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PubMed2006

The long and winding road: protein trafficking mechanisms in the Plasmodium falciparum infected erythrocyte.

Mature human erythrocytes infected with the human malarial parasite Plasmodium falciparum are extensively modified to provide a more comfortable "home" for their intracellular guests. This process is mediated by parasite-encoded factors that are exported into, and through the host erythrocyte. This intra- yet simultaneously extra-cellular protein trafficking and sorting system has, in the past decades received much attention, also due to its unusual nature. Recent reports have highlighted the importance of a short peptide sequence, referred to individually as Plasmodium export element (PEXEL), vacuolar translocation signal (VTS) or generally as host cell targeting signal (HCT) in the export of both soluble and membrane bound proteins, allowing the partial definition of the parasite's "exportome". Mechanistically however, the discovery of this sequence raises as many questions as it answers. In this article, we comment on current models of protein transport to the host cell, discuss the mechanistic problems highlighted by these signals, and suggest what might be the next important steps in studying the protein export mechanisms of an obligate intracellular parasite that chooses to inhabit a de-nucleated host cell.

Animals↗
PubMed2006

A ubiquitous Plasmodium protein displays a unique surface labeling pattern in sporozoites.

The Plasmodium sporozoite is infective for mosquito salivary glands and vertebrate host tissues. Although it is a key developmental stage of the malaria parasite, relatively few sporozoite surface or secreted proteins have been identified and characterized. Herein, we describe the molecular and cellular characterization of a novel surface molecule that is preferentially-expressed in salivary gland sporozoites as compared to oocyst and hemolymph sporozoites. This molecule, designated the sporozoite and erythrocytic stages (SES) protein (formerly known as Pg4), exhibits a spiral surface labeling pattern that spans over a known sporozoite surface antigen, the circumsporozoite protein, with only minor co-localization. SES consists of 551 amino acids encoding a putative 63.2kDa protein that has been shown to be expressed not only on particular sporozoite stages, but also during the asexual and gametocyte stages. This novel protein also has three domains of unknown function that are conserved in at least eight Plasmodium spp. that represent human, avian, non-human primate, and rodent malarias.

Aedes↗
PubMed2006

Expression, localization, and erythrocyte binding activity of Plasmodium yoelii merozoite surface protein-8.

PyMSP-8 is a member of a family of merozoite surface proteins that have been described in Plasmodium that are characterized by the presence of a glycolipid membrane anchor and 1-2 epidermal growth factor-like domains. Immunization with recombinant PyMSP-8 has also been shown to protect mice against lethal Plasmodium yoelii malaria. In this report, we demonstrate that PyMSP-8 expression is detectable throughout the entire erythrocytic life cycle of P. yoelii 17XL, reaching peak level during trophozoite development. As determined by immunofluorescence, PyMSP-8 co-localizes with PyMSP-1 on the surface of merozoites in segmented schizonts and on the surface of ring stages in newly invaded erythrocytes. PyMSP-8 binds to the surface of uninfected mouse RBCs in a species-dependent manner, suggesting a potential role in merozoite attachment to and/or invasion of erythrocytes. The receptor for PyMSP-8 on RBCs is sensitive to trypsin digestion but is resistant to treatment with chymotrypsin or neuraminidase and is putatively identified as a approximately 105kDa membrane protein. Since PyMSP-8 binds to both mature RBCs as well as reticulocytes, it appears unlikely that the function of PyMSP-8 is restricted to the invasion of normocytes. While proper folding and conformation of PyMSP-8 are important, linear determinants of PyMSP-8 also contribute to erythrocyte binding. Unexpectedly, however, PyMSP-8 specific antibodies that are protective in vivo, do not disrupt the binding of rPyMSP-8 to its receptor on erythrocytes. The data indicate that protective anti-PyMSP-8 antibodies mediate their effect in vivo by an alternate mechanism(s).

Animals↗
PubMed2006

Receptor-binding studies of the DBLgamma domain of Plasmodium falciparum erythrocyte membrane protein 1 from a placental isolate.

