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PubMed1996

CD36 and intercellular adhesion molecule 1 mediate adhesion of developing Plasmodium falciparum gametocytes.

Plasmodium falciparum trophozoite-infected erythrocytes adhere to the amelanotic melanoma C32 cell line in vitro. Here we demonstrate for the first time that immature gametocyte-infected erythrocytes also adhere to C32 cells, albeit at lower levels than trophozoites. However, anti-CD36 and anti-intercellular adhesion molecule 1 antibodies inhibit asexual and gametocyte adhesion by comparable percentages, suggesting a common dependency for binding to these cellular receptors.

Adhesiveness↗
PubMed1982

An automated assay of merozoite invasion of erythrocytes using highly synchronized Plasmodium falciparum cultures.

Plasmodium falciparum cultures were synchronized using three lytic treatments with sorbitol. Schizonts from these cultures were used in a rapid, highly sensitive assay of invasion of erythrocytes by merozoites. The parasitaemias in recipient cells after invasion were determined by flow cytofluorimetry after staining with the dye 33258 Hoechst. Invasion of erythrocytes was shown to be reduced by serum from a patient with malaria. The assay is suitable for rapidly screening large numbers of samples, such as monoclonal antibodies.

Animals↗
PubMed1985

Purification and immunochemical study of Plasmodium falciparum exoantigens.

Plasmodium falciparum, in in vitro culture, elaborated many antigens including soluble exoantigens that are released into the culture medium. Anionic and cationic methods of isolating these antigens offer a great potential for large scale purification from medium that is rich in proteins but contains relatively low concentrations of P. falciparum specific antigens. These exoantigens have cationic and anionic dependent elution profiles (pI between 3.7 and 4.8). Five apparent molecular weight entities (58, 80, 145, 200, and 290 kdaltons) have been determined by GEDELISA. Susceptibility to lipase and to a proteolytic enzyme confirmed the proteinaceous nature of the antigens. They were isolated from 4 strains of different geographic origin, indicating their ubiquitous nature. The analogy of these exoantigens to circulating antigens in patients with acute malaria and their potential usefulness in immunodiagnosis and immunoprophylaxis are discussed.

Animals↗
PubMed1993

Nucleotide binding properties of a P-glycoprotein homologue from Plasmodium falciparum.

The Plasmodium falciparum P-glycoprotein homologue 1 (PGH1) is structurally similar to several members of the ATP-binding cassette (ABC) superfamily of membrane transporters. We have examined whether the nucleotide binding domains predicted from the deduced amino sequence are functional by photoaffinity labeling of purified parasite digestive vacuoles with the analogue 8-azido-alpha-[32P]ATP (8-N3-ATP). This reagent labels a 160-kDa protein in vacuoles from both a chloroquine sensitive and a chloroquine-resistant parasite isolate. The 160-kDa protein could be immunoprecipitated with affinity-purified antibodies against the P. falciparum P-glycoprotein homologue (PGH1). Inhibition of photoaffinity labeling of PGH1 could be achieved with ATP, ADP, GTP and GDP but not with AMP or GMP. In order to map the 8-N3-ATP binding sites on PGH1, photoaffinity-labeled PGH1 was digested with trypsin and immunoprecipitated with site-specific antibodies. Taken together, these results indicate that 8-N3-ATP specifically labels PGH1 and that one binding site resides within the amino terminal half of the molecule. This supports the contention that PGH1 is involved in a nucleotide-regulated transport function across the membrane of the digestive vacuole.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

A role for apical membrane antigen 1 during invasion of hepatocytes by Plasmodium falciparum sporozoites.

