Independent origins of loss-of-function mutations conferring oxamniquine resistance in a Brazilian schistosome population

Frédéric D. Chevalier, Winka Le Clec'h, Nina Eng, Anastasia R. Rugel, Rafael Ramiro de Assis, Guilherme Oliveira, Stephen P. Holloway, Xiaohang Cao, P. John Hart, Philip T Loverde, Timothy J C Anderson

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Abstract

Molecular surveillance provides a powerful approach to monitoring the resistance status of parasite populations in the field and for understanding resistance evolution. Oxamniquine was used to treat Brazilian schistosomiasis patients (mid-1970s to mid-2000s) and several cases of parasite infections resistant to treatment were recorded. The gene underlying resistance (SmSULT-OR) encodes a sulfotransferase required for intracellular drug activation. Resistance has a recessive basis and occurs when both . SmSULT-OR alleles encode for defective proteins. Here we examine . SmSULT-OR sequence variation in a natural schistosome population in Brazil ∼40. years after the first use of this drug. We sequenced . SmSULT-OR from 189 individual miracidia (1-11 per patient) recovered from 49 patients, and tested proteins expressed from putative resistance alleles for their ability to activate oxamniquine. We found nine mutations (four non-synonymous single nucleotide polymorphisms, three non-coding single nucleotide polymorphisms and two indels). Both mutations (p.E142del and p.C35R) identified previously were recovered in this field population. We also found two additional mutations (a splice site variant and 1. bp coding insertion) predicted to encode non-functional truncated proteins. Two additional substitutions (p.G206V, p.N215Y) tested had no impact on oxamniquine activation. Three results are of particular interest: (i) we recovered the p.E142del mutation from the field: this same deletion is responsible for resistance in an oxamniquine selected laboratory parasite population; (ii) frequencies of resistance alleles are extremely low (0.27-0.8%), perhaps due to fitness costs associated with carriage of these alleles; (iii) that four independent resistant alleles were found is consistent with the idea that multiple mutations can generate loss-of-function alleles.

Original languageEnglish (US)
JournalInternational Journal for Parasitology
DOIs
StateAccepted/In press - Dec 1 2015

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Keywords

  • Biochemical assay
  • Loss-of-function
  • Oxamniquine resistance
  • Schistosoma mansoni
  • Soft selective event
  • Sulfotransferase

ASJC Scopus subject areas

  • Parasitology
  • Infectious Diseases

Cite this

Chevalier, F. D., Le Clec'h, W., Eng, N., Rugel, A. R., Assis, R. R. D., Oliveira, G., Holloway, S. P., Cao, X., Hart, P. J., Loverde, P. T., & Anderson, T. J. C. (Accepted/In press). Independent origins of loss-of-function mutations conferring oxamniquine resistance in a Brazilian schistosome population. International Journal for Parasitology. https://doi.org/10.1016/j.ijpara.2016.03.006