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) , Benoît Witkowski (1) , Rick M Fairhurst (3) , Françoise Benoit-Vical (17, 18) , Odile Mercereau-Puijalon (1) , Didier Ménard (19)

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 [CHU Toulouse]
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

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.

Domains: Santé publique et épidémiologie; Parasitology

Frédéric Ariey, Benoit Witkowski, Chanaki Amaratunga, Johann Beghain, Anne-Claire Langlois, et al.. A molecular marker of artemisinin-resistant Plasmodium falciparum malaria.. Nature, 2014, 505 (7481), pp.50-5. ⟨10.1038/nature12876⟩. ⟨pasteur-00921203⟩