We have previously identified a number of DBLgamma domains in Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) transcripts obtained from placental parasite isolates, showing that they bind specifically to chondroitin sulfate A (CSA) (Khattab A, Kun J, Deloron P, Kremsner PG, Klinkert MQ. Variants of Plasmodium falciparum erythrocyte membrane protein 1 expressed by different placental parasites are closely related and adhere to chondroitin sulfate A. J Infect Dis 2001;183:1165-9). Here we give a more detailed physico-chemical and binding characterisation of the soluble, recombinant DBLgamma domain derived from one of these isolates. Results from circular dichroism and limited proteolysis experiments are consistent with the recombinant domain being expressed with the native fold. Specific binding of DBLgamma to placental cryosections was demonstrated by labeling with antibodies raised against the recombinant domain; binding was diminished after treatment of the cryosections with chondroitinase or by blocking with anti-CSA antibody, showing that CSA mediates the interaction. Binding of the DBLgamma domain to purified placental chondroitin sulfate proteoglycan (CSPG) was also studied using surface plasmon resonance techniques, with DBLgamma as analyte and CSPG immobilised on the sensor chip; these quantitative measurements gave an affinity constant in the mu-molar range under the conditions used. The native conformation of the DBLgamma domain is essential for CSPG recognition since binding to the sensor chip is abolished when the protein is irreversibly reduced. As with the placental cryosections, association was significantly reduced after treating the immobilised CSPG with chondroitinase. Together, these results demonstrate specific interaction between the DBLgamma domain and the placental receptor.

Amino Acid Motifs↗
PubMed2004

Identification of Plasmodium falciparum reticulocyte binding protein RBP-2 homologue a and b (PfRBP-2-Ha and -Hb) sequences that specifically bind to erythrocytes.

Plasmodium falciparum reticulocyte binding protein RBP-2 homologues a and b (PfRBP-2-Ha and -Hb) have been described as being high molecular weight proteins, expressed at the P. falciparum merozoite apical extreme, belonging to a family of proteins found in other Plasmodium involved in the search for erythrocyte populations before being invaded by merozoites. 185, 20-mer-long non-overlapping peptides, spanning the entire PfRBP-2-Ha and -Hb sequences, were synthesised, radiolabelled and tested in erythrocyte binding assays. Fifteen PfRBP-2-Ha and -Hb high binding activity peptides (HBAPs) specifically binding to erythrocytes with high affinity were identified. Dissociation constants were between 70 and 300 nM and Hill coefficients were 1 approximately. HBAPs residues critical for binding to erythrocytes were determined. Cross-linking was performed allowing possible receptors for PfRBP-2-Ha and -Hb to be identified on the surface of the erythrocytes. Some of the HABPs showed merozoite invasion inhibition greater than 90% in in vitro assays.

Amino Acid Sequence↗
PubMed2005

Refolding, purification, and crystallization of apical membrane antigen 1 from Plasmodium falciparum.

Extracellular domains of malaria antigens almost invariably contain disulphide linkages but lack N- and O-linked glycosylation. The best practical approach to generating recombinant extracellular Plasmodium proteins is not established and the problems encountered when using a bacterial expression/refolding approach are discussed in detail. Limited proteolysis experiments were used to identify a relatively non-flexible core region of the Plasmodium falciparum protein apical membrane antigen 1 (AMA1), and refolding/purification was used to generate two fragments of AMA1. Several chromatographically distinct AMA1 variants were identified that are presumably differentially refolded proteins. One of these AMA1 preparations proved to be crystallizable and generated two crystal forms that diffracted X-rays to 2 A resolution.

Animals↗
PubMed2006

Plasmodium falciparum merozoite surface protein 6 (MSP-6) derived peptides bind erythrocytes and partially inhibit parasite invasion.

