Project 2: Molecular Signatures of West Nile virus susceptibility

摘要 免疫状态和功能的个体差异塑造了对感染的反应， 疾病的严重程度和结果。感染西尼罗河病毒可以是无症状的或严重的， 导致死亡，并且没有有效的治疗或疫苗可用。因此，识别分子 免疫特征和易感性表型对于指导改进的 诊断、治疗干预和未来的疫苗。我们建议进行协调的研究 研究西尼罗河病毒感染分层受试者的系统方法，以确定如何 免疫反应的不同组成部分导致不同的结果。我们将利用最新的进展 在高通量和高分辨率技术中，以描绘个体免疫应答， 确定对西尼罗河病毒感染的不同反应的分子特征。我们 将使用共享平台，如CyTOF，代谢组学和创新的细胞计数， 单细胞RNA-seq，以提供对WNV免疫反应的洞察。我们协调的深入 系统分析首次包括中性粒细胞、血小板和 代谢组学在不同的临床结果。通过整合多种免疫成分， 定义与感染成功结果相关的反应概况。我们的建议的优点是 良好表征的临床人群，多种细胞类型的协调深入询问 和反应，经验丰富和协调的研究团队，审讯和整合， 影响免疫反应的多种变量，并建立了重债穷国联盟网络。

Abstract Individual variations in immune status and function shape responses to infection and contribute to disease severity and outcome. Infections with West Nile virus can be asymptomatic or severe, even leading to death, and no effective therapies or vaccines are available. Thus, identifying molecular signatures of immunity and phenotypes of susceptibility is essential to guide development of improved diagnostics, therapeutic interventions and future vaccines. We propose studies with a coordinated Systems approach for investigation of stratified subjects with West Nile viral infections to define how components of the immune response contribute to divergent outcomes. We will employ recent advances in high-throughput and high-resolution technology to profile individual immune responses in order to identify the molecular signatures defining divergent responses to West Nile virus infections. We will use shared platforms such as CyTOF, metabolomics, and innovative nanowell cytometry linked to single cell RNA-seq to provide insight into the immune responses to WNV. Our coordinated in-depth systems analysis includes for the first time the phenotype and functionality of neutrophils, platelets, and metabolomics in divergent clinical outcomes. Through integrating multiple immune components, we will define response profiles that correlate with successful outcome of infection. Strengths of our proposal are the well characterized clinical populations, the coordinated in-depth interrogation of multiple cell types and responses, the experienced and coordinated research team, the interrogation and integration of multiple variables that influence immune responses, and established HIPC consortium networks.