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

从自由生物到寄生虫的转变是生命策略中最常见的转变之一。为了确保物种的生存，寄生虫进化出了促进其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宿主，这增加了当前宿主被下一个宿主捕食的可能性。宿主的表型改变很可能是由于寄生虫基因的表达，而不是其自身基因的表达。理查德·道金斯（Richard Dawkins）创造了“扩展表现型”（extended phenotype）这个词，用来描述基因对生物体以外的影响。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)确定寄生虫操纵其宿主的分子机制，ii)发现寄生虫基因组适应其宿主的进化机制。刺血肝吸虫（学名：Dicrocoelium dendriticum）是一种寄生于白蛉的寄生虫。这种吸虫有三个宿主的生命周期，包括蜗牛、蚂蚁和哺乳动物。我的建议集中在一个行为操纵的标志性例子上，即蚂蚁被寄生虫操纵的例子。在较低的环境温度下，受感染的蚂蚁停止觅食，爬到草或花的顶部，用下颚牢牢地固定住自己。当感染蚂蚁时，树突d幼虫的大部分居住在腹部：单个幼虫迁移并在蚂蚁的大脑底部形成囊，这可能是导致行为改变的原因。这增加了被食草哺乳动物（下一个宿主）吃掉的可能性。树突蚁操纵蚂蚁行为的分子机制有待发现。利用基因组学、生物信息学和寄生虫学方法的结合，我的研究项目在转录、蛋白质和激素水平上检查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蚂蚁固定在花上或感染蚂蚁继续觅食来验证。在基因组水平上，我们将确定参与操纵的基因的适应过程。在多基因家族中，基因复制会产生新的基因，这些基因可以从选择压力中释放出来，并产生新的功能。介导蛋白-蛋白相互作用的短蛋白基序的趋同越来越多地涉及寄生虫对宿主蛋白的模仿。最后，宿主和寄生虫之间的水平基因转移正在成为宿主-寄生虫相互作用的重要机制。总的来说，我的研究计划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。这项工作的意义超出了寄生虫学，包括：i)基因组适应新环境，以及ii)行为操纵的分子基础。

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.