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PubMed2005

Re-defining the Golgi complex in Plasmodium falciparum using the novel Golgi marker PfGRASP.

Plasmodium falciparum, the causative agent of malaria, relies on a sophisticated protein secretion system for host cell invasion and transformation. Although the parasite displays a secretory pathway similar to those of all eukaryotic organisms, a classical Golgi apparatus has never been described. We identified and characterised the putative Golgi matrix protein PfGRASP, a homologue of the Golgi re-assembly stacking protein (GRASP) family. We show that PfGRASP is expressed as a 70 kDa protein throughout the asexual life cycle of the parasite. We generated PfGRASP-GFP-expressing transgenic parasites and showed that this protein is localised to a single, juxtanuclear compartment in ring-stage parasites. The PfGRASP compartment is distinct from the ER, restricted within the boundaries of the parasite and colocalises with the cis-Golgi marker ERD2. Correct subcellular localisation of this Golgi matrix protein depends on a cross-species conserved functional myristoylation motif and is insensitive to Brefeldin A. Taken together our results define the Golgi apparatus in Plasmodium and depict the morphological organisation of the organelle throughout the asexual life cycle of the parasite.

Amino Acid Sequence↗

PubMed2000

Proteolysis of Plasmodium falciparum surface antigen, Pfs230, during gametogenesis.

During Plasmodium falciparum gametogenesis, proteolysis of Pfs230, a 360 kDa gametocyte surface protein, generates two large polypeptides, 307 and 300 kDa, that remain associated with the surface of the newly formed gamete. Using peptide specific antibodies, the amino termini of the 307 and 300 kDa forms have been mapped to between aa 477-487 and aa 523-555, respectively, which is the region between the glutamate rich repeats and the cysteine motif domains. Concomitantly, two peptides, 47 and 35 kDa, corresponding to the region upstream from the cleavage site are released into the medium. The membrane permeant cysteine protease inhibitor, E64d, blocks production of the 300 and 35 kDa forms of Pfs230, but does not alter the formation of the 307 or 47 kDa forms. In contrast, E64, which has been shown to inhibit the development of P. falciparum trophozoites, does not block proteolytic processing of Pfs230. Production of both the 307 and 300 kDa forms was reduced by a metallo-protease inhibitor, 1,10-phenanthroline, whereas the rest of the protease inhibitors tested had no effect on Pfs230 processing. This is the first study of proteolysis during gametogenesis and it demonstrates that the two large forms of Pfs230 produced are generated by proteases with different specificities. The data also suggest that Pfs230 undergoes proteolytic processing prior to emergence from the red blood cell.

Animals↗

PubMed1997

Protein trafficking in the Plasmodium-falciparum-infected erythrocyte--from models to mechanisms.

Plasmodium falciparum is a eukaryotic single cell which invades human erythrocytes. Within the host cell, the parasite is surrounded by the membrane of the parastiophorous vacuole. Parasite proteins are secreted either into the vacuolar space or are exported, by an as yet unknown mechanism, across the vacuolar membrane into erythrocyte cytoplasm. In recent years, several groups have devised experimental approaches to follow the transport pathways of proteins from the parasite into the host cell. The concepts underlying these approaches and the peculiarities of the transport pathways are discussed and compared with protein transport in higher eukaryotes.

Animals↗

PubMed1989

Construction and screening of Plasmodium falciparum cDNA library.

The HAINAN isolate of Plasmodium falciparum FCC1/HN was cultured in vitro in large quantities. The total parasite mRNA was purified and reverse transcribed into cDNA. The cDNA fragments were inserted into lambda gt11 to construct a P. falciparum FCC1/HN erythrocytic stage cDNA library. Inhibitory monoclonal antibodies (McAbs) M26-32, F6-C2, and F6-D3 were used to screen the cDNA library expressed in E. coli. A total of 27 positive clones were found to react with M26-32 alone and 34 clones with both M26-32 and F6-C2. These expressed proteins may be candidates for use in malaria vaccine.

Animals↗

PubMed1975

Occurrence of S-antigens in serum in Plasmodium falciparum infections in man.

Gambians with severe Plasmodium falciparum infections frequently have malarial S-antigens in their serum or plasma. Detection of these with the available antisera which are from immune adults is complicated because there are many different S-antigens and none of the antisera contains antibodies to them all. Despite this we found S-antigens in about 60% of a large series of malarious children and demonstrated that this was a considerable underestimate of the true incidence. We also showed that the prevalence of S-antigens was related to the malaria season and to the intensity of infection.

Antigens↗

PubMed2000

Molecular cloning of a gene encoding a 20S proteasome beta subunit from Plasmodium falciparum.

