Independent origin of plasmodium falciparum antifolate super-resistance, Uganda, Tanzania, and Ethiopia

Abstract

Super-resistant Plasmodium falciparum threatens the effectiveness of sulfadoxine-pyrimethamine in intermittent preventive treatment for malaria during pregnancy. It is characterized by the A581G Pfdhps mutation on a background of the double-mutant Pfdhps and the triple-mutant Pfdhfr. Using samples collected during 2004-2008, we investigated the evolutionary origin of the A581G mutation by characterizing microsatellite diversity flanking Pfdhps triple-mutant (437G+540E+581G) alleles from 3 locations in eastern Africa and comparing it with double-mutant (437G+540E) alleles from the same area. In Ethiopia, both alleles derived from 1 lineage that was distinct from those in Uganda and Tanzania. Uganda and Tanzania triple mutants derived from the previously characterized southeastern Africa double-mutant lineage. The A581G mutation has occurred multiple times on local Pfdhps double-mutant backgrounds; however, a novel microsatellite allele incorporated into the Tanzania lineage since 2004 illustrates the local expansion of emergent triple-mutant lineages.

Keywords: 581; Dihydrofolate reductase; Ethiopia; Pfdhfr; Pfdhps; Plasmodium falciparum; Tanzania; Uganda; dihydropteroate synthetase; eastern Africa; intermittent preventive treatment in pregnant women; malaria; microsatellite; parasites; resistance; single-nucleotide polymorphism; sulfadoxine-pyrimethamine; vector-borne infections.

Figure

Proportion of microsatellite haplotypes linked to SGEAA and SGEGA, eastern Africa. Microsatellite haplotypes associated with the Pfdhps double-mutant allele SGEAA (A) and Pfdhps triple-mutant allele SGEGA (B) in Ethiopia, Tanzania, and Uganda. Haplotype numbering (x-axis) refers to a unique combination of microsatellite allele sizes at the 3 loci linked to dhps (specific microsatellite allele combinations are listed in the Technical Appendix Table, Proportion (y-axis) is the number of alleles associated with each microsatellite haplotype expressed as a proportion of the total number of alleles sampled in each country for which the associated microsatellite haplotype could be determined.