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PubMed1993

A national survey of the prevalence of chloroquine resistant Plasmodium falciparum in Burkina Faso.

Plasmodium falciparum susceptibility to chloroquine was investigated in 10 areas of Burkina Faso in the rainy seasons in 1990-1991. The 7-days in-vivo test was carried out from August to November on children aged 2-8 years with monospecific P. falciparum infection (asexual parasitaemia > 800 microliters-1 of blood), axillary temperature < 37.5 degrees C, and a negative Bergqvist urine test for 4-aminoquinolines. Among 2190 children screened, 366 were selected. Blood samples were collected on days 0, 2, 4 and 7 by finger-prick, and 100 microscopic fields of thick and thin smears were examined for parasite density and species identification. Chloroquine was given under supervision at the standard dose of 25 mg kg-1 over three days (days 0, 1 and 2) with an observation period of one hour after treatment. Parasitaemia did not clear in 63 cases (17.2%) with a 13.4% RII response and 3.8% RIII response. The results do not seem to indicate a decline in the sensitivity of P. falciparum to chloroquine in Burkina Faso during the past two years.

Animals↗
PubMed1993

Mice immunized with a synthetic peptide construct corresponding to an epitope present on a Plasmodium falciparum antigen are protected against Plasmodium chabaudi challenge.

Inhibitory monoclonal antibody (MoAb) 8E7/55 recognizes a parasitophorous vacuole membrane (PVM) antigen in Plasmodium falciparum. Previous studies have identified the epitope, DNNLVSGP, recognized by the MoAb. A synthetic peptide containing this sequence was synthesized and coupled to diphtheria toxoid (DT) and was found capable of generating antibodies when used as an immunogen in mice which recognize the native antigen exp-1. In this study we demonstrate the ability of the MoAb and antisera generated against the peptide construct to recognize a 54 kD PVM antigen in Plasmodium chabaudi. The P. chabaudi antigen is synthesized in trophozoites and released to the surrounding culture media outside the parasitized erythrocyte. Mice immunized with the peptide conjugate are protected when challenged with a lethal strain of P. chabaudi. Protection in the mice correlated with the antibody titre prior to challenge. If the PVM antigen from P. chabaudi is a homologue of exp-1 from P. falciparum, then these experiments may provide a guide to the antibody titres required in human trials before antibody mediated protection could be expected. The discovery that a PVM localized antigen is secreted into the surrounding in vitro culture media provides us with a valuable model system for further investigation of protein trafficking pathways in malaria-infected erythrocytes.

Amino Acid Sequence↗
PubMed2000

Two MSA 2 peptides that bind to human red blood cells are relevant to Plasmodium falciparum merozoite invasion.

Plasmodium falciparum merozoite membrane surface antigen 2 (MSA2) has been associated with the development of protective immunity against malaria. MSA2 antibodies were able to inhibit in vitro merozoite invasion. In our search for experimental evidence concerning the participation of MSA2 in merozoite invasion, 40 peptides were synthesized according to sequences reported for the CAMP and FC27 prototype Plasmodium strains. These peptides were purified, 125I-radiolabeled and tested for their ability to bind to erythrocytes. Two MSA2 synthetic peptides with high specific binding to human erythrocytes were found. The peptide coded 4044 (KNESKYSNTFINNAYNMSIR), located in the MSA2 N-terminal conserved region, has an affinity coefficient of 72 nM and showed a positive cooperativity for the receptor-ligand interaction. The other peptide, coded 4053 (NPNHKNAETNPKGKGEVQKP) and located in the central variable region of MSA2, has an affinity coefficient of 49nM and also showed a positive cooperativity for the receptor-ligand interaction. The binding capacity of these peptides is affected by erythrocytes treated with neuraminidase and trypsin, but it is not affected by chymotrypsin. Both of these sequences inhibit in vitro erythrocyte parasite invasion by up to 95% suggesting that they have an important role in the parasite's invasion process. Furthermore, as published previously [A. Saul et al. (1992) J. Immunol., 148, 208-211], a protective B epitope is included in the 4044 peptide sequence.

Animals↗
PubMed2000

Antibodies against ribosomal phosphoprotein P0 of Plasmodium falciparum protect mice against challenge with Plasmodium yoelii.

