A molecular marker of artemisinin-resistant Plasmodium falciparum malaria

Nature. 2014 Jan 2;505(7481):50-5. doi: 10.1038/nature12876. Epub 2013 Dec 18.

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.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alleles
  • Animals
  • Antimalarials / pharmacology*
  • Artemisinins / pharmacology*
  • Blood Cells / parasitology
  • Cambodia
  • Drug Resistance / drug effects
  • Drug Resistance / genetics*
  • Genetic Markers / genetics
  • Half-Life
  • Humans
  • Malaria, Falciparum / drug therapy
  • Malaria, Falciparum / parasitology*
  • Mutation / genetics
  • Parasitic Sensitivity Tests
  • Plasmodium falciparum / drug effects*
  • Plasmodium falciparum / genetics*
  • Plasmodium falciparum / growth & development
  • Plasmodium falciparum / isolation & purification
  • Polymorphism, Single Nucleotide / genetics
  • Protein Structure, Tertiary / genetics
  • Protozoan Proteins / chemistry
  • Protozoan Proteins / genetics*
  • Time Factors

Substances

  • Antimalarials
  • Artemisinins
  • Genetic Markers
  • Protozoan Proteins
  • artemisinine