Zoonotic Pathogen Growth Rate - A Marker for Disease Virulence and Therapy Resistance.

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The Challenge: Fasciola hepatica (or the liver fluke) is a zoonotic pathogen that causes the disease fasciolosis in animals and humans. Control is precarious and in the absence of an effective vaccine is reliant on a small portfolio of drugs (flukicides) to which resistance is growing. More problematic is the fact that only one flukicide is effective against the migrating juvenile fluke which causes acute disease during its passage through the liver. We have compelling evidence that disease severity and drug susceptibility are profoundly impacted by pathogen growth rate, but data on pathogen growth are not readily available and therefore are not used to guide forecasts on disease outbreaks and intensity. Accurate forecasts from environmental markers are needed to guide fluke treatment regimens. This project sets out to address this shortfall for liver fluke and identify new biomarkers to inform regional differences in zoonotic parasite disease risk. Project Impetus: The project is founded on recent discoveries and state-of-the-art tool developments, including: (A) Tools-in vitro culture, the ability to switch genes off to examine their function, bioassays to understand fluke behaviour and biology; (B) Discoveries-identification of growth/development pathways that are common to both cancer and liver fluke stem cells and which govern pathogen growth rate/survival. We propose to use these new tools and resources for liver fluke to: probe the impacts of altered growth rate on pathogen biology and drug susceptibility; to use 'omics studies of juvenile fluke displaying enhanced growth to identify biomarkers (or signatures) for enhanced growth/virulence; and, use these new biomarkers to inform regional differences in disease risk. Overarching hypothesis: Enhanced disease virulence and therapy resistance in liver fluke are associated with rapid growth and a defined panel of biomarkers that can be used to identify regional differences and environmental drivers of disease intensity, thereby informing field-based pathogen control.