Antibodies against the Plasmodium falciparum P0 ribosomal phosphoprotein (PfP0) have been detected exclusively but extensively in malaria-immune persons. Polyclonal rabbit and mice sera were raised against two recombinant polypeptides of P. falciparum P0 protein, PfP0N and PfP0C, covering amino acids 17 to 61 and the remaining amino acids 61 to 316, respectively. Sera against both these domains detected a 35-kDa protein from Plasmodium yoelii subsp. yoelii, a rodent malarial parasite, and stained the surface of merozoites in immunofluorescence assays. Total immunoglobulin G (IgG) purified from rabbit and mouse anti-PfP0 sera by ammonium sulfate and DEAE-cellulose chromatography was used for passive transfer experiments in mice. Mice passively immunized with both anti-PfP0N and anti-PfP0C showed distinctly lower levels of parasitemia than control mice. With immunizations on days -1, 0, 1, 3, and 5, about 50% of both sets of mice receiving anti-PfP0N and anti-PfP0C cleared the lethal 17XL strain of P. yoelii and revived by day 25. All the control mice died by day 10. By extending the immunization schedule, the survival period of the mice could be extended for every mouse that received anti-PfP0 IgG. These data demonstrate the cross-protection of the anti-PfP0 IgG and establish parasite P0 protein as a target for invasion-blocking antibodies.

Animals↗
PubMed1988

Glucose-6-phosphate dehydrogenase activity of the malaria parasite Plasmodium falciparum.

Schizonts of Plasmodium falciparum, grown either in normal or glucose-6-phosphate dehydrogenase (G6PDH) deficient human red cells, contain an electrophoretically slow-moving form of G6PDH. The slow mobility of the G6PDH in non-dissociating polyacrylamide gels is due to its large size (Mr ca. 450,000) rather than to its charge. The activity of this enzyme was less than 10% of normal red cell G6PDH. These characteristics of the parasite-associated G6PDH were unaltered when parasites were grown in red cells from a G6PDH A+B+ heterozygote or following the introduction of a heterologous G6PDH into resealed ghosts. Differential absorption of the parasite-associated and red cell G6PDHs was demonstrated with antisera containing antibodies to red cell G6PDH. These studies show that a novel form of G6PDH is associated with P. falciparum in normal red cells without the requirements for induction by one or several cycles of multiplication in G6PDH deficient red cells.

Animals↗
PubMed1986

Immunity to malaria and naturally acquired antibodies to the circumsporozoite protein of Plasmodium falciparum.

A candidate Plasmodium falciparum sporozoite vaccine, R32tet32, which includes 32 tetrapeptide repeats derived from the circumsporozoite protein of P. falciparum, has been developed on the basis of the hypothesis that antibodies to the repeat region of this protein will protect against sporozoite infection. The results of two in vitro assays, the circumsporozoite precipitation reaction and the inhibition of sporozoite invasion into hepatoma cells, are thought to indicate protective immunity. We therefore tested serum samples from persons living in a hyperendemic malarious area of Indonesia for antibodies against R32tet32 and for their ability to produce circumsporozoite precipitation and to inhibit sporozoite invasion of hepatoma cells. The prevalence and mean titer of antibody against R32tet32 increased with the age of the subjects, whereas the prevalence of P. falciparum infection in the community decreased. Only serum samples with IgG or IgM R32tet32 antibody titers greater than or equal to 1/800 had precipitation activity and invasion-inhibiting activity of more than 75 percent. When the serum samples were fractionated by affinity chromatography, only the fractions containing purified human antibody to R32tet32 were found to contain this activity. These data support the hypotheses that antibodies to the circumsporozoite protein are important in reducing the prevalence of malaria with increasing age among persons in areas in which malaria is endemic and that vaccine-elicited antibody to the circumsporozoite repeat region will protect against infection with P. falciparum sporozoites.

Adolescent↗
PubMed1998

Developmental selection of var gene expression in Plasmodium falciparum.

