Characterization of a recombinant gC-deleted PRV-XJ variant reveals altered disease outcomes following different inoculation routes in mice

Pseudorabies virus (PRV) variants continue to threaten swine production and can cause severe neurological disease in non-natural hosts. Although glycoprotein C (gC) contributes to PRV attachment to host cells, its role in the pathogenic characteristics of currently circulating PRV variants remains unclear, particularly under different inoculation routes. In this study, we generated a marker-free gC-deleted recombinant virus, rPRV-XJ-ΔgC, based on the genotype II PRV-XJ variant and compared its pathogenic characteristics with those of parental PRV-XJ in C57BL/6 mice. rPRV-XJ-ΔgC retained the ability to cause lethal infection but, compared with PRV-XJ, showed delayed disease progression, reduced early central nervous system (CNS) viral accumulation, and milder neurological and neuropathological changes, particularly following intranasal inoculation. These differences were less evident after intramuscular inoculation. Intranasal infection with rPRV-XJ-ΔgC was also associated with attenuated disruption of the blood–brain barrier, consistent with reduced CNS injury. Collectively, these findings indicate that gC deletion in the PRV-XJ background is associated with altered infection kinetics and route-dependent CNS disease phenotypes. IMPORTANCE Pseudorabies virus (PRV) variants remain important pathogens associated with neurological disease, but the contribution of individual viral genes to the pathogenic characteristics of circulating PRV variants remains poorly understood. Here, we investigated the role of glycoprotein C (gC) in the pathogenic phenotype of the genotype II PRV-XJ variant. gC deletion resulted in route-dependent changes in PRV-XJ-induced disease outcomes, with more evident effects following intranasal than intramuscular inoculation. These findings highlight the importance of viral genetic factors and infection routes in shaping PRV-associated disease phenotypes and provide further insight into PRV neuropathogenesis.