Oxamniquine resistance alleles are widespread in Old World Schistosoma mansoni and predate drug deployment

Abstract

Do mutations required for adaptation occur de novo, or are they segregating within populations as standing genetic variation? This question is key to understanding adaptive change in nature, and has important practical consequences for the evolution of drug resistance. We provide evidence that alleles conferring resistance to oxamniquine (OXA), an antischistosomal drug, are widespread in natural parasite populations under minimal drug pressure and predate OXA deployment. OXA has been used since the 1970s to treat Schistosoma mansoni infections in the New World where S. mansoni established during the slave trade. Recessive loss-of-function mutations within a parasite sulfotransferase (SmSULT-OR) underlie resistance, and several verified resistance mutations, including a deletion (p.E142del), have been identified in the New World. Here we investigate sequence variation in SmSULT-OR in S. mansoni from the Old World, where OXA has seen minimal usage. We sequenced exomes of 204 S. mansoni parasites from West Africa, East Africa and the Middle East, and scored variants in SmSULT-OR and flanking regions. We identified 39 non-synonymous SNPs, 4 deletions, 1 duplication and 1 premature stop codon in the SmSULT-OR coding sequence, including one confirmed resistance deletion (p.E142del). We expressed recombinant proteins and used an in vitro OXA activation assay to functionally validate the OXA-resistance phenotype for four predicted OXA-resistance mutations. Three aspects of the data are of particular interest: (i) segregating OXA-resistance alleles are widespread in Old World populations (4.29–14.91% frequency), despite minimal OXA usage, (ii) two OXA-resistance mutations (p.W120R, p.N171IfsX28) are particularly common (>5%) in East African and Middle-Eastern populations, (iii) the p.E142del allele has identical flanking SNPs in both West Africa and Puerto Rico, suggesting that parasites bearing this allele colonized the New World during the slave trade and therefore predate OXA deployment. We conclude that standing variation for OXA resistance is widespread in S. mansoni.

Two-year longitudinal survey reveals high genetic diversity of Schistosoma mansoni with adult worms surviving praziquantel treatment at the start of mass drug administration in Uganda

“…The phenotypic and genetic data from this setting suggest that natural variation in this schistosome population has some praziquantel resistance or tolerance (we could not differentiate these with our data). This is consistent with evidence of natural variation in resistance within schistosomes predating drug use to a former anti-schistosomal drug, oxaminiquine, where resistance alleles are known [58].…”

Genetic analysis of praziquantel response in schistosome parasites implicates a transient receptor potential channel

“…None of these SNPs affect Ca 2+ influx: they are therefore unlikely to have determined critical residues that determine binding between PZQ and Sm.TRPMPZQ (21). We examined the mutations present in Sm.TRPMPZQ in natural schistosome populations using exome sequencing from 259 miracidia, cercariae or adult parasites from 3 African countries (Senegal, Niger, Tanzania), the Middle East (Oman) and South America (Brazil) (51,52). We were able to sequence 36/41 exons of Sm.TRPMPZQ from 122/259 parasites on average (s.e.…”

Parasite Population Genetic Contributions to the Schistosomiasis Consortium for Operational Research and Evaluation within Sub-Saharan Africa

“…These findings also suggested that resistance to PZQ may be unlikely to establish or spread in these populations at the beginning of the national control program, given the current selection of targeting school-aged children alone. 69 Nevertheless, these studies on S. mansoni susceptibility to PZQ (at least within Uganda), as recent findings have shown for oxamniquine resistance, 66 have identified standing variation in drug efficacies and clearance rates on which selection can act. This might indeed be expected to accentuate as drug pressures over time increase.…”

“…The rate and likelihood of resistance developing is influenced by a broad range of factors including, but not exclusive to, baseline parasite genetic structure and underlying standing variation in drug tolerance on which selection can act, effective population size, refugia, and gene flow in parallel to treatment frequency, dosage, and whether single or combination drug regimens. 66 , 67 Figure 4 demonstrates how population genetics can, nevertheless, help evaluate and contribute to the detection of potential changes in drug resistance efficacy.…”