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PubMed1987

Invasion of mouse erythrocytes by the human malaria parasite, Plasmodium falciparum.

Plasmodium falciparum malaria merozoites require erythrocyte sialic acid for optimal invasion of human erythrocytes. Since mouse erythrocytes have the form of sialic acid found on human erythrocytes (N-acetyl neuraminic acid), mouse erythrocytes were tested for invasion in vitro. The Camp and 7G8 strains of P. falciparum invaded mouse erythrocytes at 17-45% of the invasion rate of human erythrocytes. Newly invaded mouse erythrocytes morphologically resembled parasitized human erythrocytes as shown on Giemsa-stained blood films and by electron microscopy. The rim of parasitized mouse erythrocytes contained the P. falciparum 155-kD protein, which is on the rim of ring-infected human erythrocytes. Camp but not 7G8 invaded rat erythrocytes, indicating receptor heterogeneity. These data suggest that it may be possible to adapt the asexual erythrocytic stage of P. falciparum to rodents. The development of a rodent model of P. falciparum malaria could facilitate vaccine development.

Animals↗

PubMed2000

Population structure and recent evolution of Plasmodium falciparum.

Plasmodium falciparum is the agent of malignant malaria, one of mankind's most severe maladies. The parasite exhibits antigenic polymorphisms that have been postulated to be ancient. We have proposed that the extant world populations of P. falciparum have derived from one single parasite, a cenancestor, within the last 5, 000-50,000 years. This inference derives from the virtual or complete absence of synonymous nucleotide polymorphisms at genes not involved in immune or drug responses. Seeking to conciliate this claim with extensive antigenic polymorphism, we first note that allele substitutions or polymorphisms can arise very rapidly, even in a single generation, in large populations subject to strong natural selection. Second, new alleles can arise not only by single-nucleotide mutations, but also by duplication/deletion of short simple-repeat DNA sequences, a process several orders of magnitude faster than single-nucleotide mutation. We analyze three antigenic genes known to be extremely polymorphic: Csp, Msp-1, and Msp-2. We identify regions consisting of tandem or proximally repetitive short DNA sequences, including some previously unnoticed. We conclude that the antigenic polymorphisms are consistent with the recent origin of the world populations of P. falciparum inferred from the analysis of nonantigenic genes.

Amino Acid Sequence↗

PubMed2004

Hyper-expansion of asparagines correlates with an abundance of proteins with prion-like domains in Plasmodium falciparum.

Plasmodium falciparum encodes approximately 5300 proteins of which approximately 35% have repeats of amino acids, significantly higher than in other fully sequenced eukaryotes. The proportion of proteins with amino acid homorepeats varies from 4 to 54% amongst different functional classes of proteins. These homorepeats are dominated by asparagines, which are selected over lysines despite equivalent AT codon content. Surprisingly, asparagine repeats are absent from the variant surface antigen protein families of PfEMP1s, Stevors and Rifins. The PfEMP1 protein family is instead rich in recurrences of glutamates, similar to human cell surface proteins. Structural mapping of homorepeats suggests that these segments are likely to form surface exposed structures that protrude from the main protein cores. We also found an abundance of asparagine-rich prion-like domains in P. falciparum, significantly larger than in any other eukaryote. Domains rich in glutamines and asparagines have an innate predisposition to form self-propagating amyloid fibers, which are involved both in prion-based inheritance and in human neurodegenerative disorders. Nearly 24% (1302 polypeptides) of P. falciparum proteins contain prion-forming or prion-inducing domains, in comparison to Drosophila (approximately 3.4%) which to date showed the highest number of prion-like proteins. The unexpected properties of P. falciparum revealed here open new avenues for investigating parasite biology.

Amino Acid Sequence↗

PubMed1997

Mutations in dihydropteroate synthase are responsible for sulfone and sulfonamide resistance in Plasmodium falciparum.

