Dengue Human Immunology Project Consortium (DHIPC)

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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).