Viral Infection of the Central Nervous System and Neuroinflammation Precede Blood-Brain Barrier Disruption during Japanese Encephalitis Virus Infection
Viral Infection of the Central Nervous System and Neuroinflammation Precede Blood-Brain Barrier Disruption during Japanese Encephalitis Virus Infection
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DOI：
10.1128/jvi.00143-15
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发表时间：
2015-05-01
影响因子：
5.4
通讯作者：
Fu, Zhen F.
中科院分区：
文献类型：
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作者：
Li, Fang;Wang, Yueyun;Fu, Zhen F.
日本脑炎是由日本脑炎病毒（JEV）引起的一种急性人畜共患的蚊媒疾病。日本脑炎的特点是中枢神经系统（CNS）的广泛炎症和血脑屏障（BBB）的破坏。然而，导致血脑屏障破坏的致病机制尚不清楚。在这里，使用静脉乙脑病毒感染的小鼠模型，我们发现病毒滴度在感染后2到5天呈指数增长。这伴随着大脑中炎症细胞因子和趋化因子水平的早期急剧增加。然而，直到第4天才观察到血脑屏障通透性的增强，这表明病毒进入中枢神经系统并发生炎症发生在血脑屏障损伤之前。体外研究表明，直接感染乙脑病毒不会引起脑微血管内皮细胞单层通透性的改变。然而，来自症状性乙脑感染小鼠的脑提取物，而不是来自模拟感染小鼠的脑提取物，诱导了内皮单层的显著通透性。与炎症介质在血脑屏障破坏中的作用一致，γ干扰素中和抗体的管理改善了乙脑感染小鼠血脑屏障通透性的增强。综上所述，我们的数据表明，JEV进入中枢神经系统，在神经元中繁殖，并诱导炎症细胞因子和趋化因子的产生，从而导致血脑屏障的破坏。日本脑炎（JE）是亚洲病毒性脑炎的主要病因，每年导致70,000例病例，其中约20%至30%的病例是致命的，并且高比例的患者存活并留下严重的神经和精神后遗症。病理上，乙脑病毒感染引起急性脑病伴血脑屏障功能障碍；然而，其机制尚不清楚。因此，了解乙脑病毒感染中血脑屏障破坏的机制是重要的。我们的数据表明，JEV在血脑屏障破坏之前进入中枢神经系统。此外，并不是乙脑病毒感染本身，而是乙脑病毒感染诱导的炎症细胞因子/趋化因子抑制了TJ蛋白的表达，最终导致血脑屏障通透性增强。干扰素（ifn - γ）的中和改善了乙型脑炎感染小鼠血脑屏障通透性的增强，表明ifn - γ可能是一个潜在的治疗靶点。这项研究将有助于确定治疗乙脑病毒感染的潜在治疗途径。
Japanese encephalitis is an acute zoonotic, mosquito-borne disease caused by Japanese encephalitis virus (JEV). Japanese encephalitis is characterized by extensive inflammation in the central nervous system (CNS) and disruption of the blood-brain barrier (BBB). However, the pathogenic mechanisms contributing to the BBB disruption are not known. Here, using a mouse model of intravenous JEV infection, we show that virus titers increased exponentially in the brain from 2 to 5 days postinfection. This was accompanied by an early, dramatic increase in the level of inflammatory cytokines and chemokines in the brain. Enhancement of BBB permeability, however, was not observed until day 4, suggesting that viral entry and the onset of inflammation in the CNS occurred prior to BBB damage. In vitro studies revealed that direct infection with JEV could not induce changes in the permeability of brain microvascular endothelial cell monolayers. However, brain extracts derived from symptomatic JEV-infected mice, but not from mock-infected mice, induced significant permeability of the endothelial monolayer. Consistent with a role for inflammatory mediators in BBB disruption, the administration of gamma interferon-neutralizing antibody ameliorated the enhancement of BBB permeability in JEV-infected mice. Taken together, our data suggest that JEV enters the CNS, propagates in neurons, and induces the production of inflammatory cytokines and chemokines, which result in the disruption of the BBB.IMPORTANCEJapanese encephalitis (JE) is the leading cause of viral encephalitis in Asia, resulting in 70,000 cases each year, in which approximately 20 to 30% of cases are fatal, and a high proportion of patients survive with serious neurological and psychiatric sequelae. Pathologically, JEV infection causes an acute encephalopathy accompanied by BBB dysfunction; however, the mechanism is not clear. Thus, understanding the mechanisms of BBB disruption in JEV infection is important. Our data demonstrate that JEV gains entry into the CNS prior to BBB disruption. Furthermore, it is not JEV infection per se, but the inflammatory cytokines/chemokines induced by JEV infection that inhibit the expression of TJ proteins and ultimately result in the enhancement of BBB permeability. Neutralization of gamma interferon (IFN-gamma) ameliorated the enhancement of BBB permeability in JEV-infected mice, suggesting that IFN-gamma could be a potential therapeutic target. This study would lead to identification of potential therapeutic avenues for the treatment of JEV infection.