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PubMed1989

Plasmodium vivax interaction with the human Duffy blood group glycoprotein: identification of a parasite receptor-like protein.

The interaction between merozoites of the human pathogen, Plasmodium vivax, and the Duffy blood group glycoprotein on the surface of human erythrocytes is essential for the invasion of erythrocytes and the survival of the parasite. We have identified a P. vivax protein of 135 to 140 kDa which binds with receptor-like specificity to the human Duffy blood group glycoprotein. This interaction can be specifically inhibited by purified Duffy glycoprotein and by pretreating erythrocytes with a monoclonal antibody directed against a novel Duffy determinant. A protein with similar specificity for the Duffy glycoprotein from the phylogenetically related simian malaria, P. knowlesi, is shown to be immunologically related by the generation of cross-reactive antibodies. Despite their shared properties, these two Duffy associating proteins from P. vivax and P. knowlesi differ in some aspects of their interaction with the Duffy glycoprotein. The identification of these proteins will help elucidate the molecular mechanisms of erythrocyte invasion by Plasmodium.

Animals↗
PubMed1992

Plasmodium cynomolgi: the hsp 70 gene.

The hsp 70 gene of Plasmodium cynomolgi was isolated and characterized. As expected the gene is highly similar to that of the hsp 70 gene of Plasmodium falciparum (98% at the protein level, 82% at the nucleotide level). Surprisingly, the hsp 70 gene appears to be present in a single copy in all the P. cynomolgi strains tested, a finding that has implications for the parasite's ability to undergo a heat shock response.

Amino Acid Sequence↗
PubMed1986

Heteroduplex stabilities in highly repetitive DNA. An hypothesis for the polymorphism of Plasmodium parasite antigenic response.

Codon repeats encountered in DNA sequences may formally lead to several double-stranded structures of similar stabilities. This is observed in the highly repetitive sequences of some Plasmodium antigens (S-antigen, CS proteins). It is postulated that gene recombination may occur via various heteroduplex molecules thus leading to antigenic polymorphism of Plasmodium parasites.

Animals↗
PubMed1990

TNF and inhibition of growth of Plasmodium falciparum.

The mechanism of intra-erythrocyte death of Plasmodium chabaudi in vivo has not yet been elucidated. Here we summarise recent experiments in which serum from mice undergoing a successful immune response to this parasite did not inhibit Plasmodium falciparum in vivo unless the P. chabaudi infection and TNF levels were high enough to cause illness in the host. This was true for the 556KA and DS strains of P. chabaudi in intact mice, but not for 556KA in nude mice, which did not generate inhibitory activity at any parasitaemia. Tumour necrosis factor (TNF) inhibits malaria parasites via some undefined secondary mediator. 10 mg of r hu TNF generated this inhibitory activity, as measured against P. falciparum in vitro, in the serum of mice only if they were pretreated with Corynebacterium parvum, which activates macrophages and sensitises the mice to the toxic effects of TNF. This implies a role for activated macrophages downstream from TNF in the process involved in intra-erythrocytic death of parasites.

Animals↗
PubMed1988

Structure of the circumsporozoite gene of Plasmodium malariae.

The sequence of the gene encoding the circumsporozoite protein of Plasmodium malariae was determined. The central immunodominant region of the protein consists of 45 copies of the sequence Asn-Ala-Ala-Gly and 6 copies of the sequence Asn-Asp-Ala-Gly. The CSP of the monkey parasite Plasmodium brasilianum contains the same repetitive sequences. Further comparison of the two genes in regions outside the immunodominant domains reveals only three nucleotide differences and each results in an amino acid change. One is centered in a putative T-cell determinant bearing region, the second is in the putative liver binding site, and the third is part of a degenerate repeat at the start of the immunodominant region.

Amino Acid Sequence↗
PubMed1990

Chromosomal rearrangements and point mutations in the DHFR-TS gene of Plasmodium chabaudi under antifolate selection.

Selection of the rodent malaria Plasmodium chabaudi with low levels of the antifolate drug pyrimethamine has previously been shown by us to result in duplication of the dihydrofolate reductase-thymidylate synthase (DHFR-TS) gene by a duplication of chromosome 7 and subsequent rearrangements. We have selected this resultant parasite line with large doses of pyrimethamine and analysed the DHFR-TS gene and chromosomes for any changes. Increased drug pressure has resulted in reappearance of a chromosome with the same structure as chromosome 7 from DS the parent line. Sequencing of the DHFR gene from each of the chromosomes has identified a single point mutation that results in a serine to asparagine change at position 106. This is the equivalent mutation that has been identified as the key residue in the mechanism of resistance to pyrimethamine in Plasmodium falciparum. There is no apparent increase in transcription of the DHFR-TS gene and the large increase in resistance is most likely a result of the mutation in the DHFR gene.

