Genetic and molecular basis of triclabendazole resistance in Fasciola hepatica

肝片形吸虫三氯苯达唑耐药的遗传和分子基础

• 批准号: BB/P001912/1
• 负责人: Jane Hodgkinson
• 金额: $ 84.13万
• 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: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FP001912%2F1
• 关键词: Genetic; molecular; basis; triclabendazole; resistance

Fasciolosis is a common and important disease of livestock that results in substantial economic losses to the livestock sector. It is caused by the liver fluke, Fasciola hepatica, a flatworm found in the liver and transmitted via a mud snail. In the UK it is the most commonly reported infection associated with the digestive tract of ruminants. The immature stages of F. hepatica are responsible for acute disease, which has a negative impact on animal welfare and is often fatal in sheep. 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 pathogenic early immature stages. 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 reported in many locations worldwide. Little is known about the mechanisms of drug resistance in F. hepatica. This proposal aims to address this and other outstanding questions in drug resistance such as: Is there one genetic route to TCBZ resistance or multiple? What factors influence the emergence and spread of drug resistance alleles in liver fluke populations?This project will utilise outputs from our highly successful previous project, which produced a draft F. hepatica genome and located (mapped) areas of the genome of TCBZ resistant parasites that may explain their ability to survive drug treatment. Here, we will produce a number of sequencing resources to improve this mapping exercise, including; a) a linkage map to improve the organisation of the genome and b) whole-genome sequencing of fluke eggs from the faeces of sheep naturally infected with resistant parasites, from before and after TCBZ treatment. Analysing these sequences will allow us to close in on the gene or genes responsible for encoding TCBZ resistance and will help us understand how resistance is passed from one parasite generation to the next. To assist in identifying the genes involved we will expose our resistant and susceptible clonal parasites to TCBZ and characterise the total gene expression profile and chemical fingerprint (global metabolomic profile). At the end of the project we will have genetic markers for resistance that can be used to detect and track the emergence of resistance in populations of F. hepatica naturally infecting sheep and cattle in the UK. There will be other important outputs for the wider scientific community from the project, such as a bank of genomic, transcriptomic and metabolomic data. We will make all these resources available to liver fluke researchers worldwide; so that, together, we can more effectively control this parasite in future.

肝片吸虫病是一种常见的重要家畜疾病，给畜牧业造成巨大的经济损失。它是由肝片吸虫引起的，肝片吸虫是一种在肝脏中发现的扁形虫，通过泥螺传播。在英国，它是最常见的反刍动物消化道感染。F.肝病是急性疾病原因，急性疾病对动物福利具有负面影响，且在绵羊中常常是致命的。肝片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）。这是唯一一种对致病性早期不成熟阶段有效的药物。它也是治疗由同一种寄生虫引起的人类片形吸虫病的首选药物。1995年首次在澳大利亚报告了对TCBZ的耐药性，现在在世界许多地方都有报告。目前人们对F.肝。该提案旨在解决这一问题和其他悬而未决的耐药性问题，如：是否有一个遗传途径TCBZ耐药或多个？哪些因素影响肝吸虫种群中耐药等位基因的出现和传播？这个项目将利用我们之前非常成功的项目的成果，该项目产生了F草案。肝吸虫基因组和TCBZ耐药寄生虫基因组的定位（映射）区域，可以解释它们在药物治疗中存活的能力。在这里，我们将产生一些测序资源，以改善这种映射工作，包括：a）一个连锁图，以改善基因组的组织和B）全基因组测序的吸虫卵从粪便中自然感染耐药寄生虫，从之前和之后TCBZ治疗。分析这些序列将使我们能够接近负责编码TCBZ抗性的基因，并将帮助我们了解抗性如何从一个寄生虫世代传递到下一个。为了帮助鉴定相关基因，我们将我们的抗性和易感克隆寄生虫暴露于TCBZ，并分析总基因表达谱和化学指纹（全局代谢组学谱）。在项目结束时，我们将有抗性的遗传标记，可用于检测和跟踪F。在英国感染绵羊和牛的天然肝菌。该项目还将为更广泛的科学界提供其他重要产出，如基因组、转录组和代谢组数据库。我们将把所有这些资源提供给全世界的肝吸虫研究人员;这样，我们就可以在未来更有效地控制这种寄生虫。

项目成果

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

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

Clonal amplification of Fasciola hepatica in Galba truncatula: within and between isolate variation of triclabendazole-susceptible and -resistant clones.

• DOI: 10.1186/s13071-018-2952-z
• 发表时间: 2018-06-26
• 期刊: Parasites & vectors
• 影响因子: 3.2
• 作者: Hodgkinson JE;Cwiklinski K;Beesley N;Hartley C;Allen K;Williams DJL
• 通讯作者: Williams DJL

A survey of sheep and/or cattle farmers in the UK shows confusion over the diagnosis and control of rumen fluke and liver fluke

• DOI: 10.1016/j.vetpar.2022.109812
• 发表时间: 2022-10-18
• 期刊: VETERINARY PARASITOLOGY
• 影响因子: 2.6
• 作者: Hoyle, Rebecca C.;Vineer, Hannah Rose;Hodgkinson, Jane E.
• 通讯作者: Hodgkinson, Jane E.

Coproscopical diagnosis of patent Fasciola hepatica infections in sheep - A comparison between standard sedimentation, FLUKEFINDER® and a combination of both.

绵羊肝片形吸虫感染的腹腔镜诊断 - 标准沉降法、FLUKEFINDER® 以及两者组合之间的比较。

• DOI: 10.1016/j.vetpar.2023.109956
• 发表时间: 2023
• 期刊: Veterinary parasitology
• 影响因子: 2.6
• 作者: Kahl A