Breaching the blood–brain barrier: molecular determinants, immunopathology, and translational strategies for Orthoflavivirus control

Orthoflaviviruses, including West Nile virus (WNV), Japanese encephalitis virus (JEV), and Zika virus (ZIKV), pose significant global health challenges by causing severe neuroinvasive diseases and long-term neurological sequelae. This review synthesizes the molecular mechanisms of neurotropism via comprehensive Literature search of PubMed, Springer, Google Scholar, and Scopus databases from January 2000 to May 2026, focusing on how these viruses breach the blood–brain barrier (BBB) through transcellular, paracellular, and Trojan-horse pathways. Key determinants, including envelope (E) protein motifs and nonstructural (NS) proteins (NS1, NS4B, NS5), are highlighted for their roles in mediating central nervous system (CNS) entry and immune antagonism. Once inside the CNS, orthoflaviviruses exhibit selective tropism for neurons and neural progenitor cells (NPCs), triggering complex cell-death programs including apoptosis, necroptosis, and pyroptosis. The manuscript further explores the delicate balance between protective immunity and immunopathology, where dysregulated inflammation and glia-mediated synaptic pruning contribute to lasting cognitive deficits. Addressing the lack of licensed antivirals, we provide a roadmap for translational solutions through BBB delivery and a One Health approach integrating sentinel animal surveillance with molecular research. This synthesis identifies critical knowledge gaps to inform future therapeutic and preventive strategies against neurotropic orthoflaviviruses.