Mechanisms of West Nile virus selection and strain displacement

授予编号3R56AI069217-01A2W1 Kramer，Laura ARRA资金考虑事项 摘要 建议进行研究以解决PA-04-119生物防御和新发传染病研究机会。西尼罗河病毒是NIAID B类优先病原体。在北美一个相对特征明确的时间和地点引入一个西尼罗河病毒株，为前瞻性地研究节肢动物传播的核糖核酸病毒适应NA�ve生态位时的进化提供了一个独特的机会。虽然美洲的西尼罗河病毒仍然是一个相对同质的病毒种群，但与引入的基因不同的单一基因已经在整个北美占据主导地位，自2002年以来已经取代了美国以前存在的基因类型。我们的研究表明，这种新基因的优势很可能是由病毒和蚊子宿主之间的相互作用促进的，也可能是通过与天然禽类宿主的相互作用而促进的。然而，可能导致一种虫媒病毒基因与另一种虫媒病毒基因置换的一系列生物学机制尚未得到系统研究。因此，我们将检验一个假设，即一种西尼罗河病毒基因的优势可能是该基因在蚊子中的选择优势所致。我们建议进行实验，以确定这些表型差异是否与病毒复制事件中细胞水平的差异有关。我们将确定西尼罗河病毒关键蚊子载体中的点(S)，这些点可能导致观察到的一种病毒基因型在美国的灭绝。虫媒病毒与脊椎动物和无脊椎动物宿主之间的相互作用会影响病毒的传播强度，从而改变地方病扩增速度、病毒的遗传稳定性和随后的病毒适应性。这些研究的结果将通过增加我们对形成侵袭性媒介传播病毒种群的选择性过程的理解，对公共健康产生直接影响，该过程使用西尼罗河病毒作为模型系统，将媒介传播病原体引入到幼稚的环境中。 在当今人员和商业快速流动以及病原体随之流动的时代，这种知识获得了额外的重要性。更好地了解病毒对幼稚环境的适应机制和宿主中的基因型选择，将使我们能够更好地预测生物事件和更好地控制引入的病原体。

Grant Number 3R56AI069217-01A2W1 Kramer, Laura ARRA Funding Consideration Abstract Research is proposed to address PA-04-119 Biodefense and Emerging Infectious Disease Research Opportunities. WNV is a NIAID Category B priority pathogen. The introduction of a single WNV strain at a relatively well characterized time and place in North America has provided a unique opportunity to prospectively study the evolution of an arthropod-transmitted RNA virus as it adapts to a na�ve ecological niche. While WNV in the Americas remains a relatively homogeneous virus population, a single genotype that differs from the introduced genotype has become dominant throughout North America, and since 2002 has displaced previously existing genotypes in the United States. Our studies suggest that the dominance of this new genotype is most likely facilitated by interactions between the virus and the mosquito host, but possibly also by interactions with natural avian hosts. The range of biological mechanisms that may lead to the displacement of one arboviral genotype with another, however, has not been systematically examined. Accordingly, we will test the hypothesis that dominance of one WNV genotype may result from selective advantages of this genotype in the mosquito. We propose experiments that will determine whether these phenotypic differences are associated with differences at the cellular level in viral replication events. We will determine the point(s) in the WNV replication cycle in critical mosquito vectors that are likely to have been responsible for the observed extinction of one viral genotype as it has been displaced with another in the U.S. Interactions of an arbovirus with both vertebrate and invertebrate hosts impact the intensity of virus transmission and thereby alter the rate of enzootic amplification, genetic stability of the virus, and subsequent viral fitness. Results from these studies will have direct implications on public health by increasing our understanding of the selective processes that shape invasive vector-borne virus populations using WNV as a model system for a vector-borne disease agent introduced into a naive environment. Such knowledge gains added importance in these times of rapid movement of people and commerce and concomitant movement of pathogens. A better understanding of the mechanisms of viral adaptation to naive environments and selection of genotypes in the host, will allow us to anticipate biological events and control introduced agents better.