Plasmodium sporozoites are transmitted through the bite of infected mosquitoes and invade hepatocytes as a first and obligatory step of the parasite life cycle in man. Hepatocyte invasion involves proteins secreted from parasite vesicles called micronemes, the most characterized being the thrombospondin-related adhesive protein (TRAP). Here we investigated the expression and function of another microneme protein recently identified in Plasmodium falciparum sporozoites, apical membrane antigen 1 (AMA-1). P. falciparum AMA-1 is expressed in sporozoites and is lost after invasion of hepatocytes, and anti-AMA-1 antibodies inhibit sporozoite invasion, suggesting that the protein is involved during invasion of hepatocytes. As observed with TRAP, AMA-1 is initially mostly sequestered within the sporozoite. Upon microneme exocytosis, AMA-1 and TRAP relocate to the sporozoite surface, where they are proteolytically cleaved, resulting in the shedding of soluble fragments. A subset of serine protease inhibitors blocks the processing and shedding of both AMA-1 and TRAP and inhibits sporozoite infectivity, suggesting that interfering with sporozoite proteolytic processing may constitute a valuable strategy to prevent hepatocyte infection.

Animals↗
PubMed2003

Food vacuole plasmepsins are processed at a conserved site by an acidic convertase activity in Plasmodium falciparum.

Intraerythrocytic Plasmodium falciparum digests vast amounts of hemoglobin within an acidic food vacuole (FV). Four homologous aspartic proteases participate in hemoglobin degradation within the FV. Plasmepsin (PM) I and II are thought to initiate degradation of the native hemoglobin molecule. PM IV and histo-aspartic protease (HAP) act on denatured globin further downstream in the pathway. PM I and II have been shown to be synthesized as zymogens and activated by proteolytic removal of a propiece. In this study, we have determined that the proteolytic processing of FV plasmepsins occurs immediately after a conserved Leu-Gly dipeptidyl motif with uniform kinetics and pH and inhibitor sensitivities. We have developed a cell-free in vitro processing assay that generates correctly processed plasmepsins. Our data suggest that proplasmepsin processing is not autocatalytic, but rather is mediated by a separate processing enzyme. This convertase requires acidic conditions and is blocked only by the calpain inhibitors, suggesting that it may be an atypical calpain-like protease.

Amino Acid Motifs↗
PubMed1984

Binding of glycophorins to Plasmodium falciparum merozoites.

Plasmodium falciparum merozoites recognize and attach to glycophorins, the surface sialoglycoproteins of human erythrocytes. The structural requirements for a merozoite binding site were studied with the use of two methods. In the first, certain glycophorins and their tryptic fragments were added directly to isolated merozoites prior to their addition to erythrocytes. Low concentrations (50 micrograms ml-1) of glycophorin A inhibited merozoite invasion. At higher concentrations a mixture of glycophorins A, B and C (GPS) (100 micrograms ml-1) and glycophorin B (200 micrograms ml-1) also inhibited invasion. GPS from Tn erythrocytes which lack both sialic acid and galactose residues was almost as effective as normal GPS in blocking invasion. None of the monosaccharides present on glycophorin, including N-acetylneuraminic acid, inhibited merozoite invasion. Erythrocytes treated with lectins were only partially resistant to invasion. These results indicated that the oligosaccharide side chains are not the major structural determinant of the merozoite binding site. Glycophorin A was cleaved by trypsin and the separated fragments added to merozoites. Only the external N-terminal tryptic fragment T1 and the trypsin resistant hydrophobic core, T6, showed some, but considerably less, inhibitory activity than the intact molecule. In the second approach, the binding of 125I-labeled GPS to isolated merozoites was determined. 125I-GPS binding was saturated at 0.23 micrograms for 10(9) merozoites and was competitively inhibited by unlabeled GPS but not by free sugars. Desialylated GPS bound almost to the same extent as the intact molecule.

Animals↗
PubMed2003

The role of two novel regulatory sites in the activation of the cGMP-dependent protein kinase from Plasmodium falciparum.

The Plasmodium falciparum cGMP-dependent protein kinase (PfPKG) uniquely contains three cGMP binding sites, but also has a 'degenerate' fourth site. The role of each cGMP-binding site in PfPKG activation remains unknown. We have analysed the effect of mutation of each cGMP-binding site (individually and in combination) on PfPKG activation in vitro. The most striking result was that mutation of cGMP site 3 resulted in a 10-49-fold increase in the K (a((cGMP))) value and a 45-55% decrease in maximal activity compared with wild-type. Mutations involving only cGMP-binding sites 1 and 2 had less effect on both the K (a((cGMP))) values and the maximal activities. These results suggest that, although all three cGMP-binding sites are involved in PfPKG activation, cGMP-binding site 3 has the greatest influence on activation. A mutation in the fourth, degenerate cGMP-binding site decreased PfPKG maximal activity by 40%, but did not change the K (a((cGMP))) value for the PfPKG mutant, suggesting that this site does not bind cGMP, but is required for full activation of PfPKG. The distinct activation properties of PfPKG from mammalian isoforms may be exploitable in the design of a parasite-specific inhibitor and development of a novel anti-malarial drug.

