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A molecular marker of artemisinin-resistant Plasmodium falciparum malaria

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  • Frédéric Ariey

    (Institut Pasteur, Parasite Molecular Immunology Unit, 75724 Paris Cedex 15, France
    Centre National de la Recherche Scientifique, Unité de Recherche Associée 2581, 75724 Paris Cedex 15, France
    Present addresses: Institut Pasteur, Genetics and Genomics of Insect Vectors Unit, 75724 Paris Cedex 15, France (F.A.); Institut Pasteur, Functional Genetics of Infectious Diseases Unit, 75724 Paris Cedex 15, France (J.B.); Centre de Physiopathologie de Toulouse-Purpan, Institut National de la Santé et de la Recherche Médicale UMR1043, Centre National de la Recherche Scientifique UMR5282, Université Toulouse III, 31024 Toulouse Cedex 3, France(S.M. & A.B.); Institut Pasteur, Unité de Biologie et Génétique du Paludisme, Team Malaria Targets and Drug Development, 75724 Paris Cedex 15, France (J.-C.B.).)

  • Benoit Witkowski

    (Institut Pasteur du Cambodge, Malaria Molecular Epidemiology Unit, Phnom Penh, Cambodia)

  • Chanaki Amaratunga

    (Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health)

  • Johann Beghain

    (Institut Pasteur, Parasite Molecular Immunology Unit, 75724 Paris Cedex 15, France
    Centre National de la Recherche Scientifique, Unité de Recherche Associée 2581, 75724 Paris Cedex 15, France
    Present addresses: Institut Pasteur, Genetics and Genomics of Insect Vectors Unit, 75724 Paris Cedex 15, France (F.A.); Institut Pasteur, Functional Genetics of Infectious Diseases Unit, 75724 Paris Cedex 15, France (J.B.); Centre de Physiopathologie de Toulouse-Purpan, Institut National de la Santé et de la Recherche Médicale UMR1043, Centre National de la Recherche Scientifique UMR5282, Université Toulouse III, 31024 Toulouse Cedex 3, France(S.M. & A.B.); Institut Pasteur, Unité de Biologie et Génétique du Paludisme, Team Malaria Targets and Drug Development, 75724 Paris Cedex 15, France (J.-C.B.).)

  • Anne-Claire Langlois

    (Institut Pasteur, Parasite Molecular Immunology Unit, 75724 Paris Cedex 15, France
    Centre National de la Recherche Scientifique, Unité de Recherche Associée 2581, 75724 Paris Cedex 15, France)

  • Nimol Khim

    (Institut Pasteur du Cambodge, Malaria Molecular Epidemiology Unit, Phnom Penh, Cambodia)

  • Saorin Kim

    (Institut Pasteur du Cambodge, Malaria Molecular Epidemiology Unit, Phnom Penh, Cambodia)

  • Valentine Duru

    (Institut Pasteur du Cambodge, Malaria Molecular Epidemiology Unit, Phnom Penh, Cambodia)

  • Christiane Bouchier

    (Institut Pasteur, Plate-forme Génomique, 75724 Paris Cedex 15, France)

  • Laurence Ma

    (Institut Pasteur, Plate-forme Génomique, 75724 Paris Cedex 15, France)

  • Pharath Lim

    (Institut Pasteur du Cambodge, Malaria Molecular Epidemiology Unit, Phnom Penh, Cambodia
    Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health
    National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia)

  • Rithea Leang

    (National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia)

  • Socheat Duong

    (National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia)

  • Sokunthea Sreng

    (National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia)

  • Seila Suon

    (National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia)

  • Char Meng Chuor

    (National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia)

  • Denis Mey Bout

    (SSA WHO, Drug Monitoring in Cambodia, National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia)

