Molecular mechanism for switching of P.falciparum invasion pathways into human erythrocytes
Ontology highlight
ABSTRACT:
ORGANISM(S): Plasmodium falciparum
PROVIDER: GSE2878 | GEO | 2005/10/04
SECONDARY ACCESSION(S): PRJNA92557
REPOSITORIES: GEO
Similar Datasets
Project description:Central to the pathology of malaria disease are the repeated cycles of parasite invasion and destruction of human erythrocytes. In Plasmodium falciparum, the most virulent species causing malaria, erythrocyte invasion involves several specific receptor–ligand interactions that direct the pathway used to invade the host cell, with parasites varying in their dependency on these different pathways. Gene disruption of a key invasion ligand in the 3D7 parasite strain, the P. falciparum reticulocyte binding-like homolog 2b (PfRh2b), resulted in the parasite invading via a novel pathway. Here, we show results that suggest the molecular basis for this novel pathway is not due to a molecular switch but is instead mediated by the redeployment of machinery already present in the parent parasite but masked by the dominant role of PfRh2b. This would suggest that interactions directing invasion are organized hierarchically, where silencing of dominant invasion ligands reveal underlying alternative pathways. This provides wild parasites with the ability to adapt to immune-mediated selection or polymorphism in erythrocyte receptors and has implications for the use of invasion-related molecules in candidate vaccines. Keywords: genetic modification
2005-12-21 | GSE3877 | GEO
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: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:Variation of surface adhesins is a critical mediator of virulence and immune evasion in many medically important microbes. Phenotypic switching has been linked to transcriptional changes and the function of chromatin proteins, but the determinants of the rate of phenotypic switching remain poorly defined. We analyzed epigenetic switching of the Plasmodium falciparum erythrocyte invasion ligand PfRh4. By introducing a prokaryotic Dam methylase, we demonstrate that parasites selected for in vivo PfRh4 activation show a reversible increase in promoter accessibility while exhibiting perinuclear repositioning of the locus from a silent to a conserved activation domain. Forced activation of a proximal gene results in a similar level of repositioning of the PfRh4 locus into this domain and a concomitant increase in PfRh4 activation in a sub-population of parasites, with promoter accessibility occurring only at actively transcribed loci. Thus, we reveal two distinct epigenetic mechanisms regulating the expression of a malaria virulence gene. To examine the correlation between changes in gene expression induced by treatment with a high dose of trichostatin A (TSA) and the associated changes in chromatin accessibility. Plasmodium falciparum was treated (or not, control) with 100nm or 500nm TSA, and then the expression profiles were analyzed.
2012-10-13 | E-GEOD-41567 | biostudies-arrayexpress
Project description:During red-blood-cell-stage infection of Plasmodium falciparum, the parasite undergoes repeated rounds of replication, egress, and invasion. Erythrocyte invasion involves specific interactions between host cell receptors and parasite ligands and coordinated expression of genes specific to this step of the life cycle. We show that a parasite-specific bromodomain protein, PfBDP1, binds to chromatin at transcriptional start sites of invasion-related genes and directly controls their expression. Conditional PfBDP1 knockdown causes a dramatic defect in parasite invasion and growth and results in transcriptional downregulation of multiple invasion-related genes at a time point critical for invasion. Conversely, PfBDP1 overexpression enhances expression of these same invasion-related genes. PfBDP1 binds to acetylated histone H3 and a second bromodomain protein, PfBDP2, suggesting a potential mechanism for gene recognition and control. Collectively, these findings show that PfBDP1 critically coordinates expression of invasion genes and indicate that targeting PfBDP1 could be an invaluable tool in malaria eradication. ChIPseq mapping of the genome wide enrichment profile of the P. falciparum bromodomain protein PfBDP1 in two parasite stages and correlation with RNAseq expression data
2016-03-22 | E-GEOD-79135 | biostudies-arrayexpress
Project description:Erythrocyte invasion is an essential step in the life cycle of the malaria parasite Plasmodium falciparum that involves specific interactions between host cell receptors and parasite ligands. How the parasite regulates the expression of invasion-related genes is to date largely unknown. Here we show that a novel, parasite-specific bromodomain protein (PfBDP1) binds to chromatin at the transcriptional start site of invasion-related genes and directly controls their expression. Conditional PfBDP1 knockdown causes a dramatic defect in parasite invasion and growth and results in transcriptional down-regulation of multiple invasion-related genes at a time point critical for invasion. This is the first report of a histone binding protein that activates genes in P. falciparum and our data place PfBDP1 in a central position for controlling the coordinated expression of invasion genes. Bromodomains are emerging therapeutic targets and drugs that specifically inhibit PfBDP1 could be an invaluable tool in the effort to eradicate malaria. P. falciparum 3D7 parasites over-expressing PfBDP1-3xHA (3D7/PfBDP1 OE) [PMID: 23181666] were grown in presence of 5μg/ml BSD-S-HCl. The parasite line 3D7/cam [PMID: 22435676.] grown under the same conditions and expressing hDHFR instead of PfBDP1-3xHA from the same promoter was used as control. RNA extracted from these samples at four consecutive time points each was processed for microarray analysis.
