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

Type Article
Date 2019-10
Language English
Author(s) Chevalier Frederic D.1, Le Clec'h Winka1, McDew-White Marina1, Menon Vinay1, Guzman Meghan A.2, Holloway Stephen P.3, Cao Xiaohang3, Taylor Alexander B.3, 4, Kinung'Hi Safari5, Gouvras Anouk N.6, 7, Webster Bonnie L.6, 7, Webster Joanne P.6, 8, Emery Aidan M.6, 7, Rollinson David6, 7, Garba Djirmay Amadou9, 10, Al Mashikhi Khalid M.11, Al Yafae Salem11, Idris Mohamed A.12, Mone Helene13, Mouahid Gabriel13, Hart P. John3, 4, Loverde Philip T.2, Anderson Timothy J. C.1
Affiliation(s) 1 : Texas Biomed Res Inst, San Antonio, TX 78227 USA.
2 : Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, San Antonio, TX 78229 USA.
3 : Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem & Struct Biol, San Antonio, TX 78229 USA.
4 : Univ Texas Hlth Sci Ctr San Antonio, Xray Crystallog Core Lab, San Antonio, TX 78229 USA.
5 : Natl Inst Med Res, Mwanza, Tanzania.
6 : Imperial Collge, London Ctr Neglected Trop Dis Res LCNDTR, London, England.
7 : Nat Hist Museum, Wolfson Wellcome Biomed Labs, London, England.
8 : Univ London, Royal Vet Coll, Ctr Emerging Endem & Exot Dis, London, England.
9 : RISEAL, Niamey, Niger.
10 : World Hlth Org, Geneva, Switzerland.
11 : Dhofar Governorate, Directorate Gen Hlth Serv, Salalah, Oman.
12 : Sultan Qaboos Univ, Muscat, Oman.
13 : Univ Perpignan, Host Pathogen Environm Interact Lab, Perpignan, France.
Source Plos Pathogens (1553-7366) (Public Library Science), 2019-10 , Vol. 15 , N. 10 , P. e1007881 (25p.)
DOI 10.1371/journal.ppat.1007881
WOS© Times Cited 19

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. Author summary It has been argued that drug resistance is unlikely to spread rapidly in helminth parasites infecting humans. This is based, at least in part, on the premise that resistance mutations are rare or absent within populations prior to treatment, and take a long time to reach appreciable frequencies because helminth parasite generation time is long. This argument is critically dependent on the starting frequency of resistance alleles-if high levels of "standing variation" for resistance are present prior to deployment of treatment, resistance may spread rapidly. We examined frequencies of oxamniquine resistance alleles present in Schistosoma mansoni from Africa and the Middle East where oxamniquine has seen minimal use. We found that oxamniquine resistance alleles are widespread in the Old World, ranging from 4.29% in the Middle East to 14.91% in East African parasite populations. Furthermore, we show that resistance alleles from West African and the Caribbean schistosomes share a common origin, suggesting that these alleles travelled to the New World with S. mansoni during the transatlantic slave trade. Together, these results demonstrate extensive standing variation for oxamniquine resistance. Our results have important implications for both drug treatment policies and drug development efforts, and demonstrate the power of molecular surveillance approaches for guiding helminth control.

Full Text
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Publisher's official version 25 2 MB Open access
S1 Table. Library sequencing statistics. 45 KB Open access
S2 Table. Mutations scored in samples from West Africa (Senegal and Niger), East Africa (Tanzania) and Middle East (Oman). 24 KB Open access
S3 Table. Sampling information for the schistosome material used. 41 KB Open access
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Chevalier Frederic D., Le Clec'h Winka, McDew-White Marina, Menon Vinay, Guzman Meghan A., Holloway Stephen P., Cao Xiaohang, Taylor Alexander B., Kinung'Hi Safari, Gouvras Anouk N., Webster Bonnie L., Webster Joanne P., Emery Aidan M., Rollinson David, Garba Djirmay Amadou, Al Mashikhi Khalid M., Al Yafae Salem, Idris Mohamed A., Mone Helene, Mouahid Gabriel, Hart P. John, Loverde Philip T., Anderson Timothy J. C. (2019). Oxamniquine resistance alleles are widespread in Old World Schistosoma mansoni and predate drug deployment. Plos Pathogens, 15(10), e1007881 (25p.). Publisher's official version : https://doi.org/10.1371/journal.ppat.1007881 , Open Access version : https://archimer.ifremer.fr/doc/00659/77118/