  • Sandie Ménard

    (Service de Parasitologie et Mycologie, Centre Hospitalier Universitaire de Toulouse, 31059 Toulouse Cedex 9, France
    Present addresses: Institut Pasteur, Genetics and Genomics of Insect Vectors Unit, 75724 Paris Cedex 15, France (F.A.); Institut Pasteur, Functional Genetics of Infectious Diseases Unit, 75724 Paris Cedex 15, France (J.B.); Centre de Physiopathologie de Toulouse-Purpan, Institut National de la Santé et de la Recherche Médicale UMR1043, Centre National de la Recherche Scientifique UMR5282, Université Toulouse III, 31024 Toulouse Cedex 3, France(S.M. & A.B.); Institut Pasteur, Unité de Biologie et Génétique du Paludisme, Team Malaria Targets and Drug Development, 75724 Paris Cedex 15, France (J.-C.B.).)

  • William O. Rogers

    (Naval Medical Research Unit #2 Detachment, Phnom Penh, Cambodia)

  • Blaise Genton

    (Swiss Tropical and Public Health Institute, 4051 Basel, Switzerland)

  • Thierry Fandeur

    (Institut Pasteur, Parasite Molecular Immunology Unit, 75724 Paris Cedex 15, France
    Institut Pasteur du Cambodge, Malaria Molecular Epidemiology Unit, Phnom Penh, Cambodia)

  • Olivo Miotto

    (MRC Centre for Genomics and Global Health, University of Oxford, Oxford OX3 7BN, UK
    Mahidol-Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok 10400, Thailand
    Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK)

  • Pascal Ringwald

    (Global Malaria Program, World Health Organization, 1211 Geneva, Switzerland)

  • Jacques Le Bras

    (Centre National de Référence du Paludisme, CHU Bichat-Claude Bernard, APHP, PRES Sorbonne Paris Cité, 75018 Paris, France)

  • Antoine Berry

    (Service de Parasitologie et Mycologie, Centre Hospitalier Universitaire de Toulouse, 31059 Toulouse Cedex 9, France
    Present addresses: Institut Pasteur, Genetics and Genomics of Insect Vectors Unit, 75724 Paris Cedex 15, France (F.A.); Institut Pasteur, Functional Genetics of Infectious Diseases Unit, 75724 Paris Cedex 15, France (J.B.); Centre de Physiopathologie de Toulouse-Purpan, Institut National de la Santé et de la Recherche Médicale UMR1043, Centre National de la Recherche Scientifique UMR5282, Université Toulouse III, 31024 Toulouse Cedex 3, France(S.M. & A.B.); Institut Pasteur, Unité de Biologie et Génétique du Paludisme, Team Malaria Targets and Drug Development, 75724 Paris Cedex 15, France (J.-C.B.).)

  • Jean-Christophe Barale

    (Institut Pasteur, Parasite Molecular Immunology Unit, 75724 Paris Cedex 15, France
    Centre National de la Recherche Scientifique, Unité de Recherche Associée 2581, 75724 Paris Cedex 15, France
    Present addresses: Institut Pasteur, Genetics and Genomics of Insect Vectors Unit, 75724 Paris Cedex 15, France (F.A.); Institut Pasteur, Functional Genetics of Infectious Diseases Unit, 75724 Paris Cedex 15, France (J.B.); Centre de Physiopathologie de Toulouse-Purpan, Institut National de la Santé et de la Recherche Médicale UMR1043, Centre National de la Recherche Scientifique UMR5282, Université Toulouse III, 31024 Toulouse Cedex 3, France(S.M. & A.B.); Institut Pasteur, Unité de Biologie et Génétique du Paludisme, Team Malaria Targets and Drug Development, 75724 Paris Cedex 15, France (J.-C.B.).)

