Dataset Information

Multiple origins and regional dispersal of resistant dhps in African Plasmodium falciparum malaria.

ABSTRACT:

Background

Although the molecular basis of resistance to a number of common antimalarial drugs is well known, a geographic description of the emergence and dispersal of resistance mutations across Africa has not been attempted. To that end we have characterised the evolutionary origins of antifolate resistance mutations in the dihydropteroate synthase (dhps) gene and mapped their contemporary distribution.

Methods and findings

We used microsatellite polymorphism flanking the dhps gene to determine which resistance alleles shared common ancestry and found five major lineages each of which had a unique geographical distribution. The extent to which allelic lineages were shared among 20 African Plasmodium falciparum populations revealed five major geographical groupings. Resistance lineages were common to all sites within these regions. The most marked differentiation was between east and west African P. falciparum, in which resistance alleles were not only of different ancestry but also carried different resistance mutations.

Conclusions

Resistant dhps has emerged independently in multiple sites in Africa during the past 10-20 years. Our data show the molecular basis of resistance differs between east and west Africa, which is likely to translate into differing antifolate sensitivity. We have also demonstrated that the dispersal patterns of resistance lineages give unique insights into recent parasite migration patterns.

SUBMITTER: Pearce RJ

PROVIDER: S-EPMC2661256 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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Publications

Multiple origins and regional dispersal of resistant dhps in African Plasmodium falciparum malaria.

Pearce Richard J RJ Pota Hirva H Evehe Marie-Solange B MS Bâ El-Hadj el-H Mombo-Ngoma Ghyslain G Malisa Allen L AL Ord Rosalynn R Inojosa Walter W Matondo Alexandre A Diallo Diadier A DA Mbacham Wilfred W van den Broek Ingrid V IV Swarthout Todd D TD Getachew Asefaw A Dejene Seyoum S Grobusch Martin P MP Njie Fanta F Dunyo Samuel S Kweku Margaret M Owusu-Agyei Seth S Chandramohan Daniel D Bonnet Maryline M Guthmann Jean-Paul JP Clarke Sian S Barnes Karen I KI Streat Elizabeth E Katokele Stark T ST Uusiku Petrina P Agboghoroma Chris O CO Elegba Olufunmilayo Y OY Cissé Badara B A-Elbasit Ishraga E IE Giha Hayder A HA Kachur S Patrick SP Lynch Caroline C Rwakimari John B JB Chanda Pascalina P Hawela Moonga M Sharp Brian B Naidoo Inbarani I Roper Cally C

PLoS medicine 20090414 4

<h4>Background</h4>Although the molecular basis of resistance to a number of common antimalarial drugs is well known, a geographic description of the emergence and dispersal of resistance mutations across Africa has not been attempted. To that end we have characterised the evolutionary origins of antifolate resistance mutations in the dihydropteroate synthase (dhps) gene and mapped their contemporary distribution.<h4>Methods and findings</h4>We used microsatellite polymorphism flanking the dhps ...[more]

PMID: 19365539

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Project description:BackgroundPlasmodium falciparum has repeatedly evolved resistance to first-line anti-malarial drugs, thwarting efforts to control and eliminate the disease and in some period of time this contributed largely to an increase in mortality. Here a mathematical model was developed to map the spatiotemporal trends in the distribution of mutations in the P. falciparum dihydropteroate synthetase (dhps) gene that confer resistance to the anti-malarial sulphadoxine, and are a useful marker for the combination of alleles in dhfr and dhps that is highly correlated with resistance to sulphadoxine-pyrimethamine (SP). The aim of this study was to present a proof of concept for spatiotemporal modelling of trends in anti-malarial drug resistance that can be applied to monitor trends in resistance to components of artemisinin combination therapy (ACT) or other anti-malarials, as they emerge or spread.MethodsPrevalence measurements of single nucleotide polymorphisms in three codon positions of the dihydropteroate synthetase (dhps) gene from published studies of dhps mutations across Africa were used. A model-based geostatistics approach was adopted to create predictive surfaces of the dhps540E mutation over the spatial domain of sub-Saharan Africa from 1990-2010. The statistical model was implemented within a Bayesian framework and hence quantified the associated uncertainty of the prediction of the prevalence of the dhps540E mutation in sub-Saharan Africa.ConclusionsThe maps presented visualize the changing prevalence of the dhps540E mutation in sub-Saharan Africa. These allow prediction of space-time trends in the parasite resistance to SP, and provide probability distributions of resistance prevalence in places where no data are available as well as insight on the spread of resistance in a way that the data alone do not allow. The results of this work will be extended to design optimal sampling strategies for the future molecular surveillance of resistance, providing a proof of concept for similar techniques to design optimal strategies to monitor resistance to ACT.

Project description:Plasmodium falciparum, the most deadly of the human malaria parasites, is a member of the Laverania subgenus that also infects African Great Apes. The virulence of P. falciparum is related to cytoadhesion of infected erythrocytes in microvasculature, but the origin of dangerous parasite adhesion traits is poorly understood. To investigate the evolutionary history of the P. falciparum cytoadhesion pathogenicity determinant, we studied adhesion domains from the chimpanzee malaria parasite P. reichenowi. We demonstrate that the P. reichenowi var gene repertoire encodes cysteine-rich interdomain region (CIDR) domains which bind human CD36 and endothelial protein C receptor (EPCR) with the same levels of affinity and at binding sites similar to those bound by P. falciparum. Moreover, P. reichenowi domains interfere with the protective function of the activated protein C-EPCR pathway on endothelial cells, a presumptive virulence trait in humans. These findings provide evidence for ancient evolutionary origins of two key cytoadhesion properties of P. falciparum that contribute to human infection and pathogenicity. IMPORTANCE Cytoadhesion of P. falciparum-infected erythrocytes in the microcirculation is a major virulence determinant. P. falciparum is descended from a subgenus of parasites that also infect chimpanzees and gorillas and exhibits strict host species specificity. Despite their high genetic similarity to P. falciparum, it is unknown whether ape parasites encode adhesion properties similar to those of P. falciparum or are as virulent in their natural hosts. Consequently, it has been unclear when virulent adhesion traits arose in P. falciparum and how long they have been present in the parasite population. It is also unknown whether cytoadhesive interactions pose a barrier to cross-species transmission. We show that parasite domains from the chimpanzee malaria parasite P. reichenowi bind human receptors with specificity similar to that of P. falciparum. Our findings suggest that parasite adhesion traits associated with both mild and severe malaria have much earlier origins than previously appreciated and have important implications for virulence evolution in a major human pathogen.

Dataset Information

Multiple origins and regional dispersal of resistant dhps in African Plasmodium falciparum malaria.

Background

Methods and findings

Conclusions

Publications

Multiple origins and regional dispersal of resistant dhps in African Plasmodium falciparum malaria.

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