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PubMed2006

Multiplex PCR-RFLP methods for pfcrt, pfmdr1 and pfdhfr mutations in Plasmodium falciparum.

Plasmodium falciparum drug resistance is a major factor for the death toll of malaria. Resistance has been associated with specific single nucleotide polymorphisms (SNPs) in the parasite genes pfmdr1 (N86Y) and pfcrt (K76T) associated with quionoline antimalarial resistance, and pfdhfr (N51I, C59R, S108N) correlated with resistance of the antifolate combination sulfadoxine-pyrimethamine. These SNPs constitute the basis for the surveillance of drug resistance through high sensitive molecular methods in malaria endemic countries. In this work, we developed a multiplex PCR-RFLP protocols for the diagnosis of these molecular markers, leading to significant decreases in reagent costs, time, number of manipulations and hence human resources.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1976

The effect of human immune IgG on the in vitro development of Plasmodium falciparum.

Plasmodium falciparum parasites infecting Aotus trivirgatus erythrocytes were cultured in media (Harvard and TC199) augmented with human, foetal calf, or other sera. Conditions were established which supported growth of parasites and allowed cyclical multiplication when fresh erythrocytes (from Aotus or Homo) were added in sub-culture (mean multiplication rate: X3). Immunoglobulin G pools, prepared from plasma collected in endemic malarious areas in Africa and from unexposed Britons, were tested for effects on the in vitro growth (measured by incorporation of tritiated leucine) and multiplication of parasites. Whilst non-immune IgG was without effect, IgG from both East and West Africa inhibited the multiplication of East African (Uganda-Palo Alto strain) parasites.

Animals↗

PubMed1982

Enzymes of purine and pyrimidine metabolism from the human malaria parasite, Plasmodium falciparum.

Plasmodium falciparum trophozoites were isolated by mechanical rupture of infected human erythrocytes followed by a series of differential centrifugation steps. After lysis with sonication, the 100 000 x g supernatant of parasites and uninfected host cells was used to determine the specific activities of a number of enzymes involved in purine and pyrimidine metabolism. P. falciparum possessed the purine salvage enzymes: adenosine deaminase, purine nucleoside phosphorylase, hypoxanthine-guanine phosphoribosyltransferase (PRTase), xanthine PRTase, adenine PRTase, adenosine kinase. The last two enzymes, however, were present at much lower activity levels. Hypoxanthine was converted (presumably via IMP) into adenine and guanine nucleotides only in the presence both of supernatant and membrane fractions of P. falciparum. Two enzymes involved in the de novo synthesis of pyrimidines, orotic acid PRTase, and orotidine 5'-phosphate decarboxylase, were present in parasite extracts as were the enzymes for pyrimidine nucleotide phosphorylation: UMP-CMP kinase, dTMP kinase, nucleoside diphosphate kinase. Xanthine oxidase, CTP synthetase, cytidine deaminase and several kinases for the salvage of pyrimidine nucleosides were not detected in the parasites. Both phosphoribosyl pyrophosphate synthetase and uracil PRTase were present but at low activity levels. Human erythrocytes displayed similar but not identical enzyme patterns. Enzyme specific activities, however, were generally much lower than those of the corresponding parasite enzymes.

Adenosine Deaminase↗

PubMed1989

De novo and salvage biosynthesis of pteroylpentaglutamates in the human malaria parasite, Plasmodium falciparum.

Plasmodium falciparum was shown to synthesize pteroylpolyglutamate de novo from guanosine 5'-triphosphate (GTP), p-aminobenzoate (PABA), and L-glutamate (L-Glu). The parasite also had the capacity to synthesize pteroylpolyglutamate from both intact and degradation moieties (p-aminobenzoylglutamate and pterin-aldehyde) of exogenous folate added into the growth medium. The major product was identified as 5-methyl-tetrahydroteroylpentaglutamate following exposure to pteroylpolyglutamate hydrolase and oxidative degradation of the C9-N10 bond in the molecule and identification of products by reversed-phase high performance liquid chromatography. Inhibition of pteroylpentaglutamate synthesis from the radiolabelled metabolic precursors (GTP, PABA, L-Glu) and folate by the antifolate antimalarials, pyrimethamine and sulfadoxine at therapeutic concentrations, may suggest the existence of a unique biosynthetic pathway in the malaria parasite.