The protozoan Plasmodium falciparum causes lethal malaria. Adhesion of erythrocytes infected with P. falciparum to vascular endothelium and to uninfected red blood cells (rosetting) may be involved in the pathogenesis of severe malaria. The binding is mediated by the antigenically variant erythrocyte-membrane-protein-1 (PfEMP-1), which is encoded by members of the P. falciparum var gene family. The control of expression and switching of var genes seems to lack resemblance to mechanisms operating in variant gene families of other microbial pathogens. Here we show that multiple, distinct var gene transcripts (about 24 or more) can be detected by reverse transcription and polymerase chain reaction in bulk cultures of the rosetting parasite FCR3S1.2, despite the adhesive homogeneity of the cultures. We also detected several var transcripts in single erythrocytes infected with a ring-stage parasite of FCR3S1.2, and found that different var genes are transcribed simultaneously from several chromosomes in the same cell. In contrast, we detected only one var transcript, FCR3S1.2 var-1, which encodes the rosetting PfEMP-1 protein, in individual rosette-adhesive trophozoite-infected cells, and we found only one PfEMP-1 type at the erythrocyte surface by labelling with 125iodine and immunoprecipitation. We conclude that a single P. falciparum parasite simultaneously transcribes multiple var genes but, through a developmentally regulated process, selects only one PfEMP-1 to reach the surface of the host cell.

Adult↗
PubMed2001

Effect of drugs inhibiting spermidine biosynthesis and metabolism on the in vitro development of Plasmodium falciparum.

Treatment of Plasmodium falciparum with the potent inhibitor dicyclohexylamine completely arrests in vitro cell proliferation of the chloroquine-susceptible P. falciparum strain NF54 and the R strain, which shows less sensivity to chloroquine. The average inhibitory concentration (IC50) values determined for both strains revealed different inhibition profiles. The IC50 value for the chloroquine-sensitive NF54 strain was 97 microM and 501 microM for the R strain. Monitoring polyamine pools after treatment with dicyclohexylamine leads to a significant decrease in the intracellular spermidine content, which was nearly reversed by supplementation with spermidine. Since spermidine is an important precursor for the biosynthesis of hypusine and homospermidine in eukaryotes, we studied the developmental effect on both P. falciparum strains of 1,7-diaminoheptane as an inhibitor of deoxyhypusine synthase (EC 1.1.1.249) in mammalian cells, and agmatine as a moderate inhibitor of homospermidine synthase (EC 2.5.1.44). Inhibition profiles with 1,7-diaminoheptane resulted in an IC50 value of 466 microM for the NF54 strain and 319 microM for the R strain. Spermidine pools changed significantly. Inhibition with agmatine caused a strong decrease in parasitemia for the chloroquine-susceptible NF54 strain, with a determined IC50 value of 431 microM and an IC50 value of 340 microM for the less chloroquine-susceptible R strain. Spermidine was not detectable after inhibition. The uncommon triamine homospermidine occurred in both P. falciparum strains. To our knowledge this is the first evidence of homospermidine in P. falciparum. The use of specific inhibitors of spermidine metabolism might be a novel strategy for the design of new antimalarials, and suggests the occurrence of both enzymes in the parasite.

Agmatine↗
PubMed2005

Chloroquine accumulation by purified plasma membranes from Plasmodium falciparum.

Resistance of Plasmodium falciparum to chloroquine (CQ) has been associated with a decrease in CQ accumulation by parasitized erythrocytes. This study aimed at investigating the role of parasite plasma membranes (PPM) in the mechanism of CQ accumulation. CQ accumulation capabilities of membranes were determined using tritiated CQ. PPM isolated from chloroquine-sensitive parasites were found to accumulate less CQ than those isolated from chloroquine-resistant parasites. However, CQ accumulation was found to be ATP-independent suggesting that this accumulation results from binding rather than transport.

Animals↗
PubMed1984

African serum interference in the determination of chloroquine sensitivity in Plasmodium falciparum.

Isolates of Plasmodium falciparum from villagers in central Sudan were tested for chloroquine and mefloquine sensitivity using the WHO microtechnique procedure and a modified 48-h in vitro test for drug resistance. No drug-resistant strains were noted. In the WHO procedure, in which parasites were cultivated in the presence of the patient's plasma, 72% of the isolates failed to mature to the schizont stage, but when infected erythrocytes were washed free of the patient's plasma and cultivated in pooled nonimmune serum only 28.8% of the isolates failed to develop to the schizont stage. In subsequent experiments, sera from P. falciparum-infected patients or from noninfected "immune" adults were used to supplement standard in vitro test plates which contained parasites of known chloroquine sensitivities. Sera from malaria-infected patients or from immune adults retarded parasite development in the presence or absence of drug. The effect of these humoral factors and the antimalarial drugs was additive. The replacement of the patient's plasma with nonimmune serum in drug sensitivity tests performed with African isolates is recommended.

Adult↗
PubMed1993

N-acetylglucosamine-binding proteins on Plasmodium falciparum merozoite surface.

