Co-evolutionary Genetics of Host-Parasite Interactions

宿主-寄生虫相互作用的共同进化遗传学

• 批准号: 10399606
• 负责人: NOAH K WHITEMAN
• 金额: $ 45.12万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-11 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10399606
• 关键词: Address; Aloral; Animal Model; Animals; Basic Science; Behavior; Biological; Biology; Butterflies; CRISPR/Cas technology; Cardiac Glycosides; Cells; Congestive Heart Failure; Detection; Development; Disease; Drosophila melanogaster; Evolution; Genes; Genetic; Genetic Models; Genomics; Goals; Human; Immune; Immune system; Individual; Isothiocyanates; Knock-in; Knowledge; Malignant Neoplasms; Mediating; Medical; Mission; Modeling; Mouse-ear Cress; Mutation; National Institute of General Medical Sciences; Natural Selections; Nature; Odorant Receptors; Organism; Parasite resistance; Parasites; Parkinson Disease; Pattern; Phase; Plant Model; Population; Process; Proteins; Public Health; Research; Resistance; System; Technology; Tissues; Toxin; United States National Institutes of Health; Variant; Walking; base; common treatment; cytolethal distending toxin; flexibility; fly; foodborne; genome-wide; in vivo; interest; mustard oil; parasitism; therapy development

PROJECT SUMMARY/ABSTRACT Long-lived and directly transmitted parasitic animals are among the most potent agents of natural selection known from human populations. Yet, there is a fundamental gap in our knowledge of the co-evolutionary mechanisms producing these patterns. This is, in part, because host-parasite interactions are notoriously difficult to study. Until remedied, progress toward understanding an elusive process that has profoundly shaped our biology is impeded. New model host-parasite systems are therefore critical for advancing the field. The long- term goal of our research is to develop and leverage new model host-parasite models for mechanistic studies of co-evolution. Over the past nearly four years of ESI MIRA support, we have made considerable progress toward dissecting the genomic basis of the evolution of parasitism and host specialization, and in determining the extent to which co-evolutionary interactions maintain genome-wide variation in host and parasite populations. The rationale is that parasitism evolved repeatedly in the lineage that includes the genetic model animal Drosophila melanogaster. Conveniently, these parasitic flies complete development in the genetic model plant Arabidopsis thaliana, facilitating in-depth mechanistic study. In addition to addressing our core objectives, the MIRA’s transformative flexibility allowed pursuit of risky new leads, resulting in a number of fundamental discoveries of broad interest to biologists. This included characterization of the first odorant receptors specific to volatile mustard oil toxins (isothiocyanates or ITCs) known in animals, the first use of CRISPR-Cas9 gene editing technology to fully retrace an adaptive walk in an animal (the mutations sufficient for resistance to cardiac glycoside toxins in monarch butterflies) using an in vivo knock-in approach, and identification of the first genes from animals known to encode cytolethal distending toxin (CDT) subunit B proteins, which is our model for the evolution of toxins used by human immune cells. These discoveries now form the basis of our proposed transition to EI MIRA support over the next five years. Our specific goal in the next phase of research is to identify the evolution and mechanistic bases of interactions between hosts and parasites that are mediated by three toxin classes: ITCs, cardiac glycosides, and CDTs. Three projects already underway that will address this goal are: (1) the evolution and mechanistic basis of toxin detection by parasites (ITCs), (2) the evolution and mechanistic basis of toxin resistance by parasites (ITCs and cardiac glycosides), and (3) the evolution and mechanistic basis of toxin co-option by the immune system (CTDs). This research is expected to inform our understanding of how toxins of

项目概要/摘要 长寿且直接传播的寄生动物是自然选择最有效的媒介之一 从人类群体中得知。然而，我们对共同进化的认识存在根本差距 产生这些模式的机制。部分原因是宿主与寄生虫之间的相互作用非常困难 学习。在得到补救之前，我们将在理解一个深刻塑造我们的难以捉摸的过程方面取得进展。 生物学受到阻碍。因此，新模型的宿主-寄生虫系统对于推进该领域至关重要。长- 我们研究的长期目标是开发和利用新的宿主-寄生虫模型进行机制研究 共同进化。在过去近四年的 ESI MIRA 支持中，我们在以下方面取得了长足进展： 剖析寄生和宿主特化进化的基因组基础，并确定其程度 共同进化相互作用维持宿主和寄生虫种群的全基因组变异。这 基本原理是寄生性在包括遗传模型动物果蝇在内的谱系中反复进化 黑腹果蝇。方便的是，这些寄生蝇在遗传模型植物拟南芥中完成发育 thaliana，促进深入的机制研究。除了实现我们的核心目标外，MIRA 的 变革的灵活性允许追求有风险的新线索，从而产生了许多基本发现 生物学家的广泛兴趣。这包括对挥发性物质特异性的第一个气味受体的表征 动物中已知的芥子油毒素（异硫氰酸盐或 ITC），首次使用 CRISPR-Cas9 基因编辑 完全追溯动物适应性行走的技术（足以抵抗心脏病的突变） 帝王蝶中的糖苷毒素）使用体内敲入方法，并鉴定第一个基因 来自已知编码细胞致死膨胀毒素 (CDT) 亚基 B 蛋白的动物，这是我们的模型 人类免疫细胞使用的毒素的进化。这些发现现在构成了我们提议的过渡的基础 EI MIRA 在未来五年内提供支持。我们下一阶段研究的具体目标是确定 由三种毒素介导的宿主和寄生虫之间相互作用的进化和机制基础 类别：ITC、强心苷和 CDT。为了实现这一目标，已经在进行的三个项目是： （1）寄生虫毒素检测（ITC）的进化和机制基础，（2）进化和机制 寄生虫的毒素抗性基础（ITC 和强心苷），以及 (3) 进化和机制基础 免疫系统（CTD）对毒素的选择。这项研究有望让我们了解如何 的毒素