PfAlba1 modulation of erythrocyte invasion protein translation
Ontology highlight
ABSTRACT:
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR986808.fastq.gz | Fastqsanger.gz | |||
| ERR986809.fastq.gz | Fastqsanger.gz | |||
| ERR986810.fastq.gz | Fastqsanger.gz | |||
| ERR986811.fastq.gz | Fastqsanger.gz | |||
| ERR986812.fastq.gz | Fastqsanger.gz |
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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
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Project description:PfNIF2 is a nuclear protein phosphatase belonging to the NIF family in Plasmodium falciparum. It is characterized by a conserved ‘DLDET’ motif, which is essential for its catalytic activity. PfNIF2 primarily localizes to the perinuclear or nuclear compartment and shows peak expression during the schizont stage of the parasite's lifecycle. Genetic disruption of the pfnif2 gene significantly impaired the efficiency of merozoite invasion, resulting in a 1.65-fold reduction (P < 0.05). It also increased susceptibility to artemisinin derivatives, with the IC50 of dihydroartemisinin decreasing from 12.5 nM to 7.9 nM (P < 0.001), although the asexual development of the parasites remained viable. Site-directed mutagenesis confirmed that aspartate 65 within the ‘D63LD65ET’ motif is critical for enzymatic function and invasion competence. Transcriptomic profiling revealed extensive dysregulation of invasion-related genes, including RON4 and MSP1, in schizont-stage PfNIF2Del parasites. Integrated co-immunoprecipitation, LC-MS/MS, and phosphoproteomic analyses demonstrated that PfNIF2 interacts with DNA repair machinery, such as SR1, SUN2, and MSH2-1. It plays a role in dephosphorylating RNA-binding proteins and invasion effectors. Notably, the expression of a phosphoablative variant of serine/arginine-rich splicing factor 1 (SR1-S205A/S208A) in PfNIF2Del parasites substantially rescued defects in DNA damage repair, alternative splicing fidelity, artemisinin sensitivity, and erythrocyte invasion. These findings establish PfNIF2 as a multifunctional regulator that bridges nuclear RNA processing, genome integrity maintenance, and host cell invasion in malaria parasites.
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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.
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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
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2024-07-17 | PXD037762 | Pride
Project description:Transcriptome Analysis Reveal Molecular Targets of Erythrocyte Invasion Phenotype Diversity in Natural Plasmodium falciparum Isolates from Cameroon.
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Project description:Cyclic nucleotide signalling is a major regulator of malaria parasite differentiation. Specific phosphodiesterase (PDE) enzymes are known to control cGMP levels in the parasite, but the mechanisms by with cAMP is regulated remain enigmatic. Here we show that P. falciparum PDEbeta translocates via the ER to an apical location and finally to the plasma membrane of merozoites within the segmented schizont. PDEbeta is essential for blood stage replication, with conditional gene disruption causing a profound invasion phenotype and rapid death of those merozoites that are able to invade a host erythrocyte. Importantly we also demonstrate that PDEbeta is able to hydrolyse both cAMP and cGMP. Loss of PDEbeta activity results in significantly elevated levels of cAMP which correlate temporally with the observed reduction in merozoite invasion. Quantitative phosphoproteomic analysis revealed a >2-fold increase in phosphorylation for >250 phosphosites following silencing of PfPDEbeta. These included a highly significant increase in phosphorylation at PKA substrate consensus sequences. Our results suggest that dysregulated phosphorylation of MyoA S19 and AMA1 S610 likely contributes to the PfPDEbeta knockout invasion phenotype, that PKG activity governs cAMP levels and PKA activation prior to merozoite egress, and that PfPDEbeta has an essential function in regulation cAMP levels in early intra-erythrocytic development in P. falciparum.
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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.
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Project description:Cyclic nucleotides are important signalling molecules across evolution, but their roles in malaria parasites are poorly understood. We have investigated the role of cAMP in asexual blood stage development of Plasmodium falciparum through conditional disruption of adenylyl cyclase (ACβ) and its downstream effector, cAMP-dependent protein kinase (PKA). We show that both production of cAMP and activity of PKA are critical for erythrocyte invasion, whilst key developmental steps that precede invasion still take place in the absence of cAMP-dependent signalling. We also show that another protein with putative cyclic nucleotide binding sites, PfEpac, does not play an essential role in cyclic nucleotide signalling in blood stages. We identify over 2,000 sites whose phosphorylation is dependent on cAMP signalling and we provide mechanistic insight as to how cAMP-dependent phosphorylation of the cytoplasmic domain of the essential invasion adhesin apical membrane antigen 1 (AMA1) controls erythrocyte invasion.
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