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PubMed1990

In vitro biosynthesis and membrane translocation of the serine rich protein of Plasmodium falciparum.

The serine-rich protein (SERP) of Plasmodium falciparum is found within the parasitophorous vacuole. Exons 1 and 2 of the SERP gene were combined to a continuous open reading frame and expressed in a cell free translation/translocation system to study translocation of the protein across membranes. The protein was found to be translocated co-translationally across canine pancreatic microsomes. This process required the presence of the signal recognition particle, and it was accompanied by cleavage of a signal peptide. We conclude that the authentic SERP is exported from the parasite cell via the endoplasmic reticulum.

Animals↗
PubMed1999

Alternative oxidase inhibitors potentiate the activity of atovaquone against Plasmodium falciparum.

Recent evidence suggests that the malaria parasite Plasmodium falciparum utilizes a branched respiratory pathway including both a cytochrome chain and an alternative oxidase. This branched respiratory pathway model has been used as a basis for examining the mechanism of action of two antimalarial agents, atovaquone and proguanil. In polarographic assays, atovaquone immediately reduced the parasite oxygen consumption rate in a concentration-dependent manner. This is consistent with its previously described role as an inhibitor of the cytochrome bc1 complex. Atovaquone maximally inhibited the rate of P. falciparum oxygen consumption by 73% +/- 10%. At all atovaquone concentrations tested, the addition of the alternative oxidase inhibitor, salicylhydroxamic acid, resulted in a further decrease in the rate of parasite oxygen consumption. At the highest concentrations of atovaquone tested, the activities of salicylhydroxamic acid and atovaquone appear to overlap, suggesting that at these concentrations, atovaquone partially inhibits the alternative oxidase as well as the cytochrome chain. Drug interaction studies with atovaquone and salicylhydroxamic acid indicate atovaquone's activity against P. falciparum in vitro is potentiated by this alternative oxidase inhibitor, with a sum fractional inhibitory concentration of 0.6. Propyl gallate, another alternative oxidase inhibitor, also potentiated atovaquone's activity, with a sum fractional inhibitory concentration of 0.7. Proguanil, which potentiates atovaquone activity in vitro and in vivo, had a small effect on parasite oxygen consumption in polarographic assays when used alone or in the presence of atovaquone or salicylhydroxamic acid. This suggests that proguanil does not potentiate atovaquone by direct inhibition of either branch of the parasite respiratory chain.

Animals↗
PubMed2002

Stochastic versus stable transcriptional differences on Plasmodium falciparum DNA microarrays.

The recent availability of the Plasmodium falciparum genome sequence has opened up convenient, large-scale analysis of transcriptional products in malaria. Protocols for cDNA labelling, cDNA hybridisation, and fluorescent signal detection developed for other organisms can be applied directly to malaria. However, P. falciparum offers unique challenges in data analysis due to stochastic variability in expression of some gene products, such as variable erythrocyte surface proteins. Careful comparison of global transcriptional patterns in two well-studied clones of P. falciparum (Dd2 and HB3) indicates that reliable, stable transcriptional alterations in malaria can be readily distinguished from stochastic processes. To do this, we utilised a complex experimental design which involves a combination of self-hybridisations and cross-hybridisations between two independently grown parasite populations for each clone being examined (for short, we call this a '2x2 CombiScan'). While even a simple 2x2 CombiScan required 12 microarray hybridisations, the effort generated output that was highly interpretable. Reliable RNA transcriptional differences between Dd2 and HB3 could be readily visualised using public algorithms for data normalisation and clustering.

Animals↗
PubMed1987

Inhibition of intra-erythrocytic growth of Plasmodium falciparum by human sera from Papua New Guinea.

Plasmodium falciparum was cultured through a single intra-erythrocytic cycle of growth in the presence of sera from various areas of Papua New Guinea. Of 194 sera tested from healthy individuals or subjects with hyperreactive malarious splenomegaly (HMS), 107 (55%) significantly inhibited parasite development. Inhibition did not correlate with malaria experience or HMS, though it was to some extent a seasonal phenomenon. Sera with inhibitory activity lost this after dialysis. A possible explanation for these findings is the occurrence of a dietary toxin with antimalarial properties detectable in vitro.

