The Evolutionary and Biological Bases of Host Switching in Viruses

描述(申请人提供)：新出现的病毒是一个紧迫的生物医学问题，有可能导致严重的发病率和死亡率。我们的目标是揭示允许病毒跳跃到新宿主物种并在其体内生存的进化过程。我们将继续并扩展我们对两种具有良好特性的动物病毒的工作，这两种病毒在最近成功地跨越了对狗的物种障碍，这两种病毒代表了强大的、在实验上易于处理的人类新兴病毒模型；狗细小病毒(CPV)从猫泛白细胞减少症病毒(FPV)出现，以及H3N8马流感A病毒(EIV)跨物种转移到狗身上，导致狗流感病毒(CIV)的出现，这种病毒在过去10年里一直在美国以有限的方式传播。我们 将进行详细的研究，以确定这些病毒与它们所利用的不同宿主物种和细胞受体之间的进化相互作用，以及介导病毒出现的因素。我们将综合使用比较和实验方法来研究三个重叠的领域：1.确定中间宿主和并行宿主在跨物种病毒传播和适应中的作用。我们将研究细小病毒在多个食肉动物宿主之间的转移如何影响它们的出现，通过创建包含关键宿主特定突变组合的进化“中间产物”，或者通过产生更广泛的可能感染先前耐药的宿主的变异。2.研究病毒衣壳与敏感和耐药宿主细胞受体之间的短期和长期进化相互作用。我们将研究宿主转铁蛋白受体1型(TFR)基因在一系列对不同细小病毒敏感的食肉动物物种中的变异，并研究宿主受体和病毒衣壳之间的长期进化军备竞赛，包括内源性细小病毒中存在的进化足迹。我们将在实验中将TFR的变化与在病毒衣壳蛋白中观察到的变化联系起来。3.确定病毒的进化轨迹如何塑造跨物种传播和适应的模式。虽然H3N8EIV在1963年首次出现在马和鸟身上，但直到最近10年才跳到狗身上，并在多个场合出现。我们将确定EIV在马身上的延长传代是否改变了成功跨物种传播给狗的可能性，并确定了影响狗的宿主嗜性的病毒基因，特别是宿主唾液酸受体与病毒血凝素和神经氨酸酶基因之间的进化联系。

DESCRIPTION (provided by applicant): Emerging viruses are a pressing biomedical problem, with the potential to cause significant morbidity and mortality. We aim to reveal the evolutionary processes that allow viruses to jump to, and become established in, new host species. We will continue and extend our work on two well characterized animal viruses that have successfully jumped species barriers to dogs in the recent past and which represent powerful and experimentally tractable models for human emerging viruses; the emergence of canine parvovirus (CPV) from feline panleukopenia virus (FPV), and the cross-species transfer of H3N8 equine influenza A virus (EIV) to dogs that resulted in the emergence of a canine influenza virus (CIV) that has been circulating in a limited fashion in the United States for the past 10 years. We will perform detailed studies to determine the evolutionary interactions between these viruses and the different host species and cell receptors they utilize, and which mediates viral emergence. We will investigate three overlapping areas using a synthesis of comparative and experimental approaches: 1. To define the role of intermediate and parallel hosts in cross-species virus transmission and adaptation. We will examine how the transfer of parvoviruses among multiple carnivore hosts influences their emergence, through the creation of evolutionary 'intermediates' that contain combinations of key host specific mutations, or by generating a wider spectrum of variants with the potential to infect previously resistant hosts. 2. To examine the short-term and long-term evolutionary interplay between viral capsids and the cell receptors of susceptible and resistant hosts. We will study variants of the host transferrin receptor type-1 (TfR) genes in a range of carnivore species that are susceptible to different parvoviruses, and examine the long-term evolutionary arms race between host receptor and viral capsid, including the evolutionary footprints present in endogenous parvoviruses. We will experimentally connect the variation of the TfR with that observed in the viral capsid protein. 3. To determine how the evolutionary trajectory of a virus shapes patterns of cross-species transmission and adaptation. Although H3N8 EIV first emerged in horses from birds in 1963, only in the last ~10 years has it jumped to dogs, and on multiple occasions. We will determine whether the extended passage of EIV in horses altered the likelihood of successful cross-species transmission to dogs, and define the viral genes that influence host tropism for dogs, particularly the evolutionary connections between the host sialic acid receptors and the viral hemagglutinin and neuraminidase genes.