PRV-delgE/gI/TK immunization preserves blood-brain barrier integrity and limits CNS injury following intracerebral PRV challenge.

Pseudorabies virus (PRV) causes rapidly progressive and often fatal encephalitis in both natural and non-natural hosts, making the development of effective preventive strategies critically important. Among current vaccine candidates, the triple-gene-deleted PRV strain (PRV-delgE/gI/TK) has been widely studied; however, its protective effects against brain injury, particularly blood-brain barrier (BBB) damage, remain poorly characterized. To address this gap, we established an intracerebral challenge model in C57BL/6J mice to directly evaluate central nervous system (CNS) outcomes following wild-type PRV infection. Wild-type PRV challenge resulted in severe neurological deficits, uniform mortality, extensive neuronal degeneration, pronounced BBB disruption, downregulation of tight junction proteins, strong induction of MMP-2/9, and a robust inflammatory cytokine surge. In contrast, mice immunized with PRV-delgE/gI/TK exhibited only mild and transient symptoms, rapid functional recovery, markedly reduced viral replication, and complete viral clearance by 14 days. Immunization preserved BBB integrity, maintained ZO-1 and occludin expression, prevented MMP activation, and substantially blunted neuroinflammatory responses. Collectively, these results show that PRV-delgE/gI/TK immunization effectively protects against wild-type PRV-induced CNS injury in C57BL/6J mice, as evidenced by reduced viral burden, preserved BBB integrity, and attenuated neuroinflammatory responses, and provide new insight into the neuroprotective effects of attenuated PRV vaccination.IMPORTANCEPseudorabies virus (PRV) can cause severe and often fatal encephalitis, but the central nervous system (CNS)-protective effects of attenuated PRV vaccines remain insufficiently characterized, particularly with respect to blood-brain barrier (BBB) injury. Using a C57BL/6J intracerebral challenge model, this study shows that immunization with the triple-gene-deleted PRV-delgE/gI/TK strain markedly reduces viral replication, preserves BBB integrity, and attenuates neuroinflammatory responses after wild-type PRV challenge. These findings provide in vivo evidence that attenuated PRV immunization can protect against PRV-induced CNS injury and offer important insights for improving prevention strategies against neurotropic PRV infection.