Abstract
BackgroundAlthough the World Health Organization recommends replacing quinine (QN) by artesunate due to its increased efficacy and the higher tolerance to the drug in both adults and children, QN remains a first-line treatment for severe malaria, especially in Africa. Investigations of microsatellite Pfnhe-1 ms4760 polymorphisms in culture-adapted isolates from around the world have revealed that an increase in the number of DNNND amino acid motifs was associated with decreased QN susceptibility, whereas an increase in the number of DDNHNDNHNND motifs was associated with increased QN susceptibility.MethodsIn this context, to further analyse associations between Pfnhe-1 ms4760 polymorphisms and QN susceptibility, 393 isolates freshly collected between October 2009 and January 2010 and July 2010 and February 2011, respectively, at the Hôpital Principal de Dakar, Senegal were assessed ex vivo for QN susceptibility, and their genes were amplified and sequenced.ResultsOf the 393 Plasmodium falciparum clinical isolates collected, 145 were successfully cultured. The 145 QN IC50s ranged from 2.1 to 1291 nM, and 17 isolates (11.7%) exceed the QN reduced susceptibility threshold of 611 nM. Among the 393 P. falciparum clinical isolates, 47 different alleles were observed. The three most prevalent profiles were ms4760-1 (no = 72; 18.3%), ms4760-3 (no = 65; 16.5%) and ms4760-7 (no = 40; 10.2%). There were no significant associations observed between QN IC50 values and i) the number of repeats of DNNND in block II (p = 0.0955, Kruskal-Wallis test); ii) the number of repeats of DDNHNDNHNND in block V (p = 0.1455, Kruskal-Wallis test); or iii) ms4760 profiles (p = 0.1809, Kruskal-Wallis test).ConclusionsPfnhe-1 ms4760 was highly diverse in parasite isolates from Dakar (47 different profiles). Three profiles (ms4760-1, ms4760-3 and ms4760-7) were predominant. The number of repeats for block II (DNNND) or block V (DDNHNDNHNND) was not significantly associated with QN susceptibility. New studies, and especially in vivo studies, are necessary to confirm the role of Pfnhe-1 ms4760 as a marker of QN resistance.
Highlights
The World Health Organization recommends replacing quinine (QN) by artesunate due to its increased efficacy and the higher tolerance to the drug in both adults and children, QN remains a first-line treatment for severe malaria, especially in Africa
QN presumably acts by interference with the detoxification of haem produced during haemoglobin degradation by P. falciparum asexual blood stages [10]
Using quantitative trait loci (QTL) on the genetic cross of HB3 and Dd2 strains, Ferdig et al identified genes associated with reduced QN susceptibility on chromosome 5, encoding Pfmdr1, on chromosome 7, encoding Pfcrt, and on chromosome 13, encoding the sodium/hydrogen exchanger gene Pfnhe-1[15]
Summary
The World Health Organization recommends replacing quinine (QN) by artesunate due to its increased efficacy and the higher tolerance to the drug in both adults and children, QN remains a first-line treatment for severe malaria, especially in Africa. Despite the efficacy of QN against chloroquine-resistant Plasmodium falciparum isolates, reports of QN resistance (QNR) have been increasing. The investigations of the microsatellite ms4760 polymorphisms in culture-adapted isolates from around the world showed an association with the QN susceptibility phenotype [16]. A repetition of the amino acid motif DNNND was associated with a decreased susceptibility to QN based on the clinical failure of QN in a traveller from Senegal [17], and data from fresh isolates from Vietnam (n = 79) [18] and from culture-adapted isolates from the China-Myanmar border area (n = 60) [19], Asia, South America and Africa (n = 95) [20]. In 29 cultured-adapted isolates from the Kenya [21] and in 172 freshly obtained isolates from
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