No variation in the prevalence of point mutations in the Pfcrt and Pfmdr1 genes in isolates from Gabonese patients with uncomplicated or severe Plasmodium falciparum malaria

Mayengue, Pembé Issamou; Kalmbach, Yvonne; Issifou, Saadou; Kremsner, Peter G.; Ntoumi, Francine

doi:10.1007/s00436-006-0287-8

Cited by 26 publications

(22 citation statements)

References 46 publications

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“…We first tried to determine by qPCR the alleles present at two genes involved in chloroquine resistance: pfcrt and pfmdr1. In Gabon, the prevalence of the two point mutations conferring resistance (pfrct 76T and pfmdr1 86Y) in human P. falciparum populations is high (>85%) (15,16). Hence, we hypothesized that if the MO454 The tree was constructed by using maximum likelihood methods.…”

Section: Resultsmentioning

confidence: 99%

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African monkeys are infected by Plasmodium falciparum nonhuman primate-specific strains

Prugnolle

Ollomo²,

Durand

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Recent molecular exploration of the Plasmodium species circulating in great apes in Africa has revealed the existence of a large and previously unknown diversity of Plasmodium. For instance, gorillas were found to be infected by parasites closely related to Plasmodium falciparum, suggesting that the human malignant malaria agent may have arisen after a transfer from gorillas. Although this scenario is likely in light of the data collected in great apes, it remained to be ascertained whether P. falciparum-related parasites may infect other nonhuman primates in Africa. Using molecular tools, we here explore the diversity of Plasmodium species infecting monkeys in Central Africa. In addition to previously described Hepatocystis and Plasmodium species (Plasmodium gonderi and Plasmodium sp DAJ-2004), we have found one African monkey to be infected by a P. falciparum-related parasite. Examination of the nuclear and mitochondrial genomes of this parasite reveals that it is specific of nonhuman primates, indicating that P. falciparum-related pathogens can naturally circulate in some monkey populations in Africa. We also show that at least two distinct genetic entities of P. falciparum infect nonhuman primates and humans, respectively. Our discoveries bring into question the proposed gorilla origin of human P. falciparum.human malaria | laverania clade | parasite host transfer | cytochrome b | biological evolution U ntil very recently, only one species (Plasmodium reichenowi) was known to be a phylogenetic sister lineage of Plasmodium falciparum, the agent of malignant human malaria. These two species were the only known representatives of the subgenus Laverania (1). In 2009 and 2010, several studies have revealed the existence of a number of distinct phylogenetic species belonging to this subgenus and infecting chimpanzees, bonobos, and gorillas in Africa (2-6), drastically modifying our understanding of the evolution of the Laverania lineage, and P. falciparum in particular (7).Liu et al. (4) have proposed that the human strains of P. falciparum arose after a single gorilla-to-human transmission (4, 7). This scenario is based on the discovery of P. falciparum-related strains naturally circulating in lowland gorillas (2, 4, 6) that display greater genetic diversity than human strains (4). In contrast, no P. falciparum strains were found in wild chimpanzees or bonobos despite similar sampling efforts (4). Strains of P. falciparum had been found only in chimpanzees and bonobos living either in captivity or sanctuaries, with the possibility of a crossspecies infection from humans to them (2, 3). It, however, remains possible that P. falciparum-related strains circulate in wild chimpanzees and bonobos at a lower prevalence than in gorillas (8) and/or in geographic areas not yet explored. Given the propensity of Plasmodium parasites to switch hosts (e.g., the transfer of P. knowlesi from macaques to humans (9) and P. vivax and P. malariae between humans and New World monkeys; ref. 10), one cannot exclude that P. falciparum-r...

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Section: Resultsmentioning

confidence: 99%

“…For pfcrt, the MO454 isolate (note that Plasmodium blood stages are haploid) displayed the wild allele at codon 76 (pfcrt K76). This allele is absent in the human P. falciparum population in Lambaréné (Moyen Ogooué province), a city <30 km away from the village where MO454 was collected (16) (Fig. S1).…”

Section: Resultsmentioning

confidence: 99%

African monkeys are infected by Plasmodium falciparum nonhuman primate-specific strains

