Deciphering pUL10's mastery in duck plague virus virulence: dual coordination of host immunity and viral replication.

Interferon (IFN) critically regulates antiviral immunity, wherein its production level determines disease progression, many viruses disrupt these defenses through mechanisms that remain incompletely understood. This study investigates the effect of duck plague virus (DPV) infection on immune organs and elucidates the molecular mechanism by which its UL10 protein (pUL10) inhibits melanoma differentiation-associated protein 5 (MDA5)-mediated IFN-β production. DPV UL10 gene encodes pUL10, a virulence-associated protein critical for viral pathogenicity. The conserved cysteine residue C54 serves as a key functional site required for pathogenicity. Compared with the wild-type DPV (DPV-CHv50), both pUL10-deficiency virus (DPV-UL10) and pUL10 C54-mutation virus (DPV-UL10) exhibited attenuated viral replication efficiency. Their viral loads in immune organs of viral inoculated ducklings, and virulence were also significantly reduced. In addition, the mechanism underlying the attenuated virulence of DPV-UL10 and DPV-UL10 compared with DPV-CHv50 from the host immune response perspective was clarified. The results showed that pUL10 interacts with MDA5, accelerating the degradation of the latter via the autophagosome-lysosome pathway, thereby reducing MDA5-mediated IFN-β promoter activation and IFN-β production. Interestingly, similar antagonistic function was observed in pseudorabies virus glycoprotein M. Moreover, mutation of pUL10 C54 resulted in a weakened inhibitory effect of pUL10 and pUL49.5 co-expression on IFN-β in duck embryo fibroblasts, which was closer to what was observed in DPV-UL10-infected ducklings. In summary, our findings indicated that pUL10 inhibited MDA5 production and facilitated DPV-mediated inhibition of IFN-β, thus promoting DPV replication in the host. This study provided novel insights into DPV pathogenesis and fills a gap in understanding the immune evasion mechanisms of pUL10 homologs.