Animals↗

PubMed1992

Quantitative analysis of the response of human T cell receptor V gamma 9+ cells to Plasmodium falciparum.

Plasmodium falciparum stimulates peripheral blood gamma delta + T cells from unexposed donors. The responding cells bear V gamma 9+ chains of the T cell receptor, the majority of which, but not all, are associated with V delta 2 chains. We have analyzed whether the precursor frequency of these V gamma 9+ cells approaches that expected of superantigens or mitogens and whether, like a superantigen, the response is major histocompatibility complex (MHC) unrestricted. Limiting dilution analyses of the response of enriched gamma delta + T cells to P.falciparum using autologous and heterologous antigen-presenting cells suggest that the response is more characteristic of an antigen-specific MHC-restricted response. The frequencies are lower than would be expected if all V gamma 9+ cells respond, and there is a dramatically reduced response when allogeneic antigen-presenting cells are used.

Animals↗

PubMed1996

Structural analysis of the glycosyl-phosphatidylinositol membrane anchor of the merozoite surface proteins-1 and -2 of Plasmodium falciparum.

Plasmodium falciparum accumulates the two merozoite surface proteins-1 and -2 during schizogony. Both proteins are proposed to be anchored in membranes by glycosyl-phosphatidylinositol membrane anchors. In this report the identity of these GPI-anchors is confirmed by labelling with tritiated precursors and additionally by specific enzymatic and chemical treatments. Detailed structural analysis of the core-glycans showed that the GPI-anchors of both proteins possess an extra alpha 1-2 linked mannose at the conserved trimannosyl-core-glycan. MSP-1 and MSP-2 labelled with tritiated myristic acid possess primarily radioactive myristic acid at inositol rings in both GPI-anchors. Additionally the hydrophobic fragments released from [3H]myristic acid labelled GPI-anchors were identified as diacyl-glycerols, carrying preferentially [3H]palmitic acid in an ester-linkage.

Animals↗

PubMed1987

Possible pitfalls in the identification of glycophorin-binding proteins of Plasmodium falciparum.

Plasmodium falciparum proteins that bind to the putative erythrocyte receptor (glycophorin) have been identified in several laboratories by their ability to bind to glycophorin immobilized on aminoethyl-BioGel (AE-BioGel). We here report that several parasite proteins bind to AE-BioGel in the absence of coupled glycophorin. Binding is apparently due to the strong ion-exchange properties of the matrix, and is sensitive to ionic conditions such as the degree of equilibration of the matrix and the pH. The parasite proteins that bind to the blank column under appropriate conditions include proteins with the serological activities of S-antigen and Ag 23, which also bind to glycophorin-coupled AE-BioGel. In the light of these results, the glycophorin-binding specificity of these and other proteins reported to bind to glycophorin-coupled AE-BioGel will have to be reevaluated, preferably using a different support matrix.

Carrier Proteins↗

PubMed2005

Genetic alteration in drug resistance markers of Plasmodium falciparum.

Plasmodium falciparum shows plasticity in its genome. For its survival it can delete certain genes (or portions) if not needed for its growth and has the capability to regulate its genes under various stages of its life cycle as well as under unfavourable environmental conditions. Parasite shows enormous amount of antigenic variation under immune pressure leading to the emergence of vaccine resistant strains. Similarly, under drug pressure it allows mutations to settle in the target genes. It is becoming more and more clear that with the continuous exposure to a drug, the parasite accumulates more and more number of mutations in these genes. By measuring the number of these point mutations among field isolates one can predict the efficacy of a particular drug. Therefore, these markers are useful tools at epidemiological level. This molecular surveillance can also help in slowing down the drug resistance if supported by a careful drug usage policy. Further studies are required to develop molecular markers for rest of the antimalarial drugs as well as the improvement on the existing molecular tools for accurate and rapid detection of drug resistant malaria.

Animals↗

PubMed1987

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

Plasmodium falciparum growth is impaired in glucose-6-phosphate dehydrogenase (G6PD)-deficient red blood cells (RBCs), and malaria has been implicated in the spreading of deficient variants in malaria-endemic areas. Recent reports suggest that the malaria parasite can adapt itself to grow in these variant RBCs by producing its own G6PD, but studies on parasite G6PD are very limited. In this report, we define the properties of the parasite G6PD. G6PD was partially purