Metabolic responses in blood-stage malaria parasites associated with increased and decreased sensitivity to PfATP4 inhibitors
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PROVIDER: PRJNA906537 | ENA |
REPOSITORIES: ENA
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Project description:Spiroindolone and pyrazoleamide antimalarial compounds target Plasmodium falciparum P-type ATPase (PfATP4) and induce disruption of intra-cellular Na+ homeostasis. Recently, a PfATP4 mutation was discovered that confers resistance to a pyrazoleamide while increasing sensitivity to a spiroindolone. To understand the different cellular accommodation to PfATP4 disruptions, we examined biochemical and metabolic adaptations that underlie this seemingly contradictory response of P. falciparum to sublethal concentrations of each compound. We used a genetically engineered P. falciparum Dd2 strain (Dd2A211V) carrying an Ala211Val (A211V) mutation in PfATP4 to identify metabolic adaptations associated with the mutation that results in decreased sensitivity to PA21A092 (a pyrazoleamide) and increased sensitivity of KAE609 (a spiroindolone). We first identified sublethal doses of PA21A092 and KAE609 causing substantial reduction (30-70%) in Dd2A211V parasite replication. At this sublethal dose of PA21A092 (or KAE609), we collected metabolomic and transcriptomic data during the first intraerythrocytic developmental cycle (IDC). Finally, we integrated the time-resolved data with a whole-genome metabolic network model of P. falciparum to characterize antimalarial-induced physiological adaptations. We found that sublethal treatment with PA21A092 caused significant (p < 0.001) alterations in the abundances of 91 Plasmodium gene transcripts whereas only 21 transcripts were significantly altered due to sublethal treatment with KAE609. In the metabolomic data, we found a substantial alteration (fourfold) in the abundances of carbohydrate metabolites in the presence of either compounds. The estimated rates of macromolecule syntheses between the two antimalarial-treated conditions were also comparable, except for the rate of lipid synthesis. A closer examination of parasite metabolism in the presence of either compound indicated statistically significant differences in enzymatic activities associated with synthesis of phosphatidylcholine, phosphatidylserine, and phosphatidylinositol. Our results suggest that malaria parasites activate protein kinases via phospholipid-dependent signaling in response to the ionic perturbation induced by the Na+ homeostasis disruptor PA21A092. Therefore, we hypothesize that targeted disruption of phospholipid signaling in PA21A092-resistant parasites could be a means to block the emergence of resistance to PA21A092.
2023-02-14 | GSE218998 | GEO
Project description:Single-cell RNA-sequencing is revolutionising our understanding of seemingly homogeneous cell populations but has not yet been widely applied to single-celled organisms. Transcriptional variation in unicellular malaria parasites from the Plasmodium genus is associated with critical phenotypes including red blood cell invasion and immune evasion, yet transcriptional variation at an individual parasite level has not been examined in depth. Here, we describe the adaptation of a single-cell RNA-sequencing (scRNA-seq) protocol to deconvolute transcriptional variation for more than 500 individual parasites of both rodent and human malaria comprising asexual and sexual life-cycle stages. We uncover previously hidden discrete transcriptional signatures during the pathogenic part of the life cycle, suggesting that expression over development is not as continuous as commonly thought. In transmission stages, we find novel, sex-specific roles for differential expression of contingency gene families that are usually associated with immune evasion and pathogenesis.
2017-02-08 | E-ERAD-611 | biostudies-arrayexpress
Project description:Malaria parasites rely on a plastid organelle for survival during the blood stages of infection. However, the entire organelle is dispensable as long as the isoprenoid precursor isopentenyl pyrophosphate (IPP) is supplemented in the culture medium. We engineered parasites to produce isoprenoid precursors from a mevalonate-dependent pathway, creating a parasite line that replicates normally after the loss of the apicoplast organelle. We show that carbon-labeled mevalonate is specifically incorporated into isoprenoid products, opening new avenues for researching this essential class of metabolites in malaria parasites. We also show that essential apicoplast proteins, such as the enzyme target of the drug fosmidomycin, can be deleted in this mevalonate bypass parasite line, providing a method to determine the roles of other important apicoplast-resident proteins. Several antibacterial drugs kill malaria parasites because they target basic processes, such as transcription, in the organelle. We used metabolomic and transcriptomic methods to characterize parasite metabolism after azithromycin treatment triggered loss of the apicoplast. These results provide insight into the effects of apicoplast-disrupting drugs, several of which have been used to treat malaria infections in humans. Overall, the mevalonate bypass system provides a way to probe essential aspects of apicoplast biology and study the effects of drugs that target apicoplast processes.
