CONTROL OF MHV INFECTION IN THE CENTRAL NERVOUS SYSTEM

描述(摘自申请者摘要)：多发性硬化症(MS) 美国成年人最常见的自身免疫性神经退行性疾病 约250,000人受到影响。现有证据 提示MS的病因和发病机制可能涉及两个事件，第一个事件 在生命早期接触到环境因素，很可能是病毒， 随后在成年期早期发生第二起事件，引发疾病。链接 与宿主遗传学，特别是MHC-II类抗原和性别 但这是一个连接早期和晚期的明确的致病序列 事件尚未显示，因此动物模型系统在 提供对多发性硬化症发病机制的洞察这个项目试图 了解CD_4~+T细胞介导的免疫应答机制 中枢神经系统脱髓鞘病的发病机制--触发内流的信号 炎性细胞，以及病毒持续存在的状态和位置 中枢神经系统。C57B1/6小鼠脑内接种亲神经药物 小鼠冠状病毒MHV-JHM及其变异体V5A13.1 导致可复制的脑脊髓炎，通常在 7-14天，但随后出现急性或慢性脱髓鞘发作。 限制病毒在大脑内的复制和传播受到控制 通过T细胞反应的元素，并伴随着诱导 中枢神经系统内多种细胞因子和趋化因子的mRNAs。证据 提示CD4+T细胞反应对两种感染的控制都起着中心作用 和脱髓鞘疾病，因此布赫迈尔博士提出了三个具体目标 以阐明这种病毒-宿主相互作用的细节。这些是：1)至 在CD4基因敲除小鼠中研究脱髓鞘的要求；2) 在C57B1/6和B6CD4基因敲除小鼠中的致病作用 病毒诱导的急性和慢性脱髓鞘疾病及其证据 一种针对髓鞘成分的反自我反应 病毒感染；3)原位杂交分析， 免疫组织化学和聚合酶链式反应检测病毒的状态和细胞位置 感染后在中枢神经系统内持续存在。冠状病毒是 在人和动物中广泛存在的上呼吸道和肠道病原体，以及 冠状病毒rna最近在人类多发性脑脊髓炎的大脑中被描述。 硬化症患者。建议的研究将揭示以下基本信息 解释冠状病毒感染中的宿主-病毒关系，它们是如何 引起持续性感染，其发病机制 脱髓鞘疾病。

DESCRIPTION (Adapted from Applicant's Summary): Multiple sclerosis (MS) is the most common autoimmune neurodegenerative disease of adults in the United States, affecting approximately 250,000 individuals. Available evidence suggests that MS etiology and pathogenesis may involve two events, the first being exposure to an environmental agent, likely a virus, early in life, followed by a second event in early adulthood which triggers disease. Links with host genetics, particularly MHC-class II antigens and gender have been shown, but a definitive pathogenetic sequence linking the early and late events has not been shown, therefore animal model systems are of value in providing insight into the pathogenesis of MS. This project seeks to understand the mechanisms of CD4+ T cell mediated immune responses in the pathogenesis of CNS demyelinating disease, the signals which trigger influx of inflammatory cells, and the state and sites of virus persistence within the CNS. Intracerebral inoculation of C57B1/6 mice with the neurotropic murine coronavirus MHV-JHM and variants such as V5A13.1 derived from it results in a reproducible encephalomyelitis which usually resolves within 7-14 days but is followed by acute or chronic episodes of demyelination. Restriction of virus replication and spread within the brain is controlled by elements of the T cell response, and is accompanied by induction of multiple cytokine and chemokine mRNAs in the CNS compartment. Evidence suggests that CD4+ T cell responses are central to both control of infection and demyelinating disease, hence Dr. Buchmeier proposes three specific aims to elucidate details of this virus-host interaction. These are: 1) to investigate in CD4 knockout mice the requirements for demyelination; 2) to investigate in C57B1/6 and B6CD4 knockout mice the pathogenesis of virus-induced acute and chronic demyelinating disease and to seek evidence of an antiself response against components of the myelin sheath triggered by virus infection; and 3) to analyze by in situ hybridization, immunohistochemistry and PCR the state and cellular sites of viral persistence within the CNS following infection. Coronaviruses are widespread upper respiratory and enteric pathogens in man and animals, and coronavirus RNA has recently been described in the brains of human multiple sclerosis patients. The studies proposed will reveal basic information in interpreting the host-virus relationship in coronavirus infections, how they cause persistent infections, and the mechanisms of pathogenesis of demyelinating disease.