REPLICATION AND SPREAD OF NEUROTROPIC VIRUSES

描述：大量的DNA和RNA病毒是嗜神经性的，可以 会引起各种神经系统疾病。嗜神经性病毒的转归 感染取决于病毒和受感染的神经元。在神经元中，许多 病毒经历了向持续性感染的转变，这通常是 伴随而来的是无细胞病毒产量的急剧减少。 然而，尽管细胞外病毒减少，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 病毒可能使用新的方式在神经元之间进行细胞间的传播。这个 这项应用的总体目标是确定神经细胞抑制因子 限制病毒产生的因素并阐明如何嗜神经性 病毒绕过神经元特有的限制并在 中枢神经系统。 在拟议的研究中，神经细胞培养系统和 转基因小鼠模型将被用来比较神经元的结果。 由两种嗜神经病毒引起的感染，即淋巴细胞病毒 脉络膜脑膜炎病毒(LCMV)和麻疹病毒(MV)。两个具体目标是 提出用来检验1)神经元使用特定策略的假设 限制病毒的产生和2)嗜神经性病毒可以在 无包膜病毒颗粒神经元间传递的中枢神经系统 组件。而小鼠是LCMV和神经元感染的天然宿主 这种病毒由来已久，自然发生的MV感染 由于非人类体内缺乏病毒受体，因此仅限于人类 细胞。为了便于研究MV在体内的感染，转基因小鼠 携带人MV受体基因CD46，受 神经元特异性启动子允许CD46受体在神经元中表达 已经建立起来了。数据显示，培养的原代 转基因胚胎中的神经元支持MV感染和复制。 此外，当新生的转基因小鼠感染MV时，感染 MV仅限于神经元。被感染的转基因小鼠也 出现了严重的临床症状。因此这些转基因小鼠将 促进在体外和体内对MV感染的研究 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为诱发中枢神经系统 疾病。通过阐明病毒在持续时间内的状态 感染及其神经元间扩散的机制，希望 可以开发出干预这些过程的治疗方法，从而 改善由这些病毒引起的神经紊乱。

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.