Li Fang, Wang Yueyun, Yu Lan, Cao Shengbo, Wang Ke, Yuan Jiaolong, Wang Chong, Wang Kunlun, Cui Min, Fu Zhen F
State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, People's Republic of China.
State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, People's Republic of China
J Virol. 2015 May;89(10):5602-14. doi: 10.1128/JVI.00143-15. Epub 2015 Mar 11.
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.
Japanese 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-γ) ameliorated the enhancement of BBB permeability in JEV-infected mice, suggesting that IFN-γ could be a potential therapeutic target. This study would lead to identification of potential therapeutic avenues for the treatment of JEV infection.
日本脑炎是一种由日本脑炎病毒（JEV）引起的急性人畜共患、蚊媒传播疾病。日本脑炎的特征是中枢神经系统（CNS）广泛炎症和血脑屏障（BBB）破坏。然而，导致血脑屏障破坏的致病机制尚不清楚。在此，我们使用静脉注射JEV感染的小鼠模型，发现感染后2至5天，病毒滴度在脑中呈指数级增加。与此同时，脑中炎症细胞因子和趋化因子水平早期急剧升高。然而，直到第4天才观察到血脑屏障通透性增强，这表明病毒进入中枢神经系统以及中枢神经系统炎症的发生早于血脑屏障损伤。体外研究表明，直接感染JEV不会诱导脑微血管内皮细胞单层通透性发生变化。然而，有症状的JEV感染小鼠的脑提取物（而非假感染小鼠的脑提取物）可诱导内皮单层显著通透。与炎症介质在血脑屏障破坏中的作用一致，给予γ干扰素中和抗体可改善JEV感染小鼠血脑屏障通透性增强的情况。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产生，进而导致血脑屏障破坏。
日本脑炎（JE）是亚洲病毒性脑炎的主要病因，每年导致70000例病例，其中约20%至30%的病例死亡，且很大一部分患者存活下来后伴有严重的神经和精神后遗症。病理上，JEV感染导致急性脑病并伴有血脑屏障功能障碍；然而，其机制尚不清楚。因此，了解JEV感染中血脑屏障破坏的机制很重要。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，并非JEV感染本身，而是JEV感染诱导的炎症细胞因子/趋化因子抑制紧密连接蛋白的表达，最终导致血脑屏障通透性增强。中和γ干扰素（IFN-γ）可改善JEV感染小鼠血脑屏障通透性增强的情况，这表明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JEV感染的潜在治疗途径。
