scholarly journals A P-glycoprotein homologue of Plasmodium falciparum is localized on the digestive vacuole.

1991 ◽  
Vol 113 (5) ◽  
pp. 1033-1042 ◽  
Author(s):  
A F Cowman ◽  
S Karcz ◽  
D Galatis ◽  
J G Culvenor
Keyword(s):  
Plasmodium Falciparum ◽  
Gene Copy Number ◽  
Chloroquine Resistance ◽  
Gene Copy ◽  
Striking Similarity ◽  
Multi Drug Resistance ◽  
Digestive Vacuole ◽  
Pfmdr1 Gene ◽  
P Glycoprotein ◽  
Quantitative Immunoblotting

Resistance to chloroquine in Plasmodium falciparum bears a striking similarity to the multi-drug resistance (MDR) phenotype of mammalian tumor cells which is mediated by overexpression of P-glycoprotein. We show here that the P. falciparum homologue of the P-glycoprotein (Pgh1) is a 160,000-D protein that is expressed throughout the asexual erythrocytic life cycle of the parasite. Quantitative immunoblotting analysis has shown that the protein is expressed at approximately equal levels in chloroquine resistant and sensitive isolates suggesting that overexpression of Pgh1 is not essential for chloroquine resistance. The chloroquine-resistant cloned line FAC8 however, does express approximately threefold more Pgh1 protein than other isolates which is most likely because of the increased pfmdr1 gene copy number present in this isolate. Immunofluorescence and immunoelectron microscopy has demonstrated that Pgh1 is localized on the membrane of the digestive vacuole of mature parasites. This subcellular localization suggests that Pgh1 may modulate intracellular chloroquine concentrations and has important implications for the normal physiological function of this protein.

scholarly journals Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number

The Lancet ◽  
2004 ◽  
Vol 364 (9432) ◽  
pp. 438-447 ◽  
Author(s):  
Ric N Price ◽  
Anne-Catrin Uhlemann ◽  
Alan Brockman ◽  
Rose McGready ◽  
Elizabeth Ashley ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Copy Number ◽  
Gene Copy Number ◽  
Gene Copy ◽  
Pfmdr1 Gene

Role for the Plasmodium falciparum Digestive Vacuole in Chloroquine Resistance

1998 ◽  
Vol 56 (3) ◽  
pp. 313-320 ◽  
Author(s):  
Kevin J Saliba ◽  
Peter I Folb ◽  
Peter J Smith
Keyword(s):  
Plasmodium Falciparum ◽  
Chloroquine Resistance ◽  
Digestive Vacuole

scholarly journals Emergence of Plasmodium vivax Resistance to Chloroquine in French Guiana

2019 ◽  
Vol 63 (11) ◽  
Author(s):  
Lise Musset ◽  
Christophe Heugas ◽  
Richard Naldjinan ◽  
Denis Blanchet ◽  
Pascal Houze ◽  
...  
Keyword(s):  
Plasmodium Vivax ◽  
Therapeutic Efficacy ◽  
French Guiana ◽  
Gene Copy Number ◽  
Chloroquine Resistance ◽  
World Health ◽  
Gene Copy ◽  
Content Type ◽  
Gene Copy Number Variation ◽  
Health Organization

ABSTRACT In South America, Plasmodium vivax resistance to chloroquine was recently reported in Brazil and Bolivia. The objective of this study was to collect data on chloroquine resistance in French Guiana by associating a retrospective evaluation of therapeutic efficacy with an analysis of recurrent parasitemia from any patients. Patients with P. vivax infection, confirmed by microscopy and a body temperature of ≥37.5°C, were retrospectively identified at Cayenne Hospital between 2009 and 2015. Follow-up and treatment responses were performed according to the World Health Organization protocol. Parasite resistance was confirmed after dosage of a plasma concentration of chloroquine and microsatellite characterization. The pvmdr1 and pvcrt-o genes were analyzed for sequence and gene copy number variation. Among the 172 patients followed for 28 days, 164 presented adequate clinical and parasitological responses. Eight cases of treatment failures were identified (4.7%; n = 8/172), all after 14 days. The therapeutic efficacy of chloroquine was estimated at 95.3% (95% confidence interval [CI], 92.5 to 98.1%; n = 164/172). Among the eight failures, five were characterized: two cases were true P. vivax chloroquine resistance (1.2%; 95% CI, 0 to 2.6%; n = 2/172), and three cases were found with subtherapeutic concentrations of chloroquine. No particular polymorphism in the Plasmodium vivax pvmdr1 and pvcrt-o genes was identified in the resistant parasites. This identified level of resistance of P. vivax to chloroquine in French Guiana does not require a change in therapeutic recommendations. However, primaquine should be administered more frequently to limit the spread of resistance, and there is still a need for a reliable molecular marker to facilitate the monitoring of P. vivax resistance to chloroquine.

