Mining natural infection variation to find the genetic basis of coevolution between vertebrate hosts and helminth parasites

挖掘自然感染变异，寻找脊椎动物宿主与蠕虫寄生虫之间共同进化的遗传基础

• 批准号: 10275938
• 负责人: Jesse Nathaniel Weber
• 金额: $ 36.78万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10275938
• 关键词: Affect; Candidate Disease Gene; Cells; Cestoda; Coculture Techniques; Complement; Data; Dose; Evolution; Fishes; Gasterosteidae; Genetic; Growth; Helminths; Heritability; Human; Immune; Immunity; Infection; Lead; Livestock; Maps; Measures; Mining; Modernization; Molecular; Morbidity - disease rate; Natural Selections; Outcome; Parasites; Parasitic Diseases; Parasitic infection; Pathway interactions; Pharmacology; Physiology; Population; Prevalence; Process; Protocols documentation; Recording of previous events; Research; Series; Specificity; Time; Transgenic Organisms; Transplantation; Variant; Work; base; experimental study; forward genetics; genetic approach; genetic resource; in vitro Assay; mortality; pathogen; purge; resistance mechanism; trait

Project Summary/Abstract Helminths (i.e., parasitic worms) infect all vertebrate taxa. Hosts generally evolve to block, purge, or limit the negative effects of infection, and parasites evolve to hide from or manipulate host physiology. Numerous molecules and cellular pathways are known to modulate interactions between vertebrate hosts and helminth parasites, but little is known about how the evolution of immunity and infectivity influences natural variation in parasite infections. Data on the particular genetic differences that underlie evolved differences in immunity are similarly limited. Over the next five years, my lab will describe the genetic mechanisms and evolutionary history of coevolution between a small fish with abundant ecological and genetic resources, the threespine stickleback (Gasterosteus aculeatus), and one of its cestode parasites. This work is facilitated by lab-based protocols to efficiently intercross cestodes, expose sticklebacks to controlled doses of these pathogens, co-culture host and immune cells in vitro, and assays of host immunity and parasite viability. We can not only identify and measure heritable traits that affect infection specificity and intensity, but also apply modern genetic approaches to dissect the molecular mechanisms underlying this naturally selected variation. Our preliminary data show that threespine sticklebacks repeatedly evolved to block the initial establishment and subsequent growth of cestodes, but that the mechanisms of resistance vary across populations. Cestodes also evolved to counteract the defenses of their local hosts, eventually leading to specialization on a subset of hosts. We will use forward genetics to map the chromosomal loci associated with pathogen-driven host evolution, while crossing diverged cestode populations will uncover loci evolving due to host-driven selection. This work will be complemented with pharmacological and transgenic manipulations of candidate genes and molecular pathways, as well as forays into natural settings where we will use both experimental transplants and time-series data to understand how coevolution varies due to ecological and spatial constraints. Perhaps most exciting, there are several closely related stickleback species and cestode species that, despite millions of years of divergence, remain interfertile, and which enable us to characterize the genetics of coevolution across both micro- and macroevolutionary timescales.

项目概要/摘要 蠕虫（即寄生虫）感染所有脊椎动物类群。宿主通常会进化为阻止、清除或限制 感染的负面影响，寄生虫进化出隐藏或操纵宿主生理机能的方式。很多的 已知分子和细胞途径可调节脊椎动物宿主和蠕虫之间的相互作用 寄生虫，但人们对免疫和传染性的进化如何影响自然变异知之甚少。 寄生虫感染。关于免疫进化差异背后的特定遗传差异的数据是 同样有限。在接下来的五年里，我的实验室将描述遗传机制和进化历史 具有丰富生态和遗传资源的小鱼——三刺刺鱼之间的共同进化 （Gasterosteus aculeatus）及其绦虫寄生虫之一。这项工作是通过基于实验室的协议来促进的 有效地使绦虫杂交，将刺鱼暴露于受控剂量的这些病原体中，共培养宿主和 体外免疫细胞，以及宿主免疫和寄生虫活力的测定。我们不仅可以识别和测量 影响感染特异性和强度的遗传特征，但也应用现代遗传方法 剖析这种自然选择变异背后的分子机制。我们的初步数据表明 三刺刺鱼反复进化以阻止其最初的建立和随后的生长 绦虫，但不同人群的耐药机制有所不同。绦虫也进化来抵消 本地主机的防御，最终导致主机子集的专业化。我们将使用前向 遗传学来绘制与病原体驱动的宿主进化相关的染色体位点，同时交叉分歧 绦虫种群将发现由于宿主驱动的选择而进化的基因座。这项工作将得到补充 对候选基因和分子途径进行药理学和转基因操作，以及 涉足自然环境，我们将使用实验移植和时间序列数据来理解 共同进化如何因生态和空间限制而变化。也许最令人兴奋的是，有几个 密切相关的刺鱼物种和绦虫物种，尽管经历了数百万年的分化，但仍然存在 互育，这使我们能够描述微观和微观层面共同进化的遗传学特征。 宏观进化时间尺度。