Time-Resolved Mapping in Calves Reveals BoHV-1 Shift From Mucosal Replication to Trigeminal Neuroinvasion and IFN-α-bPML Antagonism

Bovine herpesvirus 1 (BoHV-1) causes huge cattle losses, yet the transition from mucosal replication to neuroinvasion is poorly resolved. Using a controlled calf model, we integrated quantitative virology and transcriptomics to map pathogenesis and define the role of promyelocytic leukemia protein (PML). Calves inoculated intranasally/ocularly (1.4×10^6 pfu/head) were sampled daily (1-14 dpi) for gB-qPCR; tissues at 4 and 14 dpi were analyzed for viral DNA and trigeminal ganglia (TG) mRNA-seq. Shedding peaked at 3-6 dpi (nasal > ocular >> rectal) and declined by 10-14 dpi. Tonsils bore the highest burden at 4 dpi; TG was low-positive at 4 dpi but remained positive at 14 dpi, indicating neuroinvasion. TG programs shifted from early proteostasis priming (4 dpi) to immune/ECM activation with synaptic repression (14 dpi). In MDBK/Vero cells, IFN-α increased bovine PML (bPML) and enlarged PML nuclear bodies (PML-NBs), reducing very-early viral DNA, whereas BoHV-1 disrupted PML-NB integrity. bPML isoforms diverged (bPML1/6 pro-viral; bPML3/4/5 antiviral). Cross-species STRING mapped a conserved PML-SUMO1-UBE2I-DAXX-SP100 core. These data delineate the mucosal-to-neuronal trajectory, establish PML as both effector and viral target, and nominate SUMO/ubiquitin-linked proteostasis as a tractable antiviral leverage point.