Plasmodium falciparum merozoite surface is specifically labelled with a neoglycoprotein bearing N-acetylglucosamine (GlcNAc) residues in a sugar-dependent manner, as shown by affinity cytochemistry in fluorescence and electron microscopy. To ascertain the nature of the sugar receptor, merozoite proteins were blotted and tested by a two-step method using biotinylated GlcNAc-bovine serum albumin (BSA) and streptavidin-peroxidase conjugate. Three parasite proteins were specifically revealed and designated as Pf 120, Pf 83 and Pf 45 GlcNAc-binding proteins. These proteins bind to a gel substituted with GlcNAc and are specifically eluted with 300 mM GlcNAc. Using a rabbit antiserum raised against Pf 83, the Pf 120 GlcNAc-binding protein, in addition to Pf 83, was labelled by Western blotting. Comparative analyses with an antibody against the Pf 83 MSP derived from the P. falciparum merozoite surface protein (Pf MSP) indicated that the Pf 83 GlcNAc-binding protein is not related to the fragment of the Pf MSP antigen. Similarly, the Pf 83 GlcNAc-binding protein is not related to the apical membrane antigen 1 (AMA 1) which also has the same molecular mass. Therefore the Pf 120, Pf 83 and Pf 45 GlcNAc-binding proteins which are located on the merozoite surface and recognize GlcNAc residues could be involved in the binding of merozoites to the glycoconjugates of the surface of the red blood cells.

Acetylglucosamine↗
PubMed1996

A role for erythrocyte band 3 degradation by the parasite gp76 serine protease in the formation of the parasitophorous vacuole during invasion of erythrocytes by Plasmodium falciparum.

A purified Plasmodium falciparum serine protease (gp76) implicated in erythrocyte invasion, degrades human erythrocyte band 3 and glycophorin A. Inhibition studies using synthetic peptides derived from the presumed band 3 enzymatic cleavage sites and the observed uptake of fluorescent phospholipids following gp76 treatment, suggest that band 3 degradation by this serine protease participates in the formation of the parasitophorous vacuole by restructuring the red cell cytoskeleton. These results provide a rationale for the elaboration of specific inhibitors to block red cell invasion by malaria parasites.

Amino Acid Sequence↗
PubMed2004

High throughput immuno-screening of cDNA expression libraries produced by in vitro recombination; exploring the Plasmodium falciparum proteome.

Improved Plasmodium falciparum cDNA expression libraries were constructed by combining mRNA oligo-capping with in vitro recombination and directional cloning of cDNA inserts into a plasmid vector that expresses sequences as thioredoxin fusion proteins. A novel procedure has also been developed for the rapid identification of seropositive clones on high-density filters, using direct labelling of P. falciparum immune immunoglobulin with fluorescein isothiocynate (FITC). This approach combines the advantages of recombination-assisted cDNA cloning with high throughput, non-radioactive serological screening of expression libraries. Production of replicate colony matrices allows the identification of antigens recognised by different pools with different specificities from residents of a malaria endemic region. Analyses of DNA sequences derived from sero-reactive colonies indicate that this is an effective method for producing recombinant proteins that react with antibodies from malaria-exposed individuals. This approach permits the systematic construction of a database of antigenic proteins recognised by sera from malaria-exposed individuals.

Animals↗
PubMedDate not supplied

Zinc protoporphyrin IX binds heme crystals to inhibit the process of crystallization in Plasmodium falciparum.

The intraerythrocytic Plasmodium falciparum parasite converts most of host hemoglobin heme into a nontoxic heme crystal. Erythrocyte zinc protoporphyrin IX, normally present at 0.5 microM, which is a ratio of 1:40,000 hemes, can elevate 10-fold in some of the anemias associated with malaria disease protection. This work examines a binding mechanism for zinc protoporphyrin IX inhibition of heme crystallization similar to the antimalarial quinolines. Zinc protoporphyrin IX neither forms crystals alone nor extends on preformed heme crystals. Inhibition of both seed heme crystal formation and crystal extension occurs with an inhibitory concentration (IC)50 of 5 microM. Field emission in-lens scanning electron microscopy depicts the transition and inhibition of heme monomer aggregates to heme crystals with and without seeding of preformed hemozoin templates. In vitro zinc protoporphyrin IX, like the quinolines, binds to heme crystals in a saturable, specific, pH, and time-dependent manner. The ratio at saturation is approximately 1 zinc protoporphyrin IX per 250 hemes of the crystal. Unlike the quinolines, zinc protoporphyrin IX binds measurably in the absence of heme. Isolated ring and trophozoite stage parasites have an elevated zinc protoporphyrin IX to heme ratio 6 to 10 times that in the erythrocyte cytosol, which also corresponds to elevated ratios found in heme crystals purified from Plasmodium parasites. This work implicates protection from malaria by a mechanism where elevated zinc protoporphyrin IX in anemic erythrocytes binds to heme crystals to inhibit further crystallization. In endemic malaria areas, severe iron deficiency anemia should be treated with antimalarials along with iron replenishment.

