Abstract |
In regions with high malaria endemicity, the withdrawal of chloroquine (CQ) as first-line treatment of Plasmodium falciparum infections has typically led to the restoration of CQ susceptibility through the reexpansion of the wild-type (WT) allele K76 of the chloroquine resistance transporter gene (pfcrt) at the expense of less fit mutant alleles carrying the CQ resistance (CQR) marker K76T. In low-transmission settings, such as South America, drug resistance mutations can attain 100% prevalence, thereby precluding the return of WT parasites after the complete removal of drug pressure. In French Guiana, despite the fixation of the K76T allele, the prevalence of CQR isolates progressively dropped from >90% to <30% during 17 y after CQ withdrawal in 1995. Using a genome-wide association study with CQ-sensitive (CQS) and CQR isolates, we have identified a single mutation in pfcrt encoding a C350R substitution that is associated with the restoration of CQ susceptibility. Genome editing of the CQR reference strain 7G8 to incorporate PfCRT C350R caused a complete loss of CQR. A retrospective molecular survey on 580 isolates collected from 1997 to 2012 identified all C350R mutant parasites as being CQS. This mutation emerged in 2002 and rapidly spread throughout the P. falciparum population. The C350R allele is also associated with a significant decrease in piperaquine susceptibility in vitro, suggesting that piperaquine pressure in addition to potential fitness costs associated with the 7G8-type CQR pfcrt allele may have selected for this mutation. These findings have important implications for understanding the evolutionary dynamics of antimalarial drug resistance.
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Authors | Stéphane Pelleau, Eli L Moss, Satish K Dhingra, Béatrice Volney, Jessica Casteras, Stanislaw J Gabryszewski, Sarah K Volkman, Dyann F Wirth, Eric Legrand, David A Fidock, Daniel E Neafsey, Lise Musset |
Journal | Proceedings of the National Academy of Sciences of the United States of America
(Proc Natl Acad Sci U S A)
Vol. 112
Issue 37
Pg. 11672-7
(Sep 15 2015)
ISSN: 1091-6490 [Electronic] United States |
PMID | 26261345
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Genetic Markers
- Membrane Transport Proteins
- PfCRT protein, Plasmodium falciparum
- Protozoan Proteins
- Quinolines
- Chloroquine
- piperaquine
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Topics |
- Alleles
- Chloroquine
(therapeutic use)
- Drug Resistance
(genetics)
- Evolution, Molecular
- French Guiana
- Genetic Markers
- Genome
- Genotype
- Haplotypes
- Humans
- Inhibitory Concentration 50
- Malaria
(drug therapy)
- Membrane Transport Proteins
(genetics)
- Mutation
- Phenotype
- Plasmodium falciparum
(drug effects, genetics)
- Prevalence
- Principal Component Analysis
- Protozoan Proteins
(genetics)
- Quinolines
(chemistry)
- Retrospective Studies
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