E-TABM-1101 - Transcription profiling by array of P. falciparum 3D7 strain to investigate the response to Lumefantrine
Released on 1 April 2011, last updated on 2 May 2014
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 IC50 (inhibitory concentration that kills 50% of the parasite population) was 24 nM. The resulting resistant strain V1SLM, obtained after culture for an estimated 166 cycles under LM pressure, grew steadily in 378 nM of LM; this corresponds to 15 times the IC50 of the parental strain. However, after two weeks of culturing V1SLM in drug-free medium, the IC50 returned to that of the initial, parental strain V1S. This transient drug tolerance was associated with major changes in gene expression profiles: when we explored V1SLM using the PFSANGER Affymetrix custom array, we identified 184 differentially expressed (DE) genes; amongst those 18 putative transporters including the multidrug resistance gene (pfmdr1), the multidrug resistance associated protein (pfmrp1) and the V-type H+ pumping pyrophosphatase 2 (pfvp2). Moreover, our results showed significant enrichment of genes associated with fatty acid metabolism and a clear selective advantage for two genomic loci in parasites grown under LM drug pressure, suggesting these genes may contribute to LM response in P. falciparum and could prove useful as molecular markers to monitor LM susceptibility.
transcription profiling by array, compound treatment, dose response, in vitro, replicate, co-expression
Genome wide adaptations of Plasmodium falciparum in response to lumefantrine selective drug pressure. Mwai L, Diriye A, Masseno V, Muriithi S, Feltwell T, Musyoki J, Lemieux J, Feller A, Mair GR, Marsh K, Newbold C, Nzila A, Carret CK. :e31623 (2012), PMID:22384044
Transporter Genes other than PfMDR1 and PfCRT may Alter the Response of Plasmodium falciparum to Lumefantrine. Leah Mwai, Abdi Diriye, Victor Masseno, Steven Muriithi, Theresa Feltwell, Jennifer Musyoki, Jacob Lemieux, Avi Feller, Gunnar R. Mair, Kevin Marsh, Chris Newbold, Alexis Nzila, Céline K. Carret.