  • Rick M. Fairhurst

    (Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health)

  • Françoise Benoit-Vical

    (Centre National de la Recherche Scientifique, Laboratoire de Chimie de Coordination UPR8241, 31077 Toulouse Cedex 4, France
    Université de Toulouse, UPS, Institut National Polytechnique de Toulouse, 31077 Toulouse Cedex 4, France)

  • Odile Mercereau-Puijalon

    (Institut Pasteur, Parasite Molecular Immunology Unit, 75724 Paris Cedex 15, France
    Centre National de la Recherche Scientifique, Unité de Recherche Associée 2581, 75724 Paris Cedex 15, France)

  • Didier Ménard

    (Institut Pasteur du Cambodge, Malaria Molecular Epidemiology Unit, Phnom Penh, Cambodia)

Abstract

Plasmodium falciparum resistance to artemisinin derivatives in southeast Asia threatens malaria control and elimination activities worldwide. To monitor the spread of artemisinin resistance, a molecular marker is urgently needed. Here, using whole-genome sequencing of an artemisinin-resistant parasite line from Africa and clinical parasite isolates from Cambodia, we associate mutations in the PF3D7_1343700 kelch propeller domain (‘K13-propeller’) with artemisinin resistance in vitro and in vivo. Mutant K13-propeller alleles cluster in Cambodian provinces where resistance is prevalent, and the increasing frequency of a dominant mutant K13-propeller allele correlates with the recent spread of resistance in western Cambodia. Strong correlations between the presence of a mutant allele, in vitro parasite survival rates and in vivo parasite clearance rates indicate that K13-propeller mutations are important determinants of artemisinin resistance. K13-propeller polymorphism constitutes a useful molecular marker for large-scale surveillance efforts to contain artemisinin resistance in the Greater Mekong Subregion and prevent its global spread.

Suggested Citation

  • Frédéric Ariey & Benoit Witkowski & Chanaki Amaratunga & Johann Beghain & Anne-Claire Langlois & Nimol Khim & Saorin Kim & Valentine Duru & Christiane Bouchier & Laurence Ma & Pharath Lim & Rithea Lea, 2014. "A molecular marker of artemisinin-resistant Plasmodium falciparum malaria," Nature, Nature, vol. 505(7481), pages 50-55, January.
    • Handle: RePEc:nat:nature:v:505:y:2014:i:7481:d:10.1038_nature12876
    DOI: 10.1038/nature12876
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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. Shiroh Iwanaga & Rie Kubota & Tsubasa Nishi & Sumalee Kamchonwongpaisan & Somdet Srichairatanakool & Naoaki Shinzawa & Din Syafruddin & Masao Yuda & Chairat Uthaipibull, 2022. "Genome-wide functional screening of drug-resistance genes in Plasmodium falciparum," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    3. Madhvi Chahar & Anup Anvikar & Neena Valecha, 2019. "Development and Evaluation of a Novel HNB Based Isothermal Amplification Assay for Fast Detection of Pyrimethamine Resistance (S108N) in Plasmodium falciparum," IJERPH, MDPI, vol. 16(9), pages 1-13, May.
    4. Mariateresa Cesare & Mulenga Mwenda & Anna E. Jeffreys & Jacob Chirwa & Chris Drakeley & Kammerle Schneider & Brenda Mambwe & Karolina Glanz & Christina Ntalla & Manuela Carrasquilla & Silvia Portugal, 2024. "Flexible and cost-effective genomic surveillance of P. falciparum malaria with targeted nanopore sequencing," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    5. Krittikorn Kümpornsin & Theerarat Kochakarn & Tomas Yeo & John Okombo & Madeline R. Luth & Johanna Hoshizaki & Mukul Rawat & Richard D. Pearson & Kyra A. Schindler & Sachel Mok & Heekuk Park & Anne-Ca, 2023. "Generation of a mutator parasite to drive resistome discovery in Plasmodium falciparum," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    6. Tran Dang Nguyen & Bo Gao & Chanaki Amaratunga & Mehul Dhorda & Thu Nguyen-Anh Tran & Nicholas J. White & Arjen M. Dondorp & Maciej F. Boni & Ricardo Aguas, 2023. "Preventing antimalarial drug resistance with triple artemisinin-based combination therapies," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    7. 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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