DEC-205+ Dendritic Cells are Effective at Stimulating a Protective T Cell Response Against WNV Encephalitis

项目摘要 西尼罗河病毒（WNV）是导致严重疾病的神经元损伤和炎症的重要原因 有可能致命为了减少或消除来自中枢神经系统的入侵病毒 (CNS)为了保护大脑，T细胞进入病毒感染的中枢神经系统并进行抗病毒治疗是至关重要的。 功能协调发展的然而，由于神经元的敏感性，CNS内活化的T细胞的存在也可能导致神经元的损伤。 会导致神经病理学以前的研究表明，树突状细胞（DC）是 对于在西尼罗河病毒神经侵袭性疾病期间在CNS内建立病毒学控制至关重要。然而， 这些细胞如何在不造成神经元损伤的情况下完成保护。我们假设一个特定的 DC亚群（表达DEC-205 DC）促进病毒学控制和保护免受WNV神经侵袭 通过适当激活迁移到病毒感染的CNS中的T细胞来治疗疾病。为了解决这个 假设，我们将使用一个良好建立的小鼠模型的西尼罗河病毒脑炎，其中一个实验组 将是DEC-205基因的遗传缺陷，有效地从大脑中消除了这一DC亚群， 其他地方使用这个模型，我们将能够确定这些细胞在限制病毒感染中的作用， 复制和WNV感染的CNS内的神经元损伤。我们还将对这些动物进行收养性转移 在WNV神经侵袭性疾病的关键阶段，将细胞植入遗传缺陷小鼠。通过这项研究， 我们将确定这种特定的DC亚群提供抗WNV神经保护的机制， 侵袭性疾病总之，这些研究将阐明和增强我们对免疫系统的理解。 对大脑中病毒感染的反应以及有效免疫反应和 神经元损伤的免疫病理学。这对西尼罗河病毒的控制和预防也有明确的意义 神经侵袭性疾病

PROJECT SUMMARY West Nile virus (WNV) is a significant cause of neuronal injury and inflammation that results in severe disease that can potentially be lethal. In order to reduce or eliminate invading viruses from the central nervous system (CNS) and protect the brain, it is vital that T cells enter the virally-infected CNS and perform their anti-viral functions. However, due to the sensitivity of neurons, the presence activated T cells within the CNS may also contribute to neuropathology if not rigorously regulated. Previous research showed that dendritic cells (DCs) are critical for establishing virologic control within the CNS during WNV neuro-invasive disease. Yet, little is known as to how these cells accomplish protection without causing neuronal damage. We hypothesize that a specific subset of DCs (DEC-205-expressing DCs) promote virologic control and protection against WNV neuro-invasive disease through the appropriate activation of the T cells migrating into the virally-infected CNS. To address this hypothesis, we will use a well-established mouse model of WNV encephalitis, where one experimental group will be genetically deficient for the DEC-205 gene, effectively eliminating this subset of DCs from the brain and elsewhere. Using this model, we will be able to determine the role of these cells in limiting viral infection, replication, and neuronal injury within the WNV-infected CNS. We will also perform an adoptive transfer of these cells into the genetically deficient mice at a critical stage during WNV neuro-invasive disease. Through this study, we will determine the mechanisms by which this specific subset of DCs provide protection against WNV neuro- invasive disease. Together, these studies will illuminate and enhance our understanding of our immune responses to viral infections in the brain and the balance between an effective immune response and immunopathology with injury to neurons. It also has clear implications for the control and prevention of WNV neuro-invasive disease.