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Plasmepsin II–III copy number accounts for bimodal piperaquine resistance among Cambodian Plasmodium falciparum

Author

Listed:
  • Selina Bopp

    (Harvard T.H. Chan School of Public Health)

  • Pamela Magistrado

    (Harvard T.H. Chan School of Public Health)

  • Wesley Wong

    (Harvard T.H. Chan School of Public Health)

  • Stephen F. Schaffner

    (Harvard T.H. Chan School of Public Health
    The Broad Institute of MIT and Harvard)

  • Angana Mukherjee

    (Harvard T.H. Chan School of Public Health)

  • Pharath Lim

    (National Institutes of Health)

  • Mehul Dhorda

    (Worldwide Antimalarial Resistance Network
    Mahidol-Oxford Tropical Medicine Research Unit
    Myanmar-Oxford Clinical Research Unit)

  • Chanaki Amaratunga

    (National Institutes of Health)

  • Charles J. Woodrow

    (Mahidol-Oxford Tropical Medicine Research Unit)

  • Elizabeth A. Ashley

    (Myanmar-Oxford Clinical Research Unit
    University of Oxford)

  • Nicholas J. White

    (Mahidol-Oxford Tropical Medicine Research Unit
    University of Oxford)

  • Arjen M. Dondorp

    (Mahidol-Oxford Tropical Medicine Research Unit
    University of Oxford)

  • Rick M. Fairhurst

    (National Institutes of Health)

  • Frederic Ariey

    (Cochin Hospital Paris Descartes University)

  • Didier Menard

    (Biology of Host-Parasite Interactions Unit, Institut Pasteur
    CNRS, ERL 9195
    INSERM, Unit U1201)

  • Dyann F. Wirth

    (Harvard T.H. Chan School of Public Health
    The Broad Institute of MIT and Harvard)

  • Sarah K. Volkman

    (Harvard T.H. Chan School of Public Health
    The Broad Institute of MIT and Harvard
    Simmons College)

Abstract

Multidrug resistant Plasmodium falciparum in Southeast Asia endangers regional malaria elimination and threatens to spread to other malaria endemic areas. Understanding mechanisms of piperaquine (PPQ) resistance is crucial for tracking its emergence and spread, and to develop effective strategies for overcoming it. Here we analyze a mechanism of PPQ resistance in Cambodian parasites. Isolates exhibit a bimodal dose–response curve when exposed to PPQ, with the area under the curve quantifying their survival in vitro. Increased copy number for plasmepsin II and plasmepsin III appears to explain enhanced survival when exposed to PPQ in most, but not all cases. A panel of isogenic subclones reinforces the importance of plasmepsin II–III copy number to enhanced PPQ survival. We conjecture that factors producing increased parasite survival under PPQ exposure in vitro may drive clinical PPQ failures in the field.

Suggested Citation

  • Selina Bopp & Pamela Magistrado & Wesley Wong & Stephen F. Schaffner & Angana Mukherjee & Pharath Lim & Mehul Dhorda & Chanaki Amaratunga & Charles J. Woodrow & Elizabeth A. Ashley & Nicholas J. White, 2018. "Plasmepsin II–III copy number accounts for bimodal piperaquine resistance among Cambodian Plasmodium falciparum," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04104-z
    DOI: 10.1038/s41467-018-04104-z
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    Cited by:

    1. Leyre Pernaute-Lau & Mario Recker & Mamadou Tékété & Tais Nóbrega Sousa & Aliou Traore & Bakary Fofana & Kassim Sanogo & Ulrika Morris & Juliana Inoue & Pedro E. Ferreira & Nouhoum Diallo & Jürgen Bur, 2025. "Decreased dihydroartemisinin-piperaquine protection against recurrent malaria associated with Plasmodium falciparum plasmepsin 3 copy number variation in Africa," Nature Communications, Nature, vol. 16(1), pages 1-7, December.
    2. Patrick K. Tumwebaze & Melissa D. Conrad & Martin Okitwi & Stephen Orena & Oswald Byaruhanga & Thomas Katairo & Jennifer Legac & Shreeya Garg & David Giesbrecht & Sawyer R. Smith & Frida G. Ceja & Sam, 2022. "Decreased susceptibility of Plasmodium falciparum to both dihydroartemisinin and lumefantrine in northern Uganda," Nature Communications, Nature, vol. 13(1), pages 1-12, December.

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