Schweitzer Felix, Letoha Tamás, Osterhaus Albert, Prajeeth Chittappen Kandiyil
Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine, 30559 Hannover, Germany.
Center for Systems Neuroscience (ZSN), 30559 Hannover, Germany.
Int J Mol Sci. 2025 Mar 6;26(5):2342. doi: 10.3390/ijms26052342.
Tick-borne encephalitis remains a significant burden on human health in the endemic areas in Central Europe and Eastern Asia. The causative agent, tick-borne encephalitis virus (TBEV), is a neurotropic virus belonging to the genus of . After TBEV enters the central nervous system (CNS), it mainly targets neurons, causing encephalitis and leading to life-long disabilities, coma and, in rare cases, death. The neuroinvasive mechanisms of orthoflaviviruses are poorly understood. Here we investigate the mechanism of TBEV neuroinvasion, hypothesizing that TBEV influences blood-brain barrier (BBB) properties and uses transcellular routes to cross the endothelial barrier and enter the CNS. To test this hypothesis, we employed an in vitro transwell system consisting of endothelial cell monolayers cultured on insert membranes and studied the barrier properties following inoculation to tick-borne orthoflaviviruses. It was shown that TBEV and closely related but naturally attenuated Langat virus (LGTV) crossed the intact endothelial cell monolayer without altering its barrier properties. Interestingly, transendothelial migration of TBEV was significantly affected when two cellular surface antigens, the laminin-binding protein and vimentin, were blocked with specific antibodies. Taken together, these results indicate that orthoflaviviruses use non-destructive transcellular routes through endothelial cells to establish infection within the CNS.
蜱传脑炎在中欧和东亚的流行地区仍然是人类健康的重大负担。病原体蜱传脑炎病毒（TBEV）是一种嗜神经病毒，属于……属。TBEV进入中枢神经系统（CNS）后，主要靶向神经元，引发脑炎并导致终身残疾、昏迷，在极少数情况下会导致死亡。黄病毒科病毒的神经侵袭机制尚不清楚。在此，我们研究TBEV神经侵袭的机制，假设TBEV影响血脑屏障（BBB）特性，并利用跨细胞途径穿过内皮屏障进入中枢神经系统。为了验证这一假设，我们采用了一种体外Transwell系统，该系统由培养在插入膜上的内皮细胞单层组成，并研究接种蜱传黄病毒科病毒后的屏障特性。结果表明，TBEV和密切相关但自然减毒的兰加特病毒（LGTV）穿过完整的内皮细胞单层，而不改变其屏障特性。有趣的是，当两种细胞表面抗原，即层粘连蛋白结合蛋白和波形蛋白，用特异性抗体阻断时，TBEV的跨内皮迁移受到显著影响。综上所述，这些结果表明黄病毒科病毒通过内皮细胞利用非破坏性的跨细胞途径在中枢神经系统内建立感染。
