Phenotypic and genotypic characteristics of recently adapted isolates of Plasmodium falciparum from Thailand.

Mungthin, Mathirut; Bray, Patrick G.; Ward, Stephen A.

doi:10.4269/ajtmh.1999.60.469

Cited by 16 publications

(12 citation statements)

References 40 publications

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“…We found that Pgh1 is not present in the PPM or at such a low level that it could not be detected by Western blot, and that, with the exception of FAC8, all strains tested in this study expressed Pgh1 at a similar level (20-33% expression relative to FAC8) in the FV, therefore invalidating any correlation between an overexpression of Pgh1 protein and the CQR phenotype. Nevertheless, Fac8 with three copies of pfmdr1 gene had been found more resistant to mefloquine (Barnes et al 1992) than K1 with a single copy of the gene (Mungthin et al 1999). Therefore, our data showing that FAC8 displayed a higher expression of Pgh1 protein in trophozoites and FV than any other isolates tested, including the highly CQR line K1, is in agreement with the current hypothesis stating that amplification of pfmdr1/Pgh1 expression is strongly associated with mefloquine resistance (Price et al 2004).…”

Section: Discussionsupporting

confidence: 91%

Analysis of P-glycoprotein expression in purified parasite plasma membrane and food vacuole from Plasmodium falciparum

et al. 2006

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A P-glycoprotein homologue (Pgh1) is believed to play a role in modulating levels of chloroquine resistance in Plasmodium falciparum. To study the role of Pgh1 in the mechanism of chloroquine (CQ) resistance, antisera were raised against this protein. There was no direct association between the level of Pgh1 expression and chloroquine sensitivity. We also failed to detect phosphorylation of Pgh1 in the food vacuole (FV), suggesting that other mechanisms regulate the chloroquine-resistant (CQR) phenotype. Therefore, high levels of expression of Pgh1 or phosphorylation of this protein in the FV could not account for CQ sensitivity. In addition, the lack of inhibition of CQ accumulation by anti-Pgh1 antibodies suggests that Pgh1 is not involved as a CQ transporter in the plasma membrane of P. falciparum. Furthermore, resistance reversers do not appear to act at the plasma membrane level.

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Section: Discussionsupporting

confidence: 91%

Analysis of P-glycoprotein expression in purified parasite plasma membrane and food vacuole from Plasmodium falciparum

et al. 2006

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“…Attempts to answer the question related to pfmdr1 gene amplification also have a history of conflicting results. Some studies have reported increased copy numbers with selection for mefloquine resistance (5,12), while others have not (9,10).…”

Section: Discussionmentioning

confidence: 99%

Resistance to Antimalarials in Southeast Asia and Genetic Polymorphisms in pfmdr1

Pickard

Wongsrichanalai

Purfield

et al. 2003

Antimicrob Agents Chemother

256

231

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Resistance to antimalarial drugs is a public health problem worldwide. Molecular markers for drugresistant malaria, such as pfcrt and pfmdr1 polymorphisms, could serve as useful surveillance tools. To evaluate this possibility, sequence polymorphisms in pfcrt (position 76) and pfmdr1 (positions 86, 184, 1034, 1042, and 1246) and in vitro drug sensitivities were measured for 65 Plasmodium falciparum isolates from Thailand, Myanmar, Vietnam, and Bangladesh. The pfcrt Thr76 polymorphism was present in 97% of samples, consistent with observations that chloroquine resistance is well established in this region. Polymorphisms in pfmdr1 clustered into four specific patterns: the wild type (category I), a Tyr86 polymorphism only (category II), a Phe184 polymorphism only (category III), and Phe184 in combination with Cys1034 and/or Asp1042 (category IV). Isolates in categories I and III were more sensitive to chloroquine and more resistant to mefloquine, artesunate, and artemisinin than isolates in categories II and IV (P < 0.01). Mefloquine resistance was significantly more common in category I and III isolates than in category II and IV isolates, with a prevalence ratio of 14.95 (95% confidence interval, 3.88 to 57.56). These categories identified mefloquine resistance with a sensitivity and a specificity of 94 and 91%, respectively. The pfmdr1 gene copy number was measured by real-time PCR as a ratio of the amount of pfmdr1 DNA to the amount of lactate dehydrogenase (ldh) DNA. Eight samples had pfmdr1 DNA/ldh DNA ratios >3. The isolates in all 8 samples fell into categories I and III and were significantly more resistant to mefloquine, quinine, artemisinin, and artesunate and more sensitive to chloroquine than the isolates in the 57 samples with <3 copies of the gene (P < 0.001). Thus, measurement of pfmdr1 mutations and gene copy number may be useful for surveillance of mefloquine-resistant malaria in Southeast Asia.

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“…No association was found between the mutation at codon 86 of the pfmdr1 gene and in vivo sensitivity to mefloquine, which is in contrast to the results of in vitro studies (8,19). Previous studies have mainly focused on the association of the pfmdr1 gene copy number and in vitro sensitivity to mefloquine (6,7,12,13,16,22,28). Few in vitro studies have examined the relationship between pfmdr1 gene mutations and mefloquine sensitivity, and the studies that have been conducted have obtained controversial results.…”

Section: Discussionmentioning

confidence: 99%

Pfmdr1 Alleles and Response to Ultralow-Dose Mefloquine Treatment in Gabonese Patients

Mawili-Mboumba

Kun

Lell

et al. 2002

Antimicrob Agents Chemother

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The identification of parasite molecular markers involved in resistance to antimalarial compounds is of great interest for monitoring the development and spread of resistance in the field. Polymorphisms in Plasmodium falciparum multidrug resistance gene 1 (pfmdr1) have been associated with chloroquine resistance and mefloquine susceptibility. In the present study, carried out in Lambaréné, Gabon, we investigated the relationship between the presence of mutations at codons 86, 184, 1034, 1042, and 1246 in the pfmdr1 gene and the success of ultralow-dose mefloquine treatment (1.1 mg/kg of body weight). Sixty-nine patients were included in the study, and depending on the level of in vivo resistance to mefloquine, they were classified as sensitive responders (S), patients with low-grade resistance (RI), and nonresponders (NR). We found that the prevalences of the Tyr-86 mutation among isolates from patients in groups S, RI, and NR were 100, 96, and 90%, respectively, and that the prevalence of the Phe-184 mutation among the isolates was 80% in each group. A prevalence of about 10% point mutations at codons 1042 and 1246 was detected only in isolates from patients in groups RI and NR. There was no statistically significant association between the presence of the Tyr-86 mutation and the in vivo response (P ‫؍‬ 0.79). Among the parasite isolates from patients with drug-resistant infections, 83% had the wild-type pfmdr1 genotype (S 1034 -N 1042 -D 1246 ). No link between the presence of this genotype and parasite resistance was detected (P ‫؍‬ 0.42). Among the isolates analyzed, 85 had double mutations (Y 86

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Phenotypic and genotypic characteristics of recently adapted isolates of Plasmodium falciparum from Thailand.

Cited by 16 publications

References 40 publications

Analysis of P-glycoprotein expression in purified parasite plasma membrane and food vacuole from Plasmodium falciparum

Analysis of P-glycoprotein expression in purified parasite plasma membrane and food vacuole from Plasmodium falciparum

Resistance to Antimalarials in Southeast Asia and Genetic Polymorphisms in pfmdr1

Pfmdr1 Alleles and Response to Ultralow-Dose Mefloquine Treatment in Gabonese Patients

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