title: A molecular marker of artemisinin-resistant Plasmodium falciparum malaria.
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.
authors.affiliation: 1] Institut Pasteur, Parasite Molecular Immunology Unit, 75724 Paris Cedex 15, France [2] Centre National de la Recherche Scientifique, Unité de Recherche Associée 2581, 75724 Paris Cedex 15, France [3] 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 Institut Pasteur, Unité de Biologie et Génétique du Paludisme, Team Malaria Targets and Drug Development, 75724 Paris Cedex 15, France (J.-C.B.).
authors.forename: Frédéric
authors.initials: F
authors.lastname: Ariey
authors.affiliation: Institut Pasteur du Cambodge, Malaria Molecular Epidemiology Unit, Phnom Penh, Cambodia.
authors.forename: Benoit
authors.initials: B
authors.lastname: Witkowski
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Chanaki
authors.initials: C
authors.lastname: Amaratunga
authors.affiliation: 1] Institut Pasteur, Parasite Molecular Immunology Unit, 75724 Paris Cedex 15, France [2] Centre National de la Recherche Scientifique, Unité de Recherche Associée 2581, 75724 Paris Cedex 15, France [3] 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 Institut Pasteur, Unité de Biologie et Génétique du Paludisme, Team Malaria Targets and Drug Development, 75724 Paris Cedex 15, France (J.-C.B.).
authors.forename: Johann
authors.initials: J
authors.lastname: Beghain
authors.affiliation: 1] Institut Pasteur, Parasite Molecular Immunology Unit, 75724 Paris Cedex 15, France [2] Centre National de la Recherche Scientifique, Unité de Recherche Associée 2581, 75724 Paris Cedex 15, France.
authors.forename: Anne-Claire
authors.initials: AC
authors.lastname: Langlois
authors.affiliation: Institut Pasteur du Cambodge, Malaria Molecular Epidemiology Unit, Phnom Penh, Cambodia.
authors.forename: Nimol
authors.initials: N
authors.lastname: Khim
authors.affiliation: Institut Pasteur du Cambodge, Malaria Molecular Epidemiology Unit, Phnom Penh, Cambodia.
authors.forename: Saorin
authors.initials: S
authors.lastname: Kim
authors.affiliation: Institut Pasteur du Cambodge, Malaria Molecular Epidemiology Unit, Phnom Penh, Cambodia.
authors.forename: Valentine
authors.initials: V
authors.lastname: Duru
authors.affiliation: Institut Pasteur, Plate-forme Génomique, Département Génomes et Génétique, 75724 Paris Cedex 15, France.
authors.forename: Christiane
authors.initials: C
authors.lastname: Bouchier
authors.affiliation: Institut Pasteur, Plate-forme Génomique, Département Génomes et Génétique, 75724 Paris Cedex 15, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Ma
authors.affiliation: 1] Institut Pasteur du Cambodge, Malaria Molecular Epidemiology Unit, Phnom Penh, Cambodia [2] Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA [3] National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia.
authors.forename: Pharath
authors.initials: P
authors.lastname: Lim
authors.affiliation: National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia.
authors.forename: Rithea
authors.initials: R
authors.lastname: Leang
authors.affiliation: National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia.
authors.forename: Socheat
authors.initials: S
authors.lastname: Duong
authors.affiliation: National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia.
authors.forename: Sokunthea
authors.initials: S
authors.lastname: Sreng
authors.affiliation: National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia.
authors.forename: Seila
authors.initials: S
authors.lastname: Suon
authors.affiliation: National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia.
authors.forename: Char Meng
authors.initials: CM
authors.lastname: Chuor
authors.affiliation: SSA WHO, Drug Monitoring in Cambodia, National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia.
authors.forename: Denis Mey
authors.initials: DM
authors.lastname: Bout
authors.affiliation: 1] Service de Parasitologie et Mycologie, Centre Hospitalier Universitaire de Toulouse, 31059 Toulouse Cedex 9, France [2] 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 Institut Pasteur, Unité de Biologie et Génétique du Paludisme, Team Malaria Targets and Drug Development, 75724 Paris Cedex 15, France (J.-C.B.).
