Chemokine regulation of myeloid cell populations during West Nile virus infection

描述（由申请人提供）：西尼罗河病毒（WNV）是一种高毒性的中枢神经系统（CNS）人类病原体，是美国流行性脑炎的最常见原因。目前还没有疫苗或特定的抗病毒治疗方法 为西尼罗河病毒，实现这一目标需要更全面地了解其发病机制。在CNS中，骨髓细胞，包括浸润性炎性单核细胞、巨噬细胞和活化的小胶质细胞，构成了对WNV脑炎的大部分细胞应答。目前，每个髓系亚群在调节病毒发病机制中的具体作用在很大程度上是未知的。本提案的主要目标是了解西尼罗河病毒感染期间骨髓细胞群体的基本生物学。为此，我们将1）建立WNV诱导的单核细胞动员的机制和意义，2）定义在WNV感染的CNS中表达CCR2的单核细胞的迁移和功能，3）表征在WNV脑炎期间表达CX3CR1的小胶质细胞的神经致病作用。详细了解骨髓细胞亚群的具体作用将提供深入了解其基本生物学及其对宿主防御的贡献。此外，我们的研究结果将提供新的干预策略的基础上，针对中枢神经系统中的骨髓细胞亚群，当需要有效的治疗是最关键的。

DESCRIPTION (provided by applicant): West Nile virus (WNV) is a highly virulent human pathogen of the central nervous system (CNS) and the most common cause of epidemic encephalitis in the United States. There are no vaccines or specific antiviral treatments available for WNV, and accomplishing this requires a more complete understanding of its pathogenesis. In the CNS, myeloid cells, including infiltrating inflammatory monocytes, macrophages, and activated microglia, comprise the majority of the cellular response to WNV encephalitis. Currently, the specific role of each myeloid subset in regulating viral pathogenesis is largely unknown. The primary goal of this proposal is to understand the fundamental biology of myeloid cell populations during WNV infection. To do this, we will 1) establish the mechanisms and significance of WNV-induced monocyte mobilization, 2) define the migration and function of CCR2-expressing monocytes in the WNV-infected CNS, and 3) characterize the neuropathogenic role of CX3CR1-expressing microglia during WNV encephalitis. Detailed knowledge of the specific roles of myeloid cell subsets will provide insights into their fundamental biology and their contribution to host defense. Furthermore, our results will provide the basis for novel intervention strategies targeting myeloid cell subsets in the CNS, when the need for effective treatments is most critical.