Animals↗
PubMed1991

The complete sequence of a Plasmodium malariae SSUrRNA gene and its comparison to other plasmodial SSUrRNA genes.

A gene encoding the small subunit rRNA (SSUrRNA) has been isolated from the human parasite, Plasmodium malariae. The gene has been sequenced. It contains conserved and variable regions which conform to patterns established for other eukaryotic SSUrRNA genes. Comparisons with other SSUrRNA genes from Plasmodium species reveal regions unique to P. malariae which could be used in specific diagnostic probes for this organism, and provide evidence that the gene is of the type expressed during asexual growth. In addition the '5.8S' gene has been cloned from P. malariae. The gene has been sequenced. It contains bases universally conserved in '5.8S' genes but there is considerable divergence between the P. malariae sequence and that of the P. falciparum gene.

Animals↗
PubMed1991

Cloning of the Plasmodium vivax Duffy receptor.

Plasmodium vivax and Plasmodium knowlesi merozoites invade only Duffy blood group-positive human erythrocytes. Soluble P. vivax and P. knowlesi merozoite proteins of 135 kDa bind specifically to Duffy blood group determinants. The gene encoding a member of the Duffy receptor gene family of P. knowlesi has been cloned. We report here the molecular cloning of the presumptive Duffy receptor gene of P. vivax, using the P. knowlesi gene as a probe. There is a single gene in P. vivax which codes for a protein of 1115 amino acids. The deduced amino acid sequence predicts a putative signal sequence at the amino-terminus and a transmembrane region followed by 45 amino acids at the carboxy-terminus. The three introns found at the 3' end of the P. knowlesi gene were conserved in P. vivax, including high homology for the sequences of the introns. Comparison of the portion of the proteins amino to the transmembrane region between P. vivax and the partial sequence of P. knowlesi indicated at least three domains. Two homologous regions were separated by a non-homologous region. The cysteines in the homologous regions were conserved in number and position, indicating that the folding is similar and suggesting that these regions may be the Duffy blood group binding domains. In both P. vivax and P. knowlesi, the non-homologous region is hydrophilic and proline-rich, although the position of the prolines is not conserved. As prolines tend to stiffen a protein, this region may act as a 'hinge region' similar to those in the immunoglobulin gene family.

Amino Acid Sequence↗
PubMed1992

Alpha-tubulin II is a male-specific protein in Plasmodium falciparum.

The tubulin gene family in Plasmodium falciparum consists of one beta-tubulin and two alpha-tubulin genes (alpha-tubulin I and II). We present here data indicating that alpha-tubulin II is expressed only in male sexual stage parasites. An IgM mAb, 5E7, specifically reacted with stage III (day 4-5) through mature (day 10-11) male gametocytes and with emerging, exflagellating, or freely moving male gametes. No reactivity was detected in female gametocytes, female gametes, sporozoites, or asexual parasites. mAb 5E7 also specifically recognized male gametes of the avian parasite, Plasmodium gallinaceum, and immunoblotted a 50 kDa protein in extracts of male gametes from both species. This 50 kDa antigen was localized by immunoelectron microscopy to axonemes of male gametes in a pattern similar to that obtained with anti-alpha- and anti-beta-tubulin antibodies. Furthermore, mAb 5E7 specifically reacted with recombinant alpha-tubulin II protein obtained using the PCR-amplified alpha-tubulin II gene from a gametocyte-specific cDNA library. The sex-specific expression of alpha-tubulin II and its localization to axoneme of the male parasite suggest a role for this molecule in the morphologic changes that occur during exflagellation and in the motility of the parasite. alpha-Tubulin II and mAb 5E7 may prove useful tools in studies of the biology of sexual stage differentiation and development in P. falciparum in addition to the general understanding of post-translational modifications of tubulin isoforms.

Animals↗
PubMed1994

Dimorphism and intergenic recombination within the microneme protein (MP-1) gene family of Plasmodium knowlesi.

