Neuroimmunologic Disorders Induced by Chronic Viral Infection

描述(申请人提供)：中枢神经系统(CNS)的慢性病毒感染会影响神经功能，导致行为和认知障碍。这些病毒诱导的中枢神经系统紊乱可以在没有细胞溶解和炎症的情况下发生，这一观察结果导致了一种假设，即病毒可能导致各种原因不明的中枢神经系统紊乱。因此，了解非细胞溶解性持久性病毒导致中枢神经系统功能障碍的机制是有兴趣的。典型的ArenaVirus淋巴细胞性脉络膜脑膜炎病毒(LCMV)为我们研究这一问题提供了一个重要的模型系统。先天性获得性巨细胞病毒持续感染(LCMV-CGPI)的小鼠在没有明显的组织病理学迹象的情况下，学习和记忆受到损害，与中枢神经系统基因表达改变有关。我们的总体假设是，非细胞溶解的持续性病毒脑感染可以导致宿主的固有免疫防御机制的慢性激活，特别是干扰素介导的反应。这些宿主的反应无法清除病毒，但它们的慢性激活会导致CNS基因表达的变化，导致神经元功能障碍，从而导致CNS功能异常。我们的具体目标是：1.确定LCMV-CGPI小鼠脑组织中病毒活性与基因表达变化之间的相关性。CNS基因表达谱将使用从大脑病毒分布和负载相似的LCMV-CGPI小鼠中分离出来的RNA进行，无论是高还是低，并与模拟感染的对照组小鼠进行比较。中枢神经系统基因表达的变化将与感染程度相关。2.研究LCMV对脑内基因表达的影响。LCMV-CGPI小鼠中CNS表达改变的候选基因的区域和细胞表达模式将通过IHC和ISH程序确定，并在单细胞水平上与感染相关。3.确定与长期LCMV-CGPI相关的神经元损伤。突触和树突结构将使用突触素和MAP2的抗体进行定量评估，并使用共聚焦激光扫描显微镜评估与LCMV-CGPI相关的异常。

DESCRIPTION (provided by applicant): Chronic viral infections of the central nervous system (CNS) can affect neuronal function resulting in behavioral and cognitive impairment. These virally induced CNS disturbances can occur in the absence of cytolysis and inflammation, an observation that has led to the hypothesis that viruses may contribute to a variety of CNS disorders of unknown etiology. Therefore, the interest in understanding the mechanisms whereby noncytolytic persistent viruses can contribute to CNS dysfunction. The prototypic Arenavirus lymphocytic choriomeningitis virus (LCMV) provides us with an important model system for the investigation of this problem. Mice with congenially acquired LCMV persistent infection (LCMV-cgPi) have impaired learning and memory associated with altered CNS gene expression in the absence of overt histopathological signs. Our overall hypothesis is that noncytolytic persistent viral brain infections can cause chronic activation of the host's innate immune defense mechanism, especially interferon-mediated responses, within the CNS. These host's responses fail to clear the virus, but their chronic activation causes changes in CNS gene expression that lead to disturbances in neuronal function, thus contributing to abnormal CNS function. Our specific aims are: 1. Determine the correlation between viral activity and altered gene expression in the brain of LCMV-cgPi mice. CNS gene expression profiling will be done using RNA isolated from individual LCMV-cgPi mice with similar brain viral distribution and load, both high and low, and compared to mock-infected control mice. Changes in CNS gene expression will be correlated with levels of infection. 2. Characterize LCMV-induced changes in brain gene expression. The regional and cellular expression pattern of identified candidate genes with altered CNS expression in LCMV-cgPi mice will be determined using IHC and ISH procedures, and correlated with infection at the single cell level. 3. Determine neuronal damage associated with long-term LCMV-cgPi. Synaptic and dendritic structures will be quantitatively evaluated using antibodies to synaptophysine and MAP2, and confocal laser scanning microscopy to assess abnormalities associated with LCMV-cgPi.