Endogenous retroviruses co-opted for immune defenses

 描述(申请人提供)：内源性逆转录病毒(ERV)是由染色体整合到宿主生殖系中的逆转录病毒引起的。ERV在基因组中的普遍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含量非常丰富，占人类DNA的8%。然而，令人惊讶的是，人们对这类重要移动元素的功能影响知之甚少 寄主的生理和进化。ERV可以引起动物的特定病理，包括癌症，但它们与人类疾病的关联仍然存在争议，尽管进行了半个世纪的研究。更不清楚的是ERV赋予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器库的发明和多样化，这反过来又促进了内源性病毒在免疫中对细胞功能的共同选择。我们假设，由ERV编码的预制调控和编码活动在哺乳动物进化过程中被反复选择，以增强免疫防御功能。在目标1中，我们将研究ERV在先天性免疫系统的一个主要组成部分：干扰素反应的调节进化中的作用。我们将提供直接的实验证据，证明灵长类特异性ERV已经成为人类炎症体的关键调节因子。为了对ERV在塑造哺乳动物干扰素基因网络中的作用进行比较、全基因组的评估，我们将识别在干扰素治疗人类、其他灵长类动物和啮齿动物的真皮成纤维细胞时，ERV驱动的转录和染色质变化。在细胞系中的实验操作，包括报告分析、基因组编辑和病原体感染分析，将被用于验证新发现的ERV衍生的顺式调节元件和新的干扰素刺激基因的免疫功能。在目标2中，我们将部署一种结合基因组、表达和进化序列分析的新型计算管道，以产生可能被人类基因组中的细胞功能所增选的ERV来源的包膜基因的全面目录。几种在健康组织中表达并表现出纯化和/或阳性选择特征的包膜蛋白将在细胞培养分析中进行测试 它们能够限制古代和现代逆转录病毒的感染。总之，这项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对脊椎动物免疫防御的进化可塑性做出积极贡献的人。另外，我们的研究 必然会在人类基因组中发现新的免疫基因，包括具有潜在治疗抗病毒活性的新分子。

 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.