The BUG consortium Building Upon the Genome: using H. contortus genomic resources to develop novel interventions to control endemic GI parasites

大多数生产食物的动物都感染了各种不同的蛔虫或线虫，其中许多生活在消化道。这些寄生虫在宿主中引起一系列疾病，从腹泻和贫血，到严重情况下的死亡。它们是一个重大的福利问题，在产量和待遇减少方面给农民造成了重大的经济损失。据估计，这些蠕虫每年给英国养羊业造成8400万英镑的损失。目前，这些寄生虫是通过使用被称为驱虫剂的药物来控制的，但其中许多化学物质不再有效，因为寄生虫已经对它们产生了抗药性，类似于细菌中的抗生素抗药性。驱虫剂耐药性是如何在农场的蠕虫中产生和传播的，目前尚不清楚。在英国，这个问题已经变得如此严重，以至于一些养羊企业不得不关闭，因为这种蠕虫已经无法控制。我们的项目将研究如何确保现有药物得到管理，以将耐药性的发生和传播降至最低，并将研究疫苗开发的新方法。目前检测抗药性寄生虫的方法是劳动密集型和不敏感的，使得无法及早发现，也难以分析问题的严重程度。这使得评估旨在减少耐药性传播的策略变得困难。我们需要开发更灵敏的方法来检测抗药性寄生虫，因此必须了解导致抗药性的寄生虫的基因变化。我们最近对其中一种名为扭曲血吸虫(理发师杆虫)的寄生虫的基因组进行了测序，发现它又大又复杂，含有与人类基因组相似的基因数量。研究这个基因组将确定控制线虫感染的新方法，我们的研究旨在使用新技术来确保农民能够继续有效地生产牲畜。我们计划使用基因组中的信息来识别血吸虫和一种密切相关的线虫的抗药性标记，这种线虫是在英国绵羊种群中发现的最常见的寄生虫。通过识别暴露在驱虫剂下的蠕虫的基因变化，我们的目标是了解抗药性是如何产生的，并开发标记来识别绵羊养殖场的抗药性蠕虫。这些信息将被用来帮助模拟耐药性如何传播，并在考虑到气候变化的情况下，调查不同的治疗计划如何影响耐药性的发展。从长远来看，我们希望开发针对这些蠕虫的疫苗。尽管已经进行了许多尝试，但大多数都没有成功，因为我们无法评估到目前为止测试的抗原是否在刺激宿主免疫反应方面最有效。然而，我们的项目将为识别绵羊免疫系统正在选择的因此可能是抗原性的基因提供基础。我们将把这项研究的结果与特定抗原在蠕虫中何时何地表达的知识结合起来，以优化潜在候选疫苗的选择。最后，该项目的结果将被用于设计绵羊寄生虫在面临驱虫剂耐药性和气候变化时的可持续控制策略。我们制定了强有力的计划，通过讲习班和出版物与农业社区接触，以确保将我们工作的影响转化为良好的农业做法。虽然这个项目的重点是绵羊寄生虫，但我们预计，我们了解到的许多驱虫药耐药性将直接适用于牛、马和猪的寄生虫，这些寄生虫的抗药性是一个新出现的问题。此外，随着同样的药物越来越多地用于控制人类体内的相关蠕虫，我们的工作也将影响人类健康。

Most food-producing animals are infected with a variety of different roundworms, or nematodes, many of which live in the digestive tract. These parasites cause a range of disease in their hosts, from diarrhoea and anaemia, to death, in severe cases. They are a major welfare issue and cause significant economic losses to farmers, in terms of reduced production and treatment. It is estimated that these worms cost the UK sheep industry a conservative £84 million per annum. At the present time these parasites are controlled using drugs known as anthelmintics, but many of these chemicals no longer work effectively because the parasites have developed resistance to them, analogous to antibiotic resistance in bacteria. How anthelmintic resistance arises and spreads throughout the worms on a farm is not known. The problem has become so serious in the UK that some sheep-farming enterprises have had to close because the worms can no longer be controlled. Our project will investigate ways of ensuring that the existing drugs are managed to minimise the occurrence and spread of resistance and will also study novel approaches to vaccine development. The current methods for detecting resistant parasites are labour intensive and insensitive, making early detection impossible and analysis of the extent of the problem difficult. This makes it hard to evaluate strategies aimed at reducing the spread of resistance. We need to develop more sensitive methods to detect resistant parasites and so must understand the genetic changes in the parasites that lead to resistance. We have recently sequenced the genome of one of these parasites called Haemonchus contortus (the Barber's pole worm) and found it to be large and complex, containing a similar number of genes to the human genome. Studying this genome will identify novel ways of controlling nematode infections and our research is aimed at using new technologies to ensure that farmers can continue to produce livestock effectively. We plan to use information from the genome to identify markers of drug resistance in Haemonchus and in a closely related worm called Teladorsagia circumcincta, which is the most prevalent parasite found in the UK sheep population. By identifying the genetic changes in worms exposed to anthelmintics, we aim to understand how resistance arises and to develop markers to identify resistant worms on sheep farms. This information will be used to help model how resistance spreads and to investigate how different treatment schedules affect the development of resistance, taking into account climate change scenarios. In the longer term, we would like to develop vaccines against these worms. Although many attempts have been made to do this, most have not been successful, as we have no way of assessing whether the antigens tested to date are the most effective at stimulating a host immune response. However, our project will provide the basis for identifying genes that are under selection by the sheep immune system and therefore likely to be antigenic. We will combine results from this study with knowledge of where and when specific antigens are expressed in the worm to optimise the selection of potential vaccine candidates. Finally, the results from this project will be used to design sustainable control strategies for sheep parasites in the face of anthelmintic resistance and climate change. We have robust plans to engage with the farming community through workshops and publications to ensure that the implications of our work are translated into good farming practice. While this project focuses on parasites of sheep, we anticipate that much of what we learn about anthelmintic resistance will be directly applicable to parasites of cows, horses and pigs where anthelmintic resistance is an emerging problem. Moreover, as the same drugs are increasingly used to control related worms in humans, our work will also impact on human health.