Mechanisms of CXCL10-Mediated Neuroprotection in WNV Encephalitis

描述(申请人提供)：脑炎是感染西尼罗河病毒(西尼罗河病毒)的常见和破坏性后果，西尼罗河病毒是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脑炎的一个特点是炎性浸润物从脑膜向脑实质聚集，不同脑区的严重程度不同。这种中枢神经系统炎症反应是通过招募白细胞，通过各种效应机制清除病毒来保护机体免受致死性感染所必需的。然而，这些影响中的一些也可能是有害的，并有助于神经系统疾病的进展。因此，了解在西尼罗河病毒感染中枢神经系统期间负责免疫介导的病毒清除的促炎效应是开发治疗方法的关键一步，该疗法可增强某些中枢神经系统内病毒的清除，并限制其他中枢神经系统中的炎症。众所周知，炎性趋化因子在病毒感染时上调，这些分子调节白细胞在感染组织中的募集。在初步实验中，我们观察到趋化因子CXCL10在WNV脑炎小鼠的中枢组织中高度上调，并定位于严重感染WNV的神经元亚群。此外，在西尼罗河病毒感染过程中，CXCL10活性的中和导致了死亡率的增加，体外用CXCL10处理神经元会影响其存活。基于这些观察，拟议的研究计划直接测试CXCL10在WNV脑炎小鼠模型中CD8+T细胞运输和神经元损伤中的作用。在特定目标1中，我们将确定CXCL10及其受体CXCR3在感染西尼罗河病毒的小鼠中枢神经系统中的区域和细胞来源。在特定的目的2中，我们将评估CXCL10在体外对不同群体的神经元的影响以及对西尼罗河病毒感染后体内神经病理的影响。在特定目标3中，使用CXCL10充足和缺陷的小鼠，我们将确定CXCL10在协调中枢不同区域CD8+T细胞对西尼罗河病毒的反应中的作用。总体而言，这项建议的目标是确定CXCL10在西尼罗河病毒脑炎中引起的神经元保护和可能的损伤机制。加强对控制感染后神经炎症和神经元损伤的分子信号的了解，将是开发靶向抗炎药以降低与西尼罗河病毒脑炎相关的发病率和死亡率的关键。

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.