Liver flukes and schistosome parasites are dumping their entire genetic library into yeast cells to see which genes keep the yeast alive under lethal stress. These parasitic flatworms infect hundreds of millions of people and livestock worldwide—17 million people have fasciolosis, and hundreds of millions have schistosomiasis—yet their genomes remain poorly mapped, with large stretches of parasite-specific genes that current methods simply ignore. Existing drug discovery relies on a shrinking handful of treatments, and resistance is growing. The researchers have already shown that introducing schistosome genes can rescue yeast from calcium disruption, temperature shock, and oxidative stress, identifying previously unknown gene functions. If this yeast-based screening platform works at scale, it could bypass the slow, costly process of testing parasite genes one by one in live animals. Instead, researchers would rapidly identify which parasite genes are essential for survival, then validate only the most promising targets in the parasites themselves. This would accelerate the hunt for new drugs and vaccines against diseases that quietly devastate farming economies—costing the UK £110 million annually and Europe £524 million—and sicken millions of people with chronic liver disease.
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Fasciola hepatica, usually termed “the temperate liver fluke”, is a worldwide problem for agriculture and impacts 17 million people as a neglected tropical disease. Infections, known as fasciolosis, damage ruminant animal production [1], and have been reported across Europe including the UK [2]. It is estimated that fasciolosis causes annual economic losses in the UK of £110 million [3], and across Europe £524 million [3]. Schistosome parasites currently infect hundreds of millions of people and cause the chronic liver disease schistosomiasis. Despite high re-infection rates in the millions, treatment relies upon the single drug, praziquantel. Similarly for fascioliasis the situation is precarious, with reliance on a small portfolio of flukicides to which resistance is growing. In the last 15 years, to better understand both helminth pathogens and find new interventional targets, genomic sequencing and functional genomics have been key tools for researchers. Despite efforts, many helminth genomes, including schistosomes and Fasciola remain under-annotated. The reliance of predicted functionality particularly limits new control target discovery for these important diseases. Functional genomics of the parasite itself is used extensively for the identification and assessment of potential anthelmintic targets. These approaches seek to link potential parasite gene targets, most selected from predicted importance, with a measurable phenotype incompatible with parasite survival. The reliance of initial in silico methods is a major limitation to identify parasite genes of potential interest. Since large portions of helminth genomes have no substantial homologous identity, representing an unmet potential resides in not considering these novel parasite-specific genes. Current approaches fail to consider the entire helminth gene sets, biasing target identification. We propose here to invert this low efficiency approach. Instead, we will start with a clear detrimental phenotype in the single-cell yeast model and introduce parasite genes that can induce a rescue or protective response in the yeast. We have already begun to use a yeast/schistosome-gene model; an approach not previously used for any helminth gene characterisation. In the proposed project, yeast expression libraries containing comprehensive representation of schistosome and Fasciola cDNA, will be used in a range of lethal/rescue screens of phenotypically altered yeast cells. From this yeast screen, novel targets will then be evaluated in the parasites using more traditional methods. As a proof of concept, calcium homeostasis disruption as a lethal yeast phenotype was selected for rescue through the introduction of schistosome genes. Surviving colonies sequencing identified a small range (8) of schistosome genes, including those encoding eggshell proteins. This potential role of these gene in modulating calcium homeostasis has not been reported before. We are currently further screening additional lethal yeast phenotypes for schistosome gene rescue, and have demonstrated helminth genes associated with rescue to temperature, H2O2 and EtOH stress. In the proposed project an expansion of library coverage will be performed. Libraries will be improved through reconstruction and expansion using additional schistosome lifecycle stages, as well as new Fasciola transcriptomic sources. Yeast is a well-established model system for drug discovery screening for human targets [4]. Our project will establish a novel yeast-based platform for helminth pathogens. As an unbiased, functional eukaryotic genomic screen, our data will both accelerate functional pipelines and reduce the initial labour-intensive reliance on parasites obtained from mammalian models. In advancing gene annotations of pathogenic helminth genomes, drug/vaccine discovery efforts will be enhanced. See Approach Section for references.
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