RALP1 is critical for Plasmodium falciparum merozoite invasion of erythrocytes
Ontology highlight
ABSTRACT:
ORGANISM(S): Plasmodium falciparum
PROVIDER: GSE298920 | GEO | 2026/01/01
REPOSITORIES: GEO
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:Merozoite invasion of host red blood cells (RBCs) is essential for survival of the human malaria parasite Plasmodium falciparum. Proteins involved with RBC binding and invasion are secreted from dual-club shaped organelles at the apical tip of the merozoite called the rhoptries. Here we characterise P. falciparum Cytosolically Exposed Rhoptry Leaflet Interacting protein 2 (PfCERLI2), as a rhoptry bulb protein that is essential for merozoite invasion. Phylogenetic analyses show that cerli2 arose through an ancestral gene duplication of cerli1, a related cytosolically exposed rhoptry bulb protein. We show that PfCERLI2 is essential for blood-stage growth and localises to the cytosolic face of the rhoptry bulb. Inducible knockdown of PfCERLI2 led to a proportion of merozoites failing to invade after formation of the tight junction. PfCERLI2 knockdown was associated with inhibition of rhoptry antigen processing and a significant elongation of the rhoptries, suggesting that the inability of merozoites to invade is caused by aberrant rhoptry function due to PfCERLI2 deficiency. These findings identify PfCERLI2 as a protein that has key roles in rhoptry biology during merozoite invasion.
2021-11-15 | PXD028937 | Pride
Project description:The invasion of Plasmodium merozoites into host erythrocytes is initiated through specific ligand–receptor interactions. This interaction results in subsequent invasion events, facilitated by forming a moving junction through AMA–1 and associated molecular complexes mediating parasite entry into the erythrocytic membrane. Previous studies have implicated erythrocyte surface glycosaminoglycans, particularly heparan sulfate proteoglycans, as critical receptor components in this invasion process. In this study, we sought to elucidate the molecular function of PbMAP2 (encoded by PbANKA_1137800), a previously uncharacterized Plasmodium berghei ANKA protein, in mediating merozoite attachment and invasion via heparan sulfate–dependent pathways. The PbMAP2 protein, predominantly situated at the extreme apical region of the P. berghei merozoite, binds to heparin and the erythrocyte surface during merozoite invasion. Additionally, mice either immunized with the PbMAP2 protein or passively immunized with sera derived from vaccinated mice demonstrated enhanced immunity against lethal challenges. Global mass spectrometric analysis indicates that PbMAP2 engages with several trafficking and secretion proteins associated with parasite invasion. Our findings pinpointed PbMAP2 is predominantly expressed at the extreme apical region of the P. berghei merozoite and engages in binding to the heparin–like receptors on the erythrocyte surface during merozoite invasion.
2025-03-06 | PXD061524 |
Project description:The malaria parasite, Plasmodium falciparum, exploits multiple ligand-receptor interactions, called invasion pathways, to invade the host erythrocyte. Strains of P.falciparum vary in their dependency on sialated red cell receptors for invasion. We show that switching from sialic acid-dependent to –independent invasion is reversible and depends on parasite ligand utilisation. Expression of P.falciparum reticulocyte-binding like homologue 4 (PfRh4) correlates with sialic acid-independent invasion and PfRh4 is essential for switching invasion pathways. Differential activation of PfRh4 represents a novel mechanism of invasion pathway control and provides P.falciparum with exquisite adaptability in the face of erythrocyte receptor polymorphisms and host immune responses. Keywords: Plasmodium falciparum, erythrocyte invasion, invasion pathways, EBA175, Rh4
2005-10-04 | GSE2878 | GEO
Project description:Successful invasion of human erythrocytes byPlasmodium falciparummerozoites is required for infection of the host and parasite survival. The early stages of invasion are mediated via merozoite surface proteins that interact with human erythrocytes. The nature of these interactions are currently not well understood, but it is known that merozoite surface protein 1 (MSP1) is critical for successful erythrocyte invasion. Here we show that the peripheral merozoite surface proteins MSP3, MSP6, MSPDBL1, MSPDBL2, and MSP7 bind directly to MSP1, but independently of each other, to form multiple forms of the MSP1 complex on the parasite surface. These complexes have overlapping functions that interact directly with human erythrocytes. We also show that targeting the p83 fragment of MSP1 using inhibitory antibodies inhibits all forms of MSP1 complexes and disrupts parasite growthin vitro.
