Specialized functions of endogenous retroviruses in innate immune cells

内源性逆转录病毒在先天免疫细胞中的特殊功能

• 批准号: RGPIN-2021-04302
• 负责人: Tokuyama, Maria
• 金额: $ 2.99万
• 依托单位: University of British Columbia
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=761047
• 关键词: Specialized; functions; endogenous; retroviruses; innate

The overarching goal of my research program is to understand how the persistent interaction between viruses or viral elements and components of the immune system shapes basic immune functions. My main focus is on viral sequences called endogenous retroviruses (ERVs), which have largely been ignored as "junk DNA." In 2001, the first human genome sequence was released, and it revealed that 8% of the human genome is made up of ERVs. Yet how ERVs impact our biology and our immune system remains largely unknown. My research program seeks to discover fundamental functions of ERVs in immunity, and the outcomes of our research could greatly impact our understanding of the immune system. ERVs originated from integration of exogenous retrovirus genomes into the host genome that became fixed in the germ line. ERV sequences vastly outnumber coding genes across eukaryotes. In humans, most of these were stably inherited through millions of years of evolution in the primate lineage, and ERV sequences constitute 8% of the genome versus 2% of the genome that is protein-coding. The major function of ERVs is gene regulation through their long terminal repeat (LTR) promoter sequences. However, the physiological functions of the ERVs that have retained a proviral sequence consisting of protein-coding potential are largely unknown and understudied. Moreover, there is a fundamental gap in our understanding of the basic functions of ERVs and their protein products in immunity. We propose to identify cellular interacting partners of ERV proteins in immune cells to inform us of their functionality. Neutrophils are the most abundant innate immune cell subset in the blood and are the first responders to tissue damage, viruses, bacteria, and toxins. The effector functions of neutrophils are highly conserved in vertebrates and invertebrates. Neutrophils are wired to interact with and respond to viruses including retroviruses, and a number of cellular proteins may interact with proteins derived from ERVs. We will use neutrophils as a focal point to uncover novel interactions between ERVs and components of the immune system to determine their functions. My lab will test the hypothesis that ERV proteins regulate basic innate immune functions through conserved interactions with cellular proteins. To test this, we will apply cutting-edge technologies towards three objectives (Objs.): Obj. 1: Use ribosome sequencing to comprehensively identify ERV-encoded proteins in neutrophils. Obj. 2: Map the ERV interactome between ERV proteins and cellular proteins in neutrophils. Obj. 3: Determine the role of ERVs in neutrophil function in vivo. Our work will yield novel insights into the physiological roles of viral sequences that have been largely ignored and expand our knowledge of the immune system, and in parallel, broadly impact many fields including virology, evolutionary biology, and genomics.

我的研究计划的首要目标是了解病毒或病毒成分与免疫系统成分之间的持续相互作用如何塑造基本的免疫功能。我主要关注的是被称为内源性逆转录病毒（ERVs）的病毒序列，它们在很大程度上被视为“垃圾DNA”而被忽视。“2001年，第一个人类基因组序列被公布，它揭示了8%的人类基因组由ERV组成。然而，ERV如何影响我们的生物学和我们的免疫系统在很大程度上仍然未知。我的研究项目旨在发现ERVs在免疫中的基本功能，我们的研究结果可能会极大地影响我们对免疫系统的理解。ERV起源于外源逆转录病毒基因组整合到宿主基因组中，并在生殖系中固定。在真核生物中，ERV序列的数量远远超过编码基因。在人类中，这些基因中的大多数在灵长类谱系中经过数百万年的进化而稳定遗传，ERV序列占基因组的8%，而蛋白质编码基因组的2%。ERV的主要功能是通过其长末端重复序列（LTR）启动子序列进行基因调控。然而，保留了前病毒序列的ERV的生理功能的蛋白质编码潜力在很大程度上是未知的，研究不足。此外，我们对ERV及其蛋白产物在免疫中的基本功能的理解存在根本性的差距。我们建议确定ERV蛋白在免疫细胞中的细胞相互作用伙伴，以告知我们它们的功能。中性粒细胞是血液中最丰富的先天免疫细胞亚群，是组织损伤、病毒、细菌和毒素的第一反应者。中性粒细胞的效应子功能在脊椎动物和无脊椎动物中高度保守。嗜中性粒细胞与病毒（包括逆转录病毒）相互作用并对其作出反应，许多细胞蛋白质可与ERV衍生的蛋白质相互作用。我们将使用中性粒细胞作为焦点，以揭示ERVs和免疫系统成分之间的新相互作用，以确定它们的功能。 我的实验室将测试ERV蛋白通过与细胞蛋白的保守相互作用调节基本先天免疫功能的假设。为了验证这一点，我们将把尖端技术应用于三个目标（Objs.）： 目的1：利用核糖体测序技术全面鉴定中性粒细胞ERV编码蛋白。目的2：定位ERV蛋白与中性粒细胞蛋白质的相互作用组。目的3：研究ERVs在体内中性粒细胞功能中的作用。我们的工作将对病毒序列的生理作用产生新的见解，这些生理作用在很大程度上被忽视，并扩大我们对免疫系统的了解，同时广泛影响许多领域，包括病毒学，进化生物学和基因组学。