This work shows that Plasmodium falciparum merozoite surface protein-6 (MSP-6) peptides specifically bind to membrane surface receptor on human erythrocytes. Three high activity binding peptides (HABPs) were found: peptides 31175 (41MYNNDKILSKNEVDTNIESN60) and 31178 (101YDIQATYQFPSTSGGNNVIP120) in the amino terminal region and 31191 (361EIDSTINNLVQEMIHLFSNNY380) at the carboxy terminal. Their binding to erythrocytes was saturable. HABPs 31191 and 31178 recognized 56 and 26 kDa receptors on erythrocyte membrane and inhibited in vitro Plasmodium falciparum merozoite invasion of erythrocytes by between 27% and 46% at 200 microg ml(-1) concentration, suggesting that these MSP-6 protein peptides play a possible role in the invasion process.

Amino Acid Sequence↗
PubMed2005

Plasmodium falciparum-infected red blood cells selected for binding to cultured syncytiotrophoblast bind to chondroitin sulfate A and induce tyrosine phosphorylation in the syncytiotrophoblast.

An important pathogenic complication of malaria during human pregnancy is sequestration of Plasmodium-infected red blood cells (iRBCs) in the placental intervillous spaces. This sequestration is thought to be mediated in part by binding of the iRBCs to receptors expressed on the syncytiotrophoblast (ST) membrane. We report here the use of a dynamic system to study the consequences of this cytoadherence on ST function using human syncytiotrophoblast and the choriocarcinoma cell line, BeWo. Laboratory isolates of Plasmodium falciparum were selected for their ability to bind to ST and used to investigate binding-induced cellular changes in the ST. Treatment of the ST cells with chondroitinase ABC suggested that the selected parasites bind predominantly to chondroitin sulfate A, but other receptors for parasite binding may be involved. Intracellular signaling in the ST induced by iRBCs binding was investigated by assessing tyrosine phosphorylation of ST proteins following iRBC binding. We demonstrate for the first time that iRBC cytoadherence to syncytiotrophoblast enhances tyrosine phosphorylation of a series of proteins in these cells. This approach will be useful in further studies of ST function in the malaria-infected placenta, the dynamics of selection of syncytiotrophoblast-binding parasites, and the identification of new receptors for parasite cytoadherence in the placenta.

Adult↗
PubMed2006

The structure of the Plasmodium falciparum EBA175 ligand domain and the molecular basis of host specificity.

Erythrocyte-binding antigen 175 (EBA175) is one of the best-characterized Plasmodium falciparum merozoite ligands; the recently solved crystal structure of EBA175 reveals that terminal sialic acids on the erythrocyte glycoprotein glycophorin A are a crucial factor for erythrocyte recognition by EBA175 because they lock into pockets on its surface. Comparison with Plasmodium reichenowi EBA175 indicates that these interactions have a pivotal role in the host-specific adaptations of parasite ligands.

Animals↗
PubMed2006

Plasmodium rhoptries: how things went pear-shaped.

Plasmodium parasites have three sets of specialised secretory organelles at the apical end of their invasive forms--rhoptries, micronemes and dense granules. The contents of these organelles are responsible for or contribute to host cell invasion and modification, and at least four apical proteins are leading vaccine candidates. Given the unusual nature of Plasmodium invasion, it is not surprising that unique proteins are involved in this process. Nowhere is this more evident than in rhoptries. We have collated data from several recent studies to compile a rhoptry proteome. Discussion is focussed here on rhoptry content and function.

Animals↗
PubMed2006

A case of 'hit-and-run' in Plasmodium genetics.

The ability to genetically manipulate species of the genus Plasmodium, some of which are causative organisms of malaria, has seen significant advances in the past 13 years. However, one major tool that has been lacking is the ability to undertake reverse genetics and 'hit-and-run' mutagenesis. This deficiency has been addressed in the Plasmodium berghei model.

Animals↗
PubMed2006

The origin and age of Plasmodium vivax.

