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Dynamic RNA profiling in Plasmodium falciparum synchronized blood stages exposed to lethal doses of artesunate.

Natalang O, Bischoff E, Deplaine G, Proux C, Dillies MA, Sismeiro O, Guigon G, Bonnefoy S, Patarapotikul J, Mercereau-Puijalon O, Coppée JY, David PH - BMC Genomics (2008)

Bottom Line: This pointed to the mobilization of processes shaping the interface between the parasite and its environment.In parallel, pathways were engaged which could lead to parasite death, such as interference with purine/pyrimidine metabolism, the mitochondrial electron transport chain, proteasome-dependent protein degradation or the integrity of the food vacuole.The high proportion of over-expressed genes encoding proteins exported from the parasite highlight the importance of extra-parasitic compartments as fields for exploration in drug research which, to date, has mostly focused on the parasite itself rather than on its intra and extra erythrocytic environment.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institut Pasteur, Unité d'Immunologie Moléculaire des Parasites, CNRS URA 2581, 28 Rue du Docteur Roux, F-75724, Paris, Cedex 15, France. onguma382@yahoo.com

ABSTRACT

Background: Translation of the genome sequence of Plasmodium sp. into biologically relevant information relies on high through-put genomics technology which includes transcriptome analysis. However, few studies to date have used this powerful approach to explore transcriptome alterations of P. falciparum parasites exposed to antimalarial drugs.

Results: The rapid action of artesunate allowed us to study dynamic changes of the parasite transcriptome in synchronous parasite cultures exposed to the drug for 90 minutes and 3 hours. Developmentally regulated genes were filtered out, leaving 398 genes which presented altered transcript levels reflecting drug-exposure. Few genes related to metabolic pathways, most encoded chaperones, transporters, kinases, Zn-finger proteins, transcription activating proteins, proteins involved in proteasome degradation, in oxidative stress and in cell cycle regulation. A positive bias was observed for over-expressed genes presenting a subtelomeric location, allelic polymorphism and encoding proteins with potential export sequences, which often belonged to subtelomeric multi-gene families. This pointed to the mobilization of processes shaping the interface between the parasite and its environment. In parallel, pathways were engaged which could lead to parasite death, such as interference with purine/pyrimidine metabolism, the mitochondrial electron transport chain, proteasome-dependent protein degradation or the integrity of the food vacuole.

Conclusion: The high proportion of over-expressed genes encoding proteins exported from the parasite highlight the importance of extra-parasitic compartments as fields for exploration in drug research which, to date, has mostly focused on the parasite itself rather than on its intra and extra erythrocytic environment. Further work is needed to clarify which transcriptome alterations observed reflect a specific response to overcome artesunate toxicity or more general perturbations on the path to cellular death.

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Association plots of gene expression with gene chromosomal localization, predicted export sequences and polymorphism. A : Bias in gene expression versus gene chromosomal localization (subtel = subtelomeric position of gene defined as <150 kb from telomere). B: Bias in gene expression versus presence of predicted export signals [13]. C: Bias in gene expression versus gene polymorphism (as defined by presence or absence of non synonymous SNPs, from analysis of 3D7, Dd2, HB3, Ghana1 and IT genomes). Bar width is proportional to the number of genes per category and bar height to the Pearson residuals for an independence model. Blue and red colors indicate significant bias.
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Figure 1: Association plots of gene expression with gene chromosomal localization, predicted export sequences and polymorphism. A : Bias in gene expression versus gene chromosomal localization (subtel = subtelomeric position of gene defined as <150 kb from telomere). B: Bias in gene expression versus presence of predicted export signals [13]. C: Bias in gene expression versus gene polymorphism (as defined by presence or absence of non synonymous SNPs, from analysis of 3D7, Dd2, HB3, Ghana1 and IT genomes). Bar width is proportional to the number of genes per category and bar height to the Pearson residuals for an independence model. Blue and red colors indicate significant bias.

Mentions: Interesting features were observed in the group of differentially expressed genes. For genes expressed differentially at 3 hours, there was a strong positive bias in the sub-set of over-expressed genes towards polymorphic genes located in sub-telomeric position and carrying PEXEL/HCT motifs [13] used for export beyond the parasitophorous vacuole into the erythrocyte cytoplasm, or to the red blood cell membrane/surface (Figure 1). This was determined after excluding from the analysis the strain-specific var, stevor and rifin multigene families – which are not adequately represented in our case since the parasite strain used differs from 3D7. Concomitant with this positive bias, there was a negative bias towards conserved genes in the over-expressed genes. In contrast, the group of under-expressed genes displayed a positive bias towards conserved genes and a negative bias towards polymorphic genes.