Plasmodium falciparum causes the most severe form of malaria in humans. An important class of drugs in malaria treatment is the sulfone/sulfonamide group, of which sulfadoxine is the most commonly used. The target of sulfadoxine is the enzyme dihydropteroate synthase (DHPS), and sequencing of the DHPS gene has identified amino acid differences that may be involved in the mechanism of resistance to this drug. In this study we have sequenced the DHPS gene in 10 isolates from Thailand and identified a new allele of DHPS that has a previously unidentified amino acid difference. We have expressed eight alleles of P. falciparum PPPK-DHPS in Escherichia coli and purified the functional enzymes to homogeneity. Strikingly, the Ki for sulfadoxine varies by almost three orders of magnitude from 0.14 microM for the DHPS allele from sensitive isolates to 112 microM for an enzyme expressed in a highly resistant isolate. Comparison of the Ki of different sulfonamides and the sulfone dapsone has suggested that the amino acid differences in DHPS would confer cross-resistance to these compounds. These results show that the amino acid differences in the DHPS enzyme of sulfadoxine-resistant isolates of P. falciparum are central to the mechanism of resistance to sulfones and sulfonamides.

Animals↗

PubMed2003

Characterisation of the merozoite surface protein-2 promoter using stable and transient transfection in Plasmodium falciparum.

Plasmodium falciparum merozoite surface protein (MSP)-2, is a polymorphic protein whose variable regions define two allelic families, the 3D7/IC-1 and FC27/D10 families. The gene encoding MSP-2 is located on chromosome 2 immediately 3' of the gene encoding merozoite surface protein-5 (MSP-5) with a 1096 bp intergenic region that presumably contains the MSP-2 promoter. Here we present characterization of the MSP-2 promoter using transient and stable transfection of P. falciparum. The mRNA transcription initiation site was mapped to a position 256 bp upstream of the MSP-2 translation start site. The ability of the intergenic region between MSP-5 and MSP-2 to promote the expression of chloramphenicol acetyl transferase (CAT) has been tested using a series of nested deletions in transient transfection experiments. The minimal region required for CAT expression has been defined and putative regulatory elements delineated. These nested deletions were used for heterologous expression of an FC27 family MSP-2 allele in the 3D7 allelic background in transfected 3D7 lines. In each case, the transgenic P. falciparum lines generated co-express both 3D7 and FC27 allelic forms of MSP-2 at the merozoite surface. These results have identified the functional promoter for MSP-2.

Alleles↗

PubMed1982

Genome size and DNA complexity of Plasmodium falciparum.

Plasmodium falciparum DNA was prepared from cells cultured in vitro in human erythrocytes. The P. falciparum DNA was mixed with a tritium-labeled Escherichia coli DNA standard, and the kinetics of reassociation were measured using hydroxyapatite chromatography. It was found that the P. falciparum genome size is equal to 3.8 . 10(8) nucleotide pairs, and that a repetitive component is present which contains about 10% of the DNA. The average repetition frequency in this component is 95 copies of each sequence.

Animals↗

PubMed1984

Protein and nucleic acid synthesis during synchronized growth of Plasmodium falciparum.

Plasmodium falciparum, the human malarial parasite, was synchronized for asexual growth and pulse labeled to determine when RNA, protein, and DNA synthesis occurred. RNA was synthesized during two periods in the 48-h developmental cycle, protein synthesis occurred throughout the cycle, and most DNA was synthesized just before nuclear division (schizogony).

Animals↗

PubMed1998

A comparison of the phenomenology and genetics of multidrug resistance in cancer cells and quinoline resistance in Plasmodium falciparum.