2020-02-11 | GSE136169 | GEO
Project description:The purpose of this research is to identify and evaluate the global gene expression of the rodent malaria parasites Plasmodium yoelii, Plasmodium berghei and Plasmodium chabaudi blood-stage parasites and specifically compare the blood stage gene expression profiles of samples derived from previous studies on Plasmodium falciparum, Plasmodium vivax and Plasmodium knowlesi
2016-04-08 | GSE80015 | GEO
Project description:Background Histone deacetylase (HDACs) inhibitors are being intensively pursued as potential new antimalarial drugs, and are also emerging as valuable tools for investigating transcriptional control in malaria parasites. In this study, the genome-wide transcriptional effects of three structurally related hydroxamate HDAC inhibitors were profiled in Plasmodium falciparum, the most lethal of the malaria parasite species that infects humans. Results Following 2h exposure to trichostatin A (TSA), suberoylanilide hydroxamic acid (SAHA) or a 2-aminosuberic acid derivative (2-ASA-9), ~18-28% of genes in P. falciparum trophozoite-stage parasites were regulated greater than two fold. This global induction was transitory, with fewer genes (3-5%) regulated after removing the compounds and culturing for a further 2h. Just nine genes, including alpha-II-tubulin, were up-regulated by all three compounds. Despite structural similarity, the three inhibitors caused quite diverse transcriptional effects, possibly reflecting subtle differences in mode of action or cellular distribution. Conclusions Three structurally related HDAC inhibitors have been found to cause profound, genome-wide, transcriptional changes in P. falciparum parasites, but most effects were transitory. This highlights the dynamic and exquisitely controlled nature of transcription in these malaria parasites. We also identified a small subset of nine genes over-expressed by all three HDAC inhibitors that may represent the first recognized set of transcriptional markers that signify HDAC inhibition in malaria parasites. This data set is an important contribution to our understanding of gene regulation in malaria parasites and supports growing evidence for the potential of HDAC inhibitors as new antimalarial agents.
2012-05-01 | GSE25642 | GEO
Project description:The intra-erythrocytic developmental cycle (IDC) of malaria parasites is synchronized with the time-of-day hosts feed, but the mechanism underpinning this coordination is unknown. Combining in vivo and in vitro approaches using rodent and human malaria parasites, we reveal that: (i) 57% of P. chabaudi genes exhibit 24 h “circadian” periodicity in expression; (ii) 58% of these genes lose rhythmicity when the IDC is out-of-synchrony with host rhythms; (iii) 6% of P. falciparum genes show circadian expression under free-running conditions; (iv) Serpentine receptor 10 (SR10) is circadian and disrupting it in rodent models shortens the IDC by 2-3 hours; (v) diverse processes, including DNA replication, the ubiquitin and proteasome pathways, are affected by disruption of SR10 and loss of coordination with host rhythms. Our results reveal that malaria parasites are at least in part responsible for scheduling their IDC, explaining the fitness benefits of coordination with host rhythms.
2020-04-20 | GSE144976 | GEO
Project description:PfEMP1 is a variable antigen displayed on red blood cells (RBCs) infected with the malaria parasite Plasmodium falciparum. PfEMP1 mediates binding of the infected cell to the endothelium of blood vessels, a major cause of severe manifestations of malaria. Each parasite encodes ∼60 different PfEMP1 variants of which only one is expressed at a time and switching between variants underlies immune evasion in the host and variant-specific severity of disease. PfEMP1 expression heterogeneity between parasites complicates its study and hampers genetic modification approaches as in many cells the modified locus is not expressed. Here we used selection linked integration to generate parasites all expressing the same PfEMP1 variant and permitting genomic modification of the expressed locus. Using this system, we study PfEMP1 trafficking, generate cell lines binding to all major endothelial receptors, survey the protein environment from functional PfEMP1 in the host cell and identify new proteins needed for PfEMP1 mediated sequestration. Overall, these approaches facilitate the study of the molecular and cellular biology of the key virulence factor of malaria parasites.
2024-09-01 | GSE275671 | GEO
Project description:Puf3 participates in ribosomal biogenesis in malaria parasites
| PRJNA414782 | ENA
Project description:The intra-erythrocytic developmental cycle (IDC) of malaria parasites is synchronized with the time-of-day hosts feed, but the mechanism underpinning this coordination is unknown. Combining in vivo and in vitro approaches using rodent and human malaria parasites, we reveal that: (i) 57% of P. chabaudi genes exhibit 24 h “circadian” periodicity in expression; (ii) 58% of these genes lose rhythmicity when the IDC is out-of-synchrony with host rhythms; (iii) 9% of P. falciparum genes show circadian expression under free-running conditions; (iv) Serpentine receptor 10 (SR10) is circadian and disrupting it in rodent models shortens the IDC by 2-3 hours; (v) diverse processes, including DNA replication, the ubiquitin and proteasome pathways, are affected by disruption of SR10 and loss of coordination with host rhythms. Our results reveal that malaria parasites are at least in part responsible for scheduling their IDC, explaining the fitness benefits of coordination with host rhythms.
2020-04-20 | GSE132625 | GEO
Project description:The intra-erythrocytic developmental cycle (IDC) of malaria parasites is synchronized with the time-of-day hosts feed, but the mechanism underpinning this coordination is unknown. Combining in vivo and in vitro approaches using rodent and human malaria parasites, we reveal that: (i) 57% of P. chabaudi genes exhibit 24 h “circadian” periodicity in expression; (ii) 58% of these genes lose rhythmicity when the IDC is out-of-synchrony with host rhythms; (iii) 9% of P. falciparum genes show circadian expression under free-running conditions; (iv) Serpentine receptor 10 (SR10) is circadian and disrupting it in rodent models shortens the IDC by 2-3 hours; (v) diverse processes, including DNA replication, the ubiquitin and proteasome pathways, are affected by disruption of SR10 and loss of coordination with host rhythms. Our results reveal that malaria parasites are at least in part responsible for scheduling their IDC, explaining the fitness benefits of coordination with host rhythms.
2020-04-20 | GSE132643 | GEO