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

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 登革热是一种泛热带蚊媒黄病毒，每年感染5000万至1亿人。一组四种密切相关的血清型，DENV 1-DENV 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，从载体扩张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. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Dengue is a pantropical mosquito-borne flavivirus infecting 50 to 100 million people a year. A group of four closely related serotypes, DENV1-DENV4, 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 re-emergence are probably multifold, from vector expansions to hyper-endemicity 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 co-circulating 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.