The dopaminergic signalling system in the liver fluke, Fasciola hepatica

Abstract

This thesis explores the role of the dopamine (DA) signalling system in liver fluke biology, a target system in parasitic platyhelminths. The study uses publicly available omics datasets to search for dopamine signalling components and polypyrimidine tract-binding proteins (PTBs) in flatworm parasites, focusing on the liver fluke, Fasciola hepatica. In silico identification of DA pathway components across platyhelminths revealed that essential components of the dopamine signalling machinery are evolutionarily conserved throughout most platyhelminths, except for cestodes and some monogeneans. PTBs were found to have some variability in their consensus signature motifs compared to those seen in mammals. Drug bioassays were used to expose the effects of DA and a dopamine reuptake transporter inhibitor on juvenile F. hepatica. Functional genomics in the form of RNA interference (RNAi)-induced gene silencing was combined with an in vitro liver fluke culture system to interrogate gene function. The addition of dopamine and inhibition of dopamine reuptake consistently led to altered motility and growth in juvenile F. hepatica. Combinatorial RNAi of the three putative FhPTBs severely impaired the motility and growth of juvenile worms, leading to their death and inhibiting neoblast-like cell proliferation and negatively impacting nervous system development. This validates the potential of dopamine signalling and PTBs as new flukicide targets and encourages a more focused effort on their exploitation as new drug targets for liver fluke control.

Thesis embargoed until 31 July 2028.

Date of Award	Jul 2024
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	Saudi Arabia Cultural Bureau
Supervisor	Aaron Maule (Supervisor), Tim Geary (Supervisor) & Nikki Marks (Supervisor)