Adolescent↗
PubMed1987

Changes in repeat number, sequence, and reading frame in S-antigen genes of Plasmodium falciparum.

The S antigens from different isolates of Plasmodium falciparum exhibit extensive size, charge, and serological diversity. We show here that the S-antigen genes behave as multiple alleles of a single locus. The size heterogeneity results from different numbers, lengths, and/or sequences of tandem repeat units encoded within the S-antigen genes. Two genes studied here encode antigenically different S antigens but nevertheless have closely related tandem repeat sequences. We show that antigenic differences can arise because repeats are translated in different reading frames.

Alleles↗
PubMed2001

Plasmodium falciparum: gene mutations and amplification of dihydrofolate reductase genes in parasites grown in vitro in presence of pyrimethamine.

Samples of three pyrimethamine-sensitive clones of Plasmodium falciparum were grown for periods of 22-46 weeks in media containing stepwise increases in pyrimethamine concentrations and were seen to develop up to 1000-fold increases in resistance to the drug. With clone T9/94RC17, the dihydrofolate reductase (DHFR) gene was sequenced from 10 uncloned populations and 29 pure clones, all having increased resistance to pyrimethamine, and these sequences were compared with the sequence of the original pyrimethamine-sensitive clone. No changes in amino acid sequence were found to have occurred. Some resistant clones obtained by this method were then examined by pulsed-field gel electrophoresis, and the results indicated that there had been an increase in the size of chromosome 4. This was confirmed by hybridization of Southern blots with a chromosome 4-specific probe, the vacuolar ATPase subunit B gene, and a probe to DHFR. Dot-blotting with an oligonucleotide probe to DHFR confirmed that there had been increases up to 44-fold in copy number of the DHFR gene in the resistant strains. Resistant clones obtained by this procedure were then grown in medium lacking pyrimethamine for a period of nearly 2 years, and reversion nearly to the level of pyrimethamine sensitivity of the original clone T9/94RC17 was found to occur after about 16 months. Correspondingly, the chromosome 4 of the reverted population reverted to a size like that of the original sensitive clone T9/94RC17. The procedure of growing parasites in stepwise increases of pyrimethamine concentration was repeated with two other pyrimethamine-sensitive clones: TM4CB8-2.2.3 and G112CB1.1. (The DHFR gene of these clones encodes serine at position 108, in place of threonine as in clone T9/94RC17, and it was thought that this difference might conceivably affect the rate of mutation to asparagine at this position). Clones TM4CB8-2.2.3 and G112CB1.1 also responded by developing gradually increased resistance to pyrimethamine. However, in clone TM4CB8-2.2.3 a single mutation from Ile to Met at position 164 in the DHFR gene sequence was identified, and in clone G112CB1.1 there was a single mutation from Ala to Ser at position 16, but no mutations at position 108 were obtained in any of the clones studied here. In addition, chromosome 4 of clone TM4CB8-2.2.3 increased in size, presumably due to amplification of the DHFR gene. No increase in size was seen in clone G112CB1.1. We conclude that whereas some mutations producing changes in the amino acid sequence of the DHFR molecule may occur occasionally in clones or populations of P. falciparum grown in vitro in the presence of pyrimethamine, amplification of the DHFR gene following adaptation to growth in medium containing pyrimethamine occurs as a regular feature. The bearing of these findings on the development of pyrimethamine-resistant forms of malaria parasites in endemic areas is discussed.

Amino Acids↗
PubMed1991

Plasmodium falciparum: modulation of surface antigenic expression of infected erythrocytes as revealed by cell fluorescence ELISA.

