Protein KIC5 is a novel regulator of artemisinin stress response in the malaria parasite Plasmodium falciparum
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ABSTRACT:
ORGANISM(S): Plasmodium falciparum Plasmodium falciparum NF54
PROVIDER: GSE205012 | GEO | 2022/11/29
REPOSITORIES: GEO
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Project description:This SuperSeries is composed of the following subset Series: GSE25878: Artemisinin resistance in Plasmodium falciparum is associated with an altered temporal pattern of transcription (expression) GSE25879: Artemisinin resistance in Plasmodium falciparum is associated with an altered temporal pattern of transcription (CGH) Refer to individual Series
2010-12-07 | E-GEOD-25883 | biostudies-arrayexpress
Project description:Artemisinin resistance in Plasmodium falciparum malaria has emerged in western Cambodia. This is a major threat to global plans to control and eliminate malaria as the artemisinins are a key component of antimalarial treatment throughout the world. Using DNA microarrays we identify key features of a transcriptional profile that are associated with the delayed parasite clearance phenotype. These include reduced expression of several basic metabolic and cellular pathways in the early stages, and increased expression of essentially all functionalities associated with protein metabolism in the later stages of P. falciparum intraerythrocytic development. This is consistent with the reduced ring stage susceptibility that characterizes artemisinin resistant P. falciparum. This modulation of the P. falciparum intraerythrocytic transcriptome may result from differential expression of several regulatory proteins such as transcription factors of chromatin remodeling associated factors. In addition, the artemisinin resistant phenotype is strongly associated with a specific pattern of copy number variations, some of which are linked with differential expression of several regulatory proteins such as histone 4 and zinc permease. This study reports the first global transcriptional survey of artemisinin resistant parasites and provides a set of candidate genes for further investigation.
2010-12-07 | GSE25879 | GEO
Project description:Artemisinin resistance in Plasmodium falciparum malaria has emerged in western Cambodia. This is a major threat to global plans to control and eliminate malaria as the artemisinins are a key component of antimalarial treatment throughout the world. Using DNA microarrays we identify key features of a transcriptional profile that are associated with the delayed parasite clearance phenotype. These include reduced expression of several basic metabolic and cellular pathways in the early stages, and increased expression of essentially all functionalities associated with protein metabolism in the later stages of P. falciparum intraerythrocytic development. This is consistent with the reduced ring stage susceptibility that characterizes artemisinin resistant P. falciparum. This modulation of the P. falciparum intraerythrocytic transcriptome may result from differential expression of several regulatory proteins such as transcription factors of chromatin remodeling associated factors. In addition, the artemisinin resistant phenotype is strongly associated with a specific pattern of copy number variations, some of which are linked with differential expression of several regulatory proteins such as histone 4 and zinc permease. This study reports the first global transcriptional survey of artemisinin resistant parasites and provides a set of candidate genes for further investigation.
2010-12-07 | GSE25878 | GEO
Project description:Artemisinin resistance in Plasmodium falciparum malaria has emerged in western Cambodia. This is a major threat to global plans to control and eliminate malaria as the artemisinins are a key component of antimalarial treatment throughout the world. Using DNA microarrays we identify key features of a transcriptional profile that are associated with the delayed parasite clearance phenotype. These include reduced expression of several basic metabolic and cellular pathways in the early stages, and increased expression of essentially all functionalities associated with protein metabolism in the later stages of P. falciparum intraerythrocytic development. This is consistent with the reduced ring stage susceptibility that characterizes artemisinin resistant P. falciparum. This modulation of the P. falciparum intraerythrocytic transcriptome may result from differential expression of several regulatory proteins such as transcription factors of chromatin remodeling associated factors. In addition, the artemisinin resistant phenotype is strongly associated with a specific pattern of copy number variations, some of which are linked with differential expression of several regulatory proteins such as histone 4 and zinc permease. This study reports the first global transcriptional survey of artemisinin resistant parasites and provides a set of candidate genes for further investigation. 6 P. falciparum parasites (field isolates) which are either Artemsinin resistant or sensitive from 3 study sites (Pailin in Cambodia, Xepon in Laos, Mae Sot in Thailand) were sampled and harvested for genomic DNA. gDNA from a total of 6 samples were extracted by phenol chloroform. Synthesis of labelled target DNA was carried out as previously described: Mackinnon, M.J. et al. Comparative transcriptional and genomic analysis of Plasmodium falciparum field isolates. PLoS Pathog 5, e1000644 (2009), and used in comparative genomic microarray hybridizations (CGH).
