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A molecular marker of artemisinin-resistant Plasmodium falciparum malaria.

Frédéric Ariey 1, * Benoit Witkowski 2 Chanaki Amaratunga 3 Johann Beghain 1 Anne-Claire Langlois 1 Nimol Khim 2 Saorin Kim 2 Valentine Duru 2 Christiane Bouchier 4 Laurence Ma 4 Pharath Lim 2, 3, 5 Rithea Leang 5 Socheat Duong 5 Sokunthea Sreng 5 Seila Suon 5 Char Meng Chuor 5 Denis Mey Bout 6 Sandie Ménard 7 William O Rogers 7, 8 Blaise Genton 9 Thierry Fandeur 2, 10 Olivo Miotto 11, 12, 13 Pascal Ringwald 14 Jacques Le Bras 15 Antoine Berry 16 Jean-Christophe Barale 1 Rick M Fairhurst 3 Françoise Benoit-Vical 17, 18 Odile Mercereau-Puijalon 1 Didier Ménard 19
* Corresponding author
1 Immunologie moléculaire des parasites
2 Laboratoire d'épidémiologie moléculaire
3 Laboratory of Malaria and Vector Research
4 Génomique (Plate-Forme) - Genomics Platform
5 National Center for Parasitology, Entomology and Malaria Control
6 Drug Monitoring in Cambodia
7 Service de Parasitologie et Mycologie
8 US Naval Medical Research Unit n°2
9 Swiss Tropical and Public Health Institute [Basel]
10 Unité de Parasitologie Médicale
11 MRC Centre for Genomics and Global Health
12 Mahidol-Oxford Tropical Medicine Research Unit
13 The Wellcome Trust Sanger Institute [Cambridge]
14 Global Malaria Program
15 Centre National de Référence du Paludisme
16 CPTP - Centre de Physiopathologie Toulouse Purpan
17 LCC - Laboratoire de chimie de coordination
18 Toulouse INP - Institut National Polytechnique (Toulouse)
19 Institut Pasteur du Cambodge
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.
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Frédéric Ariey, Benoit Witkowski, Chanaki Amaratunga, Johann Beghain, Anne-Claire Langlois, et al.. A molecular marker of artemisinin-resistant Plasmodium falciparum malaria.. Nature, Nature Publishing Group, 2014, 505 (7481), pp.50-5. ⟨10.1038/nature12876⟩. ⟨pasteur-00921203⟩

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