Endogenous retroviruses co-opted for immune defenses

内源性逆转录病毒选择免疫防御

• 批准号: 9107893
• 负责人: Cedric Feschotte
• 金额: $ 29.43万
• 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: 2015-07-10 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9107893
• 关键词: ATAC-seq; Accounting; Animals; Anti-Retroviral Agents; Antiviral Agents; Autoimmune Diseases; Autoimmunity; Binding; Binding Sites; Biological; Biological Assay; Biology; Cataloging; Catalogs; Cell Culture Techniques; Cell Line; Cell Surface Receptors; Cell physiology; Cells; Chickens; Chromatin; Code; Conflict (Psychology); Data; Dermal; Disease; Elements; Endogenous Retroviruses; Evolution; Family; Felis catus; Fibroblasts; Fire - disasters; Fossils; Genes; Genetic; Genetic Transcription; Genetic Variation; Genome; Genomics; HIV-1; Health; Host Defense; Human; Human Genome; Immune; Immune response; Immune system; Immunity; Immunology; Infection; Infiltration; Interferons; Investigation; Lead; Malignant Neoplasms; Mammals; Modeling; Molecular; Mus; Natural Immunity; Natural Selections; Outcome; Pathology; Perception; Physiology; Predisposition; Primates; Proteins; Race; Radiation; Recruitment Activity; Regulation; Regulatory Element; Reporter; Research Personnel; Retroviridae; Rodent; Role; STAT1 gene; Sequence Analysis; Shapes; Sheep; Source; System; Testing; Therapeutic; Time; Tissues; Untranslated RNA; Viral; Virus; arm; comparative; comparative genomics; design; env Gene Products; fighting; follow-up; functional genomics; genome editing; genome sequencing; genome-wide; human DNA; human disease; immune function; innovation; insight; invention; mammalian genome; melanoma; novel; overexpression; pathogen; receptor; response; transcription factor; transcriptome; transcriptome sequencing; transcriptomics; tumorigenesis; vertebrate genome; virology

 DESCRIPTION (provided by applicant): Endogenous retroviruses (ERVs) arise from retroviruses chromosomally integrated in the host germline. The pervasive infiltration of ERVs in genomes represents an important source of genetic variation across and within species. ERVs are highly abundant in vertebrate genomes, accounting for 8% of the human DNA. However, surprisingly little is known about the functional impact of this important class of mobile elements on the physiology and evolution of their hosts. ERVs can cause specific pathologies in animals, including cancer, but their association with human disease remains controversial, despite half a century of investigation. Even less understood are the potential beneficial functions ERVs confer on their host cells. This project is designed to yield transformative insights into the biological significance of ERVs in evolution and disease. The central and innovative idea of this proposal is that the perpetual genetic conflict between hosts and pathogens has led to the invention and diversification of molecular arsenals, which in turn promote the co-option of endogenous viruses for cellular function in immunity. We hypothesize that prefabricated regulatory and coding activities encoded by ERVs have been repeatedly co-opted during mammalian evolution to enhance immune defense functions. In Aim 1, we will investigate the role of ERVs in the regulatory evolution of a major component of the innate immune system: the interferon response. We will provide direct experimental evidence that a primate- specific ERV has become a critical regulator of the human inflammasome. To obtain a comparative, genome- wide assessment of the role of ERVs in shaping the interferon gene network across mammals, we will identify ERV-driven transcriptomic and chromatin changes induced upon interferon treatment of dermal fibroblasts from human, other primates, and rodents. Experimental manipulations in cell lines, including reporter assays, genome editing, and pathogen infection assays, will be used to validate the immune function of newly discovered ERV-derived cis-regulatory elements and novel interferon-stimulated genes. In Aim 2, we will deploy a novel computational pipeline combining genomic, expression, and evolutionary sequence analysis to produce a comprehensive catalog of ERV-derived envelope genes likely co-opted for cellular function in the human genome. Several envelope proteins expressed in healthy tissues and showing signatures of purifying and/or positive selection will be tested in cell culture assays for their ability to restrict infection of ancient and modern retroviruses. Together the outcomes of this proposal are anticipated to shift the perception of ERVs from inert retroviral fossils to actie contributors to the evolutionary plasticity of vertebrate immune defenses. In addition, our studies are bound to uncover new immunity genes in the human genome, including novel molecules with potentially therapeutic antiviral activities.

 性状（由申请方提供）：内源性逆转录病毒（ERV）来源于染色体整合到宿主生殖系中的逆转录病毒。ERVs在基因组中的广泛渗透是物种间和物种内遗传变异的重要来源。ERV在脊椎动物基因组中高度丰富，占人类DNA的8%。然而，令人惊讶的是，人们对这类重要的移动的元素的功能影响知之甚少 宿主的生理和进化ERV可以在动物中引起特定的病理，包括癌症，但尽管经过了半个世纪的研究，它们与人类疾病的关系仍然存在争议。更不了解的是ERV赋予其宿主细胞的潜在有益功能。该项目旨在对ERV在进化和疾病中的生物学意义产生变革性的见解。这一提议的核心和创新思想是宿主和病原体之间的永久遗传冲突导致了分子武库的发明和多样化，这反过来又促进了内源性病毒对免疫细胞功能的共同选择。我们推测，预制的调控和编码活动编码ERVs已被反复增选在哺乳动物进化过程中，以增强免疫防御功能。在目标1中，我们将研究ERVs在先天免疫系统的主要组成部分：干扰素反应的调节演变中的作用。我们将提供直接的实验证据，证明灵长类动物特异性ERV已成为人类炎性小体的关键调节因子。为了获得ERV在塑造哺乳动物间干扰素基因网络中的作用的比较性全基因组评估，我们将鉴定在干扰素处理来自人、其他灵长类动物和啮齿类动物的真皮成纤维细胞后诱导的ERV驱动的转录组和染色质变化。细胞系中的实验操作，包括报告基因测定、基因组编辑和病原体感染测定，将用于验证新发现的ERV衍生的顺式调节元件和新型干扰素刺激基因的免疫功能。在目标2中，我们将部署一个新的计算管道，结合基因组，表达和进化序列分析，以产生一个全面的目录ERV衍生的包膜基因可能增选在人类基因组中的细胞功能。将在细胞培养测定中测试在健康组织中表达并显示纯化和/或阳性选择特征的几种包膜蛋白， 它们限制古代和现代逆转录病毒感染的能力。这一提议的结果预计将把对ERV的看法从惰性逆转录病毒化石转变为脊椎动物免疫防御进化可塑性的积极贡献者。此外，我们的研究 必将发现人类基因组中新的免疫基因，包括具有潜在治疗抗病毒活性的新分子。