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Emerging Southeast Asian PfCRT mutations confer Plasmodium falciparum resistance to the first-line antimalarial piperaquine

Author

Listed:
  • Leila S. Ross

    (Columbia University Irving Medical Center)

  • Satish K. Dhingra

    (Columbia University Irving Medical Center)

  • Sachel Mok

    (Columbia University Irving Medical Center)

  • Tomas Yeo

    (Columbia University Irving Medical Center)

  • Kathryn J. Wicht

    (Columbia University Irving Medical Center)

  • Krittikorn Kümpornsin

    (Columbia University Irving Medical Center
    Wellcome Sanger Institute, Wellcome Genome Campus)

  • Shannon Takala-Harrison

    (University of Maryland School of Medicine)

  • Benoit Witkowski

    (Pasteur Institute in Cambodia)

  • Rick M. Fairhurst

    (Laboratory of Malaria and Vector Research, NIAID, NIH
    Parasitology and International Programs Branch, DHHS, NIAID, NIH)

  • Frederic Ariey

    (University Paris Descartes, and Laboratory of Parasitology-Mycology, Cochin Hospital)

  • Didier Menard

    (Pasteur Institute in Cambodia
    Biology of Host-Parasite Interactions Unit, Pasteur Institute)

  • David A. Fidock

    (Columbia University Irving Medical Center
    Columbia University Irving Medical Center)

Abstract

The widely used antimalarial combination therapy dihydroartemisinin + piperaquine (DHA + PPQ) has failed in Cambodia. Here, we perform a genomic analysis that reveals a rapid increase in the prevalence of novel mutations in the Plasmodium falciparum chloroquine resistance transporter PfCRT following DHA + PPQ implementation. These mutations occur in parasites harboring the K13 C580Y artemisinin resistance marker. By introducing PfCRT mutations into sensitive Dd2 parasites or removing them from resistant Cambodian isolates, we show that the H97Y, F145I, M343L, or G353V mutations each confer resistance to PPQ, albeit with fitness costs for all but M343L. These mutations sensitize Dd2 parasites to chloroquine, amodiaquine, and quinine. In Dd2 parasites, multicopy plasmepsin 2, a candidate molecular marker, is not necessary for PPQ resistance. Distended digestive vacuoles were observed in pfcrt-edited Dd2 parasites but not in Cambodian isolates. Our findings provide compelling evidence that emerging mutations in PfCRT can serve as a molecular marker and mediator of PPQ resistance.

Suggested Citation

  • Leila S. Ross & Satish K. Dhingra & Sachel Mok & Tomas Yeo & Kathryn J. Wicht & Krittikorn Kümpornsin & Shannon Takala-Harrison & Benoit Witkowski & Rick M. Fairhurst & Frederic Ariey & Didier Menard , 2018. "Emerging Southeast Asian PfCRT mutations confer Plasmodium falciparum resistance to the first-line antimalarial piperaquine," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05652-0
    DOI: 10.1038/s41467-018-05652-0
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    Cited by:

    1. Eric Zhewen Li & Tran Dang Nguyen & Thu Nguyen-Anh Tran & Robert J. Zupko & Maciej F. Boni, 2024. "Assessing emergence risk of double-resistant and triple-resistant genotypes of Plasmodium falciparum," Nature Communications, Nature, vol. 15(1), pages 1-12, 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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