Unravelling endocannabinoid biology using omics approaches in Strongyloides parasites

Abstract

Parasitic nematodes present a significant threat to global agriculture, veterinary health, and human well-being, resulting in substantial morbidity and mortality. The primary strategy of control is mass chemotherapy using anthelmintics; however, overreliance on the anthelmintic arsenal has driven the emergence of anthelmintic resistance in livestock infective nematodes, with recent evidence suggesting the evolution of resistance in human filarial nematodes. To combat resistance, novel control methods are required, including the identification of new anthelmintic classes with distinct mechanisms of action. The endocannabinoid (EC) signalling system, known for its diverse roles in mammalian physiology and therapeutic potential in human conditions such as epilepsy, Parkinson's, and multiple sclerosis, presents a promising avenue for investigation. A functional EC signalling system is present in the nematode model species Caenorhabditis elegans but data on parasitic nematode EC signalling is limited. This thesis explores parasitic nematode EC signalling function through a multifaceted approach encompassing bioinformatics, functional bioassays, and functional genomics in the model parasite Strongyloides ratti.

Homology-directed in silico approaches have revealed the conservation of the extended EC signalling network, presenting a series of potential targets linked to nematode EC signalling. Through the design and optimisation of Strongyloides phenotype bioassays significant advances have been made towards a comprehensive Strongyloides bioassay toolkit that will facilitate interrogation of key Strongyloides behaviours. Exploitation of EC signalling effectors revealed that Strongyloides possess a functional EC signalling system that is putatively linked to key parasite behaviours including nociception, motility, development, thermotolerance, and survival. Further, RNA interference in S. ratti in vitro activated infective larvae (iL3a) has revealed that silencing of an EC ligand biosynthesis enzyme disrupts S. ratti nociception. The data presented in this thesis reveals a fundamental role for EC signalling in parasitic nematode biology and highlights the EC signalling system as a putative source of attractive novel drug targets for parasite control.

Thesis is embargoed until 31st December 2025.

Date of Award	Dec 2024
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	Academy of Medical Sciences
Supervisor	Louise Atkinson (Supervisor), Angela Mousley (Supervisor) & Aaron Maule (Supervisor)