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

博尔纳病病毒（BDV）属于博尔纳病毒科，属于非节段负链RNA病毒单链病毒，其特点是高度嗜神经性、非细胞病变性复制和持续感染。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)在感染细胞中的转录和翻译调控机制以及与宿主细胞因子的相互作用。BDV P是受感染动物大脑中丰富的蛋白，据推测该蛋白与pol蛋白协同在病毒转录和复制中起关键作用。在本研究中，我们展示了以下结果。1. BDV P特异性结合30kda神经突生长因子两性素/HMGB1， P干扰HMGB1功能* P表达和感染神经细胞。2. BDV P由0.8 kb双链mRNA表达，具有泄漏扫描机制3。一个新的16 kda蛋白（P’）是由P’4相同的开放阅读框产生的。感染沙鼠的急性致死性疾病的诱发与脑干区域BDV的表达有关。5. 只有当BDV X在细胞中表达时，BDV P才能有效地定位于细胞质中。根据这些观察结果，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发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.