Alanine↗
PubMed1995

Solution structure of a polypeptide containing four heptad repeat units from a merozoite surface antigen of Plasmodium falciparum.

The Plasmodium falciparum antigen SPAM (secreted polymorphic antigen associated with merozoites) contains an unusual set of heptad repeat units with alanine at the a and d positions. Twelve heptads with the consensus sequence AXXAXXX occur in three blocks of four, linked by short nonrepetitive sequences. A 38-residue polypeptide comprising the first block of four heptad units and five flanking residues at either end, SPAM-H1, has been synthesized and its structure in aqueous solution determined from 1H NMR data. Sedimentation equilibrium showed the peptide to be monomeric in aqueous solution. Its structure was determined from 1H NMR-derived distance and dihedral angle constraints by using distance geometry calculations, restrained simulated annealing, and conjugate gradient energy minimization in the CHARMm force field. The polypeptide contains an alpha-helix extending from Ser10 (position e of the first heptad) to at least Lys32 (position f of the fourth heptad) and possibly as far as Val35. The helix is bent, partly as result of a kink around residues 19-20. The conformations of the nine N-terminal residues and the six C-terminal residues are not well defined by the NMR data. The rms deviation from the average of the 20 best structures over the well-defined region (residues 11-31, which have backbone angular order parameters > 0.8) was 1.56 A for backbone heavy atoms (N, C alpha, and C) and 2.12 A for all heavy atoms. 2H2O exchange experiments identified slowly exchanging amide protons near the C-terminus and the last two turns of the helix. The unusual stability of the C-terminus reflects the presence of a new C-capping motif, which may involve the side chain of an asparagine in a position external to the C-cap residue. Possible interactions of the H1 sequence with the other two heptad repeat units in the intact merozoite antigen are discussed.

Amino Acid Sequence↗
PubMed1999

Rapid diagnosis of falciparum malaria by detection of Plasmodium falciparum HRP-2 antigen.

OBJECTIVE: Malaria is a resurging problem all over the country and rapid diagnosis is mandatory to decrease the morbidity and mortality and for control of malaria. In the current study the aim was to evaluate the usefulness of rapid Plasmodium falciparum antigen detection and to compare its utility over conventional peripheral thick and thin smear examination. METHODS: Three hundred fifty seven randomly selected patients with pyrexia and or atypical presentations of malaria, found initially negative for malaria were subjected to thick and thin smear examination and Plasmodium falciparum antigen detection test by using commercially available Parasight F. kit. RESULTS: 54.6% of cases presented with pyrexia, while other presentations of falciparum malaria were less frequently encountered (162/357). Eighty five patients (23.8%) were diagnosed as having falciparum malaria based on smear/Parasight F. Test. Eighty- four of these patients were positive for Parasight F. test and only 34.51% of these cases were also positive on smear examination. CONCLUSION: The antigen detection test for Plasmodium falciparum is useful for rapid diagnosis of Plasmodium falciparum malaria. It could detect 65.5% cases of falciparum malaria which were initially negative by peripheral smear examination. Hence, this technique is superior to peripheral smear staining and helps early diagnosis.

Animals↗
PubMedDate not supplied

Molecular factors responsible for host cell recognition and invasion in Plasmodium falciparum.

In Plasmodium falciparum, the rhoptries involved in the invasion process are a pair of flask-shaped organelles located at the apical tip of invading stages. They, along with the more numerous micronemes and dense granules, constitute the apical complex in Plasmodium and other members of the phylum Apicomplexa. Several proteins of varying molecular weight have been identified in P. falciparum rhoptries. These include the 225-, 140/130/110-, 80/60/40-, RAP-1 80-, AMA-1 80-, QF3 80-, and 55-kDa proteins. Some of these proteins are lost during schizont rupture and release of merozoites. Others such as the 140/130/110-kDa complex are transferred to the erythrocyte membrane during invasion. The ring-infected surface antigen (RESA), a 155-kDa polypeptide located in dense granules also associates with the erythrocyte membrane during invasion. Erythrocyte-binding studies have demonstrated that both the 140/130/110-kDa rhoptry complex and RESA bind to inside-out-vesicles (IOVs) prepared from human erythrocytes. The 140/130/110-kDa complex also binds to erythrocyte membranes prepared by hypotonic lysis. These proteins, however, do not bind to intact human erythrocytes. In a heterologous erythrocyte model, both the 140/130/110-kDa complex and RESA are shown to bind directly to mouse erythrocytes. Other studies have shown that RESA associates with spectrin in the erythrocyte cytoskeleton. We have recently developed a liposome-binding assay to demonstrate the lipophilic binding properties of the P. falciparum rhoptry complex of 140/130/110 kDa. The rhoptry complex binds to liposomes containing neutrally, positively, and negatively charged phospholipids. However, liposomes containing phosphatidylethanolamine compete effectively for rhoptry protein binding to mouse erythrocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1987

Specific and nonspecific immunodiagnostic properties of recombinant and synthetic Plasmodium falciparum antigens.

Six Plasmodium falciparum/beta-galactosidase fusion proteins produced by a genomic DNA expression library, and two synthetic Plasmodium falciparum antigens were applied to ELISA and tested for their immunodiagnostic properties. Results were compared to reference methods, i.e. fluorescence antibody test with whole cell antigen and ELISA with detergent-soluble crude schizont antigen. Anti-Plasmodium falciparum antibodies could be detected by these molecular antigens to varying extents in human sera. Undesired reactivity to fusion proteins due to the high prevalence of antibodies to beta-galactosidase in human sera and undesired reactivity to one of the synthetic antigens (P12) frequently occurred. The antibodies responsible for the nonspecific reactivity could not be identified. It was concluded that the application of molecular Plasmodium falciparum antigens to ELISA represents a practicable approach to immunodiagnosis of malaria if the construction of epitopes that bind antibodies other than Plasmodium falciparum antibodies can be avoided.

Animals↗
PubMed2004

A comparison of anemia in hemoglobin C and normal hemoglobin A children with Plasmodium falciparum malaria.

Plasmodium falciparum infection accelerates the senescence of erythrocytes. Senescence in hemoglobin C (HbC) erythrocytes relative to normal hemoglobin A (HbA) erythrocytes is also increased, presumably because of the sensitivity of HbC to oxidative damage and denaturation. To test for a possible increased rate of anemia in HbC individuals with malaria, we evaluated children with uncomplicated P. falciparum malaria in Bandiagara, Mali, a village with a high prevalence of HbC. The average hematocrit was significantly lower in AC children (heterozygous for HbC) than in AA children (homozygous for normal HbA). Calculated blood hemoglobin concentrations from these groups, however, showed no significant differences because of the increased mean corpuscular hemoglobin concentration (MCHC) and decreased mean corpuscular volume (MCV) of AC relative to AA erythrocytes. Average hemoglobin concentration is a better measure of oxygen delivery capacity and anemia than hematocrit value. By this measure, HbC, a malaria-protective polymorphism with few deleterious consequences, does not appear to be associated with more frequent anemia than normal HbA in episodes of uncomplicated P. falciparum malaria.

Adolescent↗
PubMed1994

Polyclonal expansion of peripheral gamma delta T cells in human Plasmodium falciparum malaria.

