Evolutionary potential of a model poxvirus

模型痘病毒的进化潜力

• 批准号: 8274656
• 负责人: Nels C. Elde
• 金额: $ 24.58万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8274656
• 关键词: Amino Acid Substitution; Animals; Back; Biological Models; Birth; Categories; Cell Line; Cellular Assay; Centers for Disease Control and Prevention (U.S.); Conflict (Psychology); DNA Viruses; Data; Data Set; Engineering; Epidemic; Equilibrium; Evolution; Foundations; Genes; Genetic; Genome; Genomics; Health; Horizontal Gene Transfer; Human; Immunity; Infection; Integration Host Factors; Investigation; Laboratory Research; Malignant Neoplasms; Modeling; Molecular; Monitor; Monkeypox; Mouse Protein; Oncolytic; Phase; Phosphotransferases; Population; Poxviridae; Predisposition; Primates; Procedures; Process; Proteins; Race; Relative (related person); Research; Resistance to infection; Rodent; Sampling; Seeds; Shapes; Side; Signal Transduction; Smallpox; Smallpox Viruses; Source; Specificity; Terrorism; Testing; Time; Vaccines; Vaccinia; Vaccinia virus; Vaccinium; Variant; Viral; Viral Physiology; Viral Proteins; Virus; Virus Diseases; acquired factor; arm; cost; experience; insight; mimicry; pandemic disease; pathogen; potency testing; pressure; programs; protein kinase R; recombinant virus; reconstruction; research study; skills; weapons

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.

病原体产生多种因子与宿主成分相互作用以促进感染。 许多这样的因子类似或模拟宿主蛋白质。参与这些宿主-病原体相互作用的蛋白质 are some of most最rapidly迅速evolving进化factors因子in genomes基因组.然而，人们对这种情况的后果知之甚少， 宿主-病原体关系的快速进化。这项研究计划旨在研究快速进化的 相互作用的宿主和病原体蛋白质，通过集中在模型痘病毒，牛痘。目标1调查了 一种称为K3 L的快速进化痘病毒蛋白的起源和进化，该蛋白模拟抗病毒药物的底物。 蛋白激酶R（PKR）破坏抗病毒活性。进化分析将指导重建 祖先K3 L变体，而细胞测定和实验性病毒感染将测试这些变体的效力。 重建进化步骤。目的2研究K3 L从天花的进化，这是一个毁灭性的 人类病原体集中于K3 L对来自啮齿动物的PKR的敏感性的实验将检验以下假设： 天花起源于一种特定的啮齿动物宿主。该计划的目标3需要实验性的进化， 不同宿主细胞系中的牛痘病毒。牛痘将在受控条件下在细胞系中反复传代 条件下，并监测基因组变化和潜在的适应。这一目标与目标2一起沿着， 在K99项目阶段启动，并将提供有关进化适应的广泛数据 宿主和病原体因素之间的相互作用。从这些实验中产生的数据将是 为目标1和目标3中提议的将在2010年期间开展的持续项目奠定基础。 项目的独立阶段。该计划的所有实验目标将培养重要的技能， 建立独立的研究实验室。这项关于进化动力学的研究 相互作用的宿主和病原体因素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，可能会自然流行和/或用作 生物恐怖主义