{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T14:05:42Z","timestamp":1790172342345,"version":"4.1.0"},"reference-count":92,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T00:00:00Z","timestamp":1790121600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Vet. Sci."],"abstract":"<jats:p>Central nervous system (CNS) pathogenesis remains a critical but incompletely resolved aspect of flavivirus infection. Neurotropic flaviviruses usually initiate replication in peripheral tissues but can subsequently access the CNS, causing encephalitis, neurological dysfunction, or developmental abnormalities. Because these events occur along a continuum from peripheral infection to CNS injury, their temporal and mechanistic relationships are often difficult to define. In many studies, brain viral detection, blood\u2013brain barrier (BBB) dysfunction, neuroinflammation, and neurological signs are reported together, although they represent different steps in disease progression. Studies of Japanese encephalitis virus, West Nile virus, Zika virus, dengue virus, and tick-borne encephalitis virus show that BBB dysfunction is an important component of flavivirus-associated neurological disease, but no single conserved mechanism applies across flaviviruses. Endothelial activation, cytokine and chemokine signaling, tight junction remodeling, matrix metalloproteinase activity, leukocyte trafficking, glial inflammatory amplification, and viral genetic variation can each shape barrier-related phenotypes, with distinct timing and relative importance depending on virus species and experimental context. Tembusu virus (TMUV) is an evolving avian flavivirus responsible for widespread waterfowl outbreaks, with ongoing genetic diversification and an expanding recognized host and vector range. Increasing evidence of neurological signs, brain lesions, and viral detection in neural tissues indicates that CNS-associated pathogenicity is an important feature of TMUV infection. However, the routes of TMUV CNS entry, the temporal relationship between BBB dysfunction and early brain infection, the viral genetic basis of strain-dependent neurological phenotypes, and the contribution of host inflammation to BBB injury remain unclear. Here, we review current advances in flavivirus-associated BBB dysfunction and use comparative flavivirus evidence to guide a stage-specific interpretation of TMUV neuroinvasion and neuropathogenesis. We argue that TMUV-associated neurological disease should be interpreted along a peripheral-to-CNS sequence that separates CNS access, BBB dysfunction, post-entry brain replication, neuroinflammatory amplification, and clinical disease. By linking CNS-associated phenotypes to defined disease steps, this approach may help explain the emergence of TMUV strains with enhanced neurological pathogenicity and provide a clearer basis for evaluating attenuation and vaccine safety.<\/jats:p>","DOI":"10.3389\/fvets.2026.1939599","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T13:28:16Z","timestamp":1790170096000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Tembusu virus neuroinvasion and neuropathogenesis: lessons from blood\u2013brain barrier dysfunction in neurotropic flaviviruses"],"prefix":"10.3389","volume":"13","author":[{"given":"Zheng","family":"Ni","sequence":"first","affiliation":[{"name":"Institute of Animal Husbandry and Veterinary Science, Zhejiang Academy of Agricultural Sciences","place":["Hangzhou, 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