The surface reactivity of heterologous immune sera with erythrocytes infected with Plasmodium falciparum has been difficult to assess in quantitative terms because of the restricted accessibility of surface epitopes and the lack of sensitive methodologies. In a previous study we showed that cryptic antigens can become exposed on the surface of intact trophozoites if the sterol content of the membranes is increased by means conservative of cell integrity (D. Baruch and Z. I. Cabantchik, Molecular and Biochemical Parasitology 36, 127-138, 1990). In this work we introduce a novel and highly sensitive method of fluorescence cell ELISA for the quantitative estimation of immunoglobulin binding to the surface of P. falciparum-infected erythrocytes. We obtained that elevation of the membrane sterol content markedly increased the (external) surface accessibility of antigenic epitopes of trophozoites as well as rings of various strains of P. falciparum. This treatment induced exposure of similar epitope(s) on the surface of both rings and trophozoites insofar as preadsorption of sera on sterol-treated cells abolished immunoglobulin binding to either stage of infected erythrocytes (treated or not with sterol). These putative epitopes have relatively low but demonstrable accessibility on the surface of untreated rings but become virtually inaccessible at the trophozoite stage. Application of a large variety of sera (98) to sterol-treated infected cells revealed that almost 70% of the tested sera were found to give positive surface reactivity. Relatively higher intensity of binding was obtained with sera originating from clinically immune individuals. Binding of sera to cells infected with five different P. falciparum strains was essentially indistinguishable, strongly suggesting that elevation of membrane visocity induces surface exposure of cryptic epitopes common to different parasite strains.

Adult↗
PubMedDate not supplied

Treatment of Plasmodium falciparum malaria with pyrimethamine-sulfadoxine: selective pressure for resistance is a function of long elimination half-life.

In an area of continuing transmission of Plasmodium falciparum on the Kenya coast, children treated with pyrimethamine-sulfadoxine experienced rapid parasite clearance, although a high proportion became reinfected within a short time. The frequency of pyrimethamine resistance in vitro in new infections was higher during the elimination phase of drug from a previous treatment. In infections which occurred at times when predicted residual drug concentrations were no longer inhibitory, incidence of pyrimethamine resistance was no different from the natural or background frequency. These results are discussed in terms of the selective pressure for resistance which is exerted by drugs with long elimination half-lives and a consideration of possible ways by which the problem might be addressed.

Animals↗
PubMed2002

Evaluation of anti-Plasmodium falciparum antibodies in Senegalese adults using different types of crude extracts from various strains of parasite.

To date, no consensus exists on the type of crude Plasmodium falciparum Ags to be used in a standard assay for the evaluation of the overall anti-blood-stage immune response in humans. Comparison of the dose-dependent reactivity of using a pool of hyper-immune Senegalese sera to saponin and water schizont extracts of the Senegalese 07/03 isolate indicated similar reactivity on both types of antigen preparations. Water schizont extracts from three different strains of P. falciparum adapted to in vitro culture probed with a panel of specific mouse antisera and monoclonal antibodies reacting with conserved antigens showed similar antigenic content. Seroreactivity of immune individuals living in three different areas of endemicity was assessed in parallel on water crude extracts. The individual IgG, IgM and IgG subclass antibody responses to the various schizont preparations correlated positively. The specific IgM response was higher on the Senegalese schizont extract than on the FCR3 extract and was highest in Dielmo villagers. The IgG response was similar in all three locations and was strain independent. These results indicate that monitoring IgG antibody levels to the widely distributed FCR3 strain using an easily prepared crude lysate might represent a valuable reference ELISA allowing homogenisation and comparison of data from different laboratories.

Animals↗
PubMed2004

Plasmodium falciparum clonal population dynamics during malaria treatment.

We have developed a new fragment-analysis method to enumerate the clones and to quantify their proportions within Plasmodium falciparum isolates. We prospectively enrolled 20 adult patients with uncomplicated malaria who were returning to France from various sub-Saharan countries, from January 2000 through July 2001. The analysis of clonal populations was performed on blood samples obtained at 10 times: 1 before treatment with oral quinine and 9 during the first 96 h of the treatment. The resistance genotypes pfcrt and dhfr were determined for chloroquine and antifolinics. Multiple P. falciparum genotypes were detected in 19 (95%) of 20 patients: 2, 3, 4, and 5 genotypes were found in 4, 9, 4 and 2 patients, respectively. Disappearance and reappearance of some clones within a few hours was observed. Individual clones represented 0.4%-99.4% of total parasitemia. Surprisingly, in 10 of 15 subjects tested, resistance genotypes varied according to the time of blood collection. These findings may have important implications with regard to the interpretations of resistance studies.

Animals↗
PubMed2000

Cytophilic immunoglobulin responses to Plasmodium falciparum glutamate-rich protein are correlated with protection against clinical malaria in Dielmo, Senegal.

