Mechanisms of mimicry underlying the evolution of a model poxvirus

模型痘病毒进化的模仿机制

• 批准号: 9133427
• 负责人: Nels C. Elde
• 金额: $ 31.66万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9133427
• 关键词: Animals; Autoimmunity; Biological; Biological Models; Birth; Categories; Cells; Centers for Disease Control and Prevention (U.S.); Chinese Hamster Ovary Cell; Communicable Diseases; Copy Number Polymorphism; Cowpox; DNA Viruses; DNA-Directed RNA Polymerase; Disease; Engineering; Epidemic; Event; Evolution; Exhibits; Gene Dosage; Genes; Genetic; Genetic Recombination; Genome; Health; Horizontal Gene Transfer; Host Defense; Human; Immune response; Immune system; Immunity; Infection; Integration Host Factors; Intervention; Left; Modeling; Molecular; Molecular Biology; Molecular Mimicry; Monkeypox; Mutation; Natural Selections; Pathogenesis; Play; Point Mutation; Polymerase Gene; Population; Poxviridae; Prevalence; Probability; Process; Proteins; Protocols documentation; Public Health; Recording of previous events; Regulation; Retrotransposon; Role; Series; Smallpox; System; Testing; Vaccinia virus; Vaccinium; Viral; Viral Genes; Viral Oncogene; Viral Physiology; Viral Proteins; Virulence; Virus; Vulnerable Populations; Work; base; biological systems; combat; design; fitness; inhibitor/antagonist; innovation; insight; mimicry; novel strategies; pathogen; pathogen genome; protein kinase R; research study; response; sensor; success; v-src Oncogenes; vaccination strategy; viral DNA; viral RNA; viral fitness; virology; weapons

 DESCRIPTION (provided by applicant): Pathogens commonly exploit host functions with molecular mimicry. Virus-encoded mimics often arise through horizontal transfer of host genes into pathogen genomes. After acquisition, these genes diverge under strong natural selection and gain new functions disrupting or coopting host processes. Classically studied examples of mimics include viral oncogenes like v-Src and v-Ras that were acquired from host genomes. Additional cases of mimicry are increasingly recognized for playing pivotal roles in the success of a diverse array of human pathogens. Despite extensive observations of mimicry, the origins and evolutionary mechanisms underlying adaptation of such pathogen genes to mimic host forms are not well understood. We have developed innovative experimental systems using vaccinia virus, the model poxvirus, to investigate the evolution of mimicry. Poxviruses deploy an abundance of mimics to defeat host defenses and can cause devastating diseases. Smallpox, for instance, likely caused more human fatalities than any other pathogen before eradication and related viruses seem poised to emerge as epidemics. To study the evolution of molecular mimicry, we are reconstructing the origins of mimics with a series of experiments selecting for horizontal gene transfer of host genes into vaccinia genomes through experimental evolution. This system provides a versatile means of capturing horizontal gene transfer events to investigate mechanisms underlying pathogen adaptation. Once pathogens acquire host factors they often diverge in ways that increase pathogen fitness, but little is known about how this process unfolds. In another major set of experiments, we have developed a means for reconstructing the adaptive process in which newly acquired host genes diverge to become mimics. Finally, we are investigating the ongoing evolution of mimics as viruses adapt to host defenses. These studies have already revealed newly described mechanisms of virus adaptation. Evolutionary-guided approaches for studying mimicry hold great promise for enriching anti-viral interventions and bolstering traditional strategies of vaccination. Our multi-faceted approach combining virology, evolutionary genetics, and molecular biology will provide insight into fundamental mechanisms of pathogen adaptation and new prospects for leveraging mechanisms of mimicry to promote human health.

 描述（由申请方提供）：病原体通常通过分子模拟利用宿主功能。病毒编码的模拟物通常通过宿主基因水平转移到病原体基因组中而产生。获得后，这些基因在强烈的自然选择下发生分化，并获得新的功能，破坏或选择宿主过程。模拟物的经典研究实例包括从宿主基因组获得的病毒癌基因，如v-Src和v-Ras。越来越多的人认识到，模仿在各种人类病原体的成功中发挥着关键作用。尽管广泛的观察模仿，起源和进化机制的病原体基因适应模仿主机的形式还没有得到很好的理解。我们已经开发了创新的实验系统，使用牛痘病毒，模型痘病毒，调查模仿的演变。痘病毒部署大量的模拟物来击败宿主的防御，并可能导致毁灭性的疾病。例如，在天花被根除之前，它可能比任何其他病原体造成更多的人类死亡，相关病毒似乎准备成为流行病。为了研究分子拟态的进化，我们通过一系列实验重建拟态的起源，通过实验进化选择宿主基因水平转移到牛痘基因组中。该系统提供了一个通用的手段捕获水平基因转移事件，调查病原体适应的机制。一旦病原体获得宿主因子，它们通常会以增加病原体适应性的方式分化，但对这一过程如何展开知之甚少。在另一组主要的实验中，我们已经开发出一种方法来重建新获得的宿主基因分化成为模仿物的适应过程。最后，我们正在研究模仿病毒适应宿主防御的持续进化。这些研究已经揭示了新描述的病毒适应机制。研究拟态的进化引导方法对于丰富抗病毒干预措施和支持传统的疫苗接种策略具有很大的希望。我们结合病毒学，进化遗传学和分子生物学的多方面方法将提供深入了解病原体适应的基本机制和利用模仿机制促进人类健康的新前景。