The Evolutionary and Biological Bases of Host Switching in Viruses

描述（由申请人提供）：新出现的病毒是一个紧迫的生物医学问题，有可能导致显著的发病率和死亡率。我们的目标是揭示允许病毒跳跃到新宿主物种并在新宿主物种中站稳脚跟的进化过程。我们将继续并扩展我们在两种特征明确的动物病毒上的工作，这两种病毒在最近的过去已经成功地跨越了物种障碍，并且代表了人类新兴病毒的强大和实验可处理的模型；犬细小病毒（CPV）来自猫泛白细胞减少病毒（FPV）的出现，以及H3N8马流感A病毒（EIV）跨物种转移到狗身上，导致犬流感病毒（CIV）的出现，这种病毒在过去10年里在美国以有限的方式传播。我们

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.