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

BUG 联盟以基因组为基础：利用扭旋扭伤线虫基因组资源开发新的干预措施来控制地方性胃肠道寄生虫

• 批准号: BB/M003949/1
• 负责人: Eileen Devaney
• 金额: $ 375.71万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FM003949%2F1
• 关键词: BUG; consortium; Building; Upon; Genome

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.

大多数食用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中。这些寄生虫在宿主体内引起一系列疾病，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，在减产和待遇方面给农民造成重大经济损失。据估计，这些蠕虫每年给英国养羊业造成保守的8400万英镑的损失。目前，这些寄生虫使用称为驱虫剂的药物进行控制，但这些化学品中的许多不再有效，因为寄生虫已经对它们产生了抗性，类似于细菌中的抗生素抗性。驱虫剂的抗药性如何产生并在农场的蠕虫中传播尚不清楚。在英国，这个问题已经变得如此严重，以至于一些牧羊企业不得不关闭，因为蠕虫不再受到控制。我们的项目将研究如何确保现有药物的管理，以尽量减少耐药性的发生和传播，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的，而且不敏感，因此不可能进行早期检测，也难以分析问题的严重程度。这使得很难评估旨在减少耐药性传播的战略。我们需要开发更敏感的方法来检测耐药寄生虫，因此必须了解导致耐药的寄生虫的遗传变化。我们最近对其中一种名为Haemonchus contortus（理发杆虫）的寄生虫的基因组进行了测序，发现它既大又复杂，含有与人类基因组相似数量的基因。研究这种基因组将确定控制线虫感染的新方法，我们的研究旨在利用新技术确保农民能够继续有效地生产牲畜。我们计划使用来自基因组的信息来识别血矛线虫和一种名为Teladorsagia circumcincta的密切相关蠕虫的耐药性标记，Teladorsagia circumcincta是英国绵羊群体中发现的最普遍的寄生虫。通过识别暴露于驱虫剂的蠕虫的遗传变化，我们的目标是了解抗性是如何产生的，并开发标记来识别绵羊养殖场的抗性蠕虫。这些信息将用于帮助模拟耐药性如何传播，并研究不同的治疗方案如何影响耐药性的发展，同时考虑到气候变化情景。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，因为我们无法评估迄今为止测试的抗原是否最有效地刺激宿主免疫反应。然而，我们的项目将为识别绵羊免疫系统选择的基因提供基础，因此可能具有抗原性。我们将结合联合收割机的结果，从这个研究的知识，在哪里和何时特定抗原表达的蠕虫，以优化潜在的候选疫苗的选择。最后，该项目的结果将用于设计面对驱虫药耐药性和气候变化的绵羊寄生虫可持续控制策略。我们制定了强有力的计划，通过研讨会和出版物与农业社区接触，以确保我们工作的影响转化为良好的农业实践。虽然这个项目的重点是羊的寄生虫，我们预计，我们所了解的驱虫药耐药性将直接适用于牛，马和猪的寄生虫，驱虫药耐药性是一个新出现的问题。此外，随着相同的药物越来越多地用于控制人体内的相关蠕虫，我们的工作也将影响人类健康。

项目成果

Allele specific PCR for a major marker of levamisole resistance in Haemonchus contortus.

• DOI: 10.1016/j.ijpddr.2022.08.001
• 发表时间: 2022-12
• 期刊: INTERNATIONAL JOURNAL FOR PARASITOLOGY-DRUGS AND DRUG RESISTANCE
• 影响因子: 4
• 作者: Antonopoulos, Alistair;Doyle, Stephen R.;Bartley, David J.;Morrison, Alison A.;Kaplan, Ray;Howell, Sue;Neveu, Cedric;Busin, Valentina;Devaney, Eileen;Laing, Roz
• 通讯作者: Laing, Roz

Increasing resistance to multiple anthelmintic classes in gastrointestinal nematodes on sheep farms in southwest England.

• DOI: 10.1002/vetr.1531
• 发表时间: 2022-06
• 期刊: VETERINARY RECORD
• 影响因子: 2.2
• 作者: Bull, Katie;Glover, Mike J.;Vineer, Hannah Rose;Morgan, Eric R.
• 通讯作者: Morgan, Eric R.

The genome of Onchocerca volvulus, agent of river blindness.

• DOI: 10.1038/nmicrobiol.2016.216
• 发表时间: 2016-11-21
• 期刊: Nature microbiology
• 影响因子: 28.3
• 作者: Cotton JA;Bennuru S;Grote A;Harsha B;Tracey A;Beech R;Doyle SR;Dunn M;Hotopp JC;Holroyd N;Kikuchi T;Lambert O;Mhashilkar A;Mutowo P;Nursimulu N;Ribeiro JM;Rogers MB;Stanley E;Swapna LS;Tsai IJ;Unnasch TR;Voronin D;Parkinson J;Nutman TB;Ghedin E;Berriman M;Lustigman S
• 通讯作者: Lustigman S

Discovering environmental management opportunities for infectious disease control.

• DOI: 10.1038/s41598-021-85250-1
• 发表时间: 2021-03-19
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Beltrame L;Rose Vineer H;Walker JG;Morgan ER;Vickerman P;Wagener T
• 通讯作者: Wagener T