The evolutionary history of Plasmodium vivax has recently been addressed in terms of its origin as a parasite of humans and the age of extant populations. The consensus is that P. vivax originated as a result of a host switch from a non-human primate to hominids and that the extant populations did not originate as recently as previously proposed. Here, we show that, in a comparison of parasite isolates from across the world, Asian populations of P. vivax are the oldest. We discuss how this result, together with the phylogenetic evidence that P. vivax derived from Plasmodium found in Southeast Asian macaques, is most simply explained by assuming an Asian origin of this parasite. Nevertheless, the available data show only the tip of the iceberg. We discuss how sampling might affect time estimates to the most recent common ancestor for P. vivax populations and suggest that spatially explicit estimates are needed to understand the demographic history of this parasite better.

Animals↗
PubMed2005

Combinatorial gene regulation in Plasmodium falciparum.

The malaria parasite Plasmodium falciparum has a complicated life cycle with large variations in its gene expression pattern, but it contains relatively few specific transcriptional regulators. To elucidate this paradox, we identified regulatory sequences, using an approach that integrates the sequence conservation among species and the correlation in mRNA expression within a species. Our analysis identified several DNA sequence motifs that are associated with mRNA expression, two of which were previously determined experimentally. We found more putative regulatory sequences per gene in P. falciparum than in other eukaryotes, such as yeast. We propose that Plasmodium uses the few regulatory proteins it has in a combinatorial approach for gene regulation, explaining the relative paucity in regulatory proteins.

Animals↗
PubMed2004

Anti-Plasmodium properties of group IA, IB, IIA and III secreted phospholipases A2 are serum-dependent.

Antibacterial, antiparasitidal and antiviral properties have recently been attributed to members of the secreted phospholipases A(2) (sPLA(2)s) superfamily. Seven sPLA(2)s from groups IA, IB, IIA and III, were tested here in different culture conditions for inhibition of the in vitro intraerythrocytic development of Plasmodium falciparum, the causative agent of the most severe form of human malaria. In the presence of human serum, all sPLA(2)s were inhibitory, with three out of seven exhibiting IC(50)<0.1 nM. In all cases, inhibition could be induced by enzymatic pre-treatment of the serum. By contrast, no effect was observed when parasites were grown in a semi-defined medium (AlbuMAX II) devoid of lipoproteins and containing 10 times less phospholipids than the medium with human serum, strongly suggesting that hydrolysis of serum generating toxic lipid by-products, rather than a direct interaction of the sPLA(2) with the infected erythrocyte, is a general feature of the anti-Plasmodium properties of sPLA(2)s. Furthermore, in serum, six out of the seven sPLA(2)s were toxic against both trophozoite and schizont stages of the parasite development, contrasting with the trophozoite-selective bee venom enzyme's toxicity. Deciphering the molecular mechanisms at play in the phenotypic singularity of the bee venom enzyme toxicity might offer new prospects in antimalarial fight.

Animals↗
PubMed2004

Limited influence of haemoglobin variants on Plasmodium falciparum msp1 and msp2 alleles in symptomatic malaria.

Haemoglobin (Hb) S, HbC, and alpha(+)-thalassaemia confer protection from malaria. Accordingly, these traits may influence the multiplicity of infection (MOI) of Plasmodium falciparum and the presence of distinct parasite genotypes. In 840 febrile children in northern Ghana, we typed the P. falciparum merozoite surface protein genes (msp1, msp2) and examined effects of the Hb variants on MOI and parasite diversity. HbAC, HbAS, heterozygous, and homozygous alpha(+)-thalassaemia occurred in 21, 5, 29 and 4% of the children, respectively. Plasmodium falciparum was detected in 95%. The haemoglobinopathies did not influence MOI, nor did the Hb type bias the distribution of the msp allelic families. However, IC type parasites were most common among patients with homozygous alpha(+)-thalassaemia (93%), less frequent in heterozygotes (89%), and least frequent in alpha-globin normal children (84%, P(chi2 trend) = 0.03). The opposite was seen for Mad20 type parasites (34%, 47%, 53%, P(chi2 trend) = 0.02). Only a few of the 72 individual msp alleles were selected by the haemoglobinopathies. HbC and alpha(+)-thalassaemia are frequent in northern Ghana. In symptomatic children, the effect of Hb variants on parasite multiplicity and diversity appears to be limited. This may reflect an actual lack of influence or indicate abrogation in symptomatic malaria.

