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: 10456130
• 负责人: Jesse Nathaniel Weber
• 金额: $ 38.21万
• 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/10456130
• 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.

项目总结/摘要 蠕虫（即，寄生蠕虫）感染所有脊椎动物分类群。一般来说，限制会演变为阻止、清除或限制 感染的负面影响，寄生虫进化以隐藏或操纵宿主生理。许多 已知分子和细胞途径调节脊椎动物宿主和蠕虫之间的相互作用 寄生虫，但很少有人知道免疫力和传染性的进化如何影响自然变异， 寄生虫感染关于免疫力进化差异背后的特定遗传差异的数据如下： 同样有限。在接下来的五年里，我的实验室将描述 一种拥有丰富生态和遗传资源的小型鱼类，三刺鱼， （Gasterosteus aculeatus），以及其中一种绦虫寄生虫。这项工作是由实验室为基础的协议， 有效地交叉绦虫，将棘鱼暴露于控制剂量的这些病原体，共培养宿主， 体外免疫细胞，以及宿主免疫和寄生虫生存力的测定。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。初步数据显示， 三刺鱼反复进化，以阻止最初的建立和随后的增长， 绦虫，但耐药机制因种群而异。绦虫也进化成了 本地主机的防御，最终导致主机子集的专业化。我们将使用forward 遗传学绘制与病原体驱动的宿主进化相关的染色体基因座，而杂交产生分歧， 绦虫种群将揭示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 候选基因和分子途径的药理学和转基因操作，以及 我们将使用实验移植和时间序列数据来了解自然环境 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 与棘鱼和绦虫密切相关的物种，尽管数百万年的分歧， 这使我们能够表征微观和微观两个方面的共同进化的遗传学。 宏观进化的时间尺度