Exploiting stem cell receptors for parasite control

Abstract

The trematode Fasciola hepatica (the common liver fluke) is a parasite responsible for significant economic losses and health issues worldwide. Novel treatments are required due to increasing resistance against triclabendazole, the chief flukicide against fluke infection. This project investigates peptidergic G-Protein Coupled Receptors (GPCRs) within F. hepatica, potential drug targets within fluke. GPCRs account for ~33% of human drug targets but are underrepresented targets for trematode infections which warrant further investigation. Investigating two F. hepatica protein datasets revealed 50 predicted peptide GPCRs following protein analysis. Lifestage transcriptomics revealed many of these receptors are expressed at high levels in the damaging newly excysted juvenile stage of the parasite. Subsequent in vitro culturing using chicken serum supplemented with 50% RPMI (CS50) allowed for the culturing of F. hepatica where RNA interference against peptide GPCRs occurred. Silencing three neuropeptide Y G-Protein Coupled Receptors (NPY GPCRs) (FhPep 17, FhPep 24 and FhPep 25) resulted in reduced growth phenotypes with knockdown being confirmed in subsequent RT-qPCR analysis. A further three non-NPY GPCRs (FhPep 1, FhPep 11 and FhPep 21) were also silenced and caused reduced growth phenotypes. The reduced growth GPCR phenotypes inspired a return to investigating neuropeptides with updated methodologies which also caused reduced growth phenotypes, strengthening the link between peptidergic signalling and growth and development of F. hepatica and further highlighting the neuropeptidergic system as potential drug targets. Computational modelling predicted 3D structures of both GPCRs and neuropeptides in F. hepatica. Putative molecular interactions were identified between the terminal GRXR(Y/F) of fluke neuropeptide and fluke GPCRs, the first time this has been modelled in F. hepatica, inspiring future work in understanding molecular interactions and deorphanisation of GPCRs which will fuel drug discovery in F. hepatica. Overall, this project succeeded in better understanding how fluke peptidergic signalling affects growth and development within F. hepatica and lays the foundation for further drug discovery within the peptidergic signalling system of F. hepatica.

Date of Award	Jul 2026
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	Northern Ireland Department for the Economy
Supervisor	Aaron Maule (Supervisor), Irina Tikhonova (Supervisor) & David Simpson (Supervisor)