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，该计划代表了一种多学科的方法来确定病毒持久性和髓鞘丢失的机制，使用由小鼠肝炎病毒(JHMV)的嗜神经性JHV-4株(MHV-4)诱导的明确的小鼠脱髓鞘模型。这一模型为理解病原体与其自然宿主之间的相互作用提供了一种手段，在急性和持续的中枢神经系统感染过程中，这种相互作用导致脱髓鞘。宿主反应具有控制传染性病毒的能力。然而，在没有检测到传染性病毒的情况下，持续性中枢神经系统感染与慢性持续性髓鞘丢失有关。病毒持续期间中枢神经系统内的病理变化与多发性硬化症有许多相似之处，多发性硬化症是人类最常见的脱髓鞘疾病。这个项目是独一无二的，由一个核心的研究人员组成，研究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者。项目1的重点是先天免疫的促炎和抗炎作用。新的数据表明，少突胶质细胞对天生信号的有限反应能力可以保护少突胶质细胞免受功能障碍和髓鞘丢失的影响。该项目使用新开发的技术和新型转基因小鼠来展示在急性病毒性脑脊髓炎和病毒持续期间寡突胶质细胞的独特反应。项目2探索了中枢神经系统内T细胞保留和内稳态的未知领域。使用各种转基因和骨髓嵌合小鼠，确定了中枢神经系统驻留细胞和浸润性细胞在呈递病毒抗原方面的作用以及交叉激发的可能性。项目3分析了调节性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。这个项目使用了一种新型的转基因小鼠，它可以定义调节性T细胞在病毒持续存在和正在进行的脱髓鞘过程中的作用。从这些项目中获得的数据将为调节病毒持续和脱髓鞘的机制以及将中枢神经系统作为病毒持续的目标提供新的见解。重要的是，它将提供关于参与病毒持续和脱髓鞘的特定中枢神经系统细胞之间的相互作用以及宿主免疫反应的细胞和可溶性介质的有价值的信息。

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.