Characterization of Borna disease virus-mediated antagonization of the cellular interferon system

I型干扰素（IFN）系统是脊椎动物对病毒感染的先天性应答的最重要介质之一。它很可能是由病毒复制过程中产生的双链（ds）RNA触发的，该RNA被细胞传感蛋白识别。嗜神经性博尔纳病病毒（BDV）具有在细胞核中复制的非节段负链RNA基因组。虽然BDV复制可能导致dsRNA的产生，但病毒可以成功地建立组织培养细胞和某些动物物种的持续性非细胞溶解性感染。因此，BDV可以抵抗或避免先天反应的有害影响，但这种逃避的机制尚不清楚。我已经发现BDV感染抑制细胞对激活IFN系统的刺激作出反应的能力。这一发现表明BDV表达干扰诱导I型IFN基因所需的信号传导过程的基因产物。报道基因测定表明，至少有一种BDV特异性蛋白表现出这种活性。本项目的目标是鉴定和表征BDV的精确IFN拮抗蛋白，并破译这种活性的机制。预计我们将获得博尔纳病毒和可能的其他病毒病原体如何抵消先天反应并导致疾病的新机制见解。

The type I interferon (IFN) system is one of the most important mediators of the innate response of vertebrates toward virus infections. It is triggered most likely by double-strand (ds) RNA produced during viral replication which is recognized by cellular sensor proteins. The neurotropic Borna Disease Virus (BDV) possesses a non-segmented negative strand RNA genome that is replicated in the cell nucleus. Although BDV replication leads potentially to the production of dsRNA, the virus can successfully establish persistent, non-cytolytic infections of tissue culture cells and in certain animal species. Thus, BDV can resist or avoid the deleterious effects of the innate response, but the mechanism of this escape is unknown. I have discovered that a BDV infection suppresses the ability of cells to respond to stimuli that activate the IFN system. This finding demonstrates that BDV expresses a gene product(s) that interferes with the signaling processes required for induction of type I IFN genes. Reporter gene assays have indicated that at least one BDV-specific protein exhibits such an acitivity. The goals of this project are to identify and to characterize the precise IFN antagonistic protein of BDV and to decipher the mechanisms underlying this activity. It is expected that we will gain novel mechanistical insights how Borna viruses and possibly other viral pathogens counteract the innate response and cause disease.