Quasispecies dynamics in arborvirus persistence, emergence and fitness

描述（由申请人提供）：尽管公共卫生和医学取得了令人印象深刻的进步，但节肢动物传播的病毒（虫媒病毒）仍在给人类健康带来负担。将这些代理引入幼稚生态系统提出了一个持续的挑战。我们预测这些药物一旦引入和/或作为重大公共卫生威胁出现是否会持续存在的能力受到阻碍，因为我们对使它们能够适应新的和/或不断变化的环境的潜在机制知之甚少。西尼罗河病毒（WNV）在自然界中作为一群遗传多样的竞争突变体存在，这些突变体在不同程度上不同于共有序列（即作为准种）。我们的长期目标是了解虫媒病毒的传播周期是如何影响虫媒病毒种群动态的，以及这些宿主-病毒相互作用如何促进虫媒病毒的持续存在和出现。拟进行的研究将检验虫媒病毒准种与传播方式和体内表型相关的假设。这一假设将使用西尼罗河病毒，这是最近引入北美，作为一个模型系统进行测试。我们将采用一种研究策略，利用预先存在的，具有良好遗传特征的WNV种群，我们操纵WNV基因组的能力，以及我们在实验室中忠实模拟WNV传播周期的能力。这项工作建立在初步研究的基础上，表明西尼罗河病毒在自然界中作为准种存在，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的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）确定遗传多样性更高的西尼罗河病毒种群是否比遗传多样性较低的种群更适合蚊子和鸟类。这些研究的结果将增强我们对宿主-病毒相互作用的基本理解，这种相互作用使虫媒病毒在复杂的传播周期中持续存在并成为健康威胁。

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.