In vitro susceptibility to quinine and microsatellite variations of the Plasmodium falciparum Na+/H+ exchanger (Pfnhe-1) gene: the absence of association in clinical isolates from the Republic of Congo

Sébastien Briolant,Christophe Rogier,Jacky Castello,Bruno Pradines,Hervé Bogreau,Philippe Hovette,Agnès Zettor,Rémy Amalvict,Eric Baret,Stéphane Pelleau

doi:10.1186/1475-2875-10-37

Sébastien Briolant, Christophe Rogier + Show 8 more

Open Access

https://doi.org/10.1186/1475-2875-10-37

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Abstract

BackgroundQuinine is still recommended as an effective therapy for severe cases of Plasmodium falciparum malaria, but the parasite has developed resistance to the drug in some cases. Investigations into the genetic basis for quinine resistance (QNR) suggest that QNR is complex and involves several genes, with either an additive or a pairwise effect. The results obtained when assessing one of these genes, the plasmodial Na+/H+ exchanger, Pfnhe-1, were found to depend upon the geographic origin of the parasite strain. Most of the associations identified have been made in Asian strains; in contrast, in African strains, the influence of Pfnhe on QNR is not apparent. However, a recent study carried out in Kenya did show a significant association between a Pfnhe polymorphism and QNR. As genetic differences may exist across the African continent, more field data are needed to determine if this association exists in other African regions. In the present study, association between Pfnhe and QNR is investigated in a series of isolates from central Africa.MethodsThe sequence analysis of the polymorphisms at the Pfnhe-1 ms4760 microsatellite and the evaluation of in vitro quinine susceptibility (by isotopic assay) were conducted in 74 P. falciparum isolates from the Republic of Congo.ResultsPolymorphisms in the number of DNNND or NHNDNHNNDDD repeats in the Pfnhe-1 ms4760 microsatellite were not associated with quinine susceptibility.ConclusionsThe polymorphism in the microsatellite ms4760 in Pfnhe-1 that cannot be used to monitor quinine response in the regions of the Republic of Congo, where the isolates came from. This finding suggests that there exists a genetic background associated with geographic area for the association that will prevent the use of Pfnhe as a molecular marker for QNR. The contribution of Pfnhe to the in vitro response to quinine remains to be assessed in other regions, including in countries with different levels of drug pressure.

Highlights

Quinine is still recommended as an effective therapy for severe cases of Plasmodium falciparum malaria, but the parasite has developed resistance to the drug in some cases
The polymorphism in the microsatellite ms4760 in Pfnhe-1 that cannot be used to monitor quinine response in the regions of the Republic of Congo, where the isolates came from. This finding suggests that there exists a genetic background associated with geographic area for the association that will prevent the use of Pfnhe as a molecular marker for quinine resistance (QNR)
QNR has been associated with mutations in both the P. falciparum multidrug resistance gene mdr1 (Pfmdr1) [5] and the chloroquine resistance transporter gene Pfcrt [6]

Summary

Introduction

Quinine is still recommended as an effective therapy for severe cases of Plasmodium falciparum malaria, but the parasite has developed resistance to the drug in some cases. Investigations into the genetic basis for quinine resistance (QNR) suggest that QNR is complex and involves several genes, with either an additive or a pairwise effect. QNR has been associated with mutations in both the P. falciparum multidrug resistance gene mdr (Pfmdr1) [5] and the chloroquine resistance transporter gene Pfcrt [6]. Other genetic polymorphisms, such as mutations in the resistance protein gene Pfmrp [7] and variations of microsatellite length in the sodium/hydrogen exchanger gene

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