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，该项目采用多学科方法，利用小鼠肝炎病毒（JHMV）嗜神经型JHM毒株（MHV-4）诱导的脱髓鞘小鼠模型，确定病毒持久性和髓磷脂损失的机制。该模型提供了一种方法来理解病原体与其自然宿主之间的相互作用，这些相互作用在急性和持续性中枢神经系统感染期间导致脱髓鞘。宿主反应能够控制感染性病毒。然而，没有可检测到的传染性病毒的持续性中枢神经系统感染与慢性持续髓磷脂损失有关。在病毒持续存在期间，中枢神经系统内的病理改变与最常见的人类脱髓鞘疾病多发性硬化症有许多相似之处。这个项目是独一无二的，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，作为保护机制和脱髓鞘的诱导剂。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反应能力有限，可以防止少突胶质细胞功能障碍和髓磷脂丢失。本项目利用新开发的技术和新型转基因小鼠来证明少突胶质细胞对急性病毒性脑脊髓炎和病毒持续性的独特反应。项目2探索T细胞保留和中枢神经系统内稳态的未知区域。利用多种转基因小鼠和骨髓嵌合小鼠确定了中枢神经系统驻留细胞和浸润细胞在递呈病毒抗原中的作用以及交叉引物的潜力。项目3分析调节性T细胞和抗炎细胞因子IL-10在中枢神经系统病毒持续和脱髓鞘中的作用。该项目使用了一种新型转基因小鼠，它可以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为病毒持久性和脱髓鞘的调节机制以及作为病毒持久性靶点的中枢神经系统提供新的见解。重要的是，它将为参与病毒持续和脱髓鞘的特定中枢神经系统细胞与宿主免疫反应的细胞和可溶性介质的相互作用提供有价值的信息。

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.