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: 10828662
• 负责人: NOAH K WHITEMAN
• 金额: $ 3.26万
• 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/10828662
• 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; Shapes; System; Technology; Tissues; Toxin; United States National Institutes of Health; Variant; Volatilization; Walking; base; common treatment; cytolethal distending toxin; flexibility; fly; foodborne; genome-wide; in vivo; interest; mustard oil; parasitism; therapy development; transmission process

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

项目摘要/摘要 长寿命和直接传播的寄生动物是自然选择的最有效的药物之一 从人类人群中知道。但是，我们对共同进化的知识存在根本差距 产生这些模式的机制。这部分是因为众所周知，宿主 - 寄生虫相互作用很困难 学习。直到得到修复，朝着理解一个极大地影响我们的难以捉摸的过程的进展 生物学受到阻碍。因此，新的模型主寄生虫系统对于推进该领域至关重要。长期 我们研究的一项目标是开发和利用新的模型宿主寄生虫模型，以进行机械研究 共同进化。在过去将近四年的ESI MIRA支持中，我们取得了长足的进步 剖析寄生和宿主专业化进化的基因组基础，并确定程度 共同进化相互作用在宿主和寄生虫种群中保持全基因组的变化。 理由是寄生虫在包括遗传模型动物果蝇的谱系中反复进化 Melanogaster。这些寄生蝇在遗传模型植物拟南芥中的完整发育很方便地 Thaliana，支持深入的机械研究。除了解决我们的核心对象外，Mira的对象 变革性的灵活性允许追求风险的新线索，从而导致许多基本发现 生物学家的广泛兴趣。这包括特定于挥发性的第一个odorint接收器的表征 动物中已知的芥末油毒素（异硫氰酸盐或ITC），首次使用CRISPR-CAS9基因编辑 在动物中充分追回自适应步行的技术（该突变足以抵抗心脏 君主蝴蝶中的糖苷毒素）使用体内敲门方法和第一基因的鉴定 从已知的动物到编码细胞降低的毒素（CDT）亚基B蛋白，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 在接下来的五年中，EI Mira支持。我们在下一阶段研究的具体目标是确定 宿主与寄生虫之间相互作用的进化和机械基础，这些寄生虫由三种毒素介导 类：ITC，心脏糖苷和CDT。已经解决了这一目标的三个项目是： （1）通过寄生虫（ITC）检测毒素的进化和机械基础，（2）进化和机械 寄生虫抗毒素的基础（ITC和心脏糖苷），以及（3）进化和机械基础 免疫系统（CTD）的毒素合作。这项研究有望告知我们对如何的理解 毒素