| S-EPMC4817195 | biostudies-literature
Project description:Cerebral malaria is a severe multifactorial condition associated with the interaction of high numbers of infected erythrocytes to human brain endothelium without invasion into the brain. The result is coma and seizures with death in more than 20% of cases. Because the brain endothelium is at the interface of these processes, we investigated the global gene responses of human brain endothelium after the interaction with Plasmodium falciparum–infected erythrocytes with either high- or low-binding phenotypes. The most significantly up-regulated transcripts were found in gene ontology groups comprising the immune response, apoptosis and antiapoptosis, inflammatory response, cell-cell signaling, and signal transduction and nuclear factor B (NF-B) activation cascade. The proinflammatory NF-B pathway was central to the regulation of the P falciparum–modulated endothelium transcriptome. The proinflammatory molecules, for example, CCL20, CXCL1, CXCL2, IL-6, and IL-8, were increased more than 100-fold, suggesting an important role of blood-brain barrier (BBB) endothelium in the innate defense during P falciparum–infected erythrocyte (Pf-IRBC) sequestration. However, some of these diffusible molecules could have reversible effects on brain tissue and thus on neurologic function. The inflammatory pathways were validated by direct measurement of proteins in brain endothelial supernatants. This study delineates the strong inflammatory component of human brain endothelium contributing to cerebral malaria.
2009-11-10 | GSE9861 | GEO
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:Cytoadherence-linked asexual gene 9 (Clag9), a conserved Plasmodium protein expressed during the asexual blood stages, is involved in the cytoadherence of infected red blood cells (RBCs) to the endothelial lining of blood vessels. Here, we show that Plasmodium falciparum Clag9 (PfClag9) is a component of the PfClag9-RhopH complex that is involved in merozoite binding to human erythrocytes. To characterize PfClag9, we expressed four fragments of PfClag9, encompassing the entire protein. Immunostaining analysis using anti-PfClag9 antibodies showed expression and localization of PfClag9 at the apical end of the merozoites. Mass spectrometric analysis of merozoite extracts after immunoprecipitation using anti-PfClag9 antibody identified P. falciparum rhoptry-associated protein 1 (PfRAP1), PfRAP2, PfRAP3, PfRhopH2, and PfRhopH3 as associated proteins. The identified rhoptry proteins were expressed, and their association with PfClag9 domains was assessed by using protein-protein interaction tools. We further showed that PfClag9 binds human RBCs by interacting with the glycophorin A-band 3 receptor-coreceptor complex. In agreement with its cellular localization, PfClag9 was strongly recognized by antibodies generated during natural infection. Mice immunized with the C-terminal domain of PfClag9 were partially protected against a subsequent challenge infection with Plasmodium berghei, further supporting a biological role of PfClag9 during natural infection. Taken together, these results provide direct evidence for the existence of a PfRhopH-Clag9 complex on the Plasmodium merozoite surface that binds to human RBCs.
| S-EPMC6977125 | biostudies-literature
Project description:All pathogenesis and death associated with Plasmodium falciparum malaria is due to parasite-infected erythrocytes. Invasion of erythrocytes by P. falciparum merozoites requires specific interactions between host receptors and parasite ligands that are localized in apical organelles called micronemes. Here, we identify cAMP as a key regulator that triggers the timely secretion of microneme proteins enabling receptor-engagement and invasion. We demonstrate that exposure of merozoites to a low K+ environment, typical of blood plasma, activates a bicarbonate-sensitive cytoplasmic adenylyl cyclase to raise cytosolic cAMP levels and activate protein kinase A, which regulates microneme secretion. We also show that cAMP regulates merozoite cytosolic Ca2+ levels via induction of an Epac pathway and demonstrate that increases in both cAMP and Ca2+ are essential to trigger microneme secretion. Our identification of the different elements in cAMP-dependent signaling pathways that regulate microneme secretion during invasion provides novel targets to inhibit blood stage parasite growth and prevent malaria.
| S-EPMC4270784 | biostudies-literature
Project description:Inhibition of protein N-myristoylation blocks Plasmodium falciparum intracellular development and egress, but myristoylation of GAP45 is required only for erythrocyte invasion. TMT quantification used to determine protein expression changes upon inhibition of myristoylation
2021-10-07 | PXD021879 | Pride