Animals↗
PubMed1993

Purification and characterization of DNA polymerases from Plasmodium falciparum.

Fractionation of Plasmodium falciparum cellular extracts by fast protein liquid chromatography (FPLC) identified at least two different DNA polymerases. An aphidicolin-sensitive activity co-purified with a primase activity. This, in combination with other characteristics (processivity, sensitivity to other inhibitors), most likely classifies this enzyme as an alpha-like DNA polymerase. It was, however, relatively resistant to N2-(p-n-butylphenyl)deoxyguanosine 5'-triphosphate (IC50 = 6.6 microM) and differs in this aspect from the host homologue, possibly indicating structural differences between host and parasite DNA polymerase alpha. The other DNA polymerase matched eukaryotic DNA polymerase gamma in all properties tested.

Animals↗
PubMed1987

Structure and function of candidate vaccine antigens in Plasmodium falciparum.

Analysis of Plasmodium falciparum antigens expressed in Escherichia coli has identified several different proteins as potential vaccine components. Fragments of one of these antigens, the ring-infected erythrocyte surface antigen (RESA) have been used to protect Aotus monkeys against overwhelming infection with P. falciparum. In this vaccine, trial protection correlated with antibody responses to two of three repetitive sequences in RESA. RESA is released from merozoites and becomes associated with the erythrocyte membrane at the time of merozoite invasion. The 3' repeat structure of RESA encodes a polyacidic sequence that has homology with the N-terminal sequence (cytoplasmic domain) of band 3, the erythrocyte anion transporter. These homologous sequences both include a recognition sequence for a protein tyrosine kinase. It is postulated that RESA disrupts the normal intermolecular interactions of the cytoplasmic domain of band 3 and that phosphorylation of RESA by an erythrocyte membrane kinase in some way regulates this function of RESA.

Amino Acid Sequence↗
PubMed1984

Effects of mitochondrial protein synthesis inhibitors on the incorporation of isoleucine into Plasmodium falciparum in vitro.

Plasmodium falciparum was grown in human erythrocytes in vitro and the effect of chloramphenicol, erythromycin, and tetracycline on growth and maturation of the parasites and on their ability to incorporate [3H]isoleucine into protein was observed. Exposure of rings to high concentrations of chloramphenicol had little effect on subsequent maturation of the rings whereas brief (4 h) exposure of trophozoites caused a dose-dependent inhibition of subsequent ring formation. Incorporation of [3H]isoleucine into protein was not affected during at least 6 h of exposure to high concentration of the three drugs examined, but appreciable inhibition was observed after 21 h, with chloramphenicol being the least effective inhibitor. These results suggest that there is a stage-specific effect of inhibition of mitochondrial protein synthesis on subsequent development and that the mitochondria are essential for growth and development even though they lack a functional Krebs cycle.

Animals↗
PubMedDate not supplied

Structure and function of a thymic peptide is mimicked by Plasmodium falciparum peptides.

Numerous Plasmodium falciparum antigens contain repetitive amino acid sequences. Two blood stage antigens, Pf11-1 and Pf332, were characterized in our laboratories and present high cross-reactivities, defining a family of cross-reacting antigens. In this report, we show that amino acid sequence homologies might explain these cross-reactivities, but that they extend to polypeptides from the host, namely thymosin-alpha 1 (T alpha 1). An antiserum raised in chickens and Saimiri monkeys against the synthetic Pf11-1 peptide cross-reacts with synthetic T alpha 1. Synthetic Pf11-1 and Pf332 peptides share some of the biological activities of T alpha 1. These results are discussed with respect to the mechanisms devised by malaria parasites for escape from the host immune response.

Amino Acid Sequence↗