detection methods. This review can therefore provide innovative ideas and strategies for PRRSV prevention and control.

SUBMITTER: Sha H

PROVIDER: S-EPMC9309524 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Research Progress on the NSP9 Protein of Porcine Reproductive and Respiratory Syndrome Virus.

Sha Huiyang H Zhang Hang H Chen Yao Y Huang Liangzong L Zhao Mengmeng M Wang Nina N

Frontiers in veterinary science 20220711

Porcine reproductive and respiratory syndrome (PRRS) is a contagious disease caused by the porcine reproductive and respiratory syndrome virus (PRRSV). PRRS is also called "blue ear disease" because of the characteristic blue ear in infected sows and piglets. Its main clinical features are reproductive disorders of sows, breathing difficulties in piglets, and fattening in pigs, which cause considerable losses to the swine industry. NSP9, a non-structural protein of PRRSV, plays a vital role in P ...[more]

PMID: 35898550

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Project description:UnlabelledPorcine reproductive and respiratory syndrome virus (PRRSV) nucleocapsid (N) protein is the main component of the viral capsid to encapsulate viral RNA, and it is also a multifunctional protein involved in the regulation of host cell processes. Nonstructural protein 9 (Nsp9) is the RNA-dependent RNA polymerase that plays a critical role in viral RNA transcription and replication. In this study, we demonstrate that PRRSV N protein is bound to Nsp9 by protein-protein interaction and that the contacting surface on Nsp9 is located in the two predicted α-helixes formed by 48 residues at the C-terminal end of the protein. Mutagenesis analyses identified E646, E608, and E611 on Nsp9 and Q85 on the N protein as the pivotal residues participating in the N-Nsp9 interaction. By overexpressing the N protein binding fragment of Nsp9 in infected Marc-145 cells, the synthesis of viral RNAs, as well as the production of infectious progeny viruses, was dramatically inhibited, suggesting that Nsp9-N protein association is involved in the process of viral RNA production. In addition, we show that PRRSV N interacts with cellular RNA helicase DHX9 and redistributes the protein into the cytoplasm. Knockdown of DHX9 increased the ratio of short subgenomic mRNAs (sgmRNAs); in contrast, DHX9 overexpression benefited the synthesis of longer sgmRNAs and the viral genomic RNA (gRNA). These results imply that DHX9 is recruited by the N protein in PRRSV infection to regulate viral RNA synthesis. We postulate that N and DHX9 may act as antiattenuation factors for the continuous elongation of nascent transcript during negative-strand RNA synthesis.ImportanceIt is unclear whether the N protein of PRRSV is involved in regulation of the viral RNA production process. In this report, we demonstrate that the N protein of the arterivirus PRRSV participates in viral RNA replication and transcription through interacting with Nsp9 and its RdRp and recruiting cellular RNA helicase to promote the production of longer viral sgmRNAs and gRNA. Our data here provide some new insights into the discontinuous to continuous extension of PRRSV RNA synthesis and also offer a new potential anti-PRRSV strategy targeting the N-Nsp9 and/or N-DHX9 interaction.

Project description:Highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) possesses greater replicative capacity and pathogenicity than classical PRRSV. However, the factors that lead to enhanced replication and pathogenicity remain unclear. In our study, an alignment of all available full-length sequences of North American-type PRRSVs (n = 204) revealed two consistent amino acid mutations that differed between HP-PRRSV and classical PRRSV and were located at positions 519 and 544 in nonstructural protein 9. Next, a series of mutant viruses with either single or double amino acid replacements were generated from HP-PRRSV HuN4 and classical PRRSV CH-1a infectious cDNA clones. Deletion of either of the amino acids led to a complete loss of virus viability. In both Marc-145 and porcine alveolar macrophages, the replicative efficiencies of mutant viruses based on HuN4 were reduced compared to the parent, whereas the replication level of CH-1a-derived mutant viruses was increased. Plaque growth assays showed clear differences between mutant and parental viruses. In infected piglets, the pathogenicity of HuN4-derived mutant viruses, assessed through clinical symptoms, viral load in sera, histopathology examination, and thymus atrophy, was reduced. Our results indicate that the amino acids at positions 519 and 544 in NSP9 are involved in the replication efficiency of HP-PRRSV and contribute to enhanced pathogenicity. This study is the first to identify specific amino acids involved in PRRSV replication or pathogenicity. These findings will contribute to understanding the molecular mechanisms of PRRSV replication and pathogenicity, leading to better therapeutic and prognostic options to combat the virus.IMPORTANCE Porcine reproductive and respiratory syndrome (PRRS), caused by porcine reproductive and respiratory syndrome virus (PRRSV), is a significant threat to the global pig industry. Highly pathogenic PRRSV (HP-PRRSV) first emerged in China in 2006 and has subsequently spread across Asia, causing considerable damage to local economies. HP-PRRSV strains possess a greater replication capacity and higher pathogenicity than classical PRRSV strains, although the mechanisms that underlie these characteristics are unclear. In the present study, we identified two mutations in HP-PRRSV strains that distinguish them from classical PRRSV strains. Further experiments that swapped the two mutations in an HP-PRRSV strain and a classical PRRSV strain demonstrated that they are involved in the replication efficiency of the virus and its virulence. Our findings have important implications for understanding the molecular mechanisms of PRRSV replication and pathogenicity and also provide new avenues of research for the study of other viruses.

Dataset Information

Research Progress on the NSP9 Protein of Porcine Reproductive and Respiratory Syndrome Virus.

Publications

Research Progress on the NSP9 Protein of Porcine Reproductive and Respiratory Syndrome Virus.

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