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Transcriptome profiling of genetically modified P. falciparum parasite strains with distinct drug resistance phenotypes

ABSTRACT: We compared the transcriptomic profiles between P. falciparum strains displaying mutant or wild-type pfcrt or varying in pfcrt or pfmdr1 expression levels All values were normalized using a background pool constituted of 11 transcriptome data sets that constituted a baseline for gene expression fold change and gene set enrichment. In addition to that reported in the present study, the pool included two IDC transcriptome data sets generated for Dd2 parasites pressured long-term with pulses of dihydroartemisinin (the 3b1 line) and the non-pressured parent (Lisewski et al., Cell, 2014), as well as the transcriptome data set previously reported for the 3D7, Dd2 and HB3 strains (Bozdech et al., PLos Biol 2003, Llinas et al, NAR 2006)

ORGANISM(S): Plasmodium falciparum

PROVIDER: GSE75807 | GEO | 2015/12/09

SECONDARY ACCESSION(S): PRJNA305412

REPOSITORIES: GEO

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Transcriptome profiling of genetically modified P. falciparum parasite strains with distinct drug resistance phenotypes

Project description:We compared the transcriptomic profiles between P. falciparum strains displaying mutant or wild-type pfcrt or varying in pfcrt or pfmdr1 expression levels All values were normalized using a background pool constituted of 11 transcriptome data sets that constituted a baseline for gene expression fold change and gene set enrichment. In addition to that reported in the present study, the pool included two IDC transcriptome data sets generated for Dd2 parasites pressured long-term with pulses of dihydroartemisinin (the 3b1 line) and the non-pressured parent (Lisewski et al., Cell, 2014), as well as the transcriptome data set previously reported for the 3D7, Dd2 and HB3 strains (Bozdech et al., PLos Biol 2003, Llinas et al, NAR 2006) We conducted gene expression microarrays over the course of the parasite 48-hr IDC, by sampling parasites every 6-hour, representing 8 different time points. Extracted RNA was labeled with Cy5 dye, while the reference RNA pool consisted of Cy3-coupled cDNA samples prepared from RNAs representing all developmental stages at 6-hour intervals of the IDC of the 3D7 line.

2015-12-09 | E-GEOD-75807 | biostudies-arrayexpress

Piperaquine Resistance is Associated with a Copy Number Variation on Chromosome 5 in Drug-Pressured Plasmodium falciparum Parasites

Project description:The combination of piperaquine and dihydroartemisinin has recently become the official first-line therapy in several Southeast Asian countries. The pharmacokinetic mismatching of these drugs, whose plasma half lives are ∼20 days and ∼1 hr respectively, implies that recrudescent or new infections emerging shortly after treatment cessation will encounter piperaquine as a monotherapy agent. This creates substantial selection pressure for the emergence of resistance. To elucidate potential resistance determinants, we subjected cloned Plasmodium falciparum Dd2 parasites to continuous piperaquine pressure in vitro (47 nM, ∼two-fold higher than the Dd2 IC(50) value). The phenotype of outgrowth parasites was assayed in two clones, revealing an IC(50) value against piperaquine of 2.1 μM and 1.7 μM, over 100-fold greater than the parent. To identify the genetic determinant of resistance, we employed comparative whole-genome hybridization analysis. Compared to the Dd2 parent, this analysis found (in both resistant clones) a novel single nucleotide polymorphism in pfcrt, deamplification of an 82 kb region of chromosome 5 (that includes pfmdr1), and amplification of an adjacent 63 kb region of chromosome 5. Continued propagation without piperaquine selection pressure resulted in derivation of "revertant" piperaquine-sensitive parasites. These retained the pfcrt polymorphism and further deamplified the chromosome 5 segment that encompasses pfmdr1; however, these two independently generated revertants both lost the neighboring 63 kb amplification. These results suggest that a copy number variation event on chromosome 5 (825600-888300) is associated with piperaquine resistance. Transgenic studies are underway with individual genes in this segment to evaluate their contribution to piperaquine resistance.

2011-05-23 | GSE27907 | GEO

Gene expression quantitative trait loci (eQTL) study using the HB3Ã?Dd2 genetic cross progeny of P. falciparum

Project description:The determinants of transcriptional regulation in malaria parasites remain elusive. The presence of a well-characterized gene expression cascade shared by different Plasmodium falciparum strains could imply that transcriptional regulation and its natural variation do not contribute significantly to the evolution of parasite drug resistance. To clarify the role of transcriptional variation as a source of stain-specific diversity in the most deadly malaria species and to find genetic loci that dictate variations in gene expression, we examined genome-wide expression level polymorphisms (ELPs) in a genetic cross between phenotypically distinct parasite clones. Significant variation in gene expression is observed through direct co-hybridizations of RNA from different P. falciparum clones. Nearly 18% of genes were regulated by a significant eQTL. The genetic determinants of most of these ELPs resided in hotspots that are physically distant from their targets. The most prominent regulatory locus, influencing 269 transcripts, coincided with a Chromosome 5 amplification event carrying the drug resistance gene, pfmdr1, and 13 other genes. Drug selection pressure in the Dd2 parental clone lineage led not only to a copy number change in the pfmdr1 gene but also to increased copies of putative neighboring regulatory factors that, in turn, broadly influence the transcriptional network. Previously unrecognized transcriptional variation, controlled by polymorphic regulatory genes and possibly master regulators within large copy number variants, contributes to sweeping phenotypic evolution in drug-resistant malaria parasites. Keywords: Segregation patterns of gene expression levels. A total of 36 test parasite samples (Dd2, HB3, and progeny) from a single time point in the parasite life cycle (18 hours post RBC invasion) were co-hybridized to a common reference HB3 sample, each a single replicate.

