title: Differential association of Plasmodium falciparum Na+/H+ exchanger polymorphism and quinine responses in field- and culture-adapted isolates of Plasmodium falciparum.
abstract: Plasmodium falciparum isolates with decreased susceptibility to quinine are increasingly being found in malaria patients. Mechanisms involved in this resistance are not yet understood. Several studies claim that alongside mutations in the Pfcrt and Pfmdr1 genes, the Pfnhe-1 Na(+)/H(+) exchanger polymorphism plays a role in decreasing susceptibility. However, conflicting results on the link between the Pfnhe-1 gene and quinine resistance arise from field- and culture-adapted isolates. We tested the association between Pfnhe-1, Pfcrt, and Pfmdr1 polymorphisms in field- and culture-adapted isolates from various countries with their in vitro susceptibility to quinine. Field isolates presented a higher diversity of the Pfnhe-1 microsatellite sequence than culture-adapted isolates. In culture-adapted isolates but not in field isolates, mutations in the Pfcrt and Pfmdr1 genes, as well as a higher number of DNNND repeats in the Pfnhe-1 gene, were associated with a higher 50% inhibitory concentration (IC(50)) of quinine. Furthermore, most of the culture-adapted isolates with more than one DNNND repeat in the Pfnhe-1 gene also harbored mutated Pfcrt and Pfmdr1 genes with an apparent cumulative effect on quinine susceptibility. This study supports the involvement of the Pfnhe-1 gene in the modulation of the in vitro quinine response when associated with mutated Pfcrt and Pfmdr1 genes. Culture adaptation could be responsible for selection of specific haplotypes of these three genes. Methods used for drug testing might thus influence the association between Pfnhe-1 polymorphism and quinine susceptibility. However, we do not exclude the possibility that in particular settings, Pfnhe-1 polymorphism can be used as a molecular marker for surveillance of quinine resistance.
authors.affiliation: Institut Pasteur de Dakar, BP 220 Dakar, Senegal.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Pelleau
authors.forename: Lionel
authors.initials: L
authors.lastname: Bertaux
authors.forename: Sébastien
authors.initials: S
authors.lastname: Briolant
authors.forename: Michael T
authors.initials: MT
authors.lastname: Ferdig
authors.forename: Véronique
authors.initials: V
authors.lastname: Sinou
authors.forename: Bruno
authors.initials: B
authors.lastname: Pradines
authors.forename: Daniel
authors.initials: D
authors.lastname: Parzy
authors.forename: Ronan
authors.initials: R
authors.lastname: Jambou
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D003470:Culture Media; D004351:Drug Resistance / Q000235:genetics*; D006801:Humans; D020128:Inhibitory Concentration 50; D026901:Membrane Transport Proteins / Q000235:genetics; D008969:Molecular Sequence Data; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000302:isolation & purification; D011110:Polymorphism, Genetic / Q000235:genetics*; D015800:Protozoan Proteins / Q000235:genetics; D011803:Quinine / Q000494:pharmacology*; D017422:Sequence Analysis, DNA; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics*
chemical_list: D000962:Antimalarials; D003470:Culture Media; D026901:Membrane Transport Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D015800:Protozoan Proteins; D011803:Quinine; D017923:Sodium-Hydrogen Exchangers; C513498:Mdr1 protein, Plasmodium falciparum; C416369:PfCRT protein, Plasmodium falciparum