Mechanisms of CXCL10-Mediated Neuroprotection in WNV Encephalitis

描述（由申请人提供）：脑炎是一种常见的和破坏性的后果感染黄病毒西尼罗河病毒（WNV），一种迅速出现的传染病。虽然神经元是中枢神经系统（CNS）感染的主要目标，但WNV脑炎的标志是从脑膜延伸到脑实质中的炎性浸润物的积累，其在脑区域之间的严重程度不同。这种CNS炎症反应是通过募集白细胞来保护免受致死性感染所必需的，白细胞通过各种效应机制清除病毒。然而，其中一些影响也可能是有害的，并有助于神经系统疾病的进展。因此，了解在CNS的WNV感染期间负责免疫介导的病毒清除的促炎作用是开发增强某些CNS隔室中的病毒清除并限制其他隔室中的炎症的疗法的重要步骤。众所周知，炎性趋化因子响应于病毒感染而上调，并且这些分子调节白细胞向感染组织中的募集。在初步实验中，我们已经观察到趋化因子CXCL10在患有WNV脑炎的小鼠的CNS组织中高度上调，并且定位于严重感染WNV的神经元亚群。此外，在WNV感染期间CXCL10活性的中和导致死亡率增加，并且用CXCL10离体治疗神经元影响其存活。基于这些观察结果，拟议的研究计划直接测试CXCL10在明确的WNV脑炎小鼠模型中CD8+ T细胞运输和神经元损伤中的作用。在具体目标1中，我们将确定CXCL10及其受体CXCR3在感染WNV的小鼠CNS中的区域和细胞来源。在具体目标2中，我们将评估CXCL10对体外不同神经元群体和WNV感染后体内神经病理学的影响。在具体目标3中，使用CXCL10充足和缺陷小鼠，我们将确定CXCL10在协调CNS不同区域中针对WNV的CD8+ T细胞应答中的作用。总的来说，这个建议的目标是确定神经元保护的机制，可能的话，在西尼罗河脑炎CXCL10诱导的损伤。增强对感染后控制神经炎症和神经元损伤的分子信号的理解对于开发减轻与WNV脑炎相关的发病率和死亡率的靶向抗炎剂至关重要。

DESCRIPTION (provided by applicant): Encephalitis is a common and devastating consequence of infection with the fiavivirus West Nile virus (WNV), a rapidly emerging infectious disease. Although neurons are the primary target of central nervous system (CNS) infection, a hallmark of WNV encephalitis is the accumulation of inflammatory infiltrates extending from the meninges into the brain parenchyma that vary in severity between brain regions. This CNS inflammatory response is required for protection from lethal infection through the recruitment of leukocytes that clear virus through a variety of effector mechanisms. Some of these effects, however, may also be detrimental and contribute to the progression of neurologic disease. Thus, understanding the proinflammatory effects responsible for immune-mediated viral clearance during WNV infection of the CNS is an essential step for developing therapies that enhance clearance of virus in certain CNS compartments and limit inflammation in others. It is well established that inflammatory chemokines are upregulated in response to viral infections and that these molecules modulate the recruitment of leukocytes into infected tissues. In preliminary experiments, we have observed that the chemokine CXCL10 is highly upregulated in CNS tissues of mice with WNV encephalitis and localizes to subpopulations of neurons that are heavily infected with WNV. Moreover, neutralization of CXCL10 activity during WNV infection led to an increase in mortality, and treatment of neurons ex vivo with CXCL10 affects their survival. Based on these observations, the proposed research plans to directly test the role of CXCL10 in CD8+ T cell trafficking and neuronal injury in a well-defined mouse model of WNV encephalitis. In Specific Aim 1 we will determine the regional and cellular sources of CXCL10 and its receptor, CXCR3, in the CNS of mice infected with WNV. In Specific Aim 2, we will evaluate the effect of CXCL10 on different populations of neurons in vitro and on neuropathology in vivo after WNV infection. In Specific Aim 3, using CXCL10 sufficient and deficient mice, we will determine the role of CXCL10 in coordinating the CD8+ T cell response against WNV in the different regions of the CNS. Overall, the goal of this proposal is to determine the mechanisms of neuronal protection and, possibly, injury induced by CXCL10 in WNV encephalitis. An enhanced understanding of the molecular signals that govern neuroinflammation and neuronal injury after infection will be critical to the development of targeted anti-inflammatory agents that mitigate the morbidity and mortality associated with WNV encephalitis.