Dynamic RNA profiling in Plasmodium falciparum synchronized blood stages exposed to lethal doses of artesunate.

Natalang O, Bischoff E, Deplaine G, Proux C, Dillies MA, Sismeiro O, Guigon G, Bonnefoy S, Patarapotikul J, Mercereau-Puijalon O, Coppée JY, David PH - BMC Genomics (2008)

Association plots of gene expression with gene chromosomal localization, predicted export sequences and polymorphism. A : Bias in gene expression versus gene chromosomal localization (subtel = subtelomeric position of gene defined as <150 kb from telomere). B: Bias in gene expression versus presence of predicted export signals [13]. C: Bias in gene expression versus gene polymorphism (as defined by presence or absence of non synonymous SNPs, from analysis of 3D7, Dd2, HB3, Ghana1 and IT genomes). Bar width is proportional to the number of genes per category and bar height to the Pearson residuals for an independence model. Blue and red colors indicate significant bias.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2536677&req=5

Figure 1: Association plots of gene expression with gene chromosomal localization, predicted export sequences and polymorphism. A : Bias in gene expression versus gene chromosomal localization (subtel = subtelomeric position of gene defined as <150 kb from telomere). B: Bias in gene expression versus presence of predicted export signals [13]. C: Bias in gene expression versus gene polymorphism (as defined by presence or absence of non synonymous SNPs, from analysis of 3D7, Dd2, HB3, Ghana1 and IT genomes). Bar width is proportional to the number of genes per category and bar height to the Pearson residuals for an independence model. Blue and red colors indicate significant bias.
Mentions: Interesting features were observed in the group of differentially expressed genes. For genes expressed differentially at 3 hours, there was a strong positive bias in the sub-set of over-expressed genes towards polymorphic genes located in sub-telomeric position and carrying PEXEL/HCT motifs [13] used for export beyond the parasitophorous vacuole into the erythrocyte cytoplasm, or to the red blood cell membrane/surface (Figure 1). This was determined after excluding from the analysis the strain-specific var, stevor and rifin multigene families – which are not adequately represented in our case since the parasite strain used differs from 3D7. Concomitant with this positive bias, there was a negative bias towards conserved genes in the over-expressed genes. In contrast, the group of under-expressed genes displayed a positive bias towards conserved genes and a negative bias towards polymorphic genes.

Bottom Line: This pointed to the mobilization of processes shaping the interface between the parasite and its environment.In parallel, pathways were engaged which could lead to parasite death, such as interference with purine/pyrimidine metabolism, the mitochondrial electron transport chain, proteasome-dependent protein degradation or the integrity of the food vacuole.The high proportion of over-expressed genes encoding proteins exported from the parasite highlight the importance of extra-parasitic compartments as fields for exploration in drug research which, to date, has mostly focused on the parasite itself rather than on its intra and extra erythrocytic environment.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institut Pasteur, Unité d'Immunologie Moléculaire des Parasites, CNRS URA 2581, 28 Rue du Docteur Roux, F-75724, Paris, Cedex 15, France. onguma382@yahoo.com

ABSTRACT

Background: Translation of the genome sequence of Plasmodium sp. into biologically relevant information relies on high through-put genomics technology which includes transcriptome analysis. However, few studies to date have used this powerful approach to explore transcriptome alterations of P. falciparum parasites exposed to antimalarial drugs.

Results: The rapid action of artesunate allowed us to study dynamic changes of the parasite transcriptome in synchronous parasite cultures exposed to the drug for 90 minutes and 3 hours. Developmentally regulated genes were filtered out, leaving 398 genes which presented altered transcript levels reflecting drug-exposure. Few genes related to metabolic pathways, most encoded chaperones, transporters, kinases, Zn-finger proteins, transcription activating proteins, proteins involved in proteasome degradation, in oxidative stress and in cell cycle regulation. A positive bias was observed for over-expressed genes presenting a subtelomeric location, allelic polymorphism and encoding proteins with potential export sequences, which often belonged to subtelomeric multi-gene families. This pointed to the mobilization of processes shaping the interface between the parasite and its environment. In parallel, pathways were engaged which could lead to parasite death, such as interference with purine/pyrimidine metabolism, the mitochondrial electron transport chain, proteasome-dependent protein degradation or the integrity of the food vacuole.

Conclusion: The high proportion of over-expressed genes encoding proteins exported from the parasite highlight the importance of extra-parasitic compartments as fields for exploration in drug research which, to date, has mostly focused on the parasite itself rather than on its intra and extra erythrocytic environment. Further work is needed to clarify which transcriptome alterations observed reflect a specific response to overcome artesunate toxicity or more general perturbations on the path to cellular death.

Show MeSH
Related in: MedlinePlus