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PubMed1995

Plasmodium falciparum and Plasmodium vivax: lactate dehydrogenase activity and its application for in vitro drug susceptibility assay.

Lactate dehydrogenase, the terminal enzyme of anerobic Embden-Meyerhoff glycolysis, plays an important role in the carbohydrate metabolism of human malaria parasites. Based on the ability of malarial lactate dehydrogenase to use 3-acetylpyridine NAD as a coenzyme in a reaction leading to the formation of pyruvate from L-lactate, the enzymatic activity of fresh clinical isolates of Plasmodium falciparum and Plasmodium vivax was determined in relation to incubation time, asexual stages, and parasitemia and applied to a drug susceptibility assay. Lactate dehydrogenase activity was detectable at a parasitemia > 0.4%, at a hematocrit of 1.5%, and increased with parasitemia. Maximal lactate dehydrogenase activity was generally observed between 36 and 48 hr, when the trophozoites and schizonts predominated. The results of the in vitro drug susceptibility assays based on the inhibition of lactate dehydrogenase activity and on the incorporation of tritium-labeled hypoxanthine were correlated. For an optimal performance against fresh clinical malaria isolates, however, the enzymatic assay requires an initial parasitemia between 1 and 2% at a hematocrit of 1.5%.

Animals↗
PubMed2002

Mitochondrial NADH dehydrogenase from Plasmodium falciparum and Plasmodium berghei.

The mitochondrial electron transport system is necessary for growth and survival of malarial parasites in mammalian host cells. NADH dehydrogenase of respiratory complex I was demonstrated in isolated mitochondrial organelles of the human parasite Plasmodium falciparum and the mouse parasite Plasmodium berghei by using the specific inhibitor rotenone on oxygen consumption and enzyme activity. It was partially purified by two sequential steps of fast protein liquid chromatographic techniques from n-octyl glucoside solubilization of the isolated mitochondria of both parasites. In addition, physical and kinetic properties of the malarial enzymes were compared to the host mouse liver mitochondrial respiratory complex I either as intact or as partially purified forms. The malarial enzyme required both NADH and ubiquinone for maximal catalysis. Furthermore, rotenone and plumbagin (ubiquinone analog) showed strong inhibitory effect against the purified malarial enzymes and had antimalarial activity against in vitro growth of P. falciparum. Some unique properties suggest that the enzyme could be exploited as chemotherapeutic target for drug development, and it may have physiological significance in the mitochondrial metabolism of the parasite.

Animals↗
PubMed1999

The blood-stage dynamics of mixed Plasmodium malariae-Plasmodium falciparum infections.

We present the first mathematical model of the within-host dynamics of a mixed-species malaria infection in a human: the blood-stage population dynamics of a dual infection with Plasmodium malariae and Plasmodium falciparum. Our results reproduce several important features of such infections in nature, including the asymmetry of species asexual-form densities, inter-specific suppression through interactions with the human immune system, and seasonal alternations in species prevalence. Most importantly, our results suggest that an existing P. malariae infection can reduce the peak parasitemia of a subsequent P. falciparum superinfection by as much as 50%. This result integrates numerous empirical observations and supports the hypothesis that clinical outcomes of P. falciparum infections may be influenced by the presence of a congener.

Animals↗
PubMed2004

Genetic distance in housekeeping genes between Plasmodium falciparum and Plasmodium reichenowi and within P. falciparum.

The time to the most recent common ancestor of the extant populations of Plasmodium falciparum is controversial. The controversy primarily stems from the limited availability of sequences from Plasmodium reichenowi, a chimpanzee malaria parasite closely related to P. falciparum. Since the rate of nucleotide substitution differs in different loci and DNA regions, the estimation of genetic distance between P. falciparum and P. reichenowi should be performed using orthologous sequences that are evolving neutrally. Here, we obtained full-length sequences of two housekeeping genes, sarcoplasmic and endoplasmic reticulum Ca2+ -ATPase (serca) and lactate dehydrogenase (ldh), from 11 isolates of P. falciparum and 1 isolate of P. reichenowi and estimate the interspecific genetic distance (divergence) between the two species and intraspecific genetic distance (polymorphism) within P. falciparum. Interspecific distance and intraspecific distance at synonymous sites of interspecies-conserved regions of serca and ldh were 0.0672 +/- 0.0088 and 0.0011 +/- 0.0007, respectively, using the Nei and Gojobori method. Based on the ratio of interspecific distance to intraspecific distance, the time to the most recent common ancestor of P. falciparum was estimated to be (8.30 +/- 5.40) x 10(4) and (11.62 +/- 7.56) x 10(4) years ago, assuming the divergence time of the two parasite species to be 5 and 7 million years ago, respectively.

