Understanding growth and development in the liver fluke, Fasciola hepatica: exposing new targets for improved parasite control

Abstract

The liver fluke, Fasciola hepatica, exerts asignificant disease burden on ruminant livestock worldwide and is a causativeagent of fascioliasis, a neglected tropical zoonosis. Increasing reports offlukicide resistance threatens to undermine F. hepatica control andaccentuates the need for both improved diagnostics and novel therapeutic targetdiscovery. Chapter 2 exploited F. hepatica eggs to demonstrate the utility ofegg-derived data in the diagnosis of resistance. The WMicroTracker bioassayplatform shows promise as an automated, high throughput egg hatch assay.Parallels were also uncovered between the neoblast-like stem cells of eggs andpathogenic juvenile fluke. F. hepatica growth, development and virulenceare driven by the proliferation of neoblast-like cells, such that theirdysregulation represents an attractive avenue for control. Chapters 3 and 4exploited available genomic/transcriptomic datasets and an in vitro cultureplatform to identify and functionally interrogate molecular signalling pathwaysunderpinning growth, development and cell cycle events in growing juveniles.Wnt signalling was found to be conserved in fluke, with both fluorescence insitu hybridisation and RNA interference (RNAi)-induced gene silencingdemonstrating the vital roles played by Wnt pathway components in thegrowth/development of diverse cell/tissue types. Silencing a Fhβ-cateninuncovered a key role for this gene in neuromuscular development and survival,exposing the first gene to be associated with an RNAi-induced lethal phenotypein F. hepatica. “Pro-survival” signalling pathway components were foundto be essential in the regulation of the cell cycle, governing the delicatebalance between cell proliferation and apoptosis. Indeed, silencing selectcomponents profoundly reduced growth, dysregulated neoblast-like cellproliferation, increased apoptosis and proved fatal. The involvement of suchpathways in tumourigenesis provides impetus for the repurposing of anti-cancerdrugs as novel flukicides. Collectively, these data indicate that targeting developmentalpathways represents a novel strategy for F. hepatica control.