UC San Diego

Schistosomiasis is a neglected topical disease caused by trematode blood flukes of the genus Schistosoma. The disease affects impoverished communities with approximately 200 million people infected worldwide. Treatment of this disease relies on just one drug, praziquantel (PZQ). The high rates of reinfection, and concerns regarding the emergence of PZQ-resistant strains emphasize the need to identify new drugs and drug targets for schistosomiasis. The research presented here is part of a larger investigation by my research group, led by Dr. Caffrey, to characterize the proteasome as a potential drug target for treatment of schistosomiasis. Using RNA-Seq, my thesis shows that several genes and gene families are up and downregulated in Schistosoma mansoni after exposure to 1 µM carfilzomib (CFZ) for 24 h, conditions which cause parasite immobility. Changes in gene expression by CFZ were compared with those generated by another proteasome inhibitor, bortezomib, and the non-proteasome inhibitor, omaveloxolone, which is an experimental drug for Friedreichs’s ataxia. A number of genes and gene families, e.g., heat shock proteins, were upregulated by all three drugs tested, whereas other genes, specifically, the proteasome subunits and MEG-3 (micro-exon gene 3) proteins, were upregulated only after exposure to the proteasome inhibitors. Among the most downregulated genes common to all three drugs were those associated with the tegument (worm surface) and lipid metabolism. Changes in the -fold expression of exemplar genes by RNA-seq were validated by qPCR and, for the top 20 upregulated genes, I employed bioinformatics to understand their expression in different developmental stages of the parasite. The global data generated by my thesis provide a foundation to identify gene products which could be useful pharmacological targets, either independently or when combined with inhibition of the proteasome.