Amino Acid Sequence↗
PubMed1992

Inhibition of the growth of Plasmodium falciparum and Plasmodium berghei in vitro by an extract of Cochlospermum angolense (Welw.).

An extract of Cochlospermum angolense (Welw.) is used in the traditional medicine of Angola for the therapy of icterus and for the prophylaxis of malaria. From the roots of this plant red crystalline substances have been isolated and tested for their effect on Plasmodium falciparum in vitro and on the DNA and protein synthesis of Plasmodium berghei. The multiplication of P. falciparum was decreased to 50% of the control in the presence of 10 micrograms/ml extracted material and there was a total inhibition at a concentration of 50 micrograms/ml. If mice erythrocytes infected by P. berghei were incubated for 6 h with 25 micrograms/ml of the extract DNA synthesis was depressed to nearly background level. And, even more important, this effect could be demonstrated immediately. On the contrary, protein synthesis continued for at least 90 min at a reduced rate and stopped then. The results obtained show the direct antiparasitic effect of the substances extracted from C. angolense. The activity seems to be directed against DNA synthesis.

Animals↗
PubMed1992

Plasmodium falciparum and Plasmodium chabaudi: characterization of glycosylphosphatidylinositol-degrading activities.

Merozoites of malaria parasites have a membrane-bound serine protease whose solubilization and subsequent activity depend on a parasite-derived glycosylphosphatidylinositol-phospholipase C (GPI-PLC). The GPI-degrading activities from both Plasmodium falciparum and Plasmodium chabaudi have been characterized and partially purified by phenylboronate chromatography. They are membrane-bound, developmentally regulated, calcium-independent enzymes and as such they resemble GPI-PLC of Trypanosoma brucei. Furthermore, a T. brucei GPI-PLC-specific monoclonal antibody (mAT3) immunoprecipitates the plasmodial GPI-degrading activity. Thin-layer chromatography is suggestive of two activities: a GPI-PLC and a phospholipase A.

Animals↗
PubMed1995

Cutaneous delayed-type hypersensitivity responsiveness in patients during and after Plasmodium falciparum and Plasmodium vivax infections.

To assess cellular immune function in malaria, 61 patients admitted to the Bangkok Hospital for Tropical Diseases with Plasmodium falciparum (PF) or Plasmodium vivax malaria were examined with the MULTITEST CMI system (Merieux Institute, Florida) to evaluate delayed-type hypersensitivity (DTH) during and after acute disease over 4 weeks. All patients demonstrated significantly decreased responsiveness to seven commonly encountered recall antigens. This deficit was most severe immediately upon admission (prior to therapy). Uncomplicated Pf cases demonstrated significant hyporesponsiveness only during Week 1. Responses in moderate/severe falciparum and all vivax patients gradually increased in Weeks 2 and 3 but remained significantly below control values. This study confirms functional cell-mediated immune deficits in falciparum malaria and, for the first time, shows hyporesponsiveness in vivax malaria. We conclude that malaria causes a pronounced CMI deficit that is still detectable in some individuals for 3-4 weeks after treatment of acute infection. These changes in DTH should be a consideration in future vaccine development and in evaluation of immune status in endemic areas.

Acute Disease↗
PubMed1995

Characterization of a sporozoite antigen common to Plasmodium falciparum and Plasmodium berghei.

Previous studies demonstrated that immunization with Plasmodium falciparum sporozoites protected mice against Plasmodium berghei sporozoite infection and that this cross-protection was mediated, at least in part, by anti-sporozoite antibody. The experiments presented in this report show that serum and monoclonal antibodies derived from these protected mice identify a novel 42/54-kDa antigen (designated Circumsporozoite Protein 2 or CSP-2) in both P. falciparum and P. berghei sporozoites. Anti-CSP-2 monoclonal antibody blocks invasion of P. falciparum and P. berghei sporozoites into hepatoma cells in vitro and binds the cell surface of sporozoites. Passive transfer of anti-CSP-2 monoclonal antibody protected mice from P. berghei sporozoite infection. Therefore, CSP-2 appears to play a role in the cross-protective immune response observed.

Animals↗
PubMed1993

A Plasmodium vinckei cysteine proteinase shares unique features with its Plasmodium falciparum analogue.

The gene encoding a cysteine proteinase of the murine malaria parasite Plasmodium vinckei has been identified and characterized. The gene encodes a papain-family proteinase that shares unique features with a previously described P. falciparum cysteine proteinase. We hypothesize that both enzymes mediate the hydrolysis of hemoglobin, and perhaps other Plasmodium-specific functions.

