Regulation of CNS viral persistence

描述（由申请人提供）：这个新项目的长期目标是了解持续性病毒感染和中枢神经系统（CNS）脱髓鞘疾病。为此，该计划代表了一个多学科的方法来定义病毒的持久性和髓鞘损失的机制，使用一个明确的小鼠模型脱髓鞘诱导的嗜神经性JHM株（MHV-4）的小鼠肝炎病毒（JHMV）。该模型提供了一种手段，以了解病原体和其天然宿主之间的相互作用，导致脱髓鞘在急性和持续性CNS感染。宿主的反应有能力控制传染性病毒。然而，持续性CNS感染而没有可检测到的感染性病毒与慢性进行性髓鞘丢失相关。病毒持续存在期间CNS内的病理学改变与多发性硬化症（最普遍的人类脱髓鞘疾病）有许多相似之处。该计划是独一无二的，包括一个核心的研究人员解决病毒持久性和免疫反应的基本问题，既作为保护机制，也作为脱髓鞘的诱导剂。项目1侧重于先天免疫的促炎和抗炎作用。新的数据表明，少突胶质细胞对先天信号的有限反应能力可以防止少突胶质细胞功能障碍和髓鞘丢失。该项目使用新开发的技术和新型转基因小鼠来证明在急性病毒性脑脊髓炎和病毒持续存在期间少突胶质细胞的独特反应。项目2探索未知领域的T细胞滞留和稳态内的中枢神经系统。CNS驻留细胞和浸润细胞在呈递病毒抗原中的作用以及交叉致敏的潜力使用多种转基因和骨髓嵌合小鼠来定义。项目3分析了调节性T细胞和抗炎细胞因子IL-10在CNS病毒持续存在和脱髓鞘中的作用。该项目使用了一种新型的转基因小鼠，它允许定义在病毒持续存在和持续脱髓鞘过程中调节性T细胞的作用。从这些项目中获得的数据将提供新的见解调节病毒持久性和脱髓鞘以及中枢神经系统作为病毒持久性的目标的机制。重要的是，它将提供有价值的信息的相互作用的特定中枢神经系统细胞参与病毒的持久性和脱髓鞘和宿主免疫反应的细胞和可溶性介质。

DESCRIPTION (provided by applicant): The long term goals of this new program are an understanding of persistent viral infection and central nervous system (CNS) demyelinating disease. To this end, this program represents a multidisciplinary approach to defining mechanisms of viral persistence and myelin loss using a well defined murine model of demyelination induced by the neurotropic JHM strain (MHV-4) of mouse hepatitis virus (JHMV). This model provides a means to understand the interactions between a pathogen and its natural host that result in demyelination during acute and persistent CNS infection. The host response is competent to control infectious virus. However, a persistent CNS infection without detectable infectious virus is associated with chronic ongoing myelin loss. The pathological alterations within the CNS during viral persistence have numerous similarities to multiple sclerosis, the most prevalent human demyelinating disease. This program is unique, comprising a core of investigators addressing fundamental questions of viral persistence and immune responses, both as protective mechanisms and as inducers of demyelination. Project 1 focuses on the pro-inflammatory and anti-inflammatory effects of innate immunity. New data suggest that the limited capacity of oligodendroglia to respond to innate signals protect from oligodendroglial dysfunction and myelin loss. This project uses newly developed techniques and novel transgenic mice to demonstrate the unique response of oligodendroglia during both acute viral encephalomyelitis and viral persistence. Project 2 explores the unknown area of T cell retention and homeostasis within the CNS. The role of CNS resident and infiltrating cells in presenting viral antigen as well as the potential for cross priming are defined using a variety of transgenic and bone marrow chimeric mice. Project 3 analyzes the role of regulatory T cells and the anti-inflammatory cytokine IL-10 in CNS viral persistence and demyelination. This project uses a novel transgenic mouse which allows definition of the role of regulatory T cells during viral persistence and ongoing demyelination. Data obtained from these projects will provide novel insights into the mechanisms regulating viral persistence and demyelination as well as the CNS as a target for viral persistence. Importantly, it will provide valuable information on the interactions of specific CNS cells involved in viral persistence and demyelination and the cellular and soluble mediators of the host immune response.