A functional evolutionary genetic approach to combat viral infection

项目摘要 人类正面临着越来越多来自动物蓄水池溢出的病毒的威胁。大部分 这些病毒性疾病缺乏针对性的治疗。我们推测，这种未得到满足的医疗需求可能 可以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 病毒感染。在哺乳动物中，这些抗病毒效应器正在迅速进化，最有可能是在 对病毒和宿主之间不断发生的遗传“军备竞赛”的反应。此外， 某些哺乳动物目，如灵长类、啮齿动物、蝙蝠和食肉动物，特别丰富 有可能蔓延到人类体内的病毒。我们假设它们的基因组 这些人畜共患病毒库编码独特的抗病毒效应器，可以被利用来 对抗人类病毒病原体。该项目的目标是识别、描述和 验证来自不同非模式哺乳动物物种的新型抗病毒蛋白的有效性。 将使用最先进的基因筛查平台来发现初级患者的抗病毒基因 从以下哺乳动物目的多个物种获得的细胞培养：灵长类， 啮齿目、翼手目和食肉目。经过验证的效应器将从机械上进行表征 通过一套病毒学、生化、分子和细胞生物学方法。潜力 对于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。成果将包括创造出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 认为人类病毒疾病可以通过来自其他生物的自然产生的蛋白质来阻止的概念 物种。这项提议的影响将是一个新的生物医学领域的发展 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。

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.