title: Evolution of a unique Plasmodium falciparum chloroquine-resistance phenotype in association with pfcrt polymorphism in Papua New Guinea and South America.
abstract: The mechanistic basis for chloroquine resistance (CQR) in Plasmodium falciparum recently has been linked to the polymorphic gene pfcrt. Alleles associated with CQR in natural parasite isolates harbor threonine (T), as opposed to lysine (K) at amino acid 76. P. falciparum CQR strains of African and Southeast Asian origin carry pfcrt alleles encoding an amino acid haplotype of CVIET (residues 72-76), whereas most South American CQR strains studied carry an allele encoding an SVMNT haplotype; chloroquine-sensitive strains from malarious regions around the world carry a CVMNK haplotype. Upon investigating the origin of pfcrt alleles in Papua New Guinean (PNG) P. falciparum we found either the chloroquine-sensitive-associated CVMNK or CQR-associated SVMNT haplotypes previously seen in Brazilian isolates. Remarkably we did not find the CVIET haplotype observed in CQR strains from Southeast Asian regions more proximal to PNG. Further we found a previously undescribed CQR phenotype to be associated with the SVMNT haplotype from PNG and South America. This CQR phenotype is significantly less responsive to verapamil chemosensitization compared with the effect associated with the CVIET haplotype. Consistent with this, we observed that verapamil treatment of P. falciparum isolates carrying pfcrt SVMNT is associated with an attenuated increase in digestive vacuole pH relative to CVIET pfcrt-carrying isolates. These data suggest a key role for pH-dependent changes in hematin receptor concentration in the P. falciparum CQR mechanism. Our findings also suggest that P. falciparum CQR has arisen through multiple evolutionary pathways associated with pfcrt K76T.
authors.affiliation: Division of Geographic Medicine, Case Western Reserve University, University Hospitals of Cleveland, School of Medicine, W147D, 2109 Adelbert Road, Cleveland, OH 44106-4983, USA.
authors.forename: R K
authors.initials: RK
authors.lastname: Mehlotra
authors.forename: H
authors.initials: H
authors.lastname: Fujioka
authors.forename: P D
authors.initials: PD
authors.lastname: Roepe
authors.forename: O
authors.initials: O
authors.lastname: Janneh
authors.forename: L M
authors.initials: LM
authors.lastname: Ursos
authors.forename: V
authors.initials: V
authors.lastname: Jacobs-Lorena
authors.forename: D T
authors.initials: DT
authors.lastname: McNamara
authors.forename: M J
authors.initials: MJ
authors.lastname: Bockarie
authors.forename: J W
authors.initials: JW
authors.lastname: Kazura
authors.forename: D E
authors.initials: DE
authors.lastname: Kyle
authors.forename: D A
authors.initials: DA
authors.lastname: Fidock
authors.forename: P A
authors.initials: PA
authors.lastname: Zimmerman
mesh_terms: D018528:ATP-Binding Cassette Transporters; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D002738:Chloroquine / Q000494:pharmacology*; D016054:DNA, Protozoan / Q000737:chemistry; D004351:Drug Resistance; D005838:Genotype; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D026901:Membrane Transport Proteins; D010219:Papua New Guinea; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics; D011110:Polymorphism, Genetic; D015800:Protozoan Proteins / Q000235:genetics; D013020:South America
chemical_list: D018528:ATP-Binding Cassette Transporters; D000962:Antimalarials; D016054:DNA, Protozoan; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C416369:PfCRT protein, Plasmodium falciparum; D015800:Protozoan Proteins; C059987:mdr gene protein, Plasmodium; D002738:Chloroquine