Abstract
The pseudorabies virus (PRV) is a highly neurotropic zoonotic pathogen. PRV infection can lead to neuroinflammation and damage to the blood-brain barrier (BBB). Elevated matrix metalloproteinase-9 (MMP-9) expression has a detrimental impairs BBB function. However, the source of elevated MMP-9 expression and function of MMP-9 in PRV invasion of the central nervous system (CNS), and the mechanism by which PRV breaches the BBB, remain poorly understood. This study explored the role of MMP-9 in the permeation of the BBB by PRV and clarified the molecular pathways involved in PRV invasion. In PRV-infected mice, severe neurological symptoms, perivascular cuffing, and an increase in the separation of membranes at the tight junctions were observed via electron microscopy. These results indicated that PRV infection destroys the BBB. Simultaneously, we discovered that the breakdown of the BBB that occurs in viral encephalopathy induced by PRV infection was attributable to the degradation of collagen IV mediated by MMP-9. Furthermore, we determined that astrocytes contributed to the increased levels of MMP-9. Using an in vitro double-layer Transwell BBB model, we found that PRV invades the CNS through a para-cellular pathway, triggering an "inflammatory storm.” These findings highlight the pivotal role of MMP-9 in PRV penetration of the BBB, enhance our understanding of the mechanisms underlying BBB disruption caused by PRV infection, and highlight potential targets for the development of preventive and therapeutic strategies against PRV infection.