I was appointed Lecturer in Veterinary Parasitology at The Liverpool School of Tropical Medicine in 2002 and subsequently Senior Lecturer in Veterinary Parasitology at the University of Liverpool. I lead a programme of research unravelling the complex molecular mechanisms underlying anthelmintic resistance in livestock and horses. Central to my research is the development and application of genetic and genomic resources to address key questions in parasite biology, epidemiology and the evolution of drug resistance combined with improving diagnostics to detect drug resistance in the field. Current projects include mapping triclabendazole resistance in the trematode parasite, Fasciola hepatica.
The liver fluke, Fasciola hepatica is an economically important trematode parasite pathogen of livestock that frequently impacts on the health and welfare of cattle and sheep worldwide and is regarded by the WHO as a re-emerging zoonosis. With predictions for further increases in the prevalence of infection due to a changing climate, increased animal movements and anthelmintic resistance, combined with its ability to modulate the host immune system and affect diagnosis and susceptibility to other pathogens, F. hepatica infection is likely to have a substantial impact on livestock production and human health in future.
The potential for anthelmintic resistance to be complex and multigenic in nature and involving as yet unidentified genes, has promoted whole genome approaches to identify drug resistance mechanisms. In this review, we report a classical genetic mapping approach to identify the major genetic loci involved in conferring triclabendazole (TCBZ) resistance in F. hepatica. In order to dissect the spread of genes associated with TCBZ resistance we have taken an experimental approach by crossing TCBZ susceptible (TCBZ-S) and TCBZ resistant (TCBZ-R) clones of F. hepatica and mapping TCBZ-R genes through subsequent F1 and F2 populations. To ensure use of isolates representative of the current field situation and to avoid issues associated with laboratory isolates we have identified TCBZ-R field isolates from the UK. We have used single miracidial:snail infections of F. hepatica to generate clonal parental lines of TCBZ-R and TCBZ-S parasites and confirmed their TCBZ resistance status in experimental infections in sheep. These parental clones have been used to derive F1 progeny using a panel of neutral microsatellite markers we developed to track the genotypes of those parasites that had undergone cross fertilization events between TCBZ-R and TCBZ-S parasites and to allow subsequent identification of F2 recombinants. A draft genome sequence for F. hepatica has been produced and in order to support SNP discovery to map regions of the genome associated with resistance the re-sequencing of genome-wide SNPs for five isolates will be reported. Ultimately, the project relies on comparing the frequency of SNP alleles derived from the resistant parental clone and linked to the TCBZ resistance locus (or loci) in pooled, phenotyped F2 recombinants. In vivo and in vitro phenotyping of F2 recombinants will be described and pooled genotyping on >20 replicates followed by analysis of allele frequencies to associate SNPs to TCBZ resistance is underway and will be discussed.