Adaptive evolution of malaria parasites in French Guiana: Reversal of chloroquine resistance by acquisition of a mutation in pfcrt.
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.
Laboratoire de parasitologie, WHO Collaborating Center for Surveillance of Anti-Malarial Drug Resistance, Centre National de Référence du paludisme, Laboratoire associé pour la région Antilles-Guyane, Institut Pasteur de la Guyane, 97300 Cayenne, French Guiana;
Stéphane
S
Pelleau
Genome Sequencing and Analysis Program, Broad Institute, Cambridge, MA 02142;
Eli L
EL
Moss
Department of Microbiology and Immunology, Columbia University College of Physicians and Surgeons, New York, NY 10032;
Satish K
SK
Dhingra
Laboratoire de parasitologie, WHO Collaborating Center for Surveillance of Anti-Malarial Drug Resistance, Centre National de Référence du paludisme, Laboratoire associé pour la région Antilles-Guyane, Institut Pasteur de la Guyane, 97300 Cayenne, French Guiana;
Béatrice
B
Volney
Laboratoire de parasitologie, WHO Collaborating Center for Surveillance of Anti-Malarial Drug Resistance, Centre National de Référence du paludisme, Laboratoire associé pour la région Antilles-Guyane, Institut Pasteur de la Guyane, 97300 Cayenne, French Guiana;
Jessica
J
Casteras
Department of Microbiology and Immunology, Columbia University College of Physicians and Surgeons, New York, NY 10032;
Stanislaw J
SJ
Gabryszewski
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115; Infectious Disease Program, Broad Institute, Cambridge, MA 02142; School of Nursing and Health Sciences, Simmons College, Boston, MA 02115;
Sarah K
SK
Volkman
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115; Infectious Disease Program, Broad Institute, Cambridge, MA 02142;
Dyann F
DF
Wirth
Laboratoire de parasitologie, WHO Collaborating Center for Surveillance of Anti-Malarial Drug Resistance, Centre National de Référence du paludisme, Laboratoire associé pour la région Antilles-Guyane, Institut Pasteur de la Guyane, 97300 Cayenne, French Guiana;
Eric
E
Legrand
Department of Microbiology and Immunology, Columbia University College of Physicians and Surgeons, New York, NY 10032; Division of Infectious Diseases, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032.
David A
DA
Fidock
Genome Sequencing and Analysis Program, Broad Institute, Cambridge, MA 02142;
Daniel E
DE
Neafsey
Laboratoire de parasitologie, WHO Collaborating Center for Surveillance of Anti-Malarial Drug Resistance, Centre National de Référence du paludisme, Laboratoire associé pour la région Antilles-Guyane, Institut Pasteur de la Guyane, 97300 Cayenne, French Guiana; lisemusset@gmail.com.
Lise
L
Musset
D000483:Alleles; D002738:Chloroquine / Q000627:therapeutic use*; D004351:Drug Resistance / Q000235:genetics*; D019143:Evolution, Molecular; D005616:French Guiana; D005819:Genetic Markers; D016678:Genome; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D020128:Inhibitory Concentration 50; D008288:Malaria / Q000188:drug therapy; D026901:Membrane Transport Proteins / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics*; D015995:Prevalence; D025341:Principal Component Analysis; D015800:Protozoan Proteins / Q000235:genetics*; D011804:Quinolines / Q000737:chemistry; D012189:Retrospective Studies; D010879:Piperazines
D002738:Chloroquine; D005819:Genetic Markers; D026901:Membrane Transport Proteins; D015800:Protozoan Proteins; D011804:Quinolines; C416369:PfCRT protein, Plasmodium falciparum; C034759:piperaquine; D010879:Piperazines
PfCRT; Plasmodium falciparum; drug resistance; evolution; malaria