UMMS Affiliation

Program in Bioinformatics and Integrative Biology; Department of Medicine, Division of Transfusion Medicine

Publication Date

6-1-2017

Document Type

Article

Disciplines

Genomics | Parasitic Diseases | Population Biology

Abstract

Plasmodium falciparum in western Cambodia has developed resistance to artemisinin and its partner drugs, causing frequent treatment failure. Understanding this evolution can inform the deployment of new therapies. We investigated the genetic architecture of 78 falciparum isolates using whole-genome sequencing, correlating results to in vivo and ex vivo drug resistance and exploring the relationship between population structure, demographic history, and partner drug resistance. Principle component analysis, network analysis and demographic inference identified a diverse central population with three clusters of clonally expanding parasite populations, each associated with specific K13 artemisinin resistance alleles and partner drug resistance profiles which were consistent with the sequential deployment of artemisinin combination therapies in the region. One cluster displayed ex vivo piperaquine resistance and mefloquine sensitivity with a high rate of in vivo failure of dihydroartemisinin-piperaquine. Another cluster displayed ex vivo mefloquine resistance and piperaquine sensitivity with high in vivo efficacy of dihydroartemisinin-piperaquine. The final cluster was clonal and displayed intermediate sensitivity to both drugs. Variations in recently described piperaquine resistance markers did not explain the difference in mean IC90 or clinical failures between the high and intermediate piperaquine resistance groups, suggesting additional loci may be involved in resistance. The results highlight an important role for partner drug resistance in shaping the P. falciparum genetic landscape in Southeast Asia and suggest that further work is needed to evaluate for other mutations that drive piperaquine resistance.

Keywords

ACT, drug resistance, ex vivo susceptibility, kelch, malaria, mefloquine, partner drug, pfmdr1, piperaquine, plasmodium, population genetics

Rights and Permissions

Copyright © The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

DOI of Published Version

10.1093/gbe/evx126

Source

Genome Biol Evol. 2017 Jun 1;9(6):1673-1686. doi: 10.1093/gbe/evx126. Link to article on publisher's site

Journal/Book/Conference Title

Genome biology and evolution

Related Resources

Link to Article in PubMed

PubMed ID

28854635

Creative Commons License

Creative Commons Attribution-Noncommercial 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License

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