2010-12-07 | E-GEOD-25879 | biostudies-arrayexpress
Project description:Artemisinin resistance in Plasmodium falciparum malaria has emerged in western Cambodia. This is a major threat to global plans to control and eliminate malaria as the artemisinins are a key component of antimalarial treatment throughout the world. Using DNA microarrays we identify key features of a transcriptional profile that are associated with the delayed parasite clearance phenotype. These include reduced expression of several basic metabolic and cellular pathways in the early stages, and increased expression of essentially all functionalities associated with protein metabolism in the later stages of P. falciparum intraerythrocytic development. This is consistent with the reduced ring stage susceptibility that characterizes artemisinin resistant P. falciparum. This modulation of the P. falciparum intraerythrocytic transcriptome may result from differential expression of several regulatory proteins such as transcription factors of chromatin remodeling associated factors. In addition, the artemisinin resistant phenotype is strongly associated with a specific pattern of copy number variations, some of which are linked with differential expression of several regulatory proteins such as histone 4 and zinc permease. This study reports the first global transcriptional survey of artemisinin resistant parasites and provides a set of candidate genes for further investigation. 11 P. falciparum parasites (field isolates) which are either Artemsinin resistant or sensitive from 3 study sites (Pailin in Cambodia, Xepon in Laos, Mae Sot in Thailand) were sampled, grown ex-vivo over 48 hours and harvested at regular intervals. RNA from a total of 91 samples were extracted. Synthesis of target DNA was carried out as previously described: Mackinnon, M.J. et al. Comparative transcriptional and genomic analysis of Plasmodium falciparum field isolates. PLoS Pathog 5, e1000644 (2009), and used in microarray hybridizations.
2010-12-07 | E-GEOD-25878 | biostudies-arrayexpress
Project description:The role of extracellular vesicles in developing artemisinin resistance in Plasmodium falciparum is not known. We have posited a role for EVs in the development of ARTr (EVs export hypothesis) (Tandoh et al.,2022).The objective of this study was to test a prediction of the EVs export hypothesis to gain insight into a putative role for EVs in the expression of the artemisinin resistant phenotype. We compared the gene expression profile of two artemisinin resistant parasites (C580R and R539T) generated by CRISPR based editing of an artemisinin susceptible parasite (Dd2) for enrichment with an EVs module of interest using gene set enrichment analysis.
2022-09-15 | GSE210644 | GEO
Project description:Plasmodium falciparum, the most pathogenic human malaria parasite, infects millions of human beings and causes a serious public health threat. Currently, the most potent anti-malarial drugs are artemisinin and its derivatives1,2. Artemisinin is a sesquiterpene lactone with an endoperoxide bridge3. The activation of artemisinin requires the cleavage of the endoperoxide bridge in the presence of iron sources4. Once activated, artemisinins are converted into highly reactive carbon-centered radicals5,6 that attack macromolecules through alkylation and propagate a series of damages, eventually leading to parasite death7,8. Even though several parasite proteins have been reported as the targets of artemisinin9,10, the exact mechanism of artemisinin action is still controversial and its high potency and specificity against the malaria parasite could not be fully accounted. Here, we have developed an unbiased chemical proteomics approach to directly probe the mechanism of action of artemisinin in P. falciparum in situ. An alkyne-tagged artemisinin analogue coupled with biotin enables selective purification and identification of 124 artemisinin covalent-binding protein targets, many of which are involved in essential biological processes of the parasite. In vitro assays confirm the specific artemisinin binding and inhibition of selected targets. Such a broad targeting spectrum disrupts the biochemical landscape of the parasite and causes its death. Furthermore, using the alkyne-tagged artemisinin coupled with a fluorescent dye to monitor its protein binding, we showed that heme, rather than free ferrous iron, is predominantly responsible for artemisinin activation. The extremely high level of heme released from the hemoglobin digestion by the parasite make artemisinin exceptionally potent against late-stage parasites (trophozoite and schizont stages) compared to parasites at early ring stage, which have low level of heme, mainly from endogenous synthesis. The ‘blood eating’ nature of the parasite with the release of large amounts of heme confers artemisinin with extremely high specificity against the parasites, with minimum side effects towards healthy red blood cells. Taken together, our results established a unifying model to explain the action and specificity of artemisinin in parasite killing. Our findings could facilitate the development of better alternative strategies to treat malaria in times of emerging artemisinin resistance11,12.
2015-12-17 | PXD002611 | Pride
Project description:Protein KIC5 is a novel regulator of artemisinin stress response in the malaria parasite Plasmodium falciparum
| PRJNA843072 | ENA