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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
Genome wide adaptations of Plasmodium falciparum in response to Lumefantrine selective drug pressure
PLoS ONE, Volume 7, No. 2, Article e31623, Year 2012
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Description
The combination therapy of the Artemisinin-derivative Artemether (ART) with Lumefantrine (LM) (Coartem®) is an important malaria treatment regimen in many endemic countries. Resistance to Artemisinin has already been reported, and it is feared that LM resistance (LMR) could also evolve quickly. Therefore molecular markers which can be used to track Coartem® efficacy are urgently needed. Often, stable resistance arises from initial, unstable phenotypes that can be identified in vitro. Here we have used the Plasmodium falciparum multidrug resistant reference strain V1S to induce LMR in vitro by culturing the parasite under continuous drug pressure for 16 months. The initial IC 50 (inhibitory concentration that kills 50% of the parasite population) was 24 nM. The resulting resistant strain V1S LM, obtained after culture for an estimated 166 cycles under LM pressure, grew steadily in 378 nM of LM, corresponding to 15 times the IC 50 of the parental strain. However, after two weeks of culturing V1S LM in drug-free medium, the IC 50 returned to that of the initial, parental strain V1S. This transient drug tolerance was associated with major changes in gene expression profiles: using the PFSANGER Affymetrix custom array, we identified 184 differentially expressed genes in V1S LM. Among those are 18 known and putative transporters including the multidrug resistance gene 1 (pfmdr1), the multidrug resistance associated protein and the V-type H+ pumping pyrophosphatase 2 (pfvp2) as well as genes associated with fatty acid metabolism. In addition we detected a clear selective advantage provided by two genomic loci in parasites grown under LM drug pressure, suggesting that all, or some of those genes contribute to development of LM tolerance - they may prove useful as molecular markers to monitor P. falciparum LM susceptibility. © 2012 Mwai et al.
Available Materials
https://efashare.b-cdn.net/share/pmc/articles/PMC3288012/bin/pone.0031623.s001.pdf
https://efashare.b-cdn.net/share/pmc/articles/PMC3288012/bin/pone.0031623.s002.pdf
https://efashare.b-cdn.net/share/pmc/articles/PMC3288012/bin/pone.0031623.s003.pdf
https://efashare.b-cdn.net/share/pmc/articles/PMC3288012/bin/pone.0031623.s004.pdf
https://efashare.b-cdn.net/share/pmc/articles/PMC3288012/bin/pone.0031623.s005.docx
https://efashare.b-cdn.net/share/pmc/articles/PMC3288012/bin/pone.0031623.s006.docx
Authors & Co-Authors
Mwai, Leah
Kenya, Nairobi
Kenya Medical Research Institute
United Kingdom, Oxford
Nuffield Department of Medicine
Diriye, Abdi
Kenya, Nairobi
Kenya Medical Research Institute
Masseno, Victor
Kenya, Nairobi
Kenya Medical Research Institute
Muriithi, Steven
Kenya, Nairobi
Kenya Medical Research Institute
Feltwell, Theresa
United Kingdom, Hinxton
Wellcome Sanger Institute
Musyoki, Jennifer N.
Kenya, Nairobi
Kenya Medical Research Institute
Lemieux, Jacob
United Kingdom, Oxford
Mrc Weatherall Institute of Molecular Medicine
Feller, Avi
United Kingdom, Oxford
University of Oxford
Mair, Gunnar Rudolf
Portugal, Lisbon
Instituto de Medicina Molecular
Marsh, Kevin
Kenya, Nairobi
Kenya Medical Research Institute
United Kingdom, Oxford
Nuffield Department of Medicine
Newbold, Chris I.
United Kingdom, Oxford
Mrc Weatherall Institute of Molecular Medicine
Nzila, Alexis M.
Kenya, Nairobi
Kenya Medical Research Institute
United Kingdom, Oxford
Nuffield Department of Medicine
Carret, Céline Karine
Portugal, Lisbon
Instituto de Medicina Molecular
Statistics
Citations: 37
Authors: 13
Affiliations: 6
Identifiers
Doi:
10.1371/journal.pone.0031623
e-ISSN:
19326203
Research Areas
Genetics And Genomics
Infectious Diseases
Study Design
Cross Sectional Study