Invasion of Africa by a single pfcrt allele of South East Asian type

Ariey, Frédéric; Fandeur, Thierry; Durand, Rémy; Randrianarivelojosia, Milijaona; Jambou, Ronan; Legrand, Eric; Ekala, Marie-Thérèse; Bouchier, Christiane; Cojean, Sandrine; Duchemin, Jean‐Bernard; Robert, Vincent; Bras, J. Le; Mercereau‐Puijalon, Odile

doi:10.1186/1475-2875-5-34

Cited by 70 publications

(56 citation statements)

References 15 publications

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“…This is consistent with the emergence of pyrimethamine resistance in SE Asia and Africa in the 1950s. Other continent-wide surveys have been conducted in South America, SE Asia, and Africa for the dhfr or pfcrt alleles associated with pyrimethamine and chloroquine resistance, respectively [22,29,30]. Strikingly, invasion by a single resistant lineage was found in each study, indicating few independent origins for resistance alleles, at least for pyrimethamine and chloroquine resistance (for a hypothesis for these few origins, see [31,32]).…”

Section: Discussionmentioning

confidence: 94%

A Shared Asian Origin of the Triple‐MutantdhfrAllele inPlasmodium falciparumfrom Sites across Africa

et al. 2007

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Section: Discussionmentioning

confidence: 94%

A Shared Asian Origin of the Triple‐MutantdhfrAllele inPlasmodium falciparumfrom Sites across Africa

et al. 2007

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“…All but one CVIET/S alleles were associated with a type 13 microsatellite [(TAAA) 3 (TA) 15 ], i.e. presented the characteristic intragenic signature of the resistance allele of Southeast Asian origin [33]. One CVIET/S allele was associated with the related type 14 microsatellite [(TAAA) 3 (TA) 16 ] (unbiased expected heterozygosity He = 0.07, n = 31).…”

Section: Resultsmentioning

confidence: 99%

“…All sequence data with ambiguous positions were rejected. The 72-6/220 Pfcrt gene sequence was established as described [33], using the primers listed in Table S1. The entire 1.8 kb Pfdhfr-ts coding sequence was amplified by PCR in a 50 µL reaction volume containing 2 µL DNA, 10 mM Tris-HCl pH 9.0 at 25°C, 50 mM KCl, 0.1% Triton X-100, 2.5 mM MgCl 2 , 200 µM each dNTP, 0.6 µM each DhfrPfQs and DhfrPfCoasQ primers (see Table S1), with 2.5 U Taq Polymerase (Promega).…”

Section: Methodsmentioning

confidence: 99%

“…All ambiguous results were rejected from the analysis. The Pfcrt intron 4 microsatellite was analysed by direct sequencing of the PCR fragment generated using primers located within exons 4 and 5 (see primer sequence in Table S1) essentially as described [33]. The various Pfcrt intron 4 microsatellite types were assigned codes described in Table S2.…”

Section: Methodsmentioning

confidence: 99%

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Rapid Dissemination of Plasmodium falciparum Drug Resistance Despite Strictly Controlled Antimalarial Use

et al. 2007

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BackgroundInadequate treatment practices with antimalarials are considered major contributors to Plasmodium falciparum resistance to chloroquine, pyrimethamine and sulfadoxine. The longitudinal survey conducted in Dielmo, a rural Senegalese community, offers a unique frame to explore the impact of strictly controlled and quantified antimalarial use for diagnosed malaria on drug resistance.Methodology/Principal FindingsWe conducted on a yearly basis a retrospective survey over a ten-year period that included two successive treatment policies, namely quinine during 1990–1994, and chloroquine (CQ) and sulfadoxine/pyrimethamine (SP) as first and second line treatments, respectively, during 1995–1999. Molecular beacon-based genotyping, gene sequencing and microsatellite analysis showed a low prevalence of Pfcrt and Pfdhfr-ts resistance alleles of Southeast Asian origin by the end of 1994 and their effective dissemination within one year of CQ and SP implementation. The Pfcrt resistant allele rose from 9% to 46% prevalence during the first year of CQ reintroduction, i.e., after a mean of 1.66 CQ treatment courses/person/year. The Pfdhfr-ts triple mutant rose from 0% to 20% by end 1996, after a mean of 0.35 SP treatment courses/person in a 16-month period. Both resistance alleles were observed at a younger age than all other alleles. Their spreading was associated with enhanced in vitro resistance and rapidly translated in an increased incidence of clinical malaria episodes during the early post-treatment period.Conclusion/SignificanceIn such a highly endemic setting, selection of drug-resistant parasites took a single year after drug implementation, resulting in a rapid progression of the incidence of clinical malaria during the early post-treatment period. Controlled antimalarial use at the community level did not prevent dissemination of resistance haplotypes. This data pleads against reintroduction of CQ in places where resistant allele frequency has dropped to a very low level after CQ use has been discontinued, unless drastic measures are put in place to prevent selection and spreading of mutants during the post-treatment period.

