Dengue Human Immunology Project Consortium (DHIPC)

登革热人类免疫学项目联盟 (DHIPC)

• 批准号: 10153656
• 负责人: Ana Fernandez-Sesma
• 金额: $ 300万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10153656
• 关键词: Address; Arbovirus Infections; Cells; Data; Dendritic Cells; Dengue; Dengue Infection; Dengue Vaccine; Disease; Emerging Communicable Diseases; Enrollment; Epidemic; Funding Agency; Funding Opportunities; Gene Proteins; Generations; Genes; Goals; Human; Immune; Immune response; Immunity; Immunology; Infection; Infrastructure; Measures; Mediating; Nicaraguan; Outcome; Pathogenesis; Peripheral Blood Mononuclear Cell; Phenotype; Pilot Projects; Proteome; Research; Serotyping; Severity of illness; Small Interfering RNA; System; Vaccinated; Vaccination; Virus Diseases; Virus Replication; ZIKA; adaptive immunity; cell type; chikungunya; epigenome; experimental study; flexibility; genome-wide; holistic approach; network models; novel strategies; organizational structure; phenotypic data; predictive modeling; programs; response; transcriptome; vaccine candidate; vaccine efficacy

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).

登革热人类免疫学项目联盟(DHIPC)旨在确定 人类对登革热和相关虫媒病毒感染或接种疫苗的免疫反应 疾病。它有具体的目标、目的和关键里程碑，以及一个 支持这一综合计划，“组学”核心与项目整合在一起(图1)。 此外，我们希望确定可用作预测或指标的免疫特征。 保护性或疾病严重性。由于该领域不是静态的，因此核心和项目可以灵活地 允许能力建设，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(例如基孔肯雅热和寨卡病毒) 本项目头几年发生的流行病)，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)。我们是 采用综合办法处理以下具体目标： 目的1.测量DENV感染后人体免疫状况的动态变化 与人类的结局和免疫反应的产生相关。这一目标侧重于 表征与自然感染结局和疾病严重程度相关的免疫特征 DENV感染，按原发DENV感染与继发DENV感染和DENV血清型分层。此外，我们 将研究先天免疫模式如何影响体液和细胞介导的适应性免疫 在病毒感染之后。表型数据与使用不同基因组范围收集的数据的整合 平台将确定涉及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)。 目的2.比较接种疫苗的人和自然感染DENV的人的免疫状况 并确定与DENV疫苗效力相关的免疫特征。在这里，我们 将分析和整合接种DENV2疫苗的人类的全球反应，作为候选 以及那些随后参加人类挑战研究的人(项目2和核心B、C、D、E和F)。 目的3.验证由预测DENV免疫的网络模型定义的免疫特征 和发病机制。最后，我们将对选定的基因和蛋白质进行有针对性的实验 评估病毒的表型影响 复制、免疫反应和宿主 与疾病相关的签名。这里 我们将使用主要的人类系统，如 作为外周血单核细胞 (PBMC)和树突状细胞(DC) 会在体外感染选定的 尼加拉瓜DENV初代分离株和 DENV候选疫苗。我们会 在这些方面进行有针对性的研究 去除关键宿主基因的原代细胞 使用siRNA并评估其对 转录组、表观基因组和 细胞中的蛋白质组跨细胞解卷 体外活体类型(项目3和核心B、C、 D，E&F)。