Genetic and Molecular Basis of Drug Resistance and Species-Specific Drug Action in Schistosome Parasites

Abstract

Oxamniquine resistance evolved in the human blood fluke (Schistosoma mansoni) in Brazil in the 1970s. We crossed parental parasites differing ~500-fold in drug response, determined drug sensitivity and marker segregation in clonally-derived F2s, and identified a single QTL (LOD=31) on chromosome 6. A sulfotransferase was identified as the causative gene using RNAi knockdown and biochemical complementation assays and we subsequently demonstrated independent origins of loss-of-function mutations in field-derived and laboratory-selected resistant parasites. These results demonstrate the utility of linkage mapping in a human helminth parasite, while crystallographic analyses of protein-drug interactions illuminate the mode of drug action and provide a framework for rational design of oxamniquine derivatives that kill both S. mansoni and S. haematobium, the two species responsible for >99% of schistosomiasis cases worldwide.

Modelling the Effects of Mass Drug Administration on the Molecular Epidemiology of Schistosomes

“…are also now available from the Wellcome Trust Sanger Institute (http://www.sanger.ac.uk/research/initiatives/globalhealth/research/helminthgenomes/). While these data have already been put to use in studies on functional , Valentim et al, 2013 and comparative genomics , work on population genomics is in its relative infancy.…”

“…Traditional 'forward' genetics approaches based on analysis of a genetic cross are possible in Schistosoma (Criscione et al, 2009) and have been successfully applied to understanding the genetics of drug resistance to Oxamniquine in one isolate (Valentim et al, 2013). Reverse genetic approaches such as transgenesis and RNAi are also available, or under active development for Schistosoma, and while not yet sufficiently reliable for highthroughput for 'discovery' of loci underlying resistance phenotypes, such techniques may be valuable in confirming the importance of candidate loci discovered by other approaches.…”

“…Through applying NGS technology to parasite population studies, well designed research can reap the benefits of sequence data, such as locating regions of the genome under selection (Valentim et al, 2013), and understanding levels and directions of gene flow and infections within and between sub-populations (Kao et al, 2014). Such information will boost our capacity to model and predict the effects of MDA on disease transmission dynamics and selection and how best to maximise control success .…”

“…For example, WGS facilitated the finding of the locus responsible for oxamniquine resistance in Schistosoma mansoni (Smp_089320) by providing an easy means to generate SNPs between parental lines in a staged genetic cross (Valentim et al, 2013).…”

Structure–function analysis of apical membrane‐associated molecules of the tegument of schistosome parasites of humans: prospects for identification of novel targets for parasite control

“…All of these drugs have proven useful for therapeutic treatment of individuals in the clinic or of communities in mass drug administration. Of the four drugs, oxamniquine is only effective against schistosomiasis mansoni; resistance to this drug by the parasite is known and the mechanism of resistance elucidated (Valentim et al, 2013). Metrifonate is only effective against urinary schistosomiasis, caused by S. haematobium, and its use is hampered by a complex administration schedule with multiple doses required over a 2 week period.…”