Understanding the genome-phenotype relationship of host-parasite interactions across a complex life-cycle

了解复杂生命周期中宿主-寄生虫相互作用的基因组-表型关系

• 批准号: RGPIN-2020-04589
• 负责人: Wasmuth, James
• 金额: $ 3.64万
• 依托单位: University of Calgary
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=740059
• 关键词: Understanding; genome; phenotype; relationship; host

The transition from free-living organism to parasite is one of the most frequent shifts in life strategy. To ensure survival of the species, parasites have evolved systems that promote their transmission from one host to another. Many parasites manipulate their hosts by altering host behaviour, which increases the likelihood of predation of the current host by the next host. It is likely that the host's altered phenotype is due to the expression of the parasite's genes, rather than its own genes. Richard Dawkins coined the phrase the `extended phenotype' to describe the influence of genes beyond their organism. Here, the behaviour of the host is the extended phenotype of the parasite's genes. The long-term objectives of my research program are to: i) identify the molecular mechanisms by which the parasite manipulates its hosts, and ii) discover the evolutionary mechanisms by which parasite's genome adapts to its host. The lancet liver fluke, Dicrocoelium dendriticum, is a parasitic species of Platyhelminthes worm. This trematode has a three-host life-cycle involving a snail, ant, and mammal. My proposal focus on an iconic example of behavioural manipulation, that of the ant by the parasite. In cool ambient temperatures, infected ants cease foraging and climb to the top of grass or flowers and firmly fix themselves with their mandibles. When infecting the ant, the majority of the larval D. dendriticum reside in the abdomen: A single larva migrates and encysts at the base of the ant's brain and is likely responsible for the altered behaviour. This increases the likelihood of being eaten by a grazing mammal, the next host. The molecular mechanisms through which D. dendriticum manipulates the ant's behaviour await discovery. Using a combination of genomics, bioinformatics and parasitological approaches, my research program examines changes in the ant brain and brain-encysted parasite at the transcript, protein and hormone level. Candidate biomolecules will be validated by inducing an uninfected ant to fix on a flower or an infected ant to continue foraging. At the genome-level, we will identify the adaptive processes of genes involved in the manipulation. Gene duplications in multi-gene families lead to new genes which can be released from selection pressures and result in new functions. The convergence of short protein motifs, which mediate protein-protein interactions, are increasingly implicated in the mimicry of host proteins by a parasite. Finally, horizontal gene transfer between host and parasite is emerging as an important mechanism for host-parasite interactions. Overall, my research proposal aims to significantly improve our understanding of how parasites interact with their hosts at the molecular level and describe the mechanisms by which the genome evolves to adapt to a new host. This work has implications beyond parasitology, including: i) genome adaption to new environments, and ii) the molecular basis of behavioural manipulation.

从自由生活的有机体到寄生虫的转变是生命策略中最频繁的转变之一。为了确保物种的生存，寄生虫进化出了促进它们从一个宿主传播到另一个宿主的系统。许多寄生虫通过改变宿主的行为来操纵它们的宿主，这增加了下一个宿主捕食当前宿主的可能性。宿主的表型改变很可能是由于寄生虫的基因表达，而不是它自己的基因。理查德·道金斯创造了“扩展表型”这个短语，用来描述基因对机体以外的影响。在这里，宿主的行为是寄生虫基因的扩展表型。我的研究计划的长期目标是：i)确定寄生虫操纵宿主的分子机制，ii)发现寄生虫基因组适应宿主的进化机制。柳叶刀肝吸虫是扁形蠕虫的寄生种。这种吸虫有一个由蜗牛、蚂蚁和哺乳动物组成的三宿主生命周期。我的建议集中在一个行为操纵的标志性例子上，即寄生虫对蚂蚁的操纵。在凉爽的环境温度下，受感染的蚂蚁会停止觅食，爬到草或花的顶端，并牢牢地固定住自己的下颌。当感染蚂蚁时，大多数树枝状念珠菌幼虫居住在腹部：一只幼虫在蚂蚁的大脑底部迁徙和包囊，很可能是改变行为的原因。这增加了被下一个宿主--食草性哺乳动物吃掉的可能性。树枝金线虫操纵蚂蚁行为的分子机制有待发现。我的研究项目结合了基因组学、生物信息学和寄生虫学的方法，在转录本、蛋白质和激素水平上检查了蚂蚁大脑和脑囊寄生虫的变化。候选生物分子将通过诱导未感染的蚂蚁固定在花上或感染的蚂蚁继续觅食来验证。在基因组水平上，我们将识别参与操作的基因的适应过程。多基因家族中的基因复制导致新的基因，这些新的基因可以从选择压力中释放出来，从而产生新的功能。介导蛋白质-蛋白质相互作用的短蛋白质基序的趋同，越来越多地与寄生虫对宿主蛋白质的模仿有关。最后，宿主和寄生虫之间的水平基因转移正在成为宿主和寄生虫相互作用的重要机制。总体而言，我的研究提案旨在显著提高我们对寄生虫如何在分子水平上与宿主相互作用的理解，并描述基因组进化以适应新宿主的机制。这项工作的意义超越了寄生虫学，包括：i)基因组对新环境的适应，以及ii)行为操纵的分子基础。