Amplification of the multidrug resistance gene pfmdr1 in Plasmodium falciparum has arisen as multiple independent events

1991 ◽  
Vol 11 (10) ◽  
pp. 5244-5250
Author(s):  
T Triglia ◽  
S J Foote ◽  
D J Kemp ◽  
A F Cowman
Keyword(s):  
Polymerase Chain Reaction ◽  
Plasmodium Falciparum ◽  
Multidrug Resistance ◽  
Tumor Cells ◽  
Yeast Artificial Chromosome ◽  
Chloroquine Resistance ◽  
Chain Reaction ◽  
Pfmdr1 Gene ◽  
Independent Events ◽  
Polymerase Chain

The multidrug resistance (MDR) phenotype in mammalian tumor cells can involve amplification of mdr genes that results in overexpression of the protein product termed P-glycoprotein. Chloroquine resistance (CQR) in Plasmodium falciparum has similarities with the MDR phenotype in tumor cells, and some isolates of P. falciparum have amplified levels of the pfmdr1 gene. To investigate the nature and origin of pfmdr1 amplicons, we have cloned large regions of a 110-kb amplicon from the CQR cloned isolate B8 by using the yeast artificial chromosome system. We have identified and sequenced the breakpoints of the amplicon by a novel method employing inverted polymerase chain reaction that is applicable to analysis of any large-scale repeat. We show that the five copies of the amplicon in this isolate are in a head to tail configuration. A string of 30 A's flank the breakpoints on each side of the amplified segment, suggesting a mechanism for the origin of the tandem amplification. Polymerase chain reaction analysis with oligonucleotides that cross the B8 breakpoint has shown in 26 independent CQR isolates, 16 of which contain amplified copies of pfmdr1, that amplification of the pfmdr1 gene in P. falciparum has arisen as multiple independent events. These results suggest that this region of the genome is under strong selective pressure.

scholarly journals Selective sweeps and genetic lineages of Plasmodium falciparum multi-drug resistance (pfmdr1) gene in Kenya

2018 ◽  
Vol 17 (1) ◽  
Author(s):  
Peninah Muiruri ◽  
Denis W. Juma ◽  
Luicer A. Ingasia ◽  
Lorna J. Chebon ◽  
Benjamin Opot ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Multi Drug Resistance ◽  
Selective Sweeps ◽  
Pfmdr1 Gene ◽  
Genetic Lineages

scholarly journals Discordant Temporal Evolution ofPfcrtandPfmdr1Genotypes and Plasmodium falciparum In Vitro Drug Susceptibility to 4-Aminoquinolines after Drug Policy Change in French Guiana

2012 ◽  
Vol 56 (3) ◽  
pp. 1382-1389 ◽  
Author(s):  
Eric Legrand ◽  
Joséphine Yrinesi ◽  
Marie-Thérèse Ekala ◽  
Julie Péneau ◽  
Béatrice Volney ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Drug Policy ◽  
French Guiana ◽  
Target Genes ◽  
Gene Copy Number ◽  
Drug Susceptibility ◽  
Gene Copy ◽  
Poor Correlation ◽  
Content Type

ABSTRACTAnalysis of the evolution of drug target genes under changing drug policy is needed to assist monitoring ofPlasmodium falciparumdrug resistance in the field. Here we genotypePfcrtandPfdmr1of 700 isolates collected in French Guiana from 2000 (5 years after withdrawal of chloroquine) to 2008, i.e., the period when the artemether-lumefantrine combination was progressively introduced and mefloquine was abandoned. Gene sequencing showed fixation of the 7G8-typePfcrtSMVNT resistance haplotype and near fixation of the NYCDYPfdmr1haplotype.Pfdmr1gene copy number correlated with 50% inhibitory concentrations of mefloquine and halofantrine (r= 0.64 and 0.47, respectively,n= 547); its temporal changes paralleled changes inin vitromefloquine susceptibility. However, the molecular parameters studied did not account for the regainedin vitrosusceptibility to chloroquine and showed a poor correlation with susceptibility to artemether, lumefantrine, or quinine. Identification of novel markers of resistance to these antimalarials is needed in this South American area.

Sign in / Sign up

Export Citation Format

Share Document