Genes induced after BDV infection in Sprague Dawley and Lewis rats

Borna Disease Virus (BDV) is a neurotropic virus that persistently infects neurons in the central nervous system of various hosts, including rats. Although BDV is known to be an IFN sensitive virus, determination of the cellular mRNA transcript levels revealed the induction of IFN-stimulated genes in organotypic rat hippocampus slice cultures, raising the question how BDV evades this innate immune response. Using rat Mx protein as a specific marker for IFN-induced gene products, we could show that neurons lack detectable levels of Mx in these BDV infected cultures, whereas astrocytes and microglial cells were Mx positive. Neurons remained Mx negative after treatment of uninfected hippocampus cultures as well as primary dissociated neuronal cultures with high concentrations of IFN-a. This non-responsiveness correlated with a lack of a detectable nuclear translocation of pSTAT1 in rat neurons. Consistently, IFN treatment of BDV-infected rat neurons did not prevent the establishment of a viral persistence in the neuronal tissue. However, IFN treatment efficiently prevented vesicular stomatitis virus (VSV) replication, indicating that these cells can mount a weak innate immune response. In contrast, IFN treatment of mouse neurons resulted in the upregulation of Mx1 proteins and inhibition of BDV replication, indicating species-specific differences in the IFN response in neurons between mice and rats. Rat neurons may therefore represent the ideal cell type for BDV to evade the innate immune in the central nervous system.博尔纳病病毒（Borna Disease Virus, BDV）是一种嗜神经性病毒，可在包括大鼠在内的多种宿主的中枢神经系统神经元中持续感染。尽管已知BDV对干扰素（Interferon, IFN）敏感，但通过检测细胞mRNA转录水平发现，大鼠海马器官型脑片培养物中可诱导干扰素刺激基因的表达，这引发了一个关键问题：BDV是如何逃避固有免疫应答的？ 以大鼠Mx蛋白作为干扰素诱导基因产物的特异性标志物，本研究证实，在这些BDV感染的培养物中，神经元无法检测到Mx蛋白的表达，而星形胶质细胞和小胶质细胞则呈Mx蛋白阳性。在未感染的海马培养物以及原代解离神经元培养物中，经高浓度干扰素α（IFN-α）处理后，神经元仍未检测到Mx蛋白的表达。这种无应答特性与大鼠神经元中无法检测到磷酸化信号转导与转录激活因子1（pSTAT1）的核转位现象相关。 与之相符的是，对BDV感染的大鼠神经元进行IFN处理，未能阻止病毒在神经元组织中建立持续感染状态。然而，IFN处理可有效抑制水疱性口炎病毒（Vesicular Stomatitis Virus, VSV）的复制，这表明此类细胞可产生微弱的固有免疫应答。 与之形成鲜明对比的是，对小鼠神经元进行IFN处理可上调Mx1蛋白的表达并抑制BDV的复制，这提示小鼠与大鼠的神经元在IFN应答方面存在物种特异性差异。因此，大鼠神经元可能是BDV在中枢神经系统中逃避固有免疫应答的理想细胞类型。