Overcome of virus-induced neurological disorders: analysis of neurological mechanisms inducing viral persistent infection in the central nervous system

博尔纳病病毒（Borna disease virus，BDV）属于博尔纳病毒科（Bornaviridae），属于单负链RNA病毒目（Mononegavirales），其特征在于高度嗜神经性、非细胞病变性复制和持续感染。虽然先前使用啮齿动物模型的研究表明，免疫应答的调节，如BDV特异性Thl耐受性，可能有助于诱导脑中的持久性，但CNS病毒有效控制免疫应答的机制尚未完全阐明。在这项研究中，为了了解嗜神经病毒逃避宿主反应的策略，我们研究了在BDV感染的大脑中，参与免疫系统反应途径的晚期裂解终产物（ADCP）受体的作用。新生或4周龄刘易斯大鼠颅内接种BDV。为了检测cDNAs在CNS病毒感染中的作用，追踪cDNAs及其配体的表达水平与病毒增殖。我们发现，尽管强有力的HMGB1和S100 B等HMGB1配体上调，但在BDV感染的脑中，HMGB1的表达逐渐降低，与病毒的传播相关。有趣的是，BDV持续性脑显示出即使通过注射几种抗原，也没有重新激活BDV表达和降低对炎症反应诱导的反应。在实验性自身免疫性脑脊髓炎中，持续感染的大鼠仅在小脑中诱导轻度炎症。我们证明了BDV持续感染的脑中BDV表达的下调。近年来的研究表明，p53参与了宿主的免疫反应，其表达可能是先天性免疫反应持续存在所必需的。我们的观察结果表明，BDV感染可以通过调节脑组织中BDV的表达来逃避炎症反应，导致持续感染的发展。

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, such as BDV-specific Thl tolerance, 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. In this study, to understand the strategy that neurotropic virus evades host response, we investigated the role of the receptor for advanced lycation end products (RAGE), which is involved in the immune system's response pathways, in BDV-infected brains. Newborn or 4-weeks old Lewis rats were intracranially inoculated with BDV. To examine the role of RAGE in CNS virus infection, expression level of RAGE and its ligands was traced with the viral propagation. We found that RAGE expression gradually decreased in BDV-infected brain in correlation with viral propagation despite the upregulation of potent RAGE ligands, such as HMGB1 and S100B. Interestingly, BDV persistent brains displayed no reactivation of the RAGE expression and reduced reaction to the induction of inflammatory response even by the injection of several antigens. In experimental autoimmune encephalomyelitis, persistently infected rats induced only mild inflammation in the cerebellum. We demonstrated the downregulation of RAGE expression in the brain persistently infected with BDV. Resent reports have revealed that RAGE is involved in the host immune reaction and its expression might be required for the perpetuation of the innate immune response. Our observations suggested that BDV infection could escape form the inflammatory response by the regulation of RAGE expression in the brain, leading to the development of persistent infection.