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，如BDV特异性的Th1耐受，可能有助于诱导脑内的持久性，但CNS病毒有效控制免疫反应的机制尚未完全阐明。在这项研究中，为了了解嗜神经性病毒逃避宿主反应的策略，我们研究了高级裂解终末产物受体(RAGE)在BDV感染的大脑中的作用，RAGE参与了免疫系统的反应途径。新生或4周龄的Lewis大鼠脑内接种BDV。为探讨RAGE在中枢神经系统病毒感染中的作用，通过病毒增殖追踪RAGE及其配体的表达水平。我们发现，在BDV感染的脑中，RAGE的表达逐渐减少，这与病毒的传播有关，尽管强大的RAGE配体，如HMGB1和S100B上调了。有趣的是，BDV持续期的大脑没有表现出RAGE表达的重新激活，即使注射了几种抗原，对炎症反应的诱导也减少了反应。在实验性自身免疫性脑脊髓炎中，持续感染的大鼠仅导致小脑轻微炎症。我们证明了持续感染BDV的大脑中RAGE表达的下调。最近的报道显示，RAGE参与了宿主的免疫反应，其表达可能是维持先天性免疫反应所必需的。我们的观察表明，BDV感染可以通过调节脑内RAGE的表达而逃脱炎症反应，导致持续感染的发生。

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.