From Systemic Infection to Central Nervous System Pathology: Virus-Induced Neuroinflammatory Cascades and Blood–Brain Barrier Disruption

Background: Viral infections are recognized triggers of neurological disease through immune-mediated mechanisms that induce acute and chronic neuroinflammation. Although the central nervous system (CNS) is protected by the blood–brain barrier (BBB), several pathogens can access the CNS through mechanisms including leukocyte-mediated “Trojan Horse” entry, endothelial transcytosis, and neuronal transport. Neuropathology frequently seems to be primarily caused by dysregulated host immune responses that activate glial cells and compromise the integrity of the blood–brain barrier. Main Body: This mini-review summarizes current evidence linking BBB dysfunction to sustained neuroinflammatory cascades, emphasizing microglia–astrocyte interactions and downstream neuronal injury, including synaptic dysfunction and neurodegenerative changes. Using Epstein–Barr virus (EBV), human immunodeficiency virus (HIV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as representative examples, we discuss mechanisms of CNS entry, BBB disruption, microglial activation, astrocyte dysfunction, and excitotoxic neuronal injury. We further examine factors governing the transition from protective immune responses to persistent neuroinflammation, including viral latency, chronic immune activation, and microglial priming. Finally, we highlight recent advances in systems biology and systems bioinformatics that enable integration of multi-omics and network-level data to identify conserved pathways underlying virus-associated neurological disease and post-viral syndromes. Conclusions: BBB disruption represents a critical interface linking viral infection to CNS pathology. Convergent inflammatory mechanisms involving glial activation and impaired neurological and immune regulation contribute to persistent neurological dysfunction across diverse viral infections. Integrative systems-level approaches can assist in investigating these mechanisms, while they may also facilitate the identification of biomarkers and therapeutic targets capable of distinguishing resolving from persistent neuroinflammatory states.