Quasispecies dynamics in arborvirus persistence, emergence and fitness

虫媒病毒持久性、出现和适应性的准种动态

• 批准号: 7418914
• 负责人: Gregory David Ebel
• 金额: $ 36.79万
• 依托单位: UNIVERSITY OF NEW MEXICO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-15 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7418914
• 关键词: Address; Animals; Arboviruses; Area; Binding; Biological Models; Birds; Chickens; Communities; Competence; Complex; Consensus Sequence; Culex pipiens; Culicidae; Data; Dengue Virus; Disease Outbreaks; Ecosystem; Encephalitis Viruses; Environment; Epithelium; Equus caballus; Flavivirus Infections; Genetic Variation; Genome; Goals; Health; Human; Infection; Intervention; Laboratories; Medicine; Midgut; Modeling; Mus; Nature; New York City; North America; Nucleotides; Pathogenesis; Phenotype; Population; Population Dynamics; Population Heterogeneity; Production; Public Health; RNA Sequences; RNA Viruses; Research; Rift Valley fever virus; Shapes; Source; Staging; Structure; Testing; Variant; Viral; Viremia; Virus; Virus Diseases; West Nile virus; Work; arbovirus disease; base; biodefense; design; enzootic; fitness; improved; in vivo; mouse model; mutant; novel; research study; saliva secretion; transmission process; vector; vector mosquito; viral RNA; virus genetics; virus host interaction; virus pathogenesis

DESCRIPTION (provided by applicant): Arthropod-borne viruses (arboviruses) continue to burden human health in spite of impressive advances in public health and medicine. The introduction of these agents into naive ecosystems presents an ongoing challenge. Our ability to predict whether these agents will persist once introduced and/or emerge as significant public health threats is hindered because we know very little about the underlying mechanisms that allow them to adapt to novel and/or changing environments. West Nile virus (WNV) exists in nature as a genetically diverse swarm of competing mutants that differ in varying degrees from a consensus sequence (i.e. as a quasispecies). Our long-term objective is to understand how arbovirus population dynamics are shaped by their transmission cycles, and how these host-virus interactions contribute to arbovirus persistence and emergence. Proposed studies will test the hypothesis that arbovirus quasispecies are associated with mode of transmission and in vivo phenotype. This hypothesis will be tested using WNV, which was recently introduced into North America, as a model system. We will incorporate a research strategy that takes advantage of pre-existing, well genetically characterized WNV populations, our ability to manipulate the WNV genome, and our ability to faithfully model the WNV transmission cycle in the laboratory. This work builds on preliminary studies showing that WNV exists in nature as a quasispecies, and that mosquitoes provide a source of genetic variation to WNV populations while birds limit this variation. Our specific aims are to (1) determine the impact of mosquito infection and transmission on the WNV quasispecies in mosquitoes, (2) to evaluate the impact of WNV genetic diversity on mosquito vector competence, avian infectivity and viremia, and pathogenesis in mice, and (3) to determine whether more genetically diverse WNV populations are more fit in mosquitoes and birds than less diverse populations. The results of these studies will enhance our basic understanding of the host-virus interactions that allow arboviruses to persist within complex transmission cycles and emerge as health threats.

描述（由申请人提供）：尽管公共卫生和医学取得了令人瞩目的进步，节肢动物传播的病毒（虫媒病毒）仍然给人类健康带来负担。将这些代理引入幼稚的生态系统提出了持续的挑战。我们预测这些物质一旦引入和/或作为重大公共卫生威胁出现后是否会持续存在的能力受到阻碍，因为我们对允许它们适应新的和/或不断变化的环境的基本机制知之甚少。西尼罗河病毒 (WNV) 在自然界中作为一群具有不同遗传多样性的竞争突变体存在，这些突变体与共有序列有不同程度的差异（即作为准种）。我们的长期目标是了解虫媒病毒的传播周期如何影响虫媒病毒的种群动态，以及这些宿主与病毒的相互作用如何促进虫媒病毒的持续存在和出现。拟议的研究将检验虫媒病毒准种与传播模式和体内表型相关的假设。这一假设将使用最近引入北美的 WNV 作为模型系统进行检验。我们将整合一项研究策略，利用现有的、具有良好遗传特征的西尼罗河病毒种群、我们操纵西尼罗河病毒基因组的能力，以及我们在实验室中忠实模拟西尼罗河病毒传播周期的能力。这项工作建立在初步研究的基础上，初步研究表明西尼罗河病毒作为准种存在于自然界中，蚊子为西尼罗河病毒种群提供了遗传变异的来源，而鸟类限制了这种变异。我们的具体目标是（1）确定蚊子感染和传播对蚊子中西尼罗河病毒准种的影响，（2）评估西尼罗河病毒遗传多样性对蚊子媒介能力、禽类感染性和病毒血症以及小鼠发病机制的影响，以及（3）确定遗传多样性较高的西尼罗河病毒种群是否比多样性较低的西尼罗河病毒种群更适合蚊子和鸟类 人口。这些研究的结果将增强我们对宿主与病毒相互作用的基本了解，这种相互作用使虫媒病毒能够在复杂的传播周期中持续存在并成为健康威胁。