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

English version

Autoři: Frédéric D. Chevalier ^aff001; Winka Le Clec’h ^aff001; Marina McDew-White ^aff001; Vinay Menon ^aff001; Meghan A. Guzman ^aff002; Stephen P. Holloway ^aff003; Xiaohang Cao ^aff003; Alexander B. Taylor ^aff003; Safari Kinung'hi ^aff005; Anouk N. Gouvras ^aff006; Bonnie L. Webster ^aff006; Joanne P. Webster ^aff006; Aidan M. Emery ^aff006; David Rollinson ^aff006; Amadou Garba Djirmay ^aff009; Khalid M. Al Mashikhi ^aff011; Salem Al Yafae ^aff011; Mohamed A. Idris ^aff012; Hélène Moné ^aff013; Gabriel Mouahid ^aff013; P. John Hart ^aff003; Philip T. LoVerde ^aff002; Timothy J. C. Anderson ^aff001
Působiště autorů: Texas Biomedical Research Institute, San Antonio, Texas, United States of America ^aff001; Departments of Pathology and University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America ^aff002; Biochemistry & Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America ^aff003; X-ray Crystallography Core Laboratory, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America ^aff004; National Institute for Medical Research, Mwanza, United Republic of Tanzania ^aff005; London Centre for Neglected Tropical Disease Research (LCNDTR), Imperial Collge, London, United Kingdom ^aff006; Wolfson Wellcome Biomedical Laboratories, Natural History Museum, London, United Kingdom ^aff007; Centre for Emerging, Endemic and Exotic Diseases (CEEED), Royal Veterinary College, University of London, United Kingdom ^aff008; Réseau International Schistosomiases Environnemental Aménagement et Lutte (RISEAL), Niamey, Niger ^aff009; World Health Organization, Geneva, Switzerland ^aff010; Directorate General of Health Services, Dhofar Governorate, Salalah, Sultanate of Oman ^aff011; Sultan Qaboos University, Muscat, Sultanate of Oman ^aff012; Host-Pathogen-Environment Interactions laboratory, University of Perpignan, Perpignan, France ^aff013
Vyšlo v časopise: Oxamniquine resistance alleles are widespread in Old World Schistosoma mansoni and predate drug deployment. PLoS Pathog 15(10): e32767. doi:10.1371/journal.ppat.1007881
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.ppat.1007881

Souhrn

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.

Klíčová slova:

Africa – Alleles – Deletion mutation – Haplotypes – Mutation – Parasitic diseases – Schistosoma mansoni – Schistosoma

Zdroje

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