Plasmodium falciparum is the causative agent of the most deadly form of human malaria. Chemotherapy traditionally has been the main line of defense against this parasite, and chloroquine, the drug of choice, has been one of the most successful drugs ever developed. Unfortunately, the evolution and spread of resistance to chloroquine and other quinoline-containing drugs means that these compounds are now virtually useless in many endemic areas. Future prospects for the use of quinoline compounds improved considerably when it was demonstrated that chloroquine resistance could be circumvented in vitro by a number of structurally and functionally unrelated compounds such as verapamil and desipramine. The phenomenon of resistance reversal by compounds such as verapamil is also a key feature of drug resistance in mammalian cells, and this has raised the possibility that the underlying mechanisms of drug resistance of the two cell types could be similar. This hypothesis has prompted a large number of studies into the genetics and biochemistry of resistance to quinoline-containing drugs in P. falciparum. Both the genetic and the biochemical studies have raised issues of controversy and stimulated much debate. These issues are discussed in this review, in the context of a comparison with the genetics and biochemistry of multidrug resistance in mammalian cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2006

Structural and biochemical characterization of a mitochondrial peroxiredoxin from Plasmodium falciparum.

Plasmodium falciparum possesses a single mitochondrion with a functional electron transport chain. During respiration, reactive oxygen species are generated that need to be removed to protect the organelle from oxidative damage. In the absence of catalase and glutathione peroxidase, the parasites rely primarily on peroxiredoxin-linked systems for protection. We have analysed the biochemical and structural features of the mitochondrial peroxiredoxin and thioredoxin of P. falciparum. The mitochondrial localization of both proteins was confirmed by expressing green fluorescent protein fusions in parasite erythrocytic stages. Recombinant protein was kinetically characterized using the cytosolic and the mitochondrial thioredoxin (PfTrx1 and PfTrx2 respectively). The peroxiredoxin clearly preferred PfTrx2 to PfTrx1 as a reducing partner, reflected by the KM values of 11.6 microM and 130.4 microM respectively. Substitution of the two dyads asparagine-62/tyrosine-63 and phenylalanine-139/alanine-140 residues by aspartate-phenylalaine and valine-serine, respectively, reduced the KM for Trx1 but had no effect on the KM of Trx2 suggesting some role for these residues in the discrimination between the two substrates. Solution studies suggest that the protein exists primarily in a homodecameric form. The crystal structure of the mitochondrial peroxiredoxin reveals a fold typical of the 2-Cys class peroxiredoxins and a dimeric form with an intermolecular disulphide bridge between Cys67 and Cys187. These results show that the mitochondrial peroxiredoxin of P. falciparum occurs in both dimeric and decameric forms when purified under non-reducing conditions.

Amino Acid Sequence↗

PubMed1996

Structure and inhibition of plasmepsin II, a hemoglobin-degrading enzyme from Plasmodium falciparum.

Plasmodium falciparum is the major causative agent of malaria, a disease of worldwide importance. Resistance to current drugs such as chloroquine and mefloquine is spreading at an alarming rate, and our antimalarial armamentarium is almost depleted. The malarial parasite encodes two homologous aspartic proteases, plasmepsins I and II, which are essential components of its hemoglobin-degradation pathway and are novel targets for antimalarial drug development. We have determined the crystal structure of recombinant plasmepsin II complexed with pepstatin A. This represents the first reported crystal structure of a protein from P. falciparum. The crystals contain molecules in two different conformations, revealing a remarkable degree of interdomain flexibility of the enzyme. The structure was used to design a series of selective low molecular weight compounds that inhibit both plasmepsin II and the growth of P. falciparum in culture.

Amino Acid Sequence↗

PubMed2000

Isolation and functional characterization of the PfNT1 nucleoside transporter gene from Plasmodium falciparum.