A novel gene was cloned from Plasmodium falciparum. Database searches indicated this gene to be a member of the 20S proteasome beta-subunit family. Comparison of the gene's genomic DNA sequence with cDNA sequence revealed a 156-bp intron 85 bp downstream from the start codon. The nucleotide sequence of the gene contains one open reading frame encoding 265 amino acids with a predicted molecular mass of 30.9 kDa and a pI of 6.2. Northern blot analysis showed the transcript size to be approximately 1.6 kb indicating that some 800 bp of the transcript is non-coding.

Adenosine Triphosphatases↗

PubMed1999

HLA class II factors associated with Plasmodium falciparum merozoite surface antigen allele families.

In Plasmodium falciparum malaria, certain human leukocyte antigens (HLA) and the parasite's merozoite surface antigens 1 and 2 (MSA-1, MSA-2) have been shown to influence the course of the infection. This report is on associations of distinct HLA factors with the occurrence of particular MSA families in a group of patients with either severe or mild P. falciparum malaria in Gabon. Different distributions of HLA-DPB1 alleles were found in the 2 groups. DR *04 alleles were observed more frequently among patients with severe malaria. Several alleles of different loci were associated with distinct MSA allele families. In addition, carriers of the amino acid methionine at position 11 of the DPA1 allele were more often infected by MSA-1 K1 parasites and less frequently by MSA-1 RO33 parasites. Furthermore, associations of HLA factors with polyclonal infections were found.

Alleles↗

PubMed2004

Hyperhomocysteinemia in acute Plasmodium falciparum malaria: an effect of host-parasite interaction.

BACKGROUND: Plasmodium falciparum utilises the polyamine pathway, essential in proliferation and differentiation, and imposes an oxidative stress on host cell, enhancing the loss of glutathione. METHODS: Standard hematological parameters were determined in 40 black African subjects with acute P. falciparum malaria, 30 aged 5-24 months, 5 aged 4-10 years and 5 aged 19-35 years. Plasma homocysteine, cysteine, glutathione and cysteinylglycine levels were measured by HPLC method. Twenty-eight healthy black children (15 aged 6-24 months and 13 aged 3-10 years) and 20 healthy black adults (aged 20-40 years) were also included as controls. RESULTS: Plasma homocysteine levels were higher in all subjects with P. falciparum malaria and correlated positively with the disease severity and number of parasites, but negatively with Hb levels and patient ages. Cysteine level was found higher in all patients and markedly higher in 4-10 year old patients. Cysteinylglycine level was found lower particularly in 19-35 year old patients. Glutathione level was significantly lower in all patients. CONCLUSIONS: The elevated level of homocysteine during acute P. falciparum infection suggests an imbalance in the folate cycle, which could be a consequence of the reduced availability of NADPH and Vit B12, caused by increased oxidative stress. This may suggest a selection for the C677T MTHFR allele, driven by P. falciparum in sub-Saharan regions. Hence Hcy level could be useful as a predictive parameter of severity, as well as of treatment efficacy.

Acute Disease↗

PubMed2000

Antigenic diversity of Plasmodium falciparum and antibody-mediated parasite neutralization.

The malaria parasite Plasmodium falciparum, causing the most severe form of the disease in humans, is characterized by a broad antigenic diversity between different strains and isolates of the parasite. The antigenic diversity reflects on the one hand polymorphisms in allelic gene products and, on the other hand, antigenic variation as a result of expression of alternative genes in multigene families. Using selected polymorphic regions in two merozoite surface antigens, a method for genotyping P. falciparum parasites has been developed. This has resulted in new information on the clonal multiplicity and dynamics of parasite populations. Observations from in vivo and in vitro studies have identified many potential parasite-neutralizing immune responses and several of the target antigens are being explored as vaccine candidates. Studies of antibody-mediated neutralization of parasites in P. falciparum in vitro cultures, with or without leukocytes as effector cells, have been instrumental in identifying potential target antigens for protective immunity and for elucidation of the effects of immune pressure on the dynamics of parasite populations and their antigenic plasticity.

Adult↗

PubMed1997

Receptor-specific adhesion and clinical disease in Plasmodium falciparum.

