Dataset Information

Global protein quantification of changes in K13 mutant and isogenic wild-type P. falciparum parasites during the intra-erythrocytic developmental cycle

ABSTRACT: K13 mutations are causal for artemisinin resistance in Plasmodium falciparum human malaria. We characterized changes in protein abundance associated with K13 mutations during the parasite's 48h intra-erythrocytic developmental cycle by comparing protein expression profiles of K13 mutant (C580Y, R539T) and isogenic wild-type lines that were generated by zinc finger nuclease (ZFN) based editing in a laboratory-adapted clinical isolate (Cam3.II). For each parasite line, we harvested tightly synchronized ring and trophozoite parasites on two independent occasions, except for the C580Y line which was harvested only once at trophozoite stage.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Plasmodium Falciparum

TISSUE(S): Erythrocyte, Blood

SUBMITTER: Sachel Mok

LAB HEAD: David A. Fidock

PROVIDER: PXD019612 | Pride | 2020-11-23

REPOSITORIES: Pride

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Publications

Artemisinin-resistant K13 mutations rewire Plasmodium falciparum's intra-erythrocytic metabolic program to enhance survival.

Mok Sachel S Stokes Barbara H BH Gnädig Nina F NF Ross Leila S LS Yeo Tomas T Amaratunga Chanaki C Allman Erik E Solyakov Lev L Bottrill Andrew R AR Tripathi Jaishree J Fairhurst Rick M RM Llinás Manuel M Bozdech Zbynek Z Tobin Andrew B AB Fidock David A DA

Nature communications 20210122 1

The emergence and spread of artemisinin resistance, driven by mutations in Plasmodium falciparum K13, has compromised antimalarial efficacy and threatens the global malaria elimination campaign. By applying systems-based quantitative transcriptomics, proteomics, and metabolomics to a panel of isogenic K13 mutant or wild-type P. falciparum lines, we provide evidence that K13 mutations alter multiple aspects of the parasite's intra-erythrocytic developmental program. These changes impact cell-cycl ...[more]

PMID: 33483501

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Project description:Control of malaria is threatened by emerging parasite resistance to artemisinin drug (ART) therapies. The molecular details of how Plasmodium malaria parasites response to ART and how this relates to resistance is not clear. To determine how parasites respond to ART by altering gene expression, we performed a transcriptomic study of dihydroartemisinin (DHA) response in P. falciparum K1 strain and in P. berghei ANKA strain. Microarray data from DHA-treated P. falciparum trophozoite stage parasites were compared with data from other ART treatments. Genes with consistent changes in expression were identified, which includes notably down-regulation of cytosolic ribosomal protein genes. RNA-seq data revealed a similar pattern of transcriptomic change, although the pattern was much clearer in that more than one-third of P. falciparum trophozoite genes are differentially expressed with greater statistical support for down-regulation of ribosomal protein genes. The poor overlap of differentially-expressed genes between microarray and RNA-seq and less-well defined patterns for the former suggests that the accuracy of microarray is limited by technological bias. The trophozoite response to DHA is overall âring-likeâ and less âtrophozoite-likeâ, which is consistent with previous findings that Plasmodium can enter a quiescent ring-like state to resist ART. RNA-seq data from DHA-treated P. falciparum rings reveal a more muted response, although there is considerable overlap of differentially expressed genes with DHA-treated trophozoites. In contrast, P. falciparum schizonts are unresponsive to DHA, suggesting that the protective response acts mainly to arrest parasite development through the G2/M checkpoint. The transcriptional response of P. berghei to DHA treatment in vivo in infected mice is strikingly similar to the P. falciparum in vitro ring and trophozoite responses, in which ribosomal protein genes are notably down-regulated. These results suggest Plasmodium species respond to DHA in the same way. This knowledge could be applied to outwit the parasite to deliver more effective artemisinin therapies, and maybe hinder the development of drug resistance. Two condition drug-treatment experiment, Dihydroartemisinin vs. Vehicle control treatment with matched reference untreated controls. Biological replicates: 5 independently grown and harvested experimental culture replicates. One replicate of treatment/reference time-point per array.

Dataset Information

Global protein quantification of changes in K13 mutant and isogenic wild-type P. falciparum parasites during the intra-erythrocytic developmental cycle

Publications

Artemisinin-resistant K13 mutations rewire Plasmodium falciparum's intra-erythrocytic metabolic program to enhance survival.

Similar Datasets

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