Helminth (worm) parasites maintain a powerful grip on the health and economy of the world. Although they are a serious burden on agricultural productivity and animal health globally, their impact on human health is most profound in developing nations where human populations are the poorest and least able to cope with helminth induced diseases (helminthiases). Platyhelminths (flatworms) of the genus Schistosoma are notorious for topping the statistics for negative effects on human health, afflicting over 200 million worldwide. Remarkably, the impact of schistosomiasis on human health accounts for annual losses of approximately 70 million disability-adjusted life years (DALYs), exceeding that of malaria or tuberculosis and being comparable to that reported for HIV/AIDS. So far, schistosomes have proven refractory to vaccine-based control strategies such that a very small portfolio of drugs shoulders the burden of control, relying almost completely on the antischistosomal praziquantel. It is now generally accepted that drug resistance is the inevitable consequence of an over-dependence on chemotherapy. Therefore, the continued dependency of schistosomiasis control efforts on praziquantel is an unsustainable situation and demands attention from governments and charitable bodies tasked with tackling the tropical disease burden in poorer nations. The effective long-term control of schistosomiasis depends upon the discovery and development of novel chemotherapeutics. G protein-coupled receptors (GPCRs) constitute one of the largest groupings of eukaryotic proteins, and represent a particularly lucrative set of pharmaceutical targets. They play an important role in eukaryotic signal transduction and physiology, mediating cellular responses to a diverse range of extracellular stimuli. We developed and deployed a novel approach to identify schistosome GPCRs, and we discovered a new, unique clade of receptors. These receptors constitute the largest subfamily of Rhodopsin family GPCRs in schistosomes, yet their sequences are quite unique. We have labeled these platyhelminth Rhodopsin orphan family 1 (PROF1) receptors, and they are and entirely novel GPCR subfamily that is present only in flatworms. Our central hypothesis is that the PROF1 receptor family, as a flatworm-specific subset of the notoriously druggable GPCR superfamily, represents a rational target for anthelmintic drug discovery. We will define the temporal and relative expression profiles of 19 predicted schistosome PROF1 receptors. Our central hypothesis is that many PROF1 receptors will be expressed in intra-mammalian stages that would be vulnerable to chemotherapeutic intervention. Further, we will use RNAi to functionally interrogate the in vitro consequences of PROF1 transcript suppression in schistosomula and adult schistosomes. Our hypothesis is that PROF1 receptors are involved in processes vital to normal parasite function. The completion of this project will generate valuable life cycle-specific expression data for a novel phylum-specific GPCR family in an important human parasite, and identify meaningful phenotypic endpoints that result from transcript disruption in druggable intra-host stages.
This project will discover new information about a newly-discovered subfamily of receptors in the devastating human parasite Schistosoma mansoni. The studies will examine the possibility that these receptors could be targets for a new generation of antischistosomal drugs.
