Project 1 - Immune profiling of natural dengue virus infections

概要（项目1） 四种登革病毒血清型（DENV 1 -4）引起最重要的蚊媒病毒性疾病， 人类，每年约1亿例，但没有批准的疫苗或抗病毒药物存在。因素决定 DENV感染后的疾病结果还不清楚，认为部分是由 宿主免疫反应病毒因素和宿主先天免疫相互作用可能会影响免疫系统的质量。 适应性免疫应答，其可以提供保护或引起后续DENV的增强 感染登革热人类免疫学项目联盟（DHIPC）的项目1侧重于表征 与天然DENV感染结果和疾病严重程度相关的免疫特征 感染.项目1的总体方法是利用来自长期研究的独特样本集， 尼加拉瓜正在进行的登革热研究，以发现与症状相关的免疫因素， 登革病毒感染、严重登革疾病和特异性适应性免疫应答。项目1将继续 四川省儿童登革热队列研究（PDCS）从有充分记录的自然重复中收集样本 DENV感染。它还将利用正在进行的尼加拉瓜登革热医院研究， 调查严重与轻度登革热疾病，并将进行指数聚类研究，以提供样本 无症状的病毒血症个体。所有样本均附有详细的临床数据。结合 世界级的DHIPC核心，一种系统生物学方法将用于构建一个先天性的签名， 自然感染登革病毒的免疫反应。互补的尖端基因组， 转录组学、蛋白质组学、血清组学和免疫表型分析方法将使人类免疫 对登革热的反应进行了前所未有的详细和复杂的剖析。目标1将 表征具有不同临床结果的DENV感染的免疫谱：无症状和 症状性DENV感染使用指数聚类研究和PDCS中的轻度与重度疾病， 基于医院的研究目的2将描述原发性和继发性DENV感染的免疫特征， 感染的特定血清型顺序。目标3将研究先天免疫特征之间的关联 以及抗体和细胞介导的免疫应答。抗体中和、同种型和库将在下文描述。 评价的，以及内的B细胞应答的幅度和表型特异性或交叉反应性。 项目1。将通过细胞内细胞因子染色评价T细胞应答的多功能性。总的来说， 项目1将能够识别预测感染和疾病的生物标志物和免疫特征 结果，从而有助于改善临床管理，疫苗设计和开发新的 登革热的抗病毒治疗。

SUMMARY (PROJECT 1) The four dengue virus serotypes (DENV1-4) cause the most important mosquito-borne viral disease of humans, with ~100 million cases annually, yet no approved vaccines or antivirals exist. Factors that determine disease outcome following DENV infection are not well understood and are thought to be mediated in part by host immune responses. Viral factors and host innate immune interactions likely influence the quality of the adaptive immune response, which can either protection provide or cause enhancement in a subsequent DENV infection. Project 1 of the Dengue Human Immunology Project Consortium (DHIPC) focuses on characterizing immune signatures associated with infection outcomes and disease severity in natural DENV infections. The overall approach of Project 1 is to take advantage of unique sample sets from long-term ongoing studies of dengue in Nicaragua to enable discovery of immune factors associated with symptomatic DENV infection, severe dengue disease, and specific adaptive immune responses. Project 1 will continue the Nicaraguan Pediatric Dengue Cohort Study (PDCS) to collect samples from well-documented natural repeat DENV infections. It will also leverage an on-going hospital-based study of dengue in Nicaragua to enable investigation of severe vs. mild dengue disease and will conduct an index cluster study to provide samples from asymptomatic viremic individuals. Detailed clinical data will accompany all samples. In conjunction with the world-class DHIPC Cores, a systems biology approach will be used to construct a signature of innate immune responses during natural DENV infection. The constellation of complementary cutting-edge genomic, transcriptomic, proteomic, seromic, and immunophenotyping methods will enable the human immune response to dengue to be dissected with unprecedented detail and sophistication. Aim 1 will characterize immune profiles in DENV infections with different clinical outcomes: asymptomatic and symptomatic DENV infection using the index cluster study and mild vs. severe disease in the PDCS and the hospital-based study. Aim 2 will characterize immune profiles in primary and secondary DENV infections, in specific serotype order of infection. Aim 3 will investigate the association between innate immune signatures and antibody and cell-mediated immune responses. Antibody neutralization, isotype, and repertoire will be evaluated, as well as the magnitude and serotype-specificity or cross-reactivity of the B cell response within Project 1. T cell responses will be evaluated for multi-functionality by intracellular cytokine staining. Overall, Project 1 will enable identification of biomarkers and immune signatures predictive of infection and disease outcome and thus contribute to improving clinical management, vaccine design and development of novel antiviral therapies against dengue.