Enhancement of Blood-Brain Barrier Permeability and Reduction of Tight Junction Protein Expression Are Modulated by Chemokines/Cytokines Induced by Rabies Virus Infection
Enhancement of Blood-Brain Barrier Permeability and Reduction of Tight Junction Protein Expression Are Modulated by Chemokines/Cytokines Induced by Rabies Virus Infection
复制标题
DOI：
10.1128/jvi.03149-13
复制
发表时间：
2014-05-01
影响因子：
5.4
通讯作者：
Fu, Zhen F.
中科院分区：
文献类型：
--
作者：
Chai, Qingqing;He, Wen Q.;Fu, Zhen F.
实验室减毒狂犬病病毒（RABV）感染可增强血脑屏障（BBB）的通透性，这已被证明是宿主存活的重要因素，因为它允许免疫效应物进入中枢神经系统（CNS）并清除RABV。为了探索RABV感染增强BBB通透性的机制，研究了颅内接种实验室减毒或野生型（wt）RABV后CNS中紧密连接（TJ）蛋白的表达。BBB通透性显着增强实验室减毒，但不是野生型，RABV感染的小鼠。TJ蛋白（claudin-5，occludin和zonula occludens-1）的表达水平在实验室减毒的RABV感染的小鼠中降低，但不是野生型RABV，这表明BBB通透性的增强与RABV感染中TJ蛋白表达的降低有关。RABV既不感染脑微血管内皮细胞（BMEC），也不调节BMEC中TJ蛋白的表达。然而，从实验室减毒的，但不是野生型，RABV感染的小鼠脑提取物减少TJ蛋白表达BMEC。结果发现，从实验室减毒的RABV感染的小鼠的脑提取物中含有显着更高水平的炎性趋化因子/细胞因子比感染野生型RABV的小鼠。通路分析表明，γ干扰素（IFN-γ）位于中心的细胞因子网络中的RABV感染的小鼠脑，和IFN-γ的中和减少破坏BBB通透性在体内和TJ蛋白表达在体外的下调。这些发现表明，BBB通透性的增强和TJ蛋白表达的减少不是由于RABV感染本身，而是由于病毒诱导的炎性趋化因子/细胞因子。
Infection with laboratory-attenuated rabies virus (RABV) enhances blood-brain barrier (BBB) permeability, which has been demonstrated to be an important factor for host survival, since it allows immune effectors to enter the central nervous system (CNS) and clear RABV. To probe the mechanism by which RABV infection enhances BBB permeability, the expression of tight junction (TJ) proteins in the CNS was investigated following intracranial inoculation with laboratory-attenuated or wild-type (wt) RABV. BBB permeability was significantly enhanced in mice infected with laboratory-attenuated, but not wt, RABV. The expression levels of TJ proteins (claudin-5, occludin, and zonula occludens-1) were decreased in mice infected with laboratory-attenuated, but not wt, RABV, suggesting that enhancement of BBB permeability is associated with the reduction of TJ protein expression in RABV infection. RABV neither infects the brain microvascular endothelial cells (BMECs) nor modulates the expression of TJ proteins in BMECs. However, brain extracts prepared from mice infected with laboratory-attenuated, but not wt, RABV reduced TJ protein expression in BMECs. It was found that brain extracts from mice infected with laboratory-attenuated RABV contained significantly higher levels of inflammatory chemokines/cytokines than those from mice infected with wt RABV. Pathway analysis indicates that gamma interferon (IFN-gamma) is located in the center of the cytokine network in the RABV-infected mouse brain, and neutralization of IFN-gamma reduced both the disruption of BBB permeability in vivo and the downregulation of TJ protein expression in vitro. These findings indicate that the enhancement of BBB permeability and the reduction of TJ protein expression are due not to RABV infection per se but to virus-induced inflammatory chemokines/cytokines.