authors.forename: Sandie
authors.initials: S
authors.lastname: Ménard
authors.affiliation: Naval Medical Research Unit #2 Detachment, Phnom Penh, Cambodia.
authors.forename: William O
authors.initials: WO
authors.lastname: Rogers
authors.affiliation: Swiss Tropical and Public Health Institute, 4051 Basel, Switzerland.
authors.forename: Blaise
authors.initials: B
authors.lastname: Genton
authors.affiliation: 1] Institut Pasteur, Parasite Molecular Immunology Unit, 75724 Paris Cedex 15, France [2] Institut Pasteur du Cambodge, Malaria Molecular Epidemiology Unit, Phnom Penh, Cambodia.
authors.forename: Thierry
authors.initials: T
authors.lastname: Fandeur
authors.affiliation: 1] MRC Centre for Genomics and Global Health, University of Oxford, Oxford OX3 7BN, UK [2] Mahidol-Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok 10400, Thailand [3] Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Olivo
authors.initials: O
authors.lastname: Miotto
authors.affiliation: Global Malaria Program, World Health Organization, 1211 Geneva, Switzerland.
authors.forename: Pascal
authors.initials: P
authors.lastname: Ringwald
authors.affiliation: Centre National de Référence du Paludisme, CHU Bichat-Claude Bernard, APHP, PRES Sorbonne Paris Cité, 75018 Paris, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Le Bras
authors.affiliation: 1] Service de Parasitologie et Mycologie, Centre Hospitalier Universitaire de Toulouse, 31059 Toulouse Cedex 9, France [2] 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 Institut Pasteur, Unité de Biologie et Génétique du Paludisme, Team Malaria Targets and Drug Development, 75724 Paris Cedex 15, France (J.-C.B.).
authors.forename: Antoine
authors.initials: A
authors.lastname: Berry
authors.affiliation: 1] Institut Pasteur, Parasite Molecular Immunology Unit, 75724 Paris Cedex 15, France [2] Centre National de la Recherche Scientifique, Unité de Recherche Associée 2581, 75724 Paris Cedex 15, France [3] 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 Institut Pasteur, Unité de Biologie et Génétique du Paludisme, Team Malaria Targets and Drug Development, 75724 Paris Cedex 15, France (J.-C.B.).
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Barale
authors.affiliation: 1] Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA [2].
authors.forename: Rick M
authors.initials: RM
authors.lastname: Fairhurst
authors.affiliation: 1] Centre National de la Recherche Scientifique, Laboratoire de Chimie de Coordination UPR8241, 31077 Toulouse Cedex 4, France [2] Université de Toulouse, UPS, Institut National Polytechnique de Toulouse, 31077 Toulouse Cedex 4, France [3].
authors.forename: Françoise
authors.initials: F
authors.lastname: Benoit-Vical
authors.affiliation: 1] Institut Pasteur, Parasite Molecular Immunology Unit, 75724 Paris Cedex 15, France [2] Centre National de la Recherche Scientifique, Unité de Recherche Associée 2581, 75724 Paris Cedex 15, France [3].
authors.forename: Odile
authors.initials: O
authors.lastname: Mercereau-Puijalon
authors.affiliation: 1] Institut Pasteur du Cambodge, Malaria Molecular Epidemiology Unit, Phnom Penh, Cambodia [2].
authors.forename: Didier
authors.initials: D
authors.lastname: Ménard
mesh_terms: D000483:Alleles; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology*; D001773:Blood Cells / Q000469:parasitology; D002160:Cambodia; D004351:Drug Resistance / Q000187:drug effects / Q000235:genetics*; D005819:Genetic Markers / Q000235:genetics; D006207:Half-Life; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology*; D009154:Mutation / Q000235:genetics; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics* / Q000254:growth & development / Q000302:isolation & purification; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D015800:Protozoan Proteins / Q000737:chemistry / Q000235:genetics*; D013997:Time Factors
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D005819:Genetic Markers; D015800:Protozoan Proteins; C031327:artemisinin