Plasmodium falciparum
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA206190 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:The process of erythrocyte invasion by merozoites of Plasmodium falciparum involves multiple steps, including the formation of a moving junction characterized by the redundancy of many of the receptor-ligand interactions involved. Several of the parasite proteins that interact with erythrocyte receptors or participate in other steps of the process of invasion are encoded by small subtelomerically-located multigene families of four to seven members. We report here that members of the multigene families pfRh, eba, rhopH1/clag and acbp exist in either an active or a silenced state. In the case of two members of the rhopH1/clag family, clag3.1 and clag3.2, expression was mutually exclusive. Silencing occurred in the absence of detectable DNA alterations, suggesting that it is transmitted epigenetically. This was unambiguously demonstrated for eba-140, which was silenced by the formation of facultative heterochromatin. Our data demonstrate that variant expression, epigenetic silencing and mutually exclusive expression in Plasmodium are not unique to genes encoding proteins exported to the surface of the erythrocyte like var genes but also occur for genes involved in host cell invasion..
2007-11-26 | E-SGRP-9 | biostudies-arrayexpress
Project description:Identification of a New Chemical Class of Antimalarials, ACT-213615
| PRJNA170969 | ENA
Project description:Tested susceptibility to antimalarials
| PRJEB94354 | ENA
Project description:The high prevalence of sickle cell disease in some human populations likely results from the protection afforded against severe Plasmodium falciparum malaria and death by heterozygous carriage of HbS. P. falciparum remodels the erythrocyte membrane and skeleton, displaying parasite proteins at the erythrocyte surface that interact with key human proteins in the Ankyrin R and 4.1R complexes. Oxidative stress generated by HbS, as well as by parasite invasion, disrupts the kinase/phosphatase balance, potentially interfering with the molecular interactions between human and parasite proteins. HbS is known to be associated with abnormal membrane display of parasite antigens. Studying the proteome and the phosphoproteome of red cell membrane extracts from P. falciparum infected and non-infected erythrocytes, we show here that HbS heterozygous carriage, combined with infection, modulates the phosphorylation of erythrocyte membrane transporters and skeletal proteins as well as of parasite proteins. Our results highlight modifications of Ser- /Thr- and/or Tyr- phosphorylation in key human proteins, such as ankyrin, β-adducin, β-spectrin and Band 3, and key parasite proteins, such as RESA or MESA. Altered phosphorylation patterns could disturb the interactions within membrane protein complexes, affect nutrient uptake and the infected erythrocyte cytoadherence phenomenon, thus lessening the severity of malaria symptoms.
2021-04-19 | PXD023280 | Pride
Project description:The variant antigen, Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), expressed on the surface of P. falciparum infected Red Blood Cells (iRBCs) is a critical virulence factor for malaria. Each parasite encodes 60 antigenically distinct var genes encoding PfEMP1s, but during infection the clonal parasite population expresses only one gene at a time before switching to the expression of a new variant antigen as an immune evasion mechanism to avoid the hostM-bM-^@M-^Ys antibody responses. The mechanism by which 59 of the 60 var genes are silenced remains largely unknown. We used microarrays to detail the global programme changes of gene expression caused by each gene knockout with a particular view towards which gene knockout results in transcriptional upregulation of the entire var gene family. Plasmodium falciparum clones, in each of which one of different histone lysine methylation modification enzyme genes was knocked out, were synchronized in the asexual stage and collected at indicated time points post invasion of erythrocytes for RNA extraction and hybridization on Affymetrix microarrays. We sought to identify the key epigenetic enzyme that controls silencing of the whole var gene family.
2013-05-25 | E-GEOD-47349 | biostudies-arrayexpress
Project description:Plasmodium falciparum causes the most lethal form of malaria. The frontline treatments for this severe disease are combination therapies based on semisynthetic peroxide antimalarials, known as artemisinins. There is growing resistance to artemisinins and new drugs with novel mechanisms of action are urgently required. Synthetic peroxide antimalarials, known as ozonides, exhibit potent antimalarial activity both in vitro and in vivo. Here, we used chemical proteomics to investigate the protein alkylation targets of clickable artemisinin and ozonide probes, including an analogue of the ozonide clinical candidate, OZ439. We greatly expanded the list of protein targets for peroxide antimalarials and identified redox processes as being significantly enriched from the list of protein targets for both artemisinins and ozonides. Disrupted redox homeostasis was confirmed with the use of a genetically encoded fluorescence-based biosensor comprising a redox-sensitive GFP (roGFP) fused to human glutaredoxin 1. This facilitated specific and dynamic live imaging of the glutathione redox potential in the cytosol of peroxide-treated infected red blood cells with high sensitivity and temporal resolution. We also used a targeted LC-MS based thiol metabolomics assay to accurately measure relative changes in cellular thiol levels (including thiol metabolites, glutathione precursors and oxidised and reduced glutathione) within peroxide-treated P. falciparum-infected red blood cells. This work shows that peroxide antimalarials disproportionately alkylate proteins involved in redox homeostasis and that disrupted redox processes are involved in the mechanism of action of these important antimalarials.
