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Resistance-mediating polymorphisms of Plasmodium falciparum among isolates from children with severe malaria in kumasi, ghana.

ABSTRACT: BACKGROUND:Antimalarial drug resistance has been a major contributor to the failure of the battle against malaria in many developing countries. The P. falciparum genes, pfcrt and pfmdr-1, have been implicated in chloroquine resistance. The objective of this study was to determine the presence of mutant alleles of these chloroquine resistance genes among isolates of P. falciparum from children presenting with severe malaria in Ghana. METHODS:Venous blood samples were taken from patients, and plasma chloroquine levels measured. P. falciparum chromosomal DNA was isolated from the blood samples, and subjected to PCR, restriction digestion and sequencing. Resulting data were analysed using the STATA statistical software. RESULTS:Of 140 children recruited into the study, 109 (77.9%) had detectable pre-treatment chloroquine levels. PCR and restriction digestion analysis of the pfcrt gene indicated that 124 (88.6%) had the mutant T76 gene, and that this correlated with higher chloroquine levels. Sequence analysis of these showed consistent genetic sequences for chloroquine resistant and sensitive parasites with respect to Pfcrt codons 72 through 76.The Pfcrt T76 mutation was found in 88.4% of isolates having the Pfmdr-1Y86 mutation. The Pfmdr-1 Y86 mutation was found in 67.6% of isolates having the Pfcrt T76 mutation. CONCLUSION:The study affirms Pfcrt as a better chloroquine resistance marker. Both mutations are independently selected by chloroquine levels and that one mutation (Y86) might modify/increase the effect of the other (T76). This study also depicts the much-overlooked antimalarial drug resistance situation in the area and emphasizes the need for a proper treatment strategy.

SUBMITTER: Abruquah H

PROVIDER: S-EPMC2994155 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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Resistance-mediating polymorphisms of Plasmodium falciparum among isolates from children with severe malaria in kumasi, ghana.

Abruquah Hh H Bio Fy F Tay Sck S Lawson Bwl B

Ghana medical journal 20100601 2

<h4>Background</h4>Antimalarial drug resistance has been a major contributor to the failure of the battle against malaria in many developing countries. The P. falciparum genes, pfcrt and pfmdr-1, have been implicated in chloroquine resistance. The objective of this study was to determine the presence of mutant alleles of these chloroquine resistance genes among isolates of P. falciparum from children presenting with severe malaria in Ghana.<h4>Methods</h4>Venous blood samples were taken from pat ...[more]

PMID: 21327004

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Project description:BackgroundArtemisinin-based combination therapy (ACT) is the first-line treatment for uncomplicated malaria in Ghana. Artemisinin (ART) tolerance in Plasmodium falciparum has arisen in Southeast Asia and recently, in parts of East Africa. This is ascribed to the survival of ring-stage parasites post treatment. The present study sought to assess and characterize correlates of potential ART tolerance based on post-treatment parasite clearance, ex vivo and in vitro drug sensitivity, and molecular markers of drug resistance in P. falciparum isolates from children with uncomplicated malaria in Ghana.MethodsSix months to fourteen years old children presenting with acute uncomplicated malaria (n = 115) were enrolled in two hospitals and a Health Centre in Ghana's Greater Accra region and treated with artemether-lumefantrine (AL) according to body weight. Pre- and post-treatment parasitaemia (day 0 and day 3) was confirmed by microscopy. The ex vivo ring-stage survival assay (RSA) was used to detect percent ring survival while the 72 h SYBR Green I assay was used to measure the 50% inhibition concentration (IC50s) of ART and its derivatives and partner drugs. Genetic markers of drug tolerance /resistance were evaluated using selective whole genome sequencing.ResultsOf the total of 115 participants, 85 were successfully followed up on day 3 post-treatment and 2/85 (2.4%) had parasitaemia. The IC50 values of ART, artesunate (AS), artemether (AM), dihydroartemisinin (DHA), amodiaquine (AQ), and lumefantrine (LUM) were not indicative of drug tolerance. However, 7/90 (7.8%) pre-treatment isolates had > 10% ring survival rates against DHA. Of the four isolates (2 RSA positive and 2 RSA negative) with high genomic coverage, P. falciparum (Pf) kelch 13 K188* and Pfcoronin V424I mutations were only present in the two RSA positive isolates with > 10% ring survival rates.ConclusionsThe observed low proportion of participants with day-3 post-treatment parasitaemia is consistent with rapid ART clearance. However, the increased rates of survival observed in the ex vivo RSA against DHA, maybe a pointer of an early start of ART tolerance. Furthermore, the role of two novel mutations in PfK13 and Pfcoronin genes, harboured by the two RSA positive isolates that had high ring survival in the present study, remains to be elucidated.

Dataset Information

Resistance-mediating polymorphisms of Plasmodium falciparum among isolates from children with severe malaria in kumasi, ghana.

Publications

Resistance-mediating polymorphisms of Plasmodium falciparum among isolates from children with severe malaria in kumasi, ghana.

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