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Genome-wide transcriptome profiling reveals functional networks involving the Plasmodium falciparum drug resistance transporters PfCRT and PfMDR1

Sophie H. Adjalley; Daniel Scanfeld; Elyse Kozlowski; Manuel Llinás; David Armand Fidock

Title:
Genome-wide transcriptome profiling reveals functional networks involving the Plasmodium falciparum drug resistance transporters PfCRT and PfMDR1
Author(s):
Adjalley, Sophie H.
Scanfeld, Daniel
Kozlowski, Elyse
Llinás, Manuel
Fidock, David Armand
Date:
Type:
Articles
Department(s):
Medicine
Volume:
16
Persistent URL:
Book/Journal Title:
BMC Genomics
Abstract:
Background The acquisition of multidrug resistance by Plasmodium falciparum underscores the need to understand the underlying molecular mechanisms so as to counter their impact on malaria control. For the many antimalarials whose mode of action relates to inhibition of heme detoxification inside infected erythrocytes, the digestive vacuole transporters PfCRT and PfMDR1 constitute primary resistance determinants. Results Using gene expression microarrays over the course of the parasite intra-erythrocytic developmental cycle, we compared the transcriptomic profiles between P. falciparum strains displaying mutant or wild-type pfcrt or varying in pfcrt or pfmdr1 expression levels. To account for differences in the time of sampling, we developed a computational method termed Hypergeometric Analysis of Time Series, which combines Fast Fourier Transform with a modified Gene Set Enrichment Analysis. Our analysis revealed coordinated changes in genes involved in protein catabolism, translation initiation and DNA/RNA metabolism. We also observed differential expression of genes with a role in transport or coding for components of the digestive vacuole. Interestingly, a global comparison of all profiled transcriptomes uncovered a tight correlation between the transcript levels of pfcrt and pfmdr1, extending to dozens of other genes, suggesting an intricate regulatory balance in order to maintain optimal physiological processes. Conclusions This study provides insight into the mechanisms by which P. falciparum adjusts to the acquisition of mutations or gene amplification in key transporter loci that mediate drug resistance. Our results implicate several biological pathways that may be differentially regulated to compensate for impaired transporter function and alterations in parasite vacuole physiology.
Subject(s):
Drug resistance
Cell physiology
Malaria
Plasmodium
Biochemistry
Publisher DOI:
https://doi.org/10.1186/s12864-015-2320-8
Item views
60
Metadata:
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Suggested Citation:
Sophie H. Adjalley, Daniel Scanfeld, Elyse Kozlowski, Manuel Llinás, David Armand Fidock, , Genome-wide transcriptome profiling reveals functional networks involving the Plasmodium falciparum drug resistance transporters PfCRT and PfMDR1, Columbia University Academic Commons, .

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