Plasmodium falciparum, the causative agent of the most lethal form of human malaria, is incapable of de novo purine synthesis, and thus, purine acquisition from the host is an indispensable nutritional requirement. This purine salvage process is initiated by the transport of preformed purines into the parasite. We have identified a gene encoding a nucleoside transporter from P. falciparum, PfNT1, and analyzed its function and expression during intraerythrocytic parasite development. PfNT1 predicts a polypeptide of 422 amino acids with 11 transmembrane domains that is homologous to other members of the equilibrative nucleoside transporter family. Southern analysis and BLAST searching of The Institute for Genomic Research (TIGR) malaria data base indicate that PfNT1 is a single copy gene located on chromosome 14. Northern analysis of RNA from intraerythrocytic stages of the parasite demonstrates that PfNT1 is expressed throughout the asexual life cycle but is significantly elevated during the early trophozoite stage. Functional expression of PfNT1 in Xenopus laevis oocytes significantly increases their ability to take up naturally occurring D-adenosine (K(m) = 13.2 microM) and D-inosine (K(m) = 253 microM). Significantly, PfNT1, unlike the mammalian nucleoside transporters, also has the capacity to transport the stereoisomer L-adenosine (K(m) > 500 microM). Inhibition studies with a battery of purine and pyrimidine nucleosides and bases as well as their analogs indicate that PfNT1 exhibits a broad substrate specificity for purine and pyrimidine nucleosides. These data provide compelling evidence that PfNT1 encodes a functional purine/pyrimidine nucleoside transporter whose expression is strongly developmentally regulated in the asexual stages of the P. falciparum life cycle. Moreover, the unusual ability to transport L-adenosine and the vital contribution of purine transport to parasite survival makes PfNT1 an attractive target for therapeutic evaluation.

Adenosine↗

PubMed2004

Orotate phosphoribosyltransferase and orotidine 5'-monophosphate decarboxylase exist as multienzyme complex in human malaria parasite Plasmodium falciparum.

Plasmodium falciparum, the causative agent of the most lethal form of human malaria, totally depends on de novo pyrimidine biosynthetic pathway. Orotate phosphoribosyltransferase (OPRT) and orotidine 5'-monophosphate decarboxylase (OMPDC), the fifth and sixth enzymes in the pathway catalyzing formation of uridine 5'-monophosphate (UMP), remain largely uncharacterized in the protozoan parasite. In this study, we achieved purification of OPRT and OMPDC to near homogeneity from P. falciparum cultivated in vitro. The OPRT and OMPDC activities were co-eluted in all chromatographic columns during purification, suggesting the purified proteins exist as a multienzyme complex with a molecular mass of 140+/-8 kDa and contain two subunits each of OPRT and OMPDC. Monomeric forms of OPRT and OMPDC had molecular masses of 32+/-3 and 38+/-3 kDa, respectively, in agreement with those of proteins predicted from P. falciparum genome database. Interestingly, kinetic parameters and inhibitory constants of both OPRT and OMPDC activities were found to be different to those of the bifunctional human red cell UMP synthase. Our evidence provides the first example of OPRT and OMPDC existing as a multienzyme complex.

Amino Acid Sequence↗

PubMed1986

Variation in the gene encoding a major merozoite surface antigen of the human malaria parasite Plasmodium falciparum.

Plasmodium falciparum merozoites have a variable surface protein of about 195,000 molecular weight which may be involved in strain-specific immunity. We have cloned and sequenced a major portion of the gene encoding this antigen from the CAMP strain and have located sites of preferred mung bean nuclease cleavage around the gene. These sites depend on reaction conditions, but at 40% formamide and 2 units of mung bean nuclease per microgram DNA, the intact gene was excised from the chromosome. Comparison of the CAMP strain gene with the same gene from other strains of P. falciparum by matching available DNA sequences and by DNA hybridization revealed five regions of homology separated by divergent segments. Two of the variable regions encoded three amino acid repeats, predominantly Ser-Gly-Thr and Thr-Glu-Glu. Implications of these findings on the function of the antigen, and possible mechanisms for generation of variants are discussed.

Amino Acid Sequence↗

PubMed1992

Serological relationship of tumor necrosis factor-inducing exoantigens of Plasmodium falciparum and Plasmodium vivax.

Exoantigens of Plasmodium vivax-parasitized erythrocytes stimulated macrophages to secrete tumor necrosis factor, and antisera raised against the exoantigens inhibited this secretion. The antisera also inhibited the activity of Plasmodium falciparum and Plasmodium yoelii exoantigens, and conversely, antisera against the latter cross-reacted with the exoantigens of P. vivax.

