Regulation of Borna disease virus (BDV) phosphoprotein expression : Implication for BDV neuropathogenesis

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。最近的流行病学研究表明，BDV可以感染人类，并可能与某些神经精神疾病有关。最近的一系列证据表明，在没有免疫病理相关的脑损伤的情况下，BDV感染会对脑功能造成直接损害。为了阐明BDV的神经发病机制，我们研究了BDV磷酸化蛋白(P)在感染细胞转录和翻译调节机制以及与宿主细胞因子相互作用中的特点。BDV P是一种在感染动物脑中含量丰富的蛋白，推测该蛋白与Pol1蛋白相互作用，在病毒的转录和复制中发挥关键作用。在本研究中，我们展示了以下结果。1.BDV P与30 kDa神经突起生长因子两性霉素/HMGB1特异性结合，P干扰HMGB1的功能*P表达并感染神经细胞。2.BDV P是从一个0.8 kb的双顺反子m RNA中以泄漏扫描机制表达的。3.一个新的16 kDa蛋白(P‘)是从P的同一开放阅读框架中产生的。4.感染沙土鼠急性致死性疾病的诱导与BDV在脑干区的表达有关。5.只有当BDV X在细胞中表达时，BDV P才能有效地定位在细胞质中。从这些观察中，我们表明BDV P的表达和细胞内定位可能受到与其他病毒蛋白相互作用的关键调控。此外，我们还认为BDV P的表达可能在该病毒的致病机制中起重要作用。

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. Recent epidemiological studies revealed that BDV can infect humans and that it may be related with certain neuropsychiatric disorders. A line of recent evidences suggests that BDV infection causes direct damages on brain functions in the absence of immunopathology-related brain damage. In order to elucidate BDV neuropathogenesis, we investigated the features of BDV phosphoprotein (P) in the mechanism of transcriptional and translational regulation in infected cells, as well as in the interaction with host cellular factor. BDV P is an abundant protein in infected animal brains and it is assumed that the protein cooperates with the pol protein to play a pivotal role in viral transcription and replication. In this study, we demonstrate following results. 1. BDV P specifically binds to a 30-kDa neurite outgrowth factor, amphoterin/HMGB1, and P interferes with HMGB1 functions * P-expressed and infected neural cells. 2. BDV P is expressed from a 0.8-kb bicistronic mRNA with a leaky scanning mechanism 3. A novel 16-kDa protein (P') is produced from the same open reading frame of P. 4. The induction of acute fatal disorders in infected gerbils is associated with BDV expression in the brainstem region. 5. BDV P efficiently localizes in the cytoplasm only when BDV X is expressed in the cells. From these observations, we indicate that the expression and intracellular localization of BDV P could be critically regulated by the interaction with other viral proteins. Furthermore, we also suggest that the expression of BDV P may play an important role in the pathogenesis of this virus.