Mechanisms of CCR2-mediated neuroprotection in West Nile Virus infection

描述(由申请人提供)： = 注意：此摘要摘自应用程序，未经SRA校对。如果应用程序扫描过程有问题，提取的文本可能不正确或不完整。 = 西尼罗河病毒感染中CCR2介导的神经保护机制1.项目摘要：西尼罗河病毒(West Nile Virus，WNV)是一种重新出现的蚊媒病原体，是美国流行性病毒性脑膜脑炎的最常见原因。西尼罗河病毒感染的死亡率很高(约占美国疫情中有症状病例的4%)，目前还没有针对西尼罗河病毒的特效治疗方法或疫苗，对其分子发病机制的了解也有限。在小鼠模型上的研究表明，在西尼罗河病毒脑炎期间，中枢神经系统中的单核细胞调节着临床结果，但转运机制尚未完全阐明。此前，我们和其他人发现，单核细胞趋化因子受体CCR2及其三个配体CCL2、CCL7和CCL12在WNV感染的小鼠的中枢神经系统中被诱导。我们现在已经获得了初步数据，表明CCR2基因缺陷的小鼠显著增加了死亡率，这与显著和选择性地减少单核细胞在中枢神经系统的聚集有关。在缺乏CCL7的小鼠中，死亡率增加，但在缺乏CCL2的小鼠中没有。因此，我们假设CCL7：CCR2轴调节神经保护性炎性单核细胞在西尼罗河病毒感染期间进入中枢神经系统。疾病背景下依赖CCR2的单核细胞转运机制必须考虑已知的CCR2在从骨髓释放炎性单核细胞中的稳态作用。因此，在特定的目标1中，我们将确定CCR2及其配体在西尼罗河病毒感染期间单核细胞从骨髓释放到血液中的作用。在具体目标2中，我们将确定CCL7：CCR2轴在调节单核细胞从血液重新募集到炎症的中枢神经系统中的作用，以及在西尼罗河病毒脑炎期间的神经保护中的作用。对控制单核细胞向中枢神经系统迁移的精确分子机制的详细了解将有助于更深入地了解WNV脑炎的天然免疫控制，并可能为新的免疫调节策略提供基础，以改善患者的治疗结果。西尼罗河病毒(WNV)通过蚊子传播，每年在美国引发脑炎暴发。由于没有特定的治疗方法或疫苗，因此确定病毒进入大脑之前和之后控制病毒的分子机制非常重要。对这些过程的详细了解不仅将为西尼罗河病毒如何致病提供新的见解，还可能提供新的方法来阻断感染者的疾病。

DESCRIPTION (provided by applicant): ================== NOTICE: THIS ABSTRACT WAS EXTRACTED FROM APPLICATION AND HAS NOT BEEN PROOFED BY AN SRA.WHEN THERE ARE PROBLEMS WITH THE APPLICATION SCANNING PROCESS, THE EXTRACTED TEXT MAY BE INCORRECT OR INCOMPLETE. ================== Title: Mechanisms of CCR2-mediated neuroprotection in West Nile virus infection 1. Project Summary: West Nile virus (WNV) is a re-emerging mosquito-borne pathogen and the most common cause of epidemic viral meningo-encephalitis in the United States. Mortality due to WNV infection is high (~4% among symptomatic cases in the US epidemic), no specific treatments or vaccines for WNV are available, and knowledge of molecular pathogenesis is limited. Studies in a mouse model have suggested that monocytes in the CNS regulate clinical outcome during WNV encephalitis, but trafficking mechanisms have not been fully delineated. Previously, we and others showed that monocyte chemokine receptor CCR2 and three of its ligands, CCL2, CCL7, and CCL12, are induced in the CNS of WNV-infected mice. We have now obtained preliminary data indicating that mice genetically deficient in CCR2 have markedly increased mortality, and this was associated with markedly and selectively reduced monocyte accumulation in the CNS. Increased mortality was phenocopied in mice lacking CCL7, but not in mice lacking CCL2. Therefore, we hypothesize that the CCL7:CCR2 axis regulates neuroprotective inflammatory monocyte trafficking into the CNS during WNV infection. Mechanisms of CCR2- dependent monocyte trafficking in the context of disease must consider the known homeostatic role of CCR2 in the release of inflammatory monocytes from the bone marrow. Therefore, in Specific Aim 1, we will establish the role of CCR2 and its ligands in monocyte release from the bone marrow to the blood during WNV infection. In Specific Aim 2, we will determine the role of the CCL7:CCR2 axis in the regulation of monocyte recruitment from the blood into the inflamed CNS, and in neuroprotection during WNV encephalitis. Detailed knowledge of the precise molecular mechanisms controlling monocyte migration to the CNS will provide greater insight into innate immune control of WNV encephalitis and may provide the basis for novel immunomodulatory strategies to improve treatment outcomes in patients. West Nile virus (WNV) is transmitted by mosquitoes and causes annual outbreaks of encephalitis in the US. Since there are no specific therapies or vaccines, it is important to determine the molecular mechanisms involved in controlling the virus before and after it has entered the brain. A detailed understanding of these processes will not only provide new insight into how WNV causes disease but may provide new ways in which to interrupt the disease in infected people.