Chemokine regulation of myeloid cell populations during West Nile virus infection

描述(申请人提供)：西尼罗河病毒(WNV)是一种高度毒性的人类中枢神经系统(CNS)病原体，也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。 对于西尼罗河病毒来说，要做到这一点，需要对其发病机制有更全面的了解。在中枢神经系统，髓系细胞，包括浸润性炎性单核细胞、巨噬细胞和激活的小胶质细胞，构成了对西尼罗河病毒脑炎的大部分细胞反应。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。这项建议的主要目标是了解西尼罗河病毒感染期间髓系细胞群体的基本生物学。为此，我们将1)建立西尼罗河病毒诱导的单核细胞动员的机制和意义，2)确定表达CCR2的单核细胞在西尼罗河病毒感染的中枢神经系统中的迁移和功能，3)研究表达CX3CR1的小胶质细胞在西尼罗河病毒脑炎中的神经致病作用。对髓系细胞亚群具体作用的详细了解将有助于深入了解它们的基本生物学及其对宿主防御的贡献。此外，我们的结果将为针对中枢神经系统髓系细胞亚群的新型干预策略提供基础，此时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.