One important factor in the virulence of infections with Plasmodium falciparum is the adherence of infected erythrocytes to small vessel endothelium. In infections that lead to serious, life-threatening disease accumulation of large numbers of infected cells in particular organs is thought to lead to organ dysfunction or failure. This is of particular relevance when the affected organ is the brain, leading to the development of cerebral malaria. Many different endothelial receptors for infected red blood cells have been identified. Some receptors such as CD36 and thrombospondin are used by all parasite isolates, whereas others such as intercellular adhesion molecule-1 (ICAM-1) or vascular cell adhesion molecule (VCAM) are used by a subset of field and laboratory isolates. While it has been speculated that the ability to bind or affinity of binding to a particular endothelial receptor may be related to the pattern of disease, only studies with limited numbers of patients have been carried out to date and these have been in general inconclusive. Here we have taken parasite isolates from 150 patients with defined clinical syndromes as well as isolates from 50 healthy but parasitized community controls and quantitatively assessed their binding to purified endothelial receptors in vitro. Our results show that disregarding the level of adhesion, all parasites bind to CD36, most bind to ICAM-1, few bind to VCAM, and almost none bind to E-selectin. In assessing the degree of binding we show that 1) binding to all receptors was reduced in parasites taken from severely anemic patients; 2) binding to CD36 is identical in parasites from cerebral malaria patients and community controls but slightly elevated in parasites from nonsevere cases; and 3) binding to ICAM-1 is highest in cerebral malaria patients. Because rosette formation by uninfected cells has also been a phenotype associated with disease severity and one that may interfere in vitro with receptor binding, we also assessed rosette formation in all isolates. In this study the highest level of rosette-forming parasites was found in the anemic group and not the cerebral malaria group. Stratifying the data for the frequency of rosette formation showed that the above results were not significantly altered by this phenomenon. Our data are not consistent with a role for binding to CD36 in the development of severe disease but show an association between the degree of binding to ICAM-1 and clinical illness in nonanemic patients.

Anemia↗

PubMed1997

Light microscopic changes in Plasmodium falciparum from Gabonese children treated with artemether.

The changes in Plasmodium falciparum in four Gabonese children suffering from severe malaria and treated with pure artemether were observed in thin blood smears fixed and stained with Giemsa and examined by light microscopy. Peripheral blood samples were taken every 8 hr up to 72 hr from three children and every 3 hr up to 9 hr from the other child. The morphologic changes involved all development stages (trophozoites, schizonts, and gametocytes); they were first seen 3 hr after the start of treatment and all parasites were abnormal after 24 hr. After two days of treatment, all infected erythrocytes disappeared except for a few with necrotic trophozoites. The morphologic changes were similar to the ultrastructural changes previously described in vivo and in vitro in experimental models. They confirm the rapid effect of artemisinin derivatives on parasite clearance and clinical recovery, particularly in cases of cerebral malaria.

Animals↗

PubMed1995

Patterns of antibody levels to the 96 tR recombinant protein of Plasmodium falciparum in children over a six-month period.

Several Plasmodium falciparum asexual stage antigens have been reported as possible candidate antigens for vaccines against malaria. One such is the 96-kDa antigen. We used the 96 tR recombinant protein to determine the levels of antibodies to this protein over a 6-mo period in children 4 mo to 15 yr old, who make up the population at risk in Cameroon. The mean enzyme-linked immunosorbent assay (ELISA) on 83 children at the start of the study in June was 0.270, with 13% of these children having ELISA values considered to be positive (> or = 0.36). In the follow-up study in early December, the mean ELISA was 0.320 with 20% of the children having positive values. In the period between June and December, 85% of the children who returned for follow-up had had 1 or more attacks of malaria. The mean ELISA values of this latter group had increased from 0.235 in June to 0.318 in December, with 6% of the children in June having positive values compared with 18% in December. These findings reinforce our evidence from a previous study that reactivity to the 96-kDa antigen is related to adequate exposure or repeated infection.

Adolescent↗

PubMed1989

Development of the human immune response against the major surface protein (gp190) of Plasmodium falciparum.

The 190-kilodalton glycoprotein (gp190) of Plasmodium falciparum, the precursor of the major surface proteins of merozoites, is considered a promising candidate for a blood stage malaria vaccine. DNA sequences specific for the gp190 of the two isolates K1 and MAD20 were subcloned and expressed in Escherichia coli. The panel of fusion proteins obtained represents about 80% of the polymorphic sequences observed so far within various isolates of P. falciparum. Sera from individuals living in a malaria-endemic area of West Africa were tested in immunoblots against the gp190 fusion proteins, and antibody reactivity was mapped to defined regions of the gp190. Depending on the age of the individual and on the presence of parasites in the blood, distinct regions of gp190 were differentially recognized by the respective antibodies. Similarly, the analysis of sera from German patients with acute malaria revealed a distinct pattern. When grouped according to age and to parasitemia, the reactivity of the sera of people living in malaria-endemic areas may indicate a correlation between certain gp190 regions and protective immune response.

Animals↗

PubMed2002

Genes for glycosylphosphatidylinositol toxin biosynthesis in Plasmodium falciparum.

