Genetic and molecular basis of triclabendazole resistance in Fasciola hepatica

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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.