Identification and characterisation of antimicrobial peptides in parasitic helminths

Abstract

Parasitic helminths inflict a significant burden to human, animal and plant health worldwide. The control of helminth disease currently relies on a limited spectra of anthelmintic drugs and is threatened by anthelmintic resistance. Novel anthelmintic therapies are urgently required but development is hindered by our limited understanding of how helminths infect, survive and thrive in host environments. Helminths share complex interactions with a range of microorganisms including endogenous helminth microbiota, environmental microbiota and host-derived microbiota. In other invertebrate phyla, Antimicrobial Peptides (AMPs) play key roles in mitigating microbial pathogens and in shaping endogenous microbiota. In helminths, knowledge of AMP function is limited by incomplete knowledge of AMP-encoding genes. This thesis integrates multiple laboratory-based methods and computational tools including bioinformatics, microbiology and molecular biology to characterise helminth AMP diversity and begin to unravel AMP function in helminths.

Through homology-directed and machine learning AMP identification and prediction approaches, the data generated here highlight helminths as a major source of AMP diversity. These analyses reveal major differences in the distribution of putative AMP-encoding genes across phylum Nematoda and Platyhelminthes, with specific helminth taxa displaying restricted AMP profiles. Through exploitation of published RNAseq datasets, putative AMP-encoding genes were also shown to be expressed in key parasitic life stages supporting prioritisation of AMP-encoding genes for functional analyses. Eight novel helminth-derived AMPs, identified via a unique computational AMP discovery pipeline, displayed antibacterial activities against pathogenic microbes demonstrating that helminths may also be a source of antimicrobial diversity for the development of novel therapeutics. Finally, efforts to unravel the function of AMPs in adult Ascaris suum via RNA interference highlighted that novel approaches are required to uncover the role of helminth AMPs and their importance to nematode biology. The data presented in this thesis represent a significant advance in our understanding of helminth-derived AMPs and provide a springboard for functional analyses that will reveal the potential for helminth-derived AMPs as novel therapeutic targets for pathogen control.

Date of Award	Jul 2023
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	Department of Agriculture, Environment and Rural Affairs
Supervisor	Angela Mousley (Supervisor), Louise Atkinson (Supervisor) & Sharon Huws (Supervisor)