Astrocyte-derived MMP-9 is a key mediator of pseudorabies virus penetration of the blood–brain barrier and tight junction disruption

Abstract Pseudorabies virus (PRV) infection leads to viral encephalitis and neurological damage in mice, causing significant neurological symptoms and brain damage. This study aimed to investigate the cellular mechanisms of PRV-induced encephalopathy and the role of matrix metalloproteinase-9 (MMP-9) in blood–brain barrier (BBB) disruption. We found that PRV infection increased the number of astrocytes and induced a phenotypic shift from the A2 to the A1 subtype, which was associated with increased secretion of MMP-9. MMP-9 was identified as a critical mediator of PRV-induced BBB disruption, as it degrades collagen VI, leading to BBB damage. PRV was shown to penetrate the BBB via a paracellular pathway, and MMP-9 deletion reversed this damage, mitigating tight junction injury. Additionally, PRV infection caused an “inflammatory storm” in the central nervous system (CNS), with increased levels of the chemokines CCL-3, CCL-4, and CCL-5; the cytokines IL-6 and IL-18; and TNF-α. The expression of INF-γ was significantly decreased. In conclusion, PRV infection disrupts the BBB and induces an inflammatory response in the CNS, with MMP-9 playing a key role in mediating BBB damage. These findings provide insights into the pathogenesis of PRV-induced encephalopathy and potential therapeutic targets for viral encephalitis.