REPLICATION AND SPREAD OF NEUROTROPIC VIRUSES

描述：大量的DNA和RNA病毒是嗜神经的， 会导致各种神经系统紊乱 嗜神经病毒的结果 感染取决于病毒和受感染的神经元。 在神经元中，许多 病毒会转变为持续感染， 伴随着无细胞病毒产生的急剧减少。 然而，尽管细胞外病毒减少，但许多嗜神经性 病毒可以在中枢神经系统内有效传播，这表明这些 病毒可能使用神经元之间的细胞到细胞传播的新方式。 的 本申请的总体目标是鉴定神经元细胞抑制因子 限制病毒产生的因子，并阐明如何亲神经性 病毒绕过了神经元特异性的限制， CNS。 在拟议的研究中，神经元细胞培养系统和 将使用转基因小鼠模型来比较神经元 由两种嗜神经病毒引起的感染，即淋巴细胞病毒 脉络丛脑膜炎病毒（LCMV）和麻疹病毒（MV）。 两个具体目标是 提出测试的假设，1）神经元采用特定的策略 限制病毒的产生，2）嗜神经病毒可以在 CNS通过缺乏包膜的病毒颗粒的神经元间传递 件. 而小鼠是LCMV和神经元感染的天然宿主， 这种病毒是公认的，自然发生的MV感染是 由于在非人类中缺乏病毒受体， 细胞 为了促进MV感染的体内研究， 携带人MV受体CD46基因， 神经元特异性启动子，允许在神经元中表达CD46受体 已经建立。 数据显示，培养的原代 来自转基因胚胎的神经元支持MV感染和复制。 此外，当新生转基因小鼠感染MV时， MV仅限于神经元。 受感染的转基因小鼠还 出现了严重的临床症状 因此，这些转基因小鼠 促进MV感染的体外和体内研究， 这个应用程序。 拟议研究的结果最终将是 用于确定持续性病毒感染如何演变以诱导CNS 疾病 通过阐明病毒在一个持续的 感染及其神经元间扩散的机制，希望 可以开发治疗方法来干扰这些过程， 改善由这些病毒引起的神经系统疾病。

DESCRIPTION: A large number of DNA and RNA viruses are neurotropic and can cause a variety of neurological disorders. The outcome of neurotropic viral infection depends on the virus and the infected neurons. In neurons, many viruses undergo a switch to a persistent infection which is often accompanied by a drastic reduction in production of cell-free viruses. However, despite reduction of extracellular viruses, many neurotropic viruses can disseminate within the CNS efficiently suggesting that these viruses may use novel ways of cell-to-cell transmission among neurons. The overall goal of this application is to identify the neuronal cell suppressor factor that restricts virus production and to elucidate how neurotropic viruses circumvent the neuron-specific restriction and spread within the CNS. In the proposed studies, a combination of neuronal cell culture systems and a transgenic mouse model will be used to compare the outcome of neuronal infection caused by two neurotropic viruses, namely, lymphocytic choriomeningitis virus (LCMV) and measles virus (MV). Two specific aims are proposed to test the hypothesis that 1) neurons employ specific strategies to limit virus production and 2) neurotropic viruses can spread within the CNS by interneuronal transmission of viral particles that lack envelope components. While mice are natural hosts for LCMV, and neuronal infection by this virus is well-established, naturally occurring MV infections are restricted to humans due to the absence of the viral receptor in non-human cells. To facilitate studies of MV infection in vivo, transgenic mice carrying the gene of human MV receptor, CD46, controlled by the neuron-specific promoter to allow expression of the CD46 receptor in neurons have been established. Data are presented to show that cultured primary neurons from the transgenic embryos support MV infection and replication. Furthermore, when newborn transgenic mice were infected with MV, infection of MV was restricted to neurons. The infected transgenic mice also developed severe clinical signs. These transgenic mice will therefore facilitate both the in vitro and in vivo studies of MV infection proposed in this application. The results from the studies proposed will ultimately be used to determine how persistent viral infections evolve to induce CNS disease. By elucidating the state of the virus during a persistent infection and its mechanism of interneuronal spread, it is hoped that therapies can be developed to interfere with these processes and thus ameliorate the neurologic disorders induced by these viruses.