Downregulation of the host ribonucleotide reductase subunit M2 via the Wnt/β-catenin pathway is a novel mechanism for duck plague virus replication and a potential antiviral target.

Duck plague virus (DPV), a highly contagious alphaherpesvirus, poses a significant threat to the global waterfowl industry. A comprehensive understanding of virus-host interactions is critical for developing effective control strategies. While DPV replication is known to depend on host cellular machinery, the mechanisms by which it manipulates host metabolism to its advantage remain poorly defined. Using RNA-seq analysis of DPV-infected duck embryo fibroblasts (DEFs), we identified a significant downregulation of genes involved in nucleotide metabolism, particularly the ribonucleotide reductase small subunit M2 (RRM2). Both in vitro and in vivo experiments confirmed that DPV infection markedly reduced RRM2 expression at the mRNA and protein levels. Mechanistically, we demonstrated that DPV suppresses RRM2 expression in a manner dependent on viral DNA replication by activating the Wnt/β-catenin signaling pathway, leading to ubiquitin-mediated degradation of RRM2. Functional studies revealed that RRM2 acts as a host restriction factor against DPV, as its overexpression inhibited viral genome replication and propagation, whereas its knockdown or inhibition with hydroxyurea (HU) promoted viral replication. In conclusion, our study unveils a novel strategy whereby DPV enhances its replication by hijacking the Wnt/β-catenin pathway to degrade the host metabolic enzyme RRM2. These findings not only deepen our understanding of DPV pathogenesis but also identify the Wnt/β-catenin-RRM2 axis as a promising target for developing novel antiviral interventions against duck plague.