Prugnolle

Ollomo²,

Durand

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…However, Giha and collaborators found in Sudan that the lethal malaria form was rather associated with the wild type PfCRT K76 although the difference in the frequency of the chloroquine resistant parasites in patients suffering from severe malaria and from non-severe malaria was not significant [7]. Similarly, in a more recent study in Congo, Mayengue and collaborators did not find any relation between the severity of the disease and the presence of the mutant allele PfCRT 76T [13]. We note that in the Sudanese study, the sample size (n = 47) was rather small and not sufficient to support the hypothesis of increased virulence of chloroquine sensitive strain.…”

Section: Discussionmentioning

confidence: 99%

High frequency of PfCRT 76T in two Malian villages and its prevalence in severe relative to non-severe malaria

et al. 2011

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We investigated PfCRT 76T mutation in severe and non-severe malaria in Southern Mali. One hundred and ninety three severe malaria cases were each matched against two non-severe malaria cases. Patients with G6PD deficiency and any known hemoglobin abnormality were excluded. PfCRT 76T was present in 60.8% (n = 386) non-severe malaria cases and in 77.2% (n = 193) severe malaria cases (p <0.0001). In children 5 years or younger, these proportions were 62.9% (n = 294) vs. 73.5% (n = 147), respectively (p < 0.01). PfCRT 76T was therefore associated with malaria severity in this setting of Mali.

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“…Studies from India [11] and Mali [12], but not Sudan [13] or Gabon [14], showed associations between presence of the pfcrt 76T mutation and severe malaria, but these associations may have been due to clinical progression after chloroquine treatment failure, rather than variations in parasite virulence. Previously, differences in genotypes between parasites causing symptomatic and asymptomatic infections were studied in samples from a cross-sectional study of children from Tororo, Uganda.…”

Section: Introductionmentioning

confidence: 99%

Drug resistance mediating Plasmodium falciparum polymorphisms and clinical presentations of parasitaemic children in Uganda

Tukwasibwe

Tumwebaze

Conrad

et al. 2017

Malar J

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Background Plasmodium falciparum genetic polymorphisms that mediate altered drug sensitivity may impact upon virulence. In a cross-sectional study, Ugandan children with infections mutant at pfcrt K76T, pfmdr1 N86Y, or pfmdr1 D1246Y had about one-fourth the odds of symptomatic malaria compared to those with infections with wild type (WT) sequences. However, results may have been confounded by greater likelihood in those with symptomatic disease of higher density mixed infections and/or recent prior treatment that selected for WT alleles.MethodsPolymorphisms in samples from paired episodes of asymptomatic and symptomatic parasitaemia in 114 subjects aged 4–11 years were followed longitudinally in Tororo District, Uganda. Paired episodes occurred within 3–12 months of each other and had no treatment for malaria in the prior 60 days. The prevalence of WT, mixed, and mutant alleles was determined using multiplex ligase detection reaction-fluorescent microsphere assays.ResultsConsidering paired episodes in the same subject, the odds of symptomatic malaria were lower for infections with mutant compared to WT or mixed sequence at N86Y (OR 0.26, 95% CI 0.09–0.79, p = 0.018), but not K76T or D1246Y. However, symptomatic episodes (which had higher densities) were more likely than asymptomatic to be mixed (for N86Y OR 2.0, 95% CI 1.04–4.0, p = 0.036). Excluding mixed infections, the odds of symptomatic malaria were lower for infections with mutant compared to WT sequence at N86Y (OR 0.33, 95% CI 0.11–0.98, p = 0.046), but not the other alleles. However, if mixed genotypes were grouped with mutants in this analysis or assuming that mixed infections consisted of 50% WT and 50% mutant genotypes, the odds of symptomatic infection did not differ between infections that were mutant or WT at the studied alleles.ConclusionsAlthough infections with only the mutant pfmdr1 86Y genotype were associated with symptomatic infection, this association could primarily be explained by greater parasite densities and therefore greater prevalence of mixed infections in symptomatic children. These results indicate limited association between the tested polymorphisms and risk of symptomatic disease and highlight the value of longitudinal studies for assessing associations between parasite factors and clinical outcomes.

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No variation in the prevalence of point mutations in the Pfcrt and Pfmdr1 genes in isolates from Gabonese patients with uncomplicated or severe Plasmodium falciparum malaria

Cited by 26 publications

References 46 publications

African monkeys are infected by Plasmodium falciparum nonhuman primate-specific strains

African monkeys are infected by Plasmodium falciparum nonhuman primate-specific strains

High frequency of PfCRT 76T in two Malian villages and its prevalence in severe relative to non-severe malaria

Drug resistance mediating Plasmodium falciparum polymorphisms and clinical presentations of parasitaemic children in Uganda

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