Pathogenesis of Neurotropic RNA Virus Infections

神经元是必需的和不可再生的细胞;因此，不可逆的CNS疾病可能是由细胞毒性病毒的复制或细胞毒性T淋巴细胞（CTL）介导的感染神经元裂解引起的。 为了防止这些结果，必须存在免疫策略，以消除CNS病原体，使神经元死亡最小化。 我们已经获得的证据表明，麻疹病毒感染的神经元产生的趋化因子，特异性招募T淋巴细胞进入中枢神经系统，这意味着神经元在启动抗病毒免疫反应的关键作用。 此外，麻疹病毒的清除与大量T细胞浸润有关，这消除了病毒而没有伴随的神经元死亡。 重要的是，虽然这些过程发生在成年小鼠中，但新生小鼠尽管产生了强烈的免疫应答，但仍死于CNS感染。在拟议的研究中，神经元细胞培养系统和一种新的转基因小鼠模型的组合将被用来表征麻疹病毒从感染的神经元的非致细胞病变清除的基础。 由于这些小鼠的感染受人受体的转基因表达控制，因此病毒感染仅限于CNS神经元。 这个模型将被用来解决两个基本的，尚未解决的问题：1）趋化因子，合成的免疫豁免环境中的中枢神经系统，如何导致招募的抗病毒反应？（2）非溶细胞抑制病毒在神经元中复制的机制是什么？我们研究的长期目标是了解非细胞溶解性抗病毒防御是如何调节的，并将这些发现与这些防御失败的情况进行比较。最终，这些研究的结果将用于确定免疫反应如何演变，以消除破坏性病原体，同时保留关键细胞群。了解这种情况发生的机制将为开发基于免疫的策略提供信息，以解决与人类精神疾病和疾病相关的病毒感染。

Neurons are essential and nonrenewable cells; consequently, irreversible CNS disease could result from either replication of a cytotoxic virus, or from cytotoxic T lymphocyte (CTL)-mediated lysis of infected neurons. To protect against these outcomes, immune strategies must exist to eliminate CNS pathogens with a minimum of neuronal death. We have obtained evidence to suggest that measles virus-infected neurons produce chemokines that specifically recruit T lymphocytes into the CNS, implicating a crucial role for neurons in the initiation of the anti-viral immune response. Moreover, clearance of measles virus is associated with massive T cell infiltration, which eliminates the virus without concomitant neuronal death. Importantly, while these processes occur in adult mice, neonates succumb to CNS infection, despite mounting a robust immune response. In the proposed studies, a combination of neuronal cell culture systems and a novel transgenic mouse model will be used to characterize the basis for noncytopathic clearance of measles virus from infected neurons. Because infection of these mice is governed by the transgenic expression of the human receptor, virus infection is restricted to CNS neurons. This model will be used to address two fundamental, yet unresolved questions: 1) How do chemokines, synthesized within the immune-privileged environment of the CNS, result in recruitment of the antiviral response?, and 2) What is the mechanism of noncytolytic inhibition of virus replication in neurons? The long-term goals of our research are to understand how noncytolytic antiviral defenses are regulated, and to compare these findings to cases in which these defenses fail. Ultimately, the results of these studies will be used to determine how the immune response may have evolved to eliminate damaging pathogens while preserving a critical cell population. Understanding the mechanism by which this occurs will inform the development of immune-based strategies to resolve viral infections associated with human mental illness and disease.