2015-01-07 | E-GEOD-64690 | biostudies-arrayexpress
Project description:Erythrocyte invasion is an essential step in the life cycle of the malaria parasite Plasmodium falciparum that involves specific interactions between host cell receptors and parasite ligands. How the parasite regulates the expression of invasion-related genes is to date largely unknown. Here we show that a novel, parasite-specific bromodomain protein (PfBDP1) binds to chromatin at the transcriptional start site of invasion-related genes and directly controls their expression. Conditional PfBDP1 knockdown causes a dramatic defect in parasite invasion and growth and results in transcriptional down-regulation of multiple invasion-related genes at a time point critical for invasion. This is the first report of a histone binding protein that activates genes in P. falciparum and our data place PfBDP1 in a central position for controlling the coordinated expression of invasion genes. Bromodomains are emerging therapeutic targets and drugs that specifically inhibit PfBDP1 could be an invaluable tool in the effort to eradicate malaria.
2015-01-07 | GSE64690 | GEO
Project description:Plasmodium falciparum strain:P.falciparum | isolate:Ek Genome sequencing
| PRJNA834069 | ENA
Project description:Bazzani2012 - Genome scale networks of P.falciparum and human hepatocyte
This model is described in the article:
Network-based assessment of the selectivity of metabolic drug targets in Plasmodium falciparum with respect to human liver metabolism.
Bazzani S, Hoppe A, Holzhütter HG.
BMC Syst Biol.
2012 Aug 31;6(1):118. PMID: 2937810
Abstract:
ABSTRACT:
BACKGROUND: The search for new drug targets for antibiotics against Plasmodium falciparum, a major cause of human deaths, is a pressing scientific issue, as multiple resistance strains spread rapidly. Metabolic network-based analyses may help to identify those parasite's essential enzymes whose homologous counterparts in the human host cells are either absent, non-essential or relatively less essential.
RESULTS:
Using the well-curated metabolic networks PlasmoNet of the parasite Plasmodium falciparum and HepatoNet1 of the human hepatocyte, the selectivity of 48 experimental antimalarial drug targets was analyzed. Applying in silico gene deletions, 24 of these drug targets were found to be perfectly selective, in that they were essential for the parasite but non-essential for the human cell. The selectivity of a subset of enzymes, that were essential in both models, was evaluated with the reduced fitness concept. It was, then, possible to quantify the reduction in functional fitness of the two networks under the progressive inhibition of the same enzymatic activity. Overall, this in silico analysis provided a selectivity ranking that was in line with numerous in vivo and in vitro observations.
CONCLUSIONS:
Genome-scale models can be useful to depict and quantify the effects of enzymatic inhibitions on the impaired production of biomass components. From the perspective of a host-pathogen metabolic interaction, an estimation of the drug targets-induced consequences can be beneficial for the development of a selective anti-parasitic drug.
This model is hosted on BioModels Database
and identified by: MODEL1206070000
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To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. PMID: 20587024
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2005-01-01 | MODEL1206070000 | BioModels
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 host’s 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.
2013-05-25 | GSE47349 | GEO