A functional evolutionary genetic approach to combat viral infection

对抗病毒感染的功能进化遗传学方法

• 批准号: 10010238
• 负责人: John W. Schoggins
• 金额: $ 114.45万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10010238
• 关键词: Animals; Antiviral Agents; Area; Atlases; Biochemical; Biological; Biology; Biomedical Research; Carnivora; Cells; Chiroptera; Development; Ebola virus; Epidemic; Genes; Genetic; Genetic Screening; Goals; Human; Immune response; Immunology; Influenza A virus; Interferons; Mammals; Medical; Molecular; Natural Immunity; Outcome; Primary Cell Cultures; Primates; Proteins; Race; Rodent; SARS coronavirus; Testing; Viral Genome; Virus; Virus Diseases; Zoonoses; arm; combat; drug development; genetic approach; human model; mouse model; novel; pandemic disease; pathogenic virus; response; therapeutic development; virology

Project Summary Humans are under increasing threat from viruses that spill over from animal reservoirs. Most of these viral diseases lack targeted treatments. We speculate that this unmet medical need might be addressable by first understanding the evolutionary principles underlying antiviral immune responses. A major component of innate immunity in mammals is the interferon response. Interferon induces hundreds of genes, many of which encode effector proteins that suppress viral infection. In mammals, these antiviral effectors are rapidly evolving, most likely in response to the genetic "arms race" continually occurring between virus and host. Further, certain mammalian orders, such as primates, rodents, bats, and carnivores, are particularly rich in viruses that have the potential to spill over into humans. We hypothesize that the genomes of these viral zoonotic reservoirs encode unique antiviral effectors that may be harnessed to combat human viral pathogens. The goals of this project are to identify, characterize, and validate the efficacy of novel antiviral proteins from diverse non-model mammalian species. State-of-the-art genetic screening platforms will be used to discover antiviral genes in primary cell cultures obtained from multiples species in the following mammalian orders: Primate, Rodentia, Chiroptera, and Carnivora. Validated effectors will be characterized mechanistically with a suite of virological, biochemical, molecular, and cell biological approaches. The potential for these effectors to suppress human viruses will be tested in murine models of human viral disease. Outcomes will include the creation of the first comprehensive Mammalian Antiviral Protein Atlas, the discovery of new genetically-encoded antiviral mechanisms, and proof-of- concept that human viral disease can be thwarted by naturally occurring proteins from other species. The impact of this proposal will be the development of a new area of biomedical research at the intersection of virology, immunology, and evolutionary biology. Long term prospects include harnessing the results of these studies to inspire alternative approaches to antiviral drug development.

项目概要 人类正面临着来自动物宿主的病毒的日益严重的威胁。大部分 这些病毒性疾病缺乏针对性的治疗。我们推测这种未满足的医疗需求可能 通过首先了解抗病毒免疫的进化原理来解决 回应。哺乳动物先天免疫的一个主要组成部分是干扰素反应。 干扰素诱导数百个基因，其中许多编码抑制干扰素的效应蛋白 病毒感染。在哺乳动物中，这些抗病毒效应器正在迅速进化，最有可能在 对病毒和宿主之间不断发生的基因“军备竞赛”的反应。更远， 某些哺乳动物目，如灵长类动物、啮齿动物、蝙蝠和食肉动物，数量特别丰富 存在于有可能传染给人类的病毒中。我们假设基因组 这些病毒人畜共患病毒库编码独特的抗病毒效应器，可用于 对抗人类病毒病原体。该项目的目标是识别、描述和 验证来自不同非模型哺乳动物物种的新型抗病毒蛋白的功效。 最先进的基因筛查平台将用于发现原发性中的抗病毒基因 从以下哺乳动物目中的多个物种获得的细胞培养物：灵长类动物， 啮齿目、翼手目和食肉目。经验证的效应器将被机械地表征 具有一套病毒学、生化、分子和细胞生物学方法。潜力 这些抑制人类病毒的效应器将在人类病毒的小鼠模型中进行测试 疾病。成果将包括创建第一个全面的哺乳动物抗病毒药物 蛋白质图谱，新的基因编码抗病毒机制的发现，以及证明- 人类病毒性疾病可以通过其他来源的天然蛋白质来阻止的概念 物种。该提案的影响将是生物医学新领域的发展 病毒学、免疫学和进化生物学的交叉研究。长期 前景包括利用这些研究的结果来启发替代方法 抗病毒药物开发。