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Tolerance of Plasmodium falciparum mefloquine-resistant cliniczl isolates to paired mefloquine-piperaquine

ABSTRACT: Dihydroartemisinin–piperaquine plus mefloquine in a mefloquine resistance context

PROVIDER: PRJEB85790 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	ERR14369052_1.fastq.gz	Fastqsanger.gz
	ERR14369052_2.fastq.gz	Fastqsanger.gz
	ERR14369053_1.fastq.gz	Fastqsanger.gz
	ERR14369053_2.fastq.gz	Fastqsanger.gz

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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.

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Expression data from Plasmodium falciparum

Project description:Artemisinin and its derivatives exert the potent, antimalarial action, although the mechanisms by which these drugs inhibit the growth of mararia parasites is not fully understood. We used microarrays to detail the global gene expression change in early erythrocytic P. falciparum, and identified molecules that may contribute to the activity of dihydroartemisinin.

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Project description:Plasmodium parasites mount an arrest response against dihydroartemisinin [Microarray]

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Plasmodium falciparum

Project description:Structural polymorphism in the promoter of pfmrp2 confers tolerance to mefloquine and chloroquine in Plasmodium falciparum [CGH]

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Project description:Structural polymorphism in the promoter of pfmrp2 confers tolerance to mefloquine and chloroquine in Plasmodium falciparum [expression]

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

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Structural polymorphism in the promoter of pfmrp2 confers tolerance to mefloquine and chloroquine in Plasmodium falciparum [CGH]

Project description:Drug resistance in Plasmodium falciparum remains a challenge for the malaria eradication programs around the world. With the emergence of artemisinin resistance, the efficacy of the partner drugs in the artemisinin combination therapies (ACT) that include quinoline based drugs is becoming critical. So far only few resistance markers have been identified and verified from which only two ABC transmembrane transporters namely PfMDR1 and PfCRT have been experimentally verified. Another P. falciparum ABC transporter, the multidrug resistance-associated protein (PfMRP2) represents an additional possible factor of drug resistance in P. falciparum. In this study, we identify a parasite clone that is derived from the 3D7 P. falciparum strain and which shows increased resistance to chloroquine and mefloquine through the trophozoite and schizont stages. We demonstrate that the resistance phenotype is caused by a 4.1 kb deletion in the 5’ upstream region of the pfmrp2 gene that leads to an alteration in the pfmrp2 transcription that result in increased levels of PfMRP2 protein. These results also suggest the importance of putative promoter elements in regulation of gene expression during the P. falciparum intra-erythrocytic developmental cycle and the potential of such genetic polymorphisms to underlie drug resistance phenotypes. Presented here are the data from microarray-based genome-wide transcriptomic and genomic studies of the drug-sensitive and drug-resistant 3D7 clones 11C/wt and 6A/mut.

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