New strategies for parasite control: Identification of candidate target proteins using the example of thorny-headed worms (Acanthocephala)

刺头蠕虫（棘头虫）是全球范围内存在于脊椎动物肠道中的寄生虫，包括人类和牲畜。在南美洲的大型养鱼场，这种侵染达到了这样一种程度，使鱼的生长速度降低、变形和死亡，导致生产力的重大损失。然而，现有的预防措施对环境有害或不切实际。此外，许多用于对付棘头虫和其他寄生虫的驱虫剂（驱虫药）对许多生物的细胞都有毒性作用。其中一些化疗药物甚至被考虑作为细胞抑制剂在癌症治疗中的二次使用。另一个问题是，在德国和其他国家的土壤和水域中，已经检测到动物生产中使用驱虫药的残留物，这些残留物对较小的动物尤其有害。最后但并非最不重要的是，对已确定的驱虫药具有耐药性的寄生虫菌株的数量正在增加。提出的项目解决了由此产生的对新治疗策略的高需求：一种新的生物信息学概念将应用于识别蛋白质，其抑制承诺有效杀死寄生虫，同时保护人类，牲畜和环境。由于其对养鱼场的破坏作用和水产养殖对人类营养的重要意义，应建立寄生于鱼类的棘头类候选靶标鉴定程序。工作流程将包括基因组和转录组的进化和发育分析，暴露的寄生虫组织的蛋白质组学分析，以及有希望的候选目标蛋白的结构预测。为了启动高度特异性的寄生虫控制，候选靶点应该在棘头类的进化中出现或被强烈改变。此外，无论棘头类动物在不同宿主类型中的发育水平如何，都要大量生产候选靶点。以这种方式确定的候选靶点的抑制具有干预基本生命功能的前景，从而有效地杀死棘头鲸。候选靶点在暴露组织中的高表达也应该允许活性物质很容易接近，其结构应该表明与这些化合物结合的倾向。如果数据库中已经有合适的低分子量化合物，将模拟它们与候选靶点的相互作用。在该项目之后，针对候选靶点的药物可以进行调整或（进一步）开发和测试其对棘头类动物的功效。为了便于将这一概念应用于其他寄生虫，工作流程将通过互联网平台提供。最重要的是，该项目为深入了解寄生虫的进化和表型可塑性提供了视角。

Thorny-headed worms (Acanthocephala) are globally occurring parasites in the intestines of vertebrates, including humans and livestock. In the large fish farms of South America, the infestation reaches such an extent that reduced growth rates, deformations, and death of the fish result in a significant loss of productivity. However, the available preventative measures are environmentally harmful or impracticable. In addition, many deworming agents (anthelmintics), which are used against acanthocephalans and other parasites, have a toxic effect on the cells of a wide range of organisms. Some of these chemotherapeutics are even being considered for second use as cytostatic agents in cancer treatment. Another problem is that residues from the use of anthelmintics in animal production are already detectable in soils and waters of Germany and other countries, where they can damage smaller animals in particular. Last but not least, the number of strains of parasites showing resistance to established anthelmintics is growing. The proposed project addresses the resulting high demand for new treatment strategies: A novel bioinformatic concept shall be applied to identify proteins whose inhibition promises an effective killing of parasites while at the same time sparing humans, livestock and the environment. Due to their damaging effect on fish farms and the great importance of aquacultures for human nutrition, the procedure of candidate target identification shall be established on fish-parasitizing acanthocephalans. The workflow will include evolutionary and developmental analyses of genomes and transcriptomes, proteomic analysis of exposed parasite tissue, and predictions of the structure of promising candidate target proteins. In order to initiate highly specific parasite control, a candidate target should have arisen or been strongly altered in the evolution of Acanthocephala. In addition, a candidate target is to be produced in large quantities regardless of the level of development achieved by the acanthocephalans in different host types. The inhibition of a candidate target defined in this way holds the prospect for intervention in basic vital functions and thus effective killing of acanthocephalans. High expression of a candidate target in exposed tissue should also allow it to be readily accessible to active substances and its structure should indicate a propensity to bind such compounds. If suitable low molecular weight compounds are already available in the databases, their interaction with candidate targets will be simulated. After the project, drugs directed against the candidate targets can be adapted or (further) developed and tested for their efficacy against acanthocephalans. In order to facilitate the application of the concept to other parasites, the workflow is to be made available via an internet platform. Not least, the project offers the perspective to provide insights into the evolution and phenotypic plasticity of parasites.