The microneme protein-1 (MP-1) of Plasmodium knowlesi and Plasmodium vivax facilitates merozoite invasion of the erythrocyte by binding to Duffy blood group antigens. Since this protein is important in the invasion process and is a potential vaccine candidate, it is important to understand the nature of diversity within the MP-1 gene. Nine MP-1 gene sequences were compared from 2 isolates of P. knowlesi and a laboratory strain of P. vivax. The MP-1 genes of P. knowlesi were dimorphic based upon the central hydrophilic regions (III and IV) that were well conserved as alpha and beta types. Other regions were conserved among all P. knowlesi genes except for the amino cysteine-rich region (region II), a region predicted to be the initial contact site of the erythrocyte binding domain. Two distinct sequence motifs and part of a third were identified in region II that had a common identity of 68%. In some MP-1 genes recombination had occurred to create hybrids of the two sequence types. All cysteines and aromatic amino acids of region II were conserved in all genes or within a sequence type. There were 2 apparent recombination points within region II where switching occurred between sequence types. Another possible recombination site, identified as a common sequence motif, was identified in the middle of the hydrophilic region, at the beginning of regions III or IV. Nonsynonymous mutations within region II were biased towards radical amino acid changes, especially towards the carboxyl third, where there were 3 distinct types of sequence. Most synonymous and nonsynonymous nucleotide mutations within regions I, V, and VI were infrequent, individual events and not associated with any particular sequence type. Cysteine-rich regions of the P. vivax MP-1 gene compared to the P. knowlesi genes were characterized by an increased number of synonymous and nonsynonymous changes. This data identifies 2 mechanisms for generation of diversity in the MP-1 gene family, intergenic recombination and nucleotide mutations. Both may be mechanisms the parasite uses to evade the host immune response or to alter erythrocyte receptor specificity.

Amino Acid Sequence↗
PubMed1994

A gene coding for a high-molecular mass rhoptry protein of Plasmodium yoelii.

We describe the deduced amino acid sequence for a gene encoding a high molecular mass rhoptry protein of Plasmodium yoelii. The sequence was obtained from an EcoRI genomic clone that overlaps a short DraI fragment isolated previously. The open reading frame consists of 2294 codons and putative hydrophobic signal and membrane anchor sequences were identified. Similarity with sequence from a clone coding for part of a Plasmodium vivax reticulocyte-binding protein was noted. Based on the sequence and location of the protein and the biological properties of antibodies that react with it, we propose that this may be an erythrocyte-binding protein.

Amino Acid Sequence↗
PubMed1995

Processing of the Plasmodium chabaudi chabaudi AS merozoite surface protein 1 in vivo and in vitro.

Processing of the Plasmodium merozoite surface protein 1 (MSP-1) has been described for parasites maintained under in vitro conditions. We have now demonstrated, using CBA/Ca mice infected with Plasmodium chabaudi chabaudi AS, that MSP-1 processing also occurs in vivo. The major proteolytic cleavage sites and a processing scheme were deduced from N-terminal amino-acid sequences of the MSP-1 breakdown products. Comparison of MSP-1 processing in P. falciparum and P.c. chabaudi indicates a degree of conservation and in two cases the position of protease cleavage appears identical. Significant amounts of MSP-1 polypeptides are found in plasma during schizogony. Various aspects of MSP-1 processing including immunological and physiological reactions in the host during the critical period of schizogony can now be examined in vivo.

Amino Acid Sequence↗
PubMed1995

Activities of extracts and naphthylisoquinoline alkaloids from Triphyophyllum peltatum, Ancistrocladus abbreviatus and Ancistrocladus barteri against Plasmodium berghei (Anka strain) in vitro.

Extracts from three tropical medicinal plant species belonging to the Dioncophyllaceae (Triphyophyllum peltatum) and the Ancistrocladaceae (Ancistrocladus abbreviatus and Ancistrocladus barteri), and pure naphthylisoquinoline alkaloids derived from these species have been examined for the first time for their activity against asexual blood forms of Plasmodium berghei (Anka strain) in vitro. These activities were considerable and comparable with those earlier found against erythrocytic forms of Plasmodium falciparum. The extracts and constituents of species belonging to the Dioncophyllaceae (dioncophylline B, dioncopeltine A and dioncophylline A) appear to be more promising than those from the Ancistrocladaceae.

Alkaloids↗
PubMed2005

Identification and characterisation of the Plasmodium vivax rhoptry-associated protein 2.

Plasmodium vivax is currently the most widespread of the four parasite species causing malaria in humans around the world. It causes more than 75 million clinical episodes per year, mainly on the Asian and American continents. Identifying new antigens to be further tested as anti-P. vivax vaccine candidates has been greatly hampered by the difficulty of maintaining this parasite cultured in vitro. Taking into account that one of the most promising vaccine candidates against Plasmodium falciparum is the rhoptry-associated protein 2, we have identified the P. falciparum rhoptry-associated protein 2 homologue in P. vivax in the present study. This protein has 400 residues, having an N-terminal 21 amino-acid stretch compatible with a signal peptide and, as occurs with its falciparum homologue, it lacks repeat sequences. The protein is expressed in asexual stage P. vivax parasites and polyclonal sera raised against this protein recognised a 46 kDa band in parasite lysate in a Western blot assay.