About 2.5 million people die of Plasmodium falciparum malaria every year. Fatalities are associated with systemic and organ-specific inflammation initiated by a parasite toxin. Recent studies show that glycosylphosphatidylinositol (GPI) functions as the dominant parasite toxin in the context of infection. GPIs also serve as membrane anchors for several of the most important surface antigens of parasite invasive stages. GPI anchoring is a complex posttranslational modification produced through the coordinated action of a multicomponent biosynthetic pathway. Here we present eight new genes of P. falciparum selected for encoding homologs of proteins essential for GPI synthesis: PIG-A, PIG-B, PIG-M, PIG-O, GPI1, GPI8, GAA-1, and DPM1. We describe the experimentally verified mRNA and predicted amino acid sequences and in situ localization of the gene products to the parasite endoplasmic reticulum. Moreover, we show preliminary evidence for the PIG-L and PIG-C genes. The biosynthetic pathway of the malaria parasite GPI offers potential targets for drug development and may be useful for studying parasite cell biology and the molecular basis for the pathophysiology of parasitic diseases.

Acetylation↗

PubMed1984

Intranuclear structures in pyrimethamine-resistant isolates of the malaria parasite Plasmodium falciparum.

The ultrastructure of the malaria parasite Plasmodium falciparum is well known, both from natural infections and from culture material ( Aikawa , 1977, Langreth et al., 1978). It is noteworthy that all of these studies were done with pyrimethamine-sensitive strains, e.g. FCR-3/Gambia. Except for spindle microtubules during schizogony, no intranuclear structures have been described in any of the asexual erythrocytic stages. In the course of isolating clones from the pyrimethamine-resistant strain Honduras I/CDC (V.K. Bhasin and W. Trager , in print) and checking by electron microscopy for the presence or absence of knobs, we noticed intranuclear structures that might be correlated with pyrimethamine resistance. For comparison, we then examined the multi-drug-resistant strain Indochina 1. We present here a first report on these structures as a basis for further studies.

Animals↗

PubMed1988

Immunofluorescent and immunoelectron microscopic localization of protein antigens in red cells infected with the human malaria Plasmodium falciparum.

Erythrocytes infected with the human malaria Plasmodium falciparum produce elevations of the surface membrane of the red cell called knobs. Through the use of transmission electron microscopy and a post-embedding protein A-immunogold technique, it was possible to show changes in the distribution of band 3, glycophorin A and spectrin in the region of the knob. These proteins appeared to be aggregated or condensed in the area of the knob, whereas the remainder of the red cell surface showed no such dense clusters; haemoglobin and the histidine-rich protein of P. lophurae could not be localized to the knobby protuberances. It was not possible to detect any changes in protein distribution using the light microscope and indirect immunofluorescence.

Animals↗

PubMed1983

Gametocyte formation by the progeny of single Plasmodium falciparum schizonts.

Gametocytogenesis of the malaria parasite Plasmodium falciparum was studied in monolayers of erythrocytes attached to tissue culture dishes. Merozoites produced by single schizonts in erythrocytes overlaying the monolayer infected the attached erythrocytes and produced clusters of progeny. Parasites in these readily indentifiable clusters then underwent either asexual growth or sexual differentiation. The progeny of most schizonts yielded no gametocytes. However, the progeny of those schizonts that did yield gametocytes showed a marked tendency to produce multiple gametocytes. Gametocytogenesis, therefore, was not random. Instead, the progeny of certain schizonts were committed to produce gametes. However, even those clusters containing several gametocytes also contained asexual forms. Therefore, not all merozoites of a single schizont were committed to gametocytogenesis. In those cells infected with two or more merozoites the formation of a gametocyte was usually associated with a block in the further development of other parasites.

Animals↗

PubMed1993

Induction of cytolytic and antibody responses using Plasmodium falciparum repeatless circumsporozoite protein encapsulated in liposomes.

Plasmodium circumsporozoite (CS) protein-induced antibody and T-cell responses are considered to be important in protective immunity. Since the key repeat determinant of the CS protein may actually restrict the recognition of other potential T- and B-cell sites, a modified Plasmodium falciparum CS protein lacking the central repeat region, RLF, was expressed in Escherichia coli. On purification, RLF was encapsulated into liposomes [L(RLF)] and used for the in vivo induction of cytolytic T lymphocytes (CTL) and antibodies. Immunization of B10.Br (H-2k) mice with L(RLF), but not with RLF, induced CD8+ CTL specific for the P. falciparum CS protein CTL epitope, amino acid residues 368-390. Anti-L(RLF) serum reacted with antigens on intact sporozoites and inhibited sporozoite invasion of hepatoma cells. Antibody specificity studies in New Zealand White rabbits revealed new B-cell sites localized in amino acid residues 84-94, 91-99, 97-106 and 367-375. Although the mechanisms by which liposomes enhance cellular and humoral immune responses remain unknown, liposome-formulated vaccines have been well tolerated in humans; hence, their use in vaccines, when efficacy depends on antibody and CTL responses, may be broadly applicable.

Amino Acid Sequence↗