Schweitzer Felix, Schröder Lara-Jasmin, Friedrichs Alina, Gudi Viktoria, Skripuletz Thomas, Steffen Imke, Palus Martin, Růžek Daniel, Osterhaus Albert, Prajeeth Chittappen Kandiyil
Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine, Hannover, Germany.
Center for Systems Neuroscience (ZSN), Hannover, Germany.
Front Cell Infect Microbiol. 2025 Jul 2;15:1624636. doi: 10.3389/fcimb.2025.1624636. eCollection 2025.
The genus of the family includes several notable pathogens such as mosquito-borne West-Nile virus (, WNV) and Tick-borne encephalitis virus (, TBEV) that are highly neurotropic and may cause severe neurological disease leading to lifelong disabilities, coma and death. These viruses have developed mechanisms to breach the compact blood-brain barrier (BBB) and establish infection within the central nervous system (CNS). Nevertheless, neuroinvasive mechanisms of orthoflaviviruses remain poorly understood. Complex anatomy of the CNS and the organization of the BBB is a major challenge to study neuroinvasion of orthoflaviviruses . Therefore, BBB models are useful tools to study direct interaction of viruses with the endothelial barrier.
In this study, we employed an transwell BBB model comprising primary mouse brain microvascular endothelial cells and astrocytes to compare the ability of mosquito-borne and tick-borne orthoflaviviruses to cross a compact endothelial barrier and reach the basolateral compartment of the transwell system. The influence of virus inoculation on the barrier properties was determined by measuring transendothelial electrical resistance (TEER).
The results demonstrate that while pathogenic WNV and TBEV cross the endothelial barrier the ability of low pathogenic Usutu virus (USUV) and Langat virus (LGTV) was inconsistent. All viruses tested display virus replication within the endothelial cells. Nevertheless, virus replication did not affect the barrier function of endothelial cells as demonstrated by sustained TEER and absence of leakage of high molecular weight dextran molecules through the endothelial barrier even at several hours post infection.
Our findings indicate that orthoflaviviruses can infect the endothelial cells, replicate within them without affecting the cells and its barrier function. Nevertheless, only pathogenic WNV and TBEV showed the ability to cross the endothelial barrier and reach the basolateral compartment.
该病毒科的属包括几种著名的病原体，如蚊媒传播的西尼罗河病毒（WNV）和蜱媒传播的脑炎病毒（TBEV），它们具有高度嗜神经性，可能导致严重的神经疾病，进而导致终身残疾、昏迷甚至死亡。这些病毒已经形成了突破紧密血脑屏障（BBB）并在中枢神经系统（CNS）内建立感染的机制。然而，正黄病毒的神经侵袭机制仍知之甚少。中枢神经系统复杂的解剖结构和血脑屏障的组织是研究正黄病毒神经侵袭的主要挑战。因此，血脑屏障模型是研究病毒与内皮屏障直接相互作用的有用工具。
在本研究中，我们采用了一种由原代小鼠脑微血管内皮细胞和星形胶质细胞组成的转孔血脑屏障模型，以比较蚊媒传播和蜱媒传播的正黄病毒穿过紧密内皮屏障并到达转孔系统基底外侧隔室的能力。通过测量跨内皮电阻（TEER）来确定病毒接种对屏障特性的影响。
结果表明，致病性WNV和TBEV能够穿过内皮屏障，而低致病性的乌苏图病毒（USUV）和兰加特病毒（LGTV）的能力则不一致。所有测试病毒在内皮细胞内均显示病毒复制。然而，病毒复制并未影响内皮细胞的屏障功能，即使在感染后数小时，TEER仍保持稳定，且高分子量葡聚糖分子未通过内皮屏障泄漏。
我们的研究结果表明，正黄病毒可以感染内皮细胞，并在其中复制而不影响细胞及其屏障功能。然而，只有致病性WNV和TBEV显示出穿过内皮屏障并到达基底外侧隔室的能力。
Zotero 插件
