Mapping triclabendazole resistance in Fasciola hepatica using next generation sequencing technologies

使用下一代测序技术绘制肝片形吸虫中的三氯苯达唑耐药性

• 批准号: BB/I002480/1
• 负责人: Jane Hodgkinson
• 金额: $ 71.33万
• 依托单位: University of Liverpool
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2011
• 资助国家: 英国
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FI002480%2F1
• 关键词: Mapping; triclabendazole; resistance; Fasciola; hepatica

Fasciolosis is a common and important disease of livestock. In the UK it is the most commonly reported infection associated with the digestive tract of ruminants. It is caused by Fasciola hepatica, a flatworm found in the liver and transmitted by a mud snail. Fasciolosis is controlled predominantly using drug treatment and the most commonly used drug is triclabendazole (TCBZ). This is the only drug that is effective against the immature stages of the parasite that are responsible for acute, often fatal disease. It is also the drug of choice for human fasciolosis, caused by the same parasite. Resistance to TCBZ was first reported in Australia in 1995 and is now thought to be widespread worldwide. Very little is known about mechanisms of drug resistance in F. hepatica, which genes are involved and how resistance is evolving. This proposal aims to exploit our ability to create clones of resistant and susceptible F. hepatica; to derive genetically identical infections of TCBZ-susceptible and TCBZ-resistant isolates in sheep, from which we will generate second generation populations. These populations will be used to identify markers, in this case single mutations at the DNA level that associate with resistance genes during the crossing of resistant and susceptible clones. We will use rapid, high throughput, next generation sequencing technologies, which allow us to produce a preliminary F. hepatica genome map. The resistance markers will be mapped onto this preliminary genome and allow us to identify regions of the genome where the gene or genes responsible for encoding resistance are found. At the end of the project we will have genetic markers for resistance that could be used to detect and track the emergence of resistance in populations of F. hepatica in naturally infected sheep and cattle in the UK, but, importantly they will also be used in future projects to start to home in and identify genes encoding resistance. There will be other important outputs for the wider scientific community from the project, such as a bank of genome data for the parasite and clones of the parasite whose resistance status is well characterised. Genome data will be made available through a publicly accessible website and the parasite clones will be made available to other groups by lodging them with our industrial partner, Ridgeways Research Ltd.

片形吸虫病是牲畜的一种常见且重要的疾病。在英国，这是最常见的与反刍动物消化道相关的感染。它是由肝片吸虫引起的，这是一种在肝脏中发现的扁虫，由泥螺传播。片形吸虫病主要通过药物治疗来控制，最常用的药物是三氯苯达唑 (TCBZ)。这是唯一能有效对抗未成熟阶段寄生虫的药物，这种寄生虫会导致急性甚至致命的疾病。它也是治疗由同一寄生虫引起的人类片形吸虫病的首选药物。 TCBZ 耐药性最早于 1995 年在澳大利亚报道，现在被认为在全世界范围内普遍存在。关于肝镰刀菌的耐药机制、涉及哪些基因以及耐药性是如何演变的，人们知之甚少。该提案旨在利用我们创建抗性和易感肝镰刀菌克隆的能力；在绵羊中获得 TCBZ 敏感和 TCBZ 抗性分离株的基因相同的感染，我们将从中产生第二代群体。这些群体将用于识别标记，在这种情况下是 DNA 水平上的单突变，在抗性和易感克隆杂交过程中与抗性基因相关。我们将使用快速、高通量的下一代测序技术，这使我们能够生成初步的肝镰刀菌基因组图谱。抗性标记将被映射到这个初步基因组上，使我们能够识别基因组中发现负责编码抗性的基因的区域。在项目结束时，我们将拥有抗性遗传标记，可用于检测和追踪英国自然感染的羊和牛中肝镰刀菌种群中抗性的出现，但重要的是，它们也将在未来的项目中用于开始追踪和识别编码抗性的基因。该项目还将为更广泛的科学界带来其他重要成果，例如寄生虫的基因组数据库以及其抗药性状况已得到充分表征的寄生虫克隆。基因组数据将通过一个可公开访问的网站提供，寄生虫克隆将通过我们的工业合作伙伴 Ridgeways Research Ltd 提供给其他团体使用。

项目成果

The Fasciola hepatica genome: gene duplication and polymorphism reveals adaptation to the host environment and the capacity for rapid evolution.

• DOI: 10.1186/s13059-015-0632-2
• 发表时间: 2015-04-03
• 期刊: Genome biology
• 影响因子: 12.3
• 作者: Cwiklinski K;Dalton JP;Dufresne PJ;La Course J;Williams DJ;Hodgkinson J;Paterson S
• 通讯作者: Paterson S

A survey of experiences of UK cattle and sheep farmers with anthelmintic prescribers; Are best practice principles being deployed at farm level?

• DOI: 10.1016/j.prevetmed.2018.04.009
• 发表时间: 2018-07-01
• 期刊: PREVENTIVE VETERINARY MEDICINE
• 影响因子: 2.6
• 作者: Easton, Stephanie;Pinchbeck, Gina L.;Matthews, Jacqueline B.
• 通讯作者: Matthews, Jacqueline B.

Fasciola hepatica from naturally infected sheep and cattle in Great Britain are diploid

• DOI: 10.1017/s0031182015000499
• 发表时间: 2015-08-01
• 期刊: PARASITOLOGY
• 影响因子: 2.4
• 作者: Beesley, N. J.;Cwiklinski, K.;Hodgkinson, J.
• 通讯作者: Hodgkinson, J.

A major locus confers triclabendazole resistance in Fasciola hepatica and shows dominant inheritance.

• DOI: 10.1371/journal.ppat.1011081
• 发表时间: 2023-01
• 期刊: PLoS pathogens
• 影响因子: 6.7

Fasciola hepatica demonstrates high levels of genetic diversity, a lack of population structure and high gene flow: possible implications for drug resistance.

Fasciola Hepatica表现出高水平的遗传多样性，缺乏种群结构和高基因流量：对耐药性的可能影响。

• DOI: 10.1016/j.ijpara.2016.09.007
• 发表时间: 2017-01
• 期刊: International journal for parasitology
• 影响因子: 4
• 作者: Beesley NJ;Williams DJ;Paterson S;Hodgkinson J
• 通讯作者: Hodgkinson J