Abstract
Schistosomiasis is an acute and chronic disease caused by parasitic worms of the genus Schistosoma. Treatment is solely dependent on praziquantel. In the face of the worldwide dimension, projects have been initiated to develop new chemotherapies. Due to their proven druggability, G protein-coupled receptors (GPCRs) are promising targets for anthelmintics. However, to identify candidate receptors, a deeper understanding of GPCR signalling in schistosome biology is essential. Comparative transcriptomics of paired and unpaired worms and their gonads revealed 59 differentially regulated GPCR-coding genes putatively involved in neuronal processes. In general, the diversity among GPCRs and their integral membrane topology make it difficult to characterize and deorphanize these receptors. To overcome existing limitations, we performed a pilot approach and utilized the innovative Membrane-Anchored Ligand And Receptor yeast two-hybrid system (MALAR-Y2H) to associate potential neuropeptide ligands with their cognate receptors. Here, we demonstrated the ability to express full-length GPCRs of Schistosoma mansoni in a heterologous yeast-based system. Additionally, we localized GPCRs and chimeras of neuropeptides fused to the WBP1 transmembrane domain of yeast to the plasma membrane of yeast cells. Reporter gene assays indicated ligand-receptor binding, which allowed us to identify certain neuropeptides as potential ligands for two GPCRs, which had been found before to be differentially expressed in schistosomes in a pairing-dependent manner. Thus, the MALAR-Y2H system appears suitable to unravel schistosome GPCR-ligand interactions. Besides its relevance for understanding schistosome biology, identifying and characterizing GPCR-ligand interaction will also contribute to applied research aspects.
Highlights
Schistosomiasis is a neglected tropical disease caused by platyhelminths of the genus Schistosoma
For S. mansoni α integrins 2, 3 and 4 it was shown that DSM values >14 exhibited a 3′ processing signal leading to truncated proteins (Parker-Manuel et al, 2015). We addressed this by examining full-length transcription after cloning G protein-coupled receptors (GPCRs) coding sequences into a yeast expression vector, which were transformed into strain Y187
Yeasts are eukaryotic organisms, possessing the necessary machinery for post-translational processing, it is not self-evident that genes from S. mansoni are processed correctly in the heterologous yeast system
Summary
Schistosomiasis is a neglected tropical disease caused by platyhelminths of the genus Schistosoma. The disease has global impact on human and animal health. According to the WHO, approximately 600 million people live in endemic areas, of which >200 million require treatment with a mortality rate of ∼24 000 people in 2016 (WHO Global, 2016). Medical treatment is based upon a single drug, praziquantel. It is safe, affordable and effective, its widespread use for mass treatment has increased the likelihood of resistant parasites (Bergquist et al, 2017). Affordable and effective, its widespread use for mass treatment has increased the likelihood of resistant parasites (Bergquist et al, 2017) This requires the development of alternative antischistosomal compounds
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