Probing in vivo parasite biology in vitro

Helminth parasites impose a huge burden on human health and agricultural productivity. Amongst the most important parasites of livestock are Fasciola species liver fluke that cause fasciolosis - also a neglected tropical disease. The predicted impact of climate change on fluke epidemiology and growing drug resistance emphasise the need for new flukicides / vaccines. Unfortunately, major impediments to research that advances new control target discovery/validation have included the lack of good bioinformatic resources, the absence of a model system for functional studies and the reliance on host animal-based in vivo experiments to inform fluke biology; the reliance on in vivo efficacy studies in host animals impedes significantly the drug discovery process. 

The new liver fluke genome sequence and the development of functional genomics tools expose a compelling need for in vitro tools for juvenile fluke to facilitate studies of their biology. In this respect we have made significant advances in their in vitro maintenance that facilitate fluke survival for >7 months (with >70% survival). Although our methods facilitate marked growth and development of the gut, tegument and reproductive systems, these are slower than those seen in vivo. This project will build on these new resources and preliminary data to enhance in vitro fluke culture. The work will be underpinned by comparative studies (behavioural, morphological, pharmacological and transcriptomic) of in vitro and in vivo fluke to validate the utility of functional/phenotypic readouts. This project aims to deliver an in vitro toolkit for liver fluke that is robust and translational (i.e. predictive of in vivo outcomes) and enables the study fluke developmental biology, the validation of new drug targets and the screening new drug candidates. Progress made here will contribute significantly to the replacement of animals for studies of parasite biology.

McVeigh P and Maule AG (2019). Can CRISPR help in the fight against parasites? eLife 8. doi: 10.7554/eLife.44382 

McVeigh P et al. (2018). In silico analyses of protein glycosylating genes in the helminth Fasciola hepatica (liver fluke) predict protein-linked glycan simplicity and reveal temporally-dynamic expression profiles. Scientific reports 8(1):11700. doi: 10.1038/s41598-018-29673-3

McVeigh P et al. (2018). Profiling G protein-coupled receptors of Fasciola hepatica identifies orphan rhodopsins unique to phylum Platyhelminthes. International journal for parasitology. Drugs and drug resistance 8(1):87-103. doi: 10.1016/j.ijpddr.2018.01.001

McVeigh P et al. (2018). Reasons to Be Nervous about Flukicide Discovery. Trends in Parasitology 34(3):184-196. doi: 10.1016/j.pt.2017.11.010

McCammick EM et al. (2016). Calmodulin disruption impacts growth and motility in juvenile liver fluke. Parasites & vectors 9:46. doi: 10.1186/s13071-016-1324-9

McCusker P et al. (2016). Stimulating Neoblast-Like Cell Proliferation in Juvenile Fasciola hepatica Supports Growth and Progression towards the Adult Phenotype In Vitro. PLOS Neglected Tropical Diseases 10(9):e0004994. doi: 10.1371/journal.pntd.0004994

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Project grant

Status:

Active

Principal investigator

Professor Aaron Maule

Institution

Queen's University Belfast

Co-Investigator

Dr Nicola Marks
Dr Angela Mousley

Grant reference number

NC/N001486/1

Award date:

Jan 2016 - Dec 2019

Grant amount

£318,176.97