Adolescent↗
PubMed2007

The heat stability of Plasmodium lactate dehydrogenase-based and histidine-rich protein 2-based malaria rapid diagnostic tests.

Malaria rapid diagnostic tests (RDTs) have performed well in a variety of studies, but recent reports have described sensitivity for Plasmodium falciparum as significantly lower than that required for operational deployment. Exposure to high temperature has been suggested as an explanation. This study assessed the temperature stability of two different Plasmodium lactate dehydrogenase (pLDH)- and three histidine-rich protein 2 (HRP2)-detecting RDTs. One HRP2 test proved insufficiently sensitive for assessment. After incubation at 35, 45 and 60 degrees C, two RDTs detecting pLDH showed a substantial fall in percentage test line positivity over time, which was not seen with the remaining two HRP-2-based RDTs. For the particular products studied, variability was high, with the pLDH-based RDTs being less sensitive than HRP2-based RDTs against the sample of P. falciparum used and more susceptible to heat-induced damage, but the reasons for this are unclear. The performance of malaria RDTs can be adversely affected at the temperatures to which they will be exposed when transported to, and used in, the rural tropics.

Animals↗
PubMed2004

Enhanced protective immunity against malaria by vaccination with a recombinant adenovirus encoding the circumsporozoite protein of Plasmodium lacking the GPI-anchoring motif.

A major malaria vaccine candidate, the circumsporozoite (CS) protein of Plasmodium, is a pre-erythrocytic stage antigen that is attached to the surface of the sporozoites through a glycosylphosphatidylinositol (GPI) anchor. However, here we show that the motif that signals for glycosylphosphatidylinositol anchor addition interferes with the immunogenicity of this protein and reduces protection in mice upon immunization with a recombinant adenovirus. The presence of the glycosylphosphatidylinositol-anchoring motif sequentially affected total circumsporozoite protein production, cellular distribution, antigen processing and secretion, leading to less effective antigen presentation. Consistently, vaccination with an adenovirus recombinant carrying the anchoring motif-disrupted circumsporozoite gene, resulted in significant increase of the number of interferon-gamma (IFN-gamma) producing T cells and specific IgG2a isotype antibodies, ensuing more effective vaccination. Given that the anchoring motif is highly conserved among different species of Plasmodium, anti-malaria subunit vaccines encoded by recombinant vectors that aim at the induction of strong cellular immunity could maximize immunogenicity by removing anchoring motifs.

Adenoviridae↗
PubMed2006

Soluble and glyco-lipid modified baculovirus Plasmodium falciparum C-terminal merozoite surface protein 1, two forms of a leading malaria vaccine candidate.

Recombinant homologues of the Plasmodium merozoite surface protein 1 C-terminus are leading blood stage malaria vaccine candidates. MSP1 is anchored to the merozoite plasma membrane in vivo by a glycosyl-phosphatidyl-inositol (GPI) moiety, implicated in malaria pathology. Two types of recombinant Plasmodium falciparum MSP1p19 (PfMSP1p19) expressed in baculovirus/insect cells are described here: (1) a soluble, secreted form (PfMSP1p19S) and (2) detergent soluble cellular form(s) (PfMSP1p19+A), released from the infected cell surface by treatment with GPI specific phosphatidyl-inositol phospholipase C (PI-PLC). Soluble and cellular PfMSP1p19 were purified and characterized using SDS-PAGE, mass spectrometry (MS), N-terminal amino acid sequencing, gel filtration and glycan analyses. Quantitative inositol dosage suggested that surface GPI processed entities constituted only 14% of the purified cellular PfMSP1p19+A, with GPI unprocessed forms likely recovered in the endoplasmic reticulum. Nevertheless, this preparation has dramatic immuno-stimulatory activity to be described elsewhere. The interest of these results for both malaria specific and generic vaccine development are discussed.

Amino Acid Sequence↗