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“…It is likely that reduced susceptibility to AQ is a stepwise process whereby polymorphisms accumulate first on codon 72–76 stretch of the pfcrt gene, and followed by additional mutations in the same gene or in other parasite genes including pfmdr1 . A proposed AQ/DEAQ resistance pathway suggest a drive from the wild-type CVMNK pfcrt haplotype via CQ resistance associated pfcrt haplotype CVIET (Ariey et al, 2006) and then via further selection or import to the putatively DEAQ resistance associated pfcrt haplotype SVMNT (Alifrangis et al, 2006; Holmgren et al, 2007). It is also possible that the CVMNT haplotype is first selected from the CVMNK haplotype and followed by CVIET.…”

Section: Discussionmentioning

confidence: 99%

In vitro amodiaquine resistance and its association with mutations in pfcrt and pfmdr1 genes of Plasmodium falciparum isolates from Nigeria

et al. 2011

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Amodiaquine (AQ) is currently being used as a partner drug in combination with artesunate for treatment of uncomplicated malaria in most endemic countries of Africa. In the absence of molecular markers of artemisinin resistance, molecular markers of resistance to AQ may be useful for monitoring the development and spread of parasites resistance to Artesunate-Amodiaquine combination. This study was designed to assess the potential role of polymorphisms on pfcrt and pfmdr1 genes and parasite in vitro susceptibility for epidemiological surveillance of amodiaquine resistance in Plasmodium falciparum. The modified schizont inhibition assay was used to determine in vitro susceptibility profiles of 98 patients' isolates of Plasmodium falciparum to amodiaquine. Polymorphisms on parasites pfcrt and pfmdr1 genes were determined with nested PCR followed by sequencing. The geometric mean (GM) of AQ 50% inhibitory concentration (IC-50) in the 97 P. falciparum isolates was 20.48nM (95% CI 16.53–25.36nM). Based on the cut-off value for AQ in vitro susceptibility, 87% (84) of the P. falciparum isolates were sensitive to AQ (GM IC-50= 16.32nM; 95%CI 13.3–20.04nM) while 13% were resistant to AQ in vitro (GM IC-50= 88.73nM; 95%CI 69.67–113.0nM). Molecular analysis showed presence of mutant CVIET pfcrt haplotype, mutant pfmdr1Tyr86 allele and the double mutant CVIET pfcrt haplotype+pfmdr1Tyr86 in 72%, 49% and 35% respectively. The GM IC-50 of isolates harboring the wild-type pfcrt CVMNK haplotype+ pfmdr1Asn86 allele (3.93nM; 95%CI 1.82–8.46) was significantly lower (p=0.001) than those isolates harboring the double mutant pfcrtCVIET haplotype+pfmdr1Tyr86 allele (50.40nM; 95%CI 40.17–63.24). Results from this study suggest that polymorphisms in pfcrt and pfmdr1 genes are important for AQ resistance and therefore may be useful for epidemiological surveillance of P. falciparum resistance to AQ.

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Invasion of Africa by a single pfcrt allele of South East Asian type

Cited by 70 publications

References 15 publications

A Shared Asian Origin of the Triple‐MutantdhfrAllele inPlasmodium falciparumfrom Sites across Africa

A Shared Asian Origin of the Triple‐MutantdhfrAllele inPlasmodium falciparumfrom Sites across Africa

Rapid Dissemination of Plasmodium falciparum Drug Resistance Despite Strictly Controlled Antimalarial Use

In vitro amodiaquine resistance and its association with mutations in pfcrt and pfmdr1 genes of Plasmodium falciparum isolates from Nigeria

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