2022-02-17 | PXD027334 | Pride
Project description:Plasmodium falciparum Heterochromatin Protein 1 Marks Genomic Loci Linked to Phenotypic Variation of Exported Virulence Factors
| PRJNA117793 | ENA
Project description:Basigin is an essential host receptor for invasion of Plasmodium falciparum into human erythrocytes, interacting with parasite surface protein PfRH5. PfRH5 is a leading blood-stage malaria vaccine candidate and a target of growth-inhibitory antibodies. However, basigin is not alone on the erythrocyte surface. Instead, we show that it is exclusively found in one of two macromolecular complexes, bound predominantly to either plasma membrane Ca2+- ATPase 1/4, PMCA1/4, or monocarboxylate transporter 1, MCT1. PfRH5 binds to either of these complexes with a higher affinity than to isolated basigin ectodomain, making it likely that these are the physiological targets of PfRH5. PMCA-mediated Ca2+ export is not affected by PfRH5, ruling this out as the mechanism underlying changes in calcium flux at the interface between an erythrocyte and the invading parasite. However, our studies rationalise the function of the most effective growth inhibitory antibodies targeting PfRH5. While these antibodies do not reduce the binding of PfRH5 to monomeric basigin, they do reduce its binding to basigin-PMCA and basigin-MCT complexes. This indicates that the most effective PfRH5-targeting antibodies inhibit growth by sterically blocking the essential interaction of PfRH5 with basigin in its physiological context.
2024-07-17 | PXD037762 | Pride
Project description:Artemisinin (ART)-resistant Plasmodium falciparum (Pf) threatens global malaria control. Resistance, driven by mutations in Pfk13, is multifaceted but quiescence plays a central role. Epigenetic regulation may contribute, given that only a percentage of parasites survive a pulse of the active drug metabolite dihydroartemisinin (DHA). The identities or roles of these epigenetic factors, however, have yet to be identified. tRNA modifications are a conserved epigenetic translational control mechanism, whereby cellular stress leads to modification reprogramming and codon-biased translation. Here we use liquid chromatography-mass spectrometry to profile tRNA modifications in ring-stage ART-sensitive (ART-S) Dd2 and ART-resistant (ART-R) Dd2PfK13_R539T before and after drug pulse. ART-R parasites differentially reprogram their tRNA modification profiles in response to DHA, specifically by mcm5s2U hypomodification of tRNAs. Proteomic and subsequent codon usage analysis revealed that the ART-R parasite proteome displays codon bias, uncovering a new layer of proteomic regulation in drug-resistant parasites. A subset of these proteins were not transcriptionally regulated, suggesting codon-bias translation. Upregulated proteins were enriched for LysAAA, HisCAT and AspGAT and downregulated proteins were enriched for their cognate codons (LysAAG, HisCAC and AspGAC). PfK13 and its interacting partner BIP were among the codon-controlled upregulated proteins. Interestingly, mcm5s2U occurs on the U34 of LysAAA/AAG codons to regulate translational fidelity, providing a mechanistic link between tRNA modification and proteomic data. Transcriptomics revealed enrichment of wobble-base tRNA modification in ART-R parasites post-ART treatment. An anhydrotetracycline-regulated conditional knockdown (cKD) of the terminal s2U methyltransferase, PfMnmA, displayed increased ART survival, signifying that hypomodification plays a critical role in the ART-R parasite response to DHA. cKD parasites also had altered responses to proteotoxic and mitochondrial antimalarials, uncovering overlaps between epigenetic stress response pathways. This work describes a novel epigenetic pathway via tRNA s2U reprogramming that ART-R parasites may use to help survive ART-induced stress.
2024-06-22 | PXD043747 | Pride
Project description:Epigenetic regulation of Plasmodium falciparum adaptive plasticity in the mosquito
| PRJNA283324 | ENA