Evolutionary potential of a model poxvirus

模型痘病毒的进化潜力

• 批准号: 8010949
• 负责人: Nels C. Elde
• 金额: $ 4.5万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 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 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8010949
• 关键词: Address; Animals; Automobile Driving; Back; Biological; Biological Assay; Biological Models; Biological Process; Birth; Categories; Cell Line; Cells; Cellular Assay; Cellular biology; Centers for Disease Control and Prevention (U.S.); Cessation of life; Conflict (Psychology); Couples; DNA Viruses; Data; Data Set; Epidemic; Evolution; Foundations; Genes; Genome; Genomics; Health; Horizontal Gene Transfer; Human; Immunity; Infection; Integration Host Factors; Investigation; Laboratories; Laboratory Research; Lead; Left; Life; Modeling; Molecular; Monitor; Monkeypox; Mouse Protein; Mutation; Nature; Phase; Phosphotransferases; Play; Population; Poxviridae; Primates; Process; Proteins; Race; Relative (related person); Research; Rodent; Seeds; Shapes; Side; Signal Transduction; Smallpox; Smallpox Viruses; Source; Specificity; Staging; Study models; Terrorism; Testing; Training; Vaccines; Vaccinia; Vaccinia virus; Vaccinium; Variant; Viral; Viral Physiology; Viral Proteins; Virulence; Virus; Virus Diseases; acquired factor; arm; career development; cost; genome sequencing; insight; interdisciplinary approach; mimicry; pandemic disease; pathogen; potency testing; pressure; programs; protein kinase R; public health relevance; reconstruction; research study; skills; vector vaccine; virology; weapons

DESCRIPTION (provided by applicant): Pathogens produce an enormous 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 of the most rapidly evolving factors in genomes. Yet little is known about the consequences of this 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, which will be completed in the K99 phase of the project, investigates the origins and evolution of a fast evolving poxvirus protein called K3L that mimics the substrate of the 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 of these 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 of this 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 of the 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 3 that will be conducted during the independent phase of the project. All the experimental aims of this program will develop important skills for establishing an independent research laboratory. This investigation of the 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. Public Health Relevance: Poxviruses are large DNA viruses that infect animals and humans. Smallpox is a Center for Disease Control high-threat (Category A) agent and monkeypox may be poised for epidemic infections of human populations. This project takes an evolutionary approach to understanding how poxviruses adapt to exploit their hosts, so that these evolutionary strategies might be counteracted for the protection of human health.

描述（由申请人提供）：病原体产生多种因子，这些因子与宿主成分相互作用以促进感染。许多此类因子类似于或模仿宿主蛋白。参与这些宿主-病原体相互作用的蛋白质是基因组中进化最快的因素之一。然而，人们对这种快速进化对宿主与病原体关系的影响知之甚少。该研究计划旨在通过重点关注模型痘病毒（牛痘）来检查相互作用的宿主和病原体蛋白的快速进化。目标 1 将在该项目的 K99 阶段完成，研究一种名为 K3L 的快速进化痘病毒蛋白的起源和进化，该蛋白模仿抗病毒蛋白激酶 R (PKR) 的底物来破坏抗病毒活性。进化分析将指导祖先 K3L 变体的重建，而细胞分析和实验性病毒感染将测试这些重建的进化步骤的效力。目标 2 研究 K3L 从天花（一种毁灭性的人类病原体）中进化而来。专注于啮齿类动物 K3L 对 PKR 敏感性的实验将检验天花源自特定啮齿类动物宿主的假设。该计划的目标 3 需要在不同宿主细胞系中进行痘苗病毒的实验进化。牛痘将在受控条件下在细胞系中反复传代，并监测基因组变化和潜在的适应。该目标与目标 2 一起将在项目的 K99 阶段启动，并将提供有关宿主和病原体因子相互作用之间进化适应的大量数据。这些实验产生的数据将成为目标 3 中提出的持续项目的基础，这些项目将在项目的独立阶段进行。该计划的所有实验目标都将培养建立独立研究实验室的重要技能。对相互作用的宿主和病原体因素之间的进化动力学的研究将为痘病毒的进化策略提供新的见解，痘病毒是一类具有潜在危险的病原体，可能会导致自然流行病和/或用作生物恐怖主义的媒介。 公共卫生相关性：痘病毒是感染动物和人类的大型 DNA 病毒。天花是疾病控制中心的高威胁（A 类）病原体，猴痘可能会引起人群的流行性感染。该项目采用进化方法来了解痘病毒如何适应利用其宿主，以便抵消这些进化策略以保护人类健康。

项目成果

A cross-species view on viruses.

对病毒的跨物种观点。

• DOI: 10.1016/j.coviro.2012.07.003
• 发表时间: 2012
• 期刊: Current opinion in virology
• 影响因子: 5.9
• 作者: Sawyer,SaraL;Elde,NelsC
• 通讯作者: Elde,NelsC

Escape from bacterial iron piracy through rapid evolution of transferrin.

• DOI: 10.1126/science.1259329
• 发表时间: 2014-12-12
• 期刊: Science (New York, N.Y.)
• 作者: Barber MF;Elde NC
• 通讯作者: Elde NC