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 Pf crt and Pf mdr1 genes, the Pf nhe-1 Na + /H + exchanger polymorphism plays a role in decreasing susceptibility. However, conflicting results on the link between the Pf nhe-1 gene and quinine resistance arise from field- and culture-adapted isolates. We tested the association between Pf nhe-1 , Pf crt , and Pf mdr1 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 Pf nhe-1 microsatellite sequence than culture-adapted isolates. In culture-adapted isolates but not in field isolates, mutations in the Pf crt and Pf mdr1 genes, as well as a higher number of DNNND repeats in the Pf nhe-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 Pf nhe-1 gene also harbored mutated Pf crt and Pf mdr1 genes with an apparent cumulative effect on quinine susceptibility. This study supports the involvement of the Pf nhe-1 gene in the modulation of the in vitro quinine response when associated with mutated Pf crt and Pf mdr1 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 Pf nhe-1 polymorphism and quinine susceptibility. However, we do not exclude the possibility that in particular settings, Pf nhe-1 polymorphism can be used as a molecular marker for surveillance of quinine resistance.