Amino Acid Sequence↗
PubMed2005

Identifying and characterising the Plasmodium falciparum merozoite surface protein 10 Plasmodium vivax homologue.

Plasmodium vivax malaria is one of the most prevalent parasitic diseases in Asia and Latin-America. The difficulty of maintaining this parasite culture in vitro has hampered identifying and characterising proteins implied in merozoite invasion of red blood cells. We have been able to identify an open reading frame in P. vivax encoding the Plasmodium falciparum merozoite surface protein 10 homologous protein using the partial sequences from this parasite's genome reported during 2004. This new protein contains 479 amino-acids, two epidermal growth factor-like domains, hydrophobic regions at the N- and C-termini, being compatible with a signal peptide and a glycosylphosphatidylinositol anchor site, respectively. The protein is expressed during the parasite's asexual stage and is recognised by polyclonal sera in parasite lysate using Western blot. P. vivax-infected patients' sera highly recognised recombinant protein by ELISA.

Amino Acid Sequence↗
PubMed2004

Antimalarial activity of phenazines from lapachol, beta-lapachone and its derivatives against Plasmodium falciparum in vitro and Plasmodium berghei in vivo.

The antimalarial activity of benzo[a]phenazines synthesized from 1,2-naphthoquinone, lapachol, beta-lapachone and several derivatives have been tested against Plasmodium falciparum in vitro using isolates of parasites with various susceptibilities to chloroquine and/or mefloquine. Parasite growth in the presence of the test drugs was measured by incorporation of [(3)H]-hipoxanthine in comparison to controls with no drugs, always testing in parallel chloroquine, a standard antimalarial. Among seven benzophenazines tested, four had significant in vitro activities; important, the parasites resistant to chloroquine were more susceptible to the active phenazines in vitro. The doses of phenazines causing 50% inhibition of parasite growth varied from 1.67 to 9.44 microM. The two most active ones were also tested in vivo against Plasmodium berghei in mice, in parallel with lapachol and beta-lapachone. The 3-sulfonic acid-beta-lapachone-derived phenazine was the most active causing up to 98% inhibition of parasitaemia in long term treatment (7 doses) subcutaneously, whereas the phenazine from 3-bromo-beta-lapachone was inactive. Thus, these simple phenazines, containing polar (-Br,-I) and ionizable (-SO(3)H, -OH) groups, easily synthesized from cheap, natural or synthetic precursors (lapachol and beta-lapachone), at rather low cost, provide prototypes for development of new antimalarials aiming the chloroquine resistant parasites.

Animals↗
PubMed2006

Expression and function of pvcrt-o, a Plasmodium vivax ortholog of pfcrt, in Plasmodium falciparum and Dictyostelium discoideum.

Chloroquine resistance in Plasmodium vivax threatens the use of this drug as first-line treatment for millions of people infected each year worldwide. Unlike Plasmodium falciparum, in which chloroquine resistance is associated with mutations in the pfcrt gene encoding a digestive vacuole transmembrane protein, no point mutations have been associated with chloroquine resistance in the P. vivax ortholog gene, pvcrt-o (also called pvcg10). However, the question remains whether pvcrt-o can affect chloroquine response independent of mutations. Since P. vivax cannot be cultured in vitro, we used two heterologous expression systems to address this question. Results from the first system, in which chloroquine sensitive P. falciparum parasites were transformed with pvcrt-o, showed a 2.2-fold increase in chloroquine tolerance with pvcrt-o expression under a strong promoter; this effect was reversed by verapamil. In the second system, wild type pvcrt-o or a mutated form of the gene was expressed in Dictyostelium discoideum. Forms of PvCRT-o engineered to express either lysine or threonine at position 76 produced a verapamil-reversible reduction of chloroquine accumulation in this system to approximately 60% of that in control cells. Our data support an effect of PvCRT-o on chloroquine transport and/or accumulation by P. vivax, independent of the K76T amino acid substitution.

Animals↗
PubMed2004

Detection of Plasmodium vivax and Plasmodium falciparum in blood donors: comparison of new method to the conventional one.

Malaria is a parasitic infection caused by Plasmodium species and it is especially seen in tropical and subtropical areas. Our aim was to determine whether or not malaria is transmitted by blood transfusion in Turkey and to define the rate and the differences between endemic and non-endemic areas. During this study, blood samples were taken from donors who applied to Blood Banks in Istanbul (non-endemic area) and in Adana (endemic area). 2229 donors were screened using the OptilMAL Rapid Malaria Test and Giemsa staining method. Neither the OptiMAL Rapid Malaria Test nor the gold standard Giemsa staining method detected infected erythrocytes and Plasmodium lactate dehydrogenase.

