Pathogenesis of Neurotropic RNA Virus Infections

神经元是必需的和不可再生的细胞；因此，不可逆转的中枢神经系统疾病可能是由于细胞毒性病毒的复制，或者是由于细胞毒性T淋巴细胞(CTL)介导的感染神经元的裂解。为了预防这些结果，必须存在免疫策略来消除中枢神经系统病原体，并将神经元死亡降至最低。我们已经获得的证据表明，麻疹病毒感染的神经元产生趋化因子，特异性地将T淋巴细胞招募到中枢神经系统，这意味着神经元在启动抗病毒免疫反应中发挥了关键作用。此外，麻疹病毒的清除与大量的T细胞渗透有关，这可以消除病毒，而不会伴随神经元死亡。重要的是，虽然这些过程发生在成年小鼠身上，但新生小鼠尽管建立了强大的免疫反应，仍会屈服于中枢神经系统感染。在拟议的研究中，将使用神经元细胞培养系统和一种新的转基因小鼠模型来表征从感染的神经元中清除麻疹病毒的非细胞病变基础。由于这些小鼠的感染是由人类受体的转基因表达控制的，病毒感染仅限于中枢神经系统神经元。这个模型将被用来解决两个基本但尚未解决的问题：1)在中枢神经系统的免疫特权环境中合成的趋化因子是如何导致抗病毒反应的招募的？2)非细胞溶解抑制神经元中病毒复制的机制是什么？我们研究的长期目标是了解非溶细胞性抗病毒防御是如何受到调控的，并将这些发现与这些防御失败的情况进行比较。最终，这些研究的结果将被用来确定免疫反应可能是如何进化的，以消除破坏性病原体，同时保留关键的细胞种群。了解这种情况发生的机制将有助于开发基于免疫的战略，以解决与人类精神疾病和疾病相关的病毒感染问题。

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.