Amino Acid Sequence↗
PubMed2006

Sulfated cyclodextrins inhibit the entry of Plasmodium into red blood cells. Implications for malarial therapy.

The effect of sulfated cyclodextrins on Plasmodium falciparum cultures was determined. alpha-, beta-, and gamma-Cyclodextrins having equal degrees of sulfation inhibited parasite viability to a similar degree, a result suggesting that the ring size of the cyclodextrin is not a critical factor for inhibitory activity. beta-Cyclodextrins containing fewer than two sulfate groups had no inhibitory activity, however, compounds containing 7-17 sulfates were found to be active in the microM range. Examination of treated cultures indicated that intracellular forms of the parasite were unaffected; however, increased numbers of extracellular merozoites were present. Active compounds produced enhanced erythrocyte staining with cationic dyes that could be reduced by stilbene disulfonates, a result suggesting that sulfated cyclodextrins inhibit parasite growth by interacting with the anion transport protein, AE1. Compounds that were found to be active in P. falciparum cultures were also found to inhibit P. berghei merozoite entry and could reduce the parasitemia of P. berghei infection in a mouse model, results suggesting that these compounds inhibit a common step in the merozoite invasion process of at least two Plasmodium species.

Animals↗
PubMed2006

Plasmodium vivax: in vitro susceptibility of blood stages to synthetic trioxolane compounds and the diamidine DB75.

Plasmodium vivax is an important human pathogen causing malaria in more temperate climates of the world. Similar to Plasmodium falciparum, the causative agent for malaria tropica, drug resistance is beginning to emerge for this parasite species and this hampers adequate treatment of infection. We have used a short-term ex vivo drug assay to monitor activity of OZ277 (RBx-11160), a fully synthetic anti-malarial peroxide, and the diamidine DB75 against P. vivax. For both compounds as well as the anti-malarial reference compounds artesunate, artemether, and chloroquine, the in vitro IC(50) values were determined in one-cycle hypoxanthine incorporation assays. Results from such assays were found to be very similar compared to IC(50) values obtained from one-cycle P. falciparum hypoxanthine assays. We demonstrate the anti-parasite activity of OZ277 and the reference compounds to be faster than that of DB75. These data warrant clinical testing of OZ277 against P. vivax malaria and support recent data on clinical activity against P. vivax for DB75.

Animals↗
PubMed2006

In vitro and in vivo interaction of synthetic peroxide RBx11160 (OZ277) with piperaquine in Plasmodium models.

RBx11160 (OZ277) is a promising antimalarial drug candidate that Ranbaxy Laboratories Limited and Medicines for Malaria Venture (MMV) are currently developing as a fixed combination with piperaquine. Here, we describe the in vitro (Plasmodium falciparum) and in vivo (Plasmodium berghei) activities of piperaquine in combination with RBx11160 and artemether. In vitro, both combinations demonstrated a slight tendency towards antagonism with mean sums of fractional inhibitory concentrations (mean Sigma FICs) of 1.5. In vivo, piperaquine and artemether were borderline antagonistic (mean Sigma FIC of 1.4). However, an additive in vivo interaction of piperaquine and RBx11160 (mean Sigma FIC of 1.1) was identified, suggesting that a RBx11160-piperaquine combination therapy in humans should allow each molecule to exert its full antimalarial effect.

Animals↗
PubMed2005

Effect of chloroquine on the expression of genes involved in the mosquito immune response to Plasmodium infection.

Chloroquine has been described to increase Plasmodium infectivity to the mosquito vector and is known to affect the vertebrate host immune response including during malarial infection. Although knowledge of the mosquito immune response has recently improved, nothing is known about the impact of chloroquine on mosquito immunity. In order to characterize the influence of chloroquine on the mosquito immune system, we have analyzed the effect of chloroquine on Anopheles gambiae (i) serine proteases and (ii) antimicrobial peptide gene expression, in uninfected and Plasmodium berghei infected mosquitoes, using real-time PCR. We have demonstrated for the first time that mosquitoes fed on chloroquine-treated mice showed a significant down regulation of some immune-related genes. This effect was independent of midgut bacterial burden. These results suggest that chloroquine might act on the Anopheles serine proteases cascade, interfering with signal transduction pathways and at a transcriptional activation level.

Animals↗