Evolutionary potential of a model poxvirus

病原体产生各种各样的因子，这些因子与宿主成分相互作用，促进感染。 许多这样的因子类似或模仿宿主蛋白。参与这些寄主-病原体相互作用的蛋白质 是基因组中一些进化最快的因子。然而，人们对这种情况的后果知之甚少。 寄主-病原体关系的快速进化。这项研究计划旨在检查快速进化的 通过专注于模型痘病毒痘苗病毒与宿主和病原体蛋白的相互作用。目标1调查 一种快速进化的模仿抗病毒底物的痘病毒蛋白K3L的起源和进化 蛋白激酶R(PKR)阻断抗病毒活性。进化分析将指导重建 祖先的K3L变种，而细胞分析和实验性病毒感染将测试这些变种的效力 重建的进化步骤。目标2研究K3L从天花进化而来，天花是一种毁灭性的 人类病原体。专注于啮齿动物K3L对PKR敏感性的实验将检验这一假设 天花是从一种特定的啮齿动物宿主中出现的。该计划的目标3需要进行实验进化 痘苗病毒在不同宿主细胞系中的分布。牛痘病毒将在受控制的细胞系中反复传代 并监测基因组的变化和潜在的适应。这个目标，以及目标2，将是 在项目的K99阶段启动，并将提供关于进化适应的广泛数据 相互作用的寄主和致病因子之间的关系。从这些实验中产生的数据将是 为目标1和目标3中提议的持续项目奠定基础，这些项目将在 项目的独立阶段。该计划的所有实验目标都将培养重要的技能 建立独立的研究实验室。这是一项关于生物进化动力学的研究 宿主和病原体因素的相互作用将为痘病毒的进化策略提供新的见解， 一类潜在危险的病原体，有可能成为自然流行病和/或用作 生物恐怖主义。

Pathogens produce an enornrious variety of factors that interact with host components to promote infections. Many such factors resemble or mimic host proteins. Proteins involved in these host-pathogen interactions are some ofthe most rapidly evolving factors in genomes. Yet little is known about the consequences ofthis rapid evolution on host-pathogen relationships. This research program aims to examine rapid evolution of interacting host and pathogen proteins by focusing on the model poxvirus, vaccinia. Aim 1 investigates the origins and evolution of a fast evolving poxvirus protein called K3L that mimics the substrate ofthe anti-viral Protein kinase R (PKR) to disrupt anti-viral activity. Evolutionary analysis will guide the reconstruction of ancestral K3L variants, while cellular assays and experimental viral infections will test the potency ofthese reconstructed evolutionary steps. Aim 2 investigates the evolution of K3L from smallpox, a devastating human pathogen. Experiments focusing on K3L sensitivity to PKR from rodents will test the hypothesis that smallpox emerged from a specific rodent host. Aim 3 ofthis program entails experimental evolution of vaccinia virus in different host cell lines. Vaccinia will be repeatedly passaged in cell lines under controlled conditions and monitored for genomic changes and potential adaptations. This aim, along with Aim 2, will be initiated during the K99 phase ofthe project, and will provide extensive data on evolutionary adaptations between interacting host and pathogen factors. The data generated from these experiments will be the foundation of continuing projects proposed in Aim 1 and Aim 3 that will be conducted during the independent phase ofthe project. All the experimental aims ofthis program will develop important skills for establishing an independent research laboratory. This investigation ofthe evolutionary dynamics between interacting host and pathogen factors will provide new insights into the evolutionary strategies of poxviruses, a potentially dangerous class of pathogens poised for natural epidemics and/or use as agents of bio-terrorism.