Marek's disease virus hijacks host nucleotide metabolism via UL23-mediated c-Myc activation

Marek's disease virus (MDV), an avian α-herpesvirus, heavily relies on host metabolic reprogramming during infection. However, the precise regulatory mechanisms governing MDV-induced nucleotide metabolic remodeling remain poorly characterized. The study explores how MDV induces changes in nucleotide metabolism during infection. Our results demonstrated that MDV infection significantly upregulates nucleotide synthesis metabolism, particularly purine de novo synthesis in chicken embryonic fibroblast (CEF) cells. Metabolomic analysis identified 19 upregulated metabolites related to nucleotide metabolism post-infection. Functional assays revealed that adenine and guanine supplementation enhanced MDV replication, while the purine inhibitor 6-mercaptopurine (6MP) suppressed it. The transcription factor c-Myc was found to activate purine synthesis enzymes during MDV infection, with c-Myc knocked down reducing viral replication and overexpression increasing it. Additionally, MDV thymidine kinase UL23 was identified as crucial in reprogramming nucleotide metabolism, promoting c-Myc-mediated nucleotide anabolism and viral replication. This research highlights the potential of targeting nucleotide metabolism as an antiviral strategy.