The goal of this study was to analyze antibody responses to Plasmodium falciparum glutamate-rich protein (GLURP) using clinical data and plasma samples obtained from villagers of Dielmo, Senegal. This molecule was chosen because it is targeted by human antibodies which induce parasite growth inhibition in antibody-dependent cellular inhibition (ADCI) assays. The results showed a strong correlation between protection against malaria attacks and levels of immunoglobulin G2 (IgG2) and IgG3 against GLURP(94-489) (R0) and IgG3 against GLURP(705-1178) (R2) when corrected for the confounding effect of age-related exposure to malaria. Thus, GLURP may play a role in the induction of protective immunity against P. falciparum malaria.

Adolescent↗
PubMed1992

Ingestion of Plasmodium falciparum sporozoites during transmission by anopheline mosquitoes.

We investigated the process of sporozoite transmission during blood feeding for Anopheles gambiae and An. stephensi experimentally infected with Plasmodium falciparum. When infective mosquitoes were fed 22-25 days postinfection on an anesthetized rat, sporozoites were detected in the midgut of 96.5% of 57 An. gambiae (geometric mean [GM] = 32.5, range 3-374) and in 96.2% of 26 An. stephensi (GM = 19.5, range 1-345). There were no significant differences between species either in salivary gland sporozoite loads or in the number of ingested sporozoites. There was a significant linear relationship between sporozoite loads and the numbers of ingested sporozoites for both An. gambiae (r = 0.38) and An. stephensi (r = 0.69). Subsequently, An. gambiae were tested for sporozoite transmission by allowing them to feed individually on a suspended capillary tube containing 10 microliters of blood. A total of 83.3% of 18 infective mosquitoes transmitted a GM of 5.9 (range 1-36) sporozoites. The same mosquitoes contained a GM of 23.4 (range 2-165) ingested sporozoites. The number of ingested sporozoites was related to sporozoite loads (r = 0.42) but not to the number of sporozoites ejected into capillary tubes. Ingested sporozoites remained in the midgut up to 10 hr after feeding. The comparable numbers of sporozoites ingested by infective mosquitoes in both experiments indicates that the actual number of sporozoites transmitted to the vertebrate host during blood feeding is significantly reduced by the blood ingestion process.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2000

Antibiotics for prophylaxis of Plasmodium falciparum infections: in vitro activity of doxycycline against Senegalese isolates.

The in vitro activities of doxycycline, chloroquine, quinine, amodiaquine, artemether, pyrimethamine, and cycloguanil were evaluated against Plasmodium falciparum isolates from Senegal (Dielmo and Ndiop), using an isotopic, micro, drug susceptibility test. The 71-50% inhibitory concentration (IC50) values for doxycycline ranged from 0.7 to 108.0 microM and the geometric mean IC50 for the 71 isolates was 11.3 microM (95% confidence interval = 9.5-13.4 microM). The activity of doxycycline did not differ significantly (P = 0.0858) between the chloroquine-susceptible isolates and the chloroquine-resistant isolates. There was no in vitro correlation between the responses to doxycycline and those to artemether, chloroquine, quinine, amodiaquine, pyrimethamine, and cycloguanil, suggesting no in vitro cross-resistance among these drugs. Potency was increased by prolonged exposure. In 96-hr incubations, the activity of doxycycline was 4-5-fold more increased than in 48-hr incubations. The in vitro activity of doxycycline against intraerythrocytic stages of multidrug-resistant P. falciparum, its action against the preerythrocytic forms, the lack of correlation between the responses in vitro of P. falciparum to doxycycline and the other antimalarial drugs, and its original potential site of action are factors that favor its use as antimalarial drug.

Amodiaquine↗
PubMed1995

An analytical presentation of drug resistance in Plasmodium falciparum and guidelines to formulate a drug strategy.

The present paper describes the advantage/limitation of presently available 'in-vivo' methods to detect sensitivity status of Plasmodium falciparum to commonly used antimalarial drugs. The paper is based on a retrospective analysis of 890 P. falciparum cases and various parameters used to define the level of drug resistance. The presented quantification methodology with weightage system to different epidemiological variables of resistance may provide a guideline as to the level of parasite resistance, and a switch over to another antimalarial of firstline treatment which is of the considerable importance to provide early diagnosis and prompt treatment to avert the severe cases/deaths due to malaria.