2010-05-16 | E-GEOD-12515 | biostudies-arrayexpress

Expression and genomic changes after exposing drug-selected mutants to short term CQ treatment in Plasmodium falciparum.

Project description:Mutations in PfCRT confer chloroquine (CQ) resistance in P. falciparum. Point mutations in the homolog of the mammalian multidrug resistance gene (pfmdr1) can also modulate the levels of CQ response. However, parasites with the same pfcrt and pfmdr1 alleles exhibit a wide range of drug sensitivity, suggesting that additional genes contribute to levels of CQ resistance (CQR). We used 3 isogenic lines which have different drug resistance profiles corresponding to unique mutations in the pfcrt gene (106/1K76, 106/176I, and 106/76I-352K) to study changes in gene expression with and without CQ and genomic variations, i.e. copy number (CN) changes. RNA transcription levels from 45 genes were significantly altered in one or both mutants relative to the parent line. Of particular interest are genes encoding proteins involved in transport and/or regulation of cytoplasmic or compartmental pH, e.g. the V-type H+ pumping pyrophosphatase 2, Ca2+/H+ antiporter VCX1 and copy number changes in pfmdr1. A series of deletion (including 15 genes) also occurred at the beginning of chromosome 10. Keywords: low-dose 3h Chloroquine response, copy number variation

2008-06-26 | GSE10022 | GEO

Transcription profiling of Plasmodium falciparum after exposing drug-selected mutants to short term CQ treatment

Project description:Mutations in PfCRT confer chloroquine (CQ) resistance in P. falciparum. Point mutations in the homolog of the mammalian multidrug resistance gene (pfmdr1) can also modulate the levels of CQ response. However, parasites with the same pfcrt and pfmdr1 alleles exhibit a wide range of drug sensitivity, suggesting that additional genes contribute to levels of CQ resistance (CQR). We used 3 isogenic lines which have different drug resistance profiles corresponding to unique mutations in the pfcrt gene (106/1K76, 106/176I, and 106/76I-352K) to study changes in gene expression with and without CQ and genomic variations, i.e. copy number (CN) changes. RNA transcription levels from 45 genes were significantly altered in one or both mutants relative to the parent line. Of particular interest are genes encoding proteins involved in transport and/or regulation of cytoplasmic or compartmental pH, e.g. the V-type H+ pumping pyrophosphatase 2, Ca2+/H+ antiporter VCX1 and copy number changes in pfmdr1. A series of deletion (including 15 genes) also occurred at the beginning of chromosome 10. Experiment Overall Design: Three isogenic parasite lines were treated with and without 3h CQ and synchronized for total RNA extraction and hybridization to Affymetrix GeneChipsÂ® to study gene expression profiles. Genomic DNA from mixed culture was also extracted and hybridized to the same Affymetrix GeneChips. Total 18 total RNA samples (3 biological replicates per condition) and 6 genomic DNA samples (2 biological replicates per condition).

2008-11-06 | E-GEOD-10022 | biostudies-arrayexpress

Piperaquine-resistant PfCRT mutations differentially impact drug transport, hemoglobin catabolism and parasite physiology in Plasmodium falciparum asexual blood stages

Project description:The emergence of multidrug resistance in Plasmodium falciparum parasites presents a significant obstacle to the malaria elimination agenda. Resistance to piperaquine (PPQ), an important first-line partner drug, has spread across Southeast Asia where it has contributed to widespread treatment failures. The genetic cause of resistance to PPQ is attributable to a novel set of amino acid substitutions in the P. falciparum chloroquine resistance transporter (PfCRT). The objective of our study is to characterize gene expression signatures associated with PPQ-resistance associated PfCRT mutations by comparing transcriptional profiles of PPQ-resistant PfCRT mutants (F145I, G353V, M343L) and isogenic PPQ-sensitive lines that were generated by zinc finger nuclease (ZFN) based editing in a long-term adapted (Dd2).

2022-10-18 | GSE205515 | GEO

Plasmodium falciparum CNV-SNP chip optimization

Project description:Optimize SNP genotyping probes and demonstrate a new P. falciparum microarray platform that includes CGH and resequencing probes on the same chip 3D7 common reference; lab samples: HB3, Dd2, SC05, 7C126; field patient samples: M1176, M1069, M1094, M1321, M1064, M1111

2011-04-01 | E-GEOD-28287 | biostudies-arrayexpress

SeaIce, Espegrend, Microscosm, Mnemi

Project description:454 dataset for Hosia, et al. Torstensson et al. Dinasquet et al.

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Sources of Transcription Variation in Plasmodium falciparum

Project description:The parasite strains HB3 and Dd2 were cloned via limiting dilution and then sub-cloned. The uncloned parental line, 4 clones and 4 sub-clones were thawed in two different culture batches using different media lots and RBC donors but were otherwise maintained in identical standard culture conditions and synchronized by 3 rounds of sorbitol synchronization. Total RNA samples were collected at 24 hours post invasion (hpi).

2021-01-31 | GSE126876 | GEO

Plasmodium falciparum strain:3D7,DD2,HB3

Project description:Plasmodium falciparum strain:3D7,DD2,HB3 Raw sequence reads

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