Mechanisms of CXCL10-Mediated Neuroprotection in WNV Encephalitis

描述（由申请人提供）：脑炎是西尼罗病毒（WNV）感染的常见和破坏性后果，西尼罗病毒是一种快速出现的传染病。尽管神经元是中枢神经系统（CNS）感染的主要目标，但西尼罗河病毒脑炎的一个特征是炎症浸润从脑膜延伸到脑实质，其严重程度在脑区域之间有所不同。这种中枢神经系统的炎症反应是保护免受致命感染所必需的，通过白细胞的募集，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，了解西尼罗河病毒感染中枢神经系统期间免疫介导的病毒清除的促炎作用是开发增强某些中枢神经系统区室病毒清除和限制其他区室炎症的治疗方法的重要一步。炎症趋化因子在病毒感染反应中被上调，这些分子调节白细胞向感染组织的募集。在初步实验中，我们观察到趋化因子CXCL10在西尼罗河病毒脑炎小鼠的中枢神经系统组织中高度上调，并定位于严重感染西尼罗河病毒的神经元亚群。此外，在西尼罗河病毒感染期间，CXCL10活性的中和会导致死亡率增加，并且用CXCL10体外治疗神经元会影响它们的存活。基于这些观察结果，本研究计划在明确定义的西尼罗河病毒脑炎小鼠模型中直接测试CXCL10在CD8+ T细胞运输和神经元损伤中的作用。在特异性目的1中，我们将确定西尼罗河病毒感染小鼠中枢神经系统中CXCL10及其受体CXCR3的区域和细胞来源。在特异性目的2中，我们将评估CXCL10对西尼罗河病毒感染后体外不同神经元群和体内神经病理学的影响。在特异性目的3中，我们将使用CXCL10充足和缺乏的小鼠，确定CXCL10在中枢神经系统不同区域协调CD8+ T细胞对西尼罗河病毒的反应中的作用。总的来说，本研究的目的是确定CXCL10在西尼罗河病毒脑炎中神经元保护和可能损伤的机制。加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，对于开发靶向抗炎药以减轻与西尼罗河病毒脑炎相关的发病率和死亡率至关重要。

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.