Studies on the heterogeneity in the correlation between Borna disease virus location in the central nervous system(CNS) and induced CNS pathogenesis

博尔纳病病毒（Borna disease virus，BDV）是一种高度嗜神经性的负链RNA病毒，是引起马和羊博尔纳病、脑炎的病原。BDV在人类中的感染，特别是在一些精神疾病患者中，有报道。事实上，在来自BDV血清阳性患者的一些尸检大脑中鉴定出了BDV信号。本研究的目的是从体内外水平和分子水平分析BDV的毒力，以阐明BDV在中枢神经系统的致病机制。使用神经元细胞培养物的研究揭示了1）BDV p24磷蛋白（P）与多功能蛋白HMGB 1（也称为磷脂）之间的相互作用; 2）通过与P蛋白的相互作用阻断HMGB 1的功能;和3）显著降低宿主抗应激（例如加热）反应。此外，我们还发现在BDV持续感染的条件下，应激（腹腔注射LPS）可诱导大鼠出现神经系统症状。进一步制备了脑内表达BDVP蛋白的转基因小鼠，发现转基因小鼠表现出攻击行为，空间参考记忆明显受损，但对自主活动无明显影响。这些转基因小鼠还显示脑内脑源性神经营养因子（BDNF）、突触密度、5-羟色胺受体（5-THR_1<1A>和5-THR_2<1B>）的水平显著降低。因此，使用几种模型系统，阐明了CNS发病机制可以通过CNS中BDV的持续感染而出现。

Borna disease virus(BDV) is a highly neurotropic, negative-, single-stranded RNA virus and is the etiological agent of Borna disease, encephalitis in horses and sheep. Infection with BDV in humans, especially in some of the patients with psychiatric disorders, was reported. In fact, BDV signals were identified in some of the autopsied brains from the BDV-seropositive patients. The objective in this study is to analyze the BDV virulence at in vivo and in vitro levels as well as molecular level in order to clarify the mechanism of BDV-induced pathogenesis at the central nervous system. Studies using neuronal cell cultures, revealed 1)the interaction between BDV p24 phosphoprotein (P) and multi-functional protein HMGB1 (also named amphoterin) ; 2)blocking of functions of HMGB1 by the interaction with P protein ; and 3)significant decrease of host anti-stress (such as heating) responses. In addition, we found that neurological symptoms were induced in the rats by stress (intraperitoneal injection with LPS) under the condition with persistent infection with BDV. Further, we prepared transgenic mice expressing BDVP protein under the GFAP promoter in the brain and found that the transgenic mice showed aggressive behavior and significant impairement of spatial reference memory, but no significant effect in the locomotor activity. These transgenic mice also showed the significant decreases in the levels of brain-derived neurotrophic factor(BDNF), synapse density, serotonin receptors (5-THR_<1A> and 5-THR_<1B>) in the brains. Thus, using several model systems, it was clarified that the CNS pathogenesis could appear by the persistent infection with BDV in the CNS.