Hongxia Wu,Hansong Qi,Bing Wang,Mingzhi Li,Liang Qu,Su Li,Yuzi Luo,Lian-Feng Li,Guang-Lai Zheng,Hua-Ji Qiu,Yuan Sun

J Biol Chem.2023 Oct 12:105347.doi: 10.1016/j.jbc.2023.105347. Online ahead of print.

Abstract

The pseudorabies virus (PRV) TJ strain, a variant of PRV, induces more severe neurological symptoms and higher mortality in piglets and mice compared to the PRV SC strain isolated in 1980. However, the mechanism underlying responsible for the discrepancy in virulence between these strains remains unclear. Our study investigated the differences in neurotropism between PRV TJ and PRV SC using both in vitro and in vivo models. We discovered that PRV TJ enters neural cells more efficiently than PRV SC. Furthermore, we found that PRV TJ has indistinguishable genomic DNA replication capability and axonal retrograde transport dynamics compared to the PRV SC. To gain deeper insights into the mechanisms underlying these differences, we constructed gene-interchanged chimeric virus constructs and assessed the affinity between envelope glycoprotein B (gB), C (gC), and D (gD), and corresponding receptors. Our findings confirmed that mutations in these envelope proteins, particularly gD, significantly contributed to the heightened attachment and penetration capabilities of PRV TJ. Our study revealed the critical importance of the gD^ΔR278/P279 and gD^V338A in facilitating viral invasion. Furthermore, our observations indicated that mutations in envelope proteins have a more significant impact on viral invasion than on virulence in the mouse model. Our findings provide valuable insights into the roles of natural mutations on the PRV envelope glycoproteins in cell tropism, which sheds light on the relationship between cell tropism and clinical symptoms and offers clues about viral evolution.

Keywords: envelope protein; neurotropism; pseudorabies virus; variant strain; virulence.