Animals↗
PubMed1994

Plasmodium falciparum infection of splenectomized and intact Guyanan Saimiri monkeys.

Spleen-intact and splenectomized Saimiri monkeys of Guyanan origin were examined for their potential suitability for Plasmodium falciparum protection studies. The animals could be readily infected with adapted strains of P. falciparum (Indochina 1/CDC and Uganda Palo Alto FUP strains), but spontaneously recovered without drug treatment and without development of severe clinical disease. In intact animals, peak parasitemia prior to recovery generally ranged from 0.1% to 10%, whereas in splenectomized animals the peak parasitemia was generally higher so that some animals were given drug treatment to assist in recovery from infection. In reinfection studies, previously infected spleen-intact monkeys demonstrated sterile immunity to the homologous parasite strain but not to a heterologous strain. However, in monkeys infected with the heterologous strain, the peak parasitemia was less than in the first infection and of shorter duration. Splenectomized animals did not demonstrate sterile immunity although the peak parasitemia achieved was less than in the previous infection of each of these monkeys. While the lack of major clinical disease indicated that these monkeys did not provide a good animal model for human malaria, the development of protective immunity was consistent with a useful role in evaluating candidate vaccine antigens.

Animals↗
PubMed1997

Recognition of phage-expressed peptides containing Asx-Pro sequences by monoclonal antibodies produced against Plasmodium falciparum circumsporozoite protein.

The immunodominant region of the Plasmodium falciparum circumsporozoite protein is comprised mainly of a series of tetrapeptide repeats that can, depending on the starting cadence chosen, be described as (NANP)n, (ANPN)n, (NPNA)n or (PNAN)n in one-letter amino acid code. Data from several studies suggest that the NPNA cadence alone is structurally correct, in that each NPNA tetrapeptide effectively forms a structural unit initiated by an Asx-Pro turn. To explore this idea further and to assess the immunological relevance of peptide conformation as it relates to the cadence of these tetrapeptide repeats, we used ELISA to compare the abilities of monoclonal antibodies (MAbs) produced against P. falciparum sporozoites to recognize repeat-related heptapeptides expressed on the surface of filamentous bacteriophage. Having included representatives of both NANP and NPNA cadences and other peptides in which the number and location of Asx-Pro sequences varied, we provide evidence that Asx-Pro sequences play an important role in peptide conformation and antibody recognition, that peptide conformation is influenced by the cadence of the tetrapeptide repeats and that peptide conformation is important to the abilities of these MAbs to recognize their epitopes.

Amino Acid Sequence↗
PubMed1988

In vitro cultivation of southern African strains of Plasmodium falciparum and gametocytogenesis.

Sixteen southern African isolates of Plasmodium falciparum were successfully established and maintained in gassed tissue culture flasks which were either held in a static position or shaken. Shaken cultures yielded 48-hour growth rates ranging from 3.9-fold to 9.5-fold and peak parasitaemias ranging from 9% to 27%. Growth rates in static flasks were lower, ranging from 1.8-fold to 4.2-fold every 48 hours with peak parasitaemias ranging from 4% to 12%. Four of the established isolates were treated so as to promote gametocytogenesis and the rate of gametocyte production was found to be high. The mean percentage gametocytes by day 20-25 was 4.2% of erythrocytes, which represented approximately 50% of total parasites.

Animals↗
PubMed1998

X-ray microscopic visualization of specific labeling of adhesive molecule CD36 and cytoadherence by Plasmodium falciparum infected erythrocytes.

We investigated the cytoadherence of Plasmodium falciparum infected erythrocytes to target cells that express CD36 by soft x-ray microscopy. Using immunogold beads enhanced with silver, we localized CD36 on the surface of intact melanoma cells and throughout Triton extracted melanoma cells. We examined the orientation of parasites within erythrocytes that bound to target cells, and the interactions between the red cell membrane and the target cell, and we confirmed that fibrillar structures on the surface of melanoma and endothelial cells can be involved in the association between infected erythrocytes and melanoma cells or endothelial cells.

Animals↗