Animals↗

PubMed1979

Studies on the 2,4-diamino-6-substituted quinazolines. III. The capacity of sulfadiazine to enhance the activities of WR-158,122 and WR-159,412 against infections with various drug-susceptible and drug-resistant strains of Plasmodium falciparum and Plasmodium vivax in owl monkeys.

Previous studies showed: 1) that the activities of the 2,4-diamino-6-substituted quinazolines. WR-158,122 and WR-159,412, against Plasmodium falciparum and Plasmodium vivax infections in owl monkeys, were seriously impaired when infecting strains were pyrimethamine-resistant; and 2) that primary treatment failure with either agent led frequently to emergence of parasites resistant to these derivatives. Taking advantage of the potencies of WR-158,122 and WR-159,412 as dihydrofolic acid reductase inhibitors, the current studies were aimed at determining whether the above liabilities could be reduced to manageable levels or eliminated by concomitant administration of a rho-aminobenzoic acid inhibitor such as sulfadiazine. Application of these combinations prevented emergence of parasites resistant to WR-158,122 or WR-159,412, but did not abolish the differences in effectiveness of either compound against infections with pyrimethamine-susceptible and pyrimethamine-resistant strains; however, activities against infections with either susceptible or resistant strains were enhanced markedly. With WR-158,122, this enhancement ranged from greater than 7-fold to 75-fold; with WR-159,412, it ranged from greater than 5-fold to 13-fold. Maximal increases in activity were attained with a remarkedly small dose of sulfadiazine, 5.0 mg per kg of body weight daily. With this augmentation of activity, acceptably small doses of WR-158,122 regularly cured infections with even the most highly pyrimethamine-resistant strain.

Animals↗

PubMed1992

Muramyl peptide adjuvants for Plasmodium falciparum and Plasmodium vivax circumsporozoite vaccines in rodent model systems.

Circumsporozoite proteins from the malaria parasites Plasmodium falciparum and Plasmodium vivax were expressed at high levels in the yeast Saccharomyces cerevisiae. Recombinant proteins varied both in length and in number of the natural amino acid repeat motifs. The proteins were purified and used to immunize mice, guinea pigs, and rabbits. Novel muramyl peptide adjuvants were used that increased the immune response as measured by ELISA assays, indirect immunofluorescence of fixed sporozoites, and the invasion of cultured liver cells by live sporozoites. These results suggest that an improved humoral response to recombinant circumsporozoite vaccines might be achieved by varying the design of the recombinant protein and by the use of novel adjuvant systems.

Adjuvants, Immunologic↗

PubMed1992

[In vitro development of sodium artesunate resistance in Plasmodium falciparum].

Plasmodium falciparum (Lab. culture FCR3 isolate) developed resistance to sodium artesunate after exposure to the drug in vitro. The drug effective concentration which resulted in 50 per cent schizont maturation inhibition (IC50) was 1.6 ng/ml (4.1 nmol/L) before exposure to the drug. After 130 days of discontiguous exposure to sodium artesunate in a stepwise fashion, the sensitivity of the isolate to the drug decreased, with its IC50 3-fold higher than that of the parent isolate. The resistance to artesunate decreased significantly after the resistant line was grown in drug-free medium.

Animals↗

PubMed2003

[Real-time PCR for detection of molecular markers of resistance in Plasmodium falciparum].

Plasmodium falciparum drug resistance is a major problem in malaria endemic areas. Molecular markers and in vitro tests have been developed to study and monitor drug resistance. However, none used alone, can provide sufficient data concerning the level of drug resistance and to issue precise guideline for drug use policies in endemic areas. We propose real-time PCR for the simultaneous detection of pfcrt and pfmdr1 genes mutations. The aim of this study was not to provide definitive data concerning the rate of mutations in an endemic area, but to describe a powerful method allowing the detection of major pfmdr1 and pfcrt mutations.

Animals↗