Comparative analysis of PRV-induced neuropathology and blood-brain barrier disruption identifies C57BL/6 as the most...

Pseudorabies virus (PRV), an emerging zoonotic alphaherpesvirus, can cause severe central nervous system (CNS) injury in non-natural hosts. Although mice are widely used for PRV neuropathogenesis studies, strain-dependent differences remain incompletely characterized. In this study, we established both intranasal and intramuscular PRV infection models in three commonly used mouse strains, KM, BALB/c, and C57BL/6, and performed comparative evaluations at early fixed post-infection timepoints as well as at moribund stages. After intranasal infection, C57BL/6 mice exhibited the highest absolute LD₅₀ value among the three strains. Consistently, C57BL/6 mice showed the earliest onset of neurological symptoms, the fastest decline in survival, and significantly higher neurological deficit scores compared with KM and BALB/c mice. Viral load measurements at both early and moribund stages revealed significantly higher PRV replication in the brains of C57BL/6 mice, accompanied by more severe histopathological lesions. Moreover, C57BL/6 mice displayed markedly greater Evans blue extravasation and more pronounced downregulation of tight-junction proteins ZO-1 and occludin, indicating more extensive blood-brain barrier (BBB) disruption. Across all strains, intranasal inoculation induced stronger CNS pathology and BBB damage compared with intramuscular injection. Collectively, these findings demonstrate that C57BL/6 mice exhibit the highest susceptibility to PRV, with more severe neuropathology and BBB impairment at both early and terminal stages. These results provide important guidance for selecting appropriate mouse models for PRV-induced CNS injury research.