Project 2: Molecular Signatures of West Nile virus susceptibility

摘要 免疫状态和功能的个体差异形成了对感染的反应，并有助于 疾病的严重程度和结局。感染西尼罗河病毒可能是无症状的或严重的，甚至 导致死亡，并且没有有效的治疗方法或疫苗可用。因此，识别分子 免疫标志和易感表型是指导改良的发展必不可少的 诊断、治疗干预和未来的疫苗。我们建议进行协调一致的研究 西尼罗河病毒感染分层受试者调查的系统方法 免疫反应的组成部分导致了不同的结果。我们将利用最新的进展 在高通量和高分辨率技术中分析个体免疫反应，以便 确定定义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、新陈代谢组学和创新的纳米细胞细胞术 单细胞RNA-seq，提供对西尼罗河病毒免疫反应的洞察。我们协调深入的 系统分析首次包括中性粒细胞、血小板和 代谢组学在不同临床结果中的应用。通过整合多种免疫成分，我们将 定义与感染成功结局相关的响应配置文件。我们的建议的优点是 良好的临床人群特征，对多种细胞类型的协调深入询问 和回应，经验丰富和协调的研究团队，讯问和整合 影响免疫反应的多个变量，并建立了HIPC联合体网络。

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.