Systems based approaches to unravelling neuropeptide-receptor interactions in nematodes

Abstract

Nematode parasite infections cause disease in humans and animals and threaten global food security by reducing productivity in livestock and crop farming. The escalation of anthelmintic resistance in economically important nematode parasites underscores the need for the identification of novel drug targets in these worms. Neuropeptide G protein-coupled receptors (NP-GPCRs) are an appealing anthelmintic target, however, a lack of knowledge on the profiles and functions of neuropeptide ligands and receptors in nematode parasites currently limits their exploitation. NP-GPCR deorphanisation, i.e. the linking of a receptor with its endogenous ligand, will be key in the investigation of these receptors, but tools for deorphanisation in parasitic nematode species are currently lacking. This thesis employed a bioinformatic search approach to profile the neuropeptide complements of selected parasitic nematodes and utilised an in silico pipeline for the prediction of neuropeptide-receptor interactions in these species. The neuropeptide profiles and predicted neuropeptide-receptor interactions presented advance our knowledge of neuropeptide signalling systems in nematode parasites and can inform and direct functional deorphanisation studies in a range of nematode species. Secondly, established physiology tools and available transcriptomic and peptidomics data in the nematode parasite Ascaris suum were used to investigate neuropeptide signalling in the reproductive system of this species, revealing putative conservation of neuropeptide function between the model nematode Caenorhabditis elegans and A. suum. Finally, progress was made in the development of a novel receptor deorphanisation platform in A. suum, combining an established bioassay with functional genomics in this parasite. This method will enable the identification of post-RNA interference (RNAi) knockdown phenotypes and facilitate ligand-receptor matching in a parasitic nematode. The first successful transcript knockdown for an NP-gpcr gene in the ovijector of A. suum is reported. In addition, an established A. suum body-posture assay shows promise as a post-RNAi bioassay for NP-GPCR deorphanisation.

Date of Award	Jul 2021
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	Northern Ireland Department for the Economy
Supervisor	Angela Mousley (Supervisor) & Aaron Maule (Supervisor)