ACT 3 PROJ 1: MOLECULAR EVOLUTIONARY PATHOGENESIS OF DENGUE VIRUS INFECTION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 登革热是一种泛热带蚊媒病毒，每年感染5000万至1亿人。一组密切相关的四种血清型，DENV-1-4，它们可引起广泛的疾病，从相对轻微的登革热(DF)到较严重的登革出血热(DHF)和休克综合征(DSS)。近几十年来，登革热活动在整个范围内都有所增加，其特点是更频繁和更严重的流行病。虽然病毒重新出现的原因可能是多方面的，从载体扩张到导致抗体依赖增强(ADE)的高度流行，但病毒株变异在毒力方面的重要性已被其他研究所牵连，并得到了我们的初步发现的支持。我们将加勒比海地区流行的登革热病毒的纵向进化研究与细胞模型和蚊子爆发株的实验感染配对，以确定流行潜力和疾病出现的遗传决定因素和表型相关性。我们的发现将提供对疾病出现的进化驱动因素的更好理解，以及一套表征新出现菌株的信息模型。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Dengue is a pantropical mosquito-borne virus infecting 50 to 100 million people a year. A group of four closely related serotypes, DENV-1-4, they cause a wide spectrum of disease, from relatively mild dengue fever (DF) to the more severe dengue hemorrhagic fever (DHF) and shock syndrome (DSS). Recent decades have seen an increase in dengue activity throughout its range, marked by more frequent and severe epidemics. Although the causes of this reemergence are probably multifold, from vector expansions to hyperendemicity leading to antibody-dependent enhancement (ADE), the importance of virus strain variation in virulence has been implicated in other studies and supported by our preliminary findings. We pair a longitudinal evolutionary study of dengue viruses cocirculating in the Caribbean and demonstrating dramatic outbreak dynamics over two decades, with experimental infections by outbreak strains of cellular models and mosquitoes, to identify the genetic determinants and phenotypic correlates of epidemic potential and disease emergence. Our findings will provide a better understanding of the evolutionary drivers of disease emergence along with a set of informative models for characterizing emergent strains.