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

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


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


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