Overcome of virus-induced neurological disorders : a novel strategy based on the functions of a pattern recognition receptor, RAGE

博尔纳病病毒(Borna Disease Virus，BDV)属博尔纳病毒科，属非节段性负链RNA病毒Mononegavirales，具有高度嗜神经性、非细胞病理性复制和持续感染等特点。虽然先前使用啮齿动物模型的研究表明，免疫反应的调节有助于诱导脑内的持久性，但中枢神经系统病毒有效控制免疫反应的机制尚未完全阐明。此外，神经胶质反应对病毒在中枢神经系统中的持久性和免疫调节作用知之甚少。在这项研究中，我们研究了模式识别受体RAGE(高级糖基化终产物受体)和星形胶质细胞衍生因子S100B在持续感染BDV的Lewis大鼠大脑中的作用。RAGE参与免疫系统的反应途径。S100B在促进血管炎症反应…中的重要作用通过与愤怒的互动产生更多的焦虑。我们发现，在BDV感染的大脑中，S100B的表达显著减少，尽管严重的星形细胞增多，胶质纤维酸性蛋白免疫反应增强。有趣的是，在持续感染的大脑中，即使在包括内毒素在内的几种炎症刺激下，也没有观察到S100B或RAGE的表达上调。此外，在用髓鞘碱性蛋白免疫诱导实验性自身免疫性脑脊髓炎的持续感染的脑中，血管细胞黏附分子VCAM-1的表达以及脑源性T细胞的渗透显著减少。此外，我们还证明，S1008在脑内的持续激活可能是新生感染大鼠脑血管免疫反应进展所必需的。我们的结果提示，BDV感染可能通过下调S100B的表达而损害星形胶质细胞的功能，导致持续感染。较少

Borna disease virus (BDV) belongs to the Bornaviridae family, within the nonsegmented negative-strand RNA virus, Mononegavirales, which is characterized by highly neurotropic, noncytopathic replication, and persistent infection. Although previous studies using rodent models indicated that modulation of the immune response could contribute to the induction of persistence in the brain, the mechanisms by which CNS viruses efficiently control immune response have not been yet fully elucidated. Furthermore, little is known about the glial reactions contributing to the viral persistence and immune modulation in the CNS. In this study, we investigated the role of a pattern recognition receptor, RAGE (receptor for advanced glycation end products), which is involved in the immune system's response pathways, as well as an astrocyte-derived factor, S100B, in the brains of Lewis rats persistently infected with BDV. A prominent role of S100B appears to be the promotion of vascular inflammatory resp … More onses through interaction with the RAGE. We demonstrated that the expression of S100B is significantly reduced in BDV-infected brains despite severe astrocytosis with increased glial fibrillary acidic protein immunoreactivity. Interestingly, no upregulation of the expression of S100B, or RAGE, was observed in the persistently infected brains even on incitation with several inflammatory stimuli, including lipopolysaccharide. In addition, the expression of the vascular cell adhesion molecule, VCAM-1, as well as the infiltration of encephalitogenic T-cells, was significantly reduced in persistently infected brains in which an experimental autoimmune encephalomyelitis was induced by immunization with myelin-basic protein. Furthermore, we demonstrated that the continuous activation of S1008 in the brain may be necessary for the progression of vascular immune responses in neonatally infected rat brains. Our results suggested that BDV infection may impair astrocyte functions via a downregulation of S100B expression, leading to the maintenance of a persistent infection. Less