Plasmodium falciparum malaria in humans is associated with an increase in the percentage and absolute number of gamma delta T cells in the peripheral blood. This increase begins during the acute infection phase and persists for at least 4 weeks during convalescence. In the present study, 25 to 30% of the gamma delta T cells expressed HLA-DR antigens in vivo and in some patients they proliferated in response to further stimulation by purified human interleukin 2 in vitro. However, there was no in vitro proliferative response to various malarial antigens, including a 75-kDa heat shock protein and a 72-kDa glucose-regulated protein of P. falciparum during the acute infection phase. Cytofluorographic studies showed that although an increase of V delta 1- gamma delta T cells was largely responsible for the expansion of the total number of gamma delta T cells, there was also a proportional increase in V delta 1+ cells. These results were confirmed with anchored PCR and by DNA sequencing to characterize at the molecular level the set of T-cell receptor (TCR) delta mRNAs expressed in the peripheral blood of two patients with high levels of gamma delta T cells. In each case, most of the TCR delta mRNA transcripts corresponded to nonproductively rearranged delta genes (unrearranged J delta or near J delta spliced to C delta). In those sequences which did represent productively rearranged genes, most of the transcripts originated from a V delta 2/J delta 1 joining, as in normal individuals. A minority of transcripts originated from a V delta 1/J delta 1 rearrangement, and one originated from a V alpha 4/J delta 1 rearrangement. Polyclonal activation of gamma delta T cells was inferred from the extensive junctional diversity seen in the delta mRNAs analyzed. Expansion of a heterogeneous set of both V delta 1(-)- and V delta 1(+)-bearing T cells suggests that the elevated levels of gamma delta T cells seen during acute P. falciparum malaria arose from immune responses to multiple distinct parasite antigens or unidentified host factors.

Adult↗
PubMedDate not supplied

[Kidney failure associated with Plasmodium falciparum infection].

Plasmodium falciparum infection may be a cause of acute renal failure (ARF). Whereas renal failure appears to be a common complication of severe malaria in adults, it seldom occurs in children. The authors report a case of a previously healthy 9-year-old child, who was admitted with fever, vomits, diarrhoea, jaundice and obnubilation of consciencious. The results of laboratory tests performed confirmed the diagnosis of falciparum malaria. At the 2nd day of hospitalization she was in ARF and dialysis was necessary. We admitted that the probable underlying factors leading to this complication were: intravascular haemolysis, volume depletion, hypotension and hyperparasitaemia. Despite the presence of predictive factors of bad outcome the evolution was favourable with gradual recuperation of renal function.

Child↗
PubMed1994

Lymphocyte responses to Plasmodium falciparum ring-infected erythrocyte surface antigen (Pf155/RESA) peptides in individuals with naturally acquired Plasmodium falciparum malaria.

Antibody titers and lymphocyte responses to synthetic peptides corresponding to repeated amino acid sequences of the 3' and 5' regions of Pf155/ring-infected erythrocyte surface antigen (RESA) were studied in two groups of Thai subjects, soldiers (Rangers), and villagers who differed in their history of malaria exposure. The frequency of Pf155/RESA seropositivity was similar in the two groups while the frequency of high titer antibody was significantly greater in villagers than in Rangers. Lymphocyte responsiveness in vitro to all Pf155/RESA peptides was infrequent for both groups although half of the subjects studied responded to crude Plasmodium falciparum asexual blood stage malaria antigen (MA). Among responders, Pf155/RESA peptides elicited lymphocyte responses in which proliferation and interferon-gamma (IFN-gamma) production were not associated, whereas with MA, the two responses were associated. The MA-stimulated lymphocyte proliferation and IFN-gamma production for both groups of volunteers appeared to be independent of antibody titer. In this study, antibody, but not lymphocyte, responses to Pf155/RESA peptides were shown to reflect differences in prior exposure and levels of acquired immunity to falciparum malaria.

Adult↗
PubMedDate not supplied

Evaluation of the antimalarial activity of new compounds against Plasmodium falciparum in vitro, and Plasmodium berghei in vivo.

Various hydrazones of thiophene carboxaldehyde were tested in vitro on two Plasmodium falciparum strains and in vivo on mice experimentally infected with Plasmodium berghei. These hydrazones were obtained by condensation of appropriate hydrazines with thiophene-2-carboxaldehyde (series 1), thiophene-3- carboxaldehyde (series 2) and 5-Nitrothiophene-2-carboxaldehyde (series 3). Compounds of series 3, 5-Nitrothiophene-2-carboxaldehyde presented significant effects in vitro. In vivo tests confirmed the antimalarial activity observed in vitro with two compounds of this series.

Animals↗