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

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 登革热是一种泛热带蚊媒病毒，每年感染5000万至1亿人。一组四种密切相关的血清型，DENV-1-4，它们引起广泛的疾病，从相对温和的登革热（DF）到更严重的登革出血热（DHF）和休克综合征（DSS）。 近几十年来，登革热活动在其整个范围内有所增加，其特点是更频繁和严重的流行病。虽然这种重新出现的原因可能是多方面的，从载体扩增到导致抗体依赖性增强（ADE）的高流行性，但病毒株毒力变异的重要性已在其他研究中得到证实，并得到我们初步研究结果的支持。我们对在加勒比地区共同传播的登革热病毒进行了纵向进化研究，并展示了二十多年来戏剧性的爆发动态，通过细胞模型和蚊子的爆发菌株进行实验感染，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。我们的研究结果将提供一个更好的理解疾病出现的进化驱动力沿着一组信息模型，用于表征紧急应变。

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.