Dengue Human Immunology Project Consortium (DHIPC)

登革热人类免疫学项目联盟（DHIPC）旨在确定 人对登革热和相关虫媒病毒感染或疫苗接种的免疫应答 疾病它有具体的目标、目的和重要的里程碑，以及一个组织结构， 支持这一全面的计划，“组学”核心与项目相结合，以（图1）。 此外，我们期望鉴定出可用作免疫缺陷的预测因子或指标的免疫特征。 保护或疾病的严重程度。由于该领域不是静态的，核心和项目具有灵活性， 开展能力建设，以评估解决人类免疫其他方面问题的新方法 通过发现研究或其他新出现的传染病（例如基孔肯雅和寨卡病毒）， 该项目最初几年发生的流行病），并已提议进行试点研究 （通过使用重债穷国基础设施和机会基金或其他资金来源）。我们 采用综合办法实现以下具体目标： 目标1。测量DENV感染后人体免疫谱的动态变化， 与人类免疫反应的产生和结果相关。这一目标的重点是 表征与自然感染结果和疾病严重程度相关的免疫特征 DENV感染，按原发性与继发性DENV感染和DENV血清型分层。另外我们 将研究先天免疫特征如何影响体液和细胞介导的适应性免疫 病毒感染后。表型数据与使用不同全基因组收集的数据的整合 这些平台将确定参与宿主免疫和疾病发病机制的关键基因和网络 （项目1和核心B、C、D、E和F）。 目标二。比较接种疫苗的人与自然获得的DENV患者的免疫特征 感染并识别与DENV疫苗功效相关的免疫特征。这里我们 将分析和整合接种DENV2候选疫苗的人类的全球反应， 以及随后参加人体挑战研究的那些人（项目2和核心B、C、D、E和F）。 目标3。验证由预测DENV免疫力的网络模型定义的免疫特征 和发病机制。最后，我们将针对选定的基因和蛋白质进行靶向实验 评估对病毒表型的影响 复制、免疫应答和宿主 与疾病相关的特征这里 我们将使用主要的人类系统， 作为外周血单核细胞 （PBMC）和树突状细胞（DC）， 将被体外感染所选择的 莫桑比克DENV原代分离株和 登革病毒候选疫苗。我们将 开展针对性研究， 消除宿主关键基因的原代细胞 使用siRNA并评估其对 转录组、表观基因组和 细胞内蛋白质组跨细胞去卷积 离体类型（项目3和核心B，C， D、E和F）。

The Dengue Human Immunology Project Consortium (DHIPC) aims to identify mechanisms underlying the human immune response to infection by or vaccination against dengue and related arboviral diseases. It has specific goals, objectives, and critical milestones and an organizational structure that supports this comprehensive program, and the ‘omics’ Cores are integrated with the Projects to (Figure 1). Further, we expect to identify immune signatures that can be used as predictors or indicators of protection or disease severity. Because the field is not static, the Cores and Projects has the flexibility to allow for capacity building to assess new approaches that address other aspects of human immunity through discovery research or other emerging infectious diseases (for example, the chikungunya and Zika epidemics that occurred during the first years of this project) and have been proposed for pilot studies (through the use of the HIPC Infrastructure and Opportunity Funds (IOF) or other funding sources). We are using a holistic approach to address the following specific aims: Aim 1. Measure the dynamic changes in human immune profiles following DENV infection that correlate with outcome and the generation of immune responses in humans. This aim focuses on characterizing immune signatures associated with infection outcomes and disease severity in natural DENV infections, stratified by primary vs. secondary DENV infection and DENV serotype. In addition, we will investigate how innate immune profiles influence humoral and cell-mediated adaptive immunity following viral infection. Integration of phenotype data with data collected using different genome-wide platforms will identify key genes and networks involved in host immunity and disease pathogenesis (Project 1 and Cores B, C, D, E & F). Aim 2. Compare the immune profiles in vaccinated people to people with naturally acquired DENV infections and identify the immune signatures that correlate with DENV vaccine efficacy. Here, we will analyze and integrate the global responses in humans vaccinated with DENV2 vaccine candidates as well as those who are then enrolled in human challenge studies (Project 2 and Cores B, C, D, E & F). Aim 3. Validate the immune signatures defined by the network models that predict DENV immunity and pathogenesis. Lastly, we will perform targeted experiments focusing on selected genes and proteins to assess the phenotypic impact on virus replication, immune responses and host signatures correlating with disease. Here we will use primary human systems, such as peripheral blood mononuclear cells (PBMCs) and dendritic cells (DCs) that will be infected ex vivo with the selected Nicaraguan DENV primary isolates and DENV vaccine candidates. We will undertake targeted studies in those primary cells that ablate key host genes using siRNA and assess their impact on the transcriptome, epigenome, and proteome in cells deconvoluted across cell types ex vivo (Project 3 and Cores B, C, D, E & F).