Genetic signatures of dengue virus emergence

登革热（DENV）在过去25年中重新出现，成为最重要的新兴传染病之一， 疾病，对美国构成重大的A类生物防御威胁， 波多黎各的流行病，以及最近在夏威夷（2001年）和得克萨斯州（1999年、2005年、2006年）的疫情。其全球 复苏，而部分原因是人口统计学的变化，增加hyperendemicity， 蚊子传播媒介的扩张，仍然知之甚少，特别是关于病毒的重要性， 进化我们通过对登革病毒株进行比较进化研究来填补这一关键空白 从亚太竞技场的重复人群中， 针对与流行病相关的病毒表型变化的组织和动物模型测定。我们的长期 我们的目标是解决病毒基因变化如何驱动疾病的出现。建议的目标 研究的目的是描述从流行病中分离出的登革热病毒相对于其地方性流行病的进化特征， 形成并证实了实验模型中遗传变化的影响，其基本原理是， 对这种病毒遗传变化及其固定机制的鉴定将阐明 登革热的流行潜力和最终发病机制。 具体目标1：确定DENV在地方性和流行性传播阶段之间的演变， 识别出具有更高流行潜力的突触形态。 具体目标2：确认登革病毒流行株的遗传变化与其感染的关系。 体外模型中的表型效应。 具体目标3：确认登革病毒流行株的遗传变化与其 体内模型中的表型效应

Dengue (DENV) has re-emerged in the last 25 years as one of the most significant emerging infectious diseases worldwide, posing a significant category A biodefense threat to the United States with ongoing epidemics in Puerto Rico, and recent outbreaks in Hawaii (2001) and Texas (1999, 2005, 2006). Its global resurgence, while partly explained by changing human demographics, increasing hyperendemicity, and mosquito vector expansions, remains poorly understood, especially with respect to the importance of virus evolution. We fill this critical gap by conducting a comparative evolutionary examination of DENV strains undergoing epidemic expansion, from replicate populations across the Asia-Pacific arena, paired with directed tissue and animal model assays for changes in virus phenotype related to epidemics. Our long-term goal is to resolve how viral genetic change drives disease emergence. The objective of the proposed research is to characterize evolution in dengue viruses isolated from epidemics relative to their endemic forms and confirm the impact of genetic changes in experimental models, the rationale being that identification of such viral genetic changes and their mechanisms of fixation will illuminate determinants of dengue epidemic potential and ultimately pathogenesis. Specific Aim 1: Determine the evolution of DENV between endemic and epidemic transmission phases to identify synapomorphies of higher epidemic potential. Specific Aim 2: Confirm the relationship between genetic changes in DENV epidemic strains and their phenotypic effects in in vitro models. Specific Aim 3: Confirm the relationship between genetic changes in DENV epidemic strains and their phenotypic effects in in vivo models