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

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。近年来流行病学研究表明，BDV可感染人类，并可能与某些神经精神疾病有关。最近的一系列证据表明，在没有免疫病理学相关脑损伤的情况下，BDV感染会导致脑功能的直接损害。为了阐明BDV的神经发病机制，我们研究了BDV磷蛋白（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相互作用的特征。BDV P是感染动物脑中丰富的蛋白质，推测该蛋白质与pol蛋白协同作用在病毒的转录和复制中起关键作用。在这项研究中，我们证明了以下结果。1. BDV P特异性结合30-kDa的神经突生长因子，HMGB 1，P干扰HMGB 1功能 * P表达和感染的神经细胞。2. BDV P由0.8-kb双顺反子mRNA表达，具有泄漏扫描机制3。一种新的16-kDa蛋白质（P '）是从P. 4的相同开放阅读框产生的。感染沙鼠急性致死性疾病的诱导与脑干区域BDV表达相关。5.只有当BDV X在细胞中表达时，BDV P才有效地定位于细胞质中。从这些观察结果，我们表明，表达和细胞内定位的BDV P可以严格调节与其他病毒蛋白的相互作用。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.