Plasmodium falciparumMultidrug Resistance Protein 1 and Artemisinin‐Based Combination Therapy in Africa

Sabina Dahlström,Anders Björkman,Akira Kaneko,Christin Sisowath,Gwenaëlle Conseil,Andreas Mårtensson,Anna Färnert,Björn Andersson,J Pedro Gil,Lisa Wiklund,Nazli Sedighi,Lyda Osório,Hamid Darban,M Isabel Veiga,Pedro E Ferreira

doi:10.1086/606009

Abstract

Plasmodium falciparum response mechanisms to the major artemisinin-based combination therapies (ACTs) are largely unknown. Multidrug-resistance protein (MRP)-like adenosine triphosphate (ATP)-binding cassette transporters are known to be related to multidrug resistance in many organisms. Therefore, we hypothesized that sequence variation in pfmrp1 can contribute to decreased parasite sensitivity to ACT. Through sequencing of the pfmrp1 open reading frame for 103 geographically diverse P. falciparum infections, we identified 27 single-nucleotide polymorphisms (SNPs), of which 21 were nonsynonymous and 6 synonymous. Analyses of clinical efficacy trials with artesunate-amodiaquine and artemether-lumefantrine detected a specific selection of the globally prevalent I876V SNP in recurrent infections after artemether-lumefantrine treatment. Additional in silico studies suggested an influence of variation in amino acid 876 on the ATP hydrolysis cycle of pfMRP1 with potential impact on protein functionality. Our data suggest for the first time, to our knowledge, the involvement of pfMRP1 in P. falciparum in vivo response to ACT.

Highlights

Plasmodium falciparum malaria remains a major public health problem
We focused on the pfmrp1 gene, which codes for pf MRP1 (PFA0590w), an 1822–amino acid protein situated in the parasite plasma membrane [9]
The genetic region around amino acids 191 and 437 in pf MRP1 was sequenced in 70 samples from the ACO study and 30 from the FUKA study, because single-nucleotide polymorphisms (SNPs) in these positions were previously identified in Kenya [23]

Summary

Introduction

Plasmodium falciparum malaria remains a major public health problem. Recent findings, support the idea that new control strategies, including artemisininbased combination therapy (ACT) and strengthened vector control, may provide a dramatic reduction in the burden of disease [1]. The genetic region around amino acids 191 and 437 in pf MRP1 was sequenced in 70 samples from the ACO study and 30 from the FUKA study, because SNPs in these positions were previously identified in Kenya [23].

Results

Conclusion