Population genetics and genomics of ovine nematode parasites and their application to study the molecular basis of anthelmintic resistance.

寄生蠕虫（线虫）是英国和全世界放牧牲畜（绵羊、牛和山羊）最严重的健康问题之一，造成重大的经济损失和动物福利问题。最重要的寄生蠕虫生活在动物宿主的胃和肠中。有些会引起腹泻，可能很严重，而其他人则以血液为食，引起内出血和贫血。严重受影响的动物可能会死亡，或者出于福利考虑而必须被销毁，而较轻度受影响的动物的生长率不理想，这可能对农民产生严重的经济影响。事实上，寄生蠕虫是绵羊最重要的经济疾病，估计每年给绵羊业造成8000万英镑的损失。它们在牛中同样重要。这些经济损失与感染的严重程度直接相关，因此通过减少感染牲畜的寄生虫数量，我们可以按比例降低该行业的成本，并改善动物福利。这些寄生虫的控制在很大程度上依赖于用药物（驱虫药，通常称为蠕虫）对牲畜进行常规治疗，目前只有三种主要类型可用。在世界许多地方，寄生蠕虫现在对所有这些药物都有抗药性。在英国，超过60%的羊蠕虫对至少一种药物具有耐药性，并且多重耐药性正在增加。因此，抗药性蠕虫的问题是对英国绵羊和牛产业可持续性的重大威胁。检测耐药性是有问题的，目前的方法是老式的，劳动密集型和非常不敏感，使诊断不可靠，早期检测是不可能的。因此，有必要开发现代敏感测试，用于常规诊断和监测，并作为研究抗药性寄生虫出现和传播方式的工具。了解这些问题对于设计有效和可持续的寄生虫控制制度至关重要，并开发使用这些重要药物的方法，这些药物不会加剧耐药性的发展。该项目旨在开发和应用工具，以阐明这些寄生虫的生物学和遗传学的一些关键方面，这将有助于我们了解耐药性如何发展以及如何对抗。羊蠕虫将进行研究，因为抗药性是最先进的这些寄生虫，他们是服从实验工作。该项目还将开发一个基因组序列数据库，不仅使我们能够研究耐药性问题，而且将帮助其他研究人员开发疫苗，并确定这些寄生虫的新药靶点。该研究小组将是多学科的，包括兽医和科学家在遗传学，分子生物学，基因组学，流行病学，统计学，寄生虫学和临床兽医学的专业知识。该项目的第一阶段将是建立所需的工具，包括待研究的两种主要寄生虫的DNA序列和遗传标记。在这项工作的同时，将从英国各地的绵羊中收集寄生虫样本，并使用基于分子的诊断测试来确定存在的物种。然后，已经开发的遗传标记将被用来对寄生虫种群进行“指纹识别”，以调查它们的遗传多样性。将对已知具有耐药性的寄生虫基因进行测序，以研究寄生虫对这些药物产生耐药性的不同方式，并提供信息，为开发基于寄生虫DNA分型的敏感诊断测试铺平道路。最后，一个系统的遗传分析，以前不适用于寄生虫，将进行调查，将扫描蠕虫的基因组，以确定区域包含以前未知的抗性赋予基因。

Parasitic worms (nematodes) represent one of the most serious health problems of grazing livestock (sheep, cattle and goats) in the UK and throughout the world, causing significant economic loss and animal welfare problems. The most important types of parasitic worms live in the stomach and intestine of their animal host. Some cause diarrhoea, which can be severe, whilst others feed on blood and cause internal bleeding and anaemia. Severely affected animals may die, or have to be destroyed on welfare grounds, whilst more mildly affected animals have sub-optimal growth rates which can have serious economic implications for the farmer. Indeed, parasitic worms the most economically important disease of sheep and have been estimated to cost the sheep industry in the region of £80M per annum. They are similarly important in cattle. These economic losses are directly related to the severity of infection and so by reducing the number of parasites infecting livestock, we can proportionally reduce the costs to the industry as well as improving animal welfare. Control of these parasites is heavily dependent upon the routine treatment of livestock with drugs (anthelmintics, commonly called wormers) and there are only three major types available. In many parts of the world, parasitic worms are now resistant to all of these drugs. In the UK, over 60% of sheep worms are resistant to at least one drug class and multiple resistance is increasing. Consequently, the problem of drug resistant worms is a significant threat to the sustainability of the UK sheep and cattle industries. Detection of resistance is problematic and current methods are old fashioned, labour-intensive and very insensitive, making diagnosis unreliable and early detection impossible. Consequently, there is a need to develop modern sensitive tests for routine diagnosis and surveillance and as tools to study the way in which drug resistant parasites appear and spread. An understanding of these issues is critical for the design of parasite control regimes that are both effective and sustainable and to develop ways of using these important drugs that do not exacerbate the development of resistance This project aims to develop and apply tools to elucidate a number of key aspects of the biology and genetics of these parasites that will help us understand how drug resistance develops and how it may be combated. Sheep worms will be studied because drug resistance is the most advanced in these parasites and they are amenable to experimental work. The project will also develop a genome sequence database that will not only enable us to study the problem of resistance but will assist other researchers to develop vaccines and identify new drug targets in these parasites. The research team will be multidisciplinary and include vets and scientists with expertise in genetics, molecular biology, genomics, epidemiology, statistics, parasitology and clinical veterinary medicine. The first stage of the project will be to establish the tools needed, including DNA sequence and genetic markers from the two major parasite species of parasite to be studied. In parallel to this work, parasite samples will be collected from sheep throughout the UK and molecular-based diagnostic tests used to determine the species present. The genetic markers that have been developed will then be used to 'fingerprint' the parasite populations to investigate their genetic diversity. Parasite genes that are already known to confer resistance will be sequenced to investigate the different ways parasites are becoming resistant to these drugs and to provide information that will pave the way for the development sensitive diagnostic tests based on parasite DNA typing. Finally, a system of genetic analysis, not previously applied to parasitic worms, will be investigated that will scan the worm's genome to identify regions containing previously unknown resistance-conferring genes.