Animals↗
PubMed1999

The aspartic proteinase from the rodent parasite Plasmodium berghei as a potential model for plasmepsins from the human malaria parasite, Plasmodium falciparum.

The gene encoding an aspartic proteinase precursor (proplasmepsin) from the rodent malaria parasite Plasmodium berghei has been cloned. Recombinant P. berghei plasmepsin hydrolysed a synthetic peptide substrate and this cleavage was prevented by the general aspartic proteinase inhibitor, isovaleryl pepstatin and by Ro40-4388, a lead compound for the inhibition of plasmepsins from the human malaria parasite Plasmodium falciparum. Southern blotting detected only one proplasmepsin gene in P. berghei. Two plasmepsins have previously been reported in P. falciparum. Here, we describe two further proplasmepsin genes from this species. The suitability of P. berghei as a model for the in vivo evaluation of plasmepsin inhibitors is discussed.

Amino Acid Sequence↗
PubMed2001

The high molecular mass rhoptry protein, RhopH1, is encoded by members of the clag multigene family in Plasmodium falciparum and Plasmodium yoelii.

Malarial merozoite rhoptries contain a high molecular mass protein complex called RhopH. RhopH is composed of three polypeptides, RhopH1, RhopH2, and RhopH3, encoded by distinct genes. Using monoclonal antibody-purified protein complex from both Plasmodium falciparum and Plasmodium yoelii, peptides were obtained by digestion of RhopH1 and their sequence determined either by mass spectrometry or Edman degradation. In both species the genes encoding RhopH1 were identified as members of the cytoadherence linked asexual gene (clag) family. In P. falciparum the family members on chromosome 3 were identified as encoding RhopH1. In P. yoelii two related genes were identified and sequenced. One of the genes, pyrhoph1a, was positively identified as encoding RhopH1 by the peptide analysis and the other gene, pyrhoph1a-p, was at least transcribed. Genes in the clag family present in both parasite species have a number of conserved features. The size and location of the P. yoelii protein complex in the rhoptries was confirmed. The first clag gene identified on chromosome 9 was implicated in cytoadherence, the binding of infected erythrocytes to host endothelial cells; this study shows that other members of the family encode merozoite rhoptry proteins, proteins that may be involved in merozoite-erythrocyte interactions. We propose that the family should be renamed as rhoph1/clag.

Amino Acid Sequence↗
PubMed2003

Characterisation of the rhoph2 gene of Plasmodium falciparum and Plasmodium yoelii.

The high molecular mass protein complex (RhopH) in the rhoptries of the malaria parasite consists of three distinct polypeptides with estimated sizes in Plasmodium falciparum of 155kDa (PfRhopH1), 140kDa (PfRhopH2) and 110kDa (PfRhopH3). Using a number of reagents, including a new mAb 4E10 that is specific for the PfRhopH complex, it was shown that the RhopH complex is synthesised during schizogony and transferred intact to the ring stage in newly invaded erythrocytes. The genes encoding RhopH1 and RhopH3 have already been identified and characterised in both P. falciparum and Plasmodium yoelii. In this report, we describe the identification of the gene for RhopH2 in both these parasite species. Peptide sequences were obtained from purified RhopH2 proteins and used to generate oligonucleotide primers and search malaria sequence databases. In a parallel approach, mAb 4E10 was used to identify a clone coding for RhopH2 from a P. falciparum cDNA library. The sequences of both P. falciparum and P. yoelii genes for RhopH2 were completed and compared. They both contain nine introns and there is a high degree of similarity between the deduced amino acid sequences of the two proteins. The P. falciparum gene is a single copy gene located on chromosome 9, and is transcribed in schizonts.

Amino Acid Sequence↗
PubMed1999

The putative gene for the first enzyme of glutathione biosynthesis in Plasmodium berghei and Plasmodium falciparum.

The putative gene for gamma-glutamylcysteine synthetase, the rate-limiting enzyme in glutathione biosynthesis, has been characterized both in Plasmodium berghei and Plasmodium falciparum. Protein sequence comparison between these two species reveals large conserved regions sharing more than 80% similarity, separated by less conserved portions. When the comparison is extended to known gamma-glutamylcysteine synthetases from other eukaryotes, a number of high similarity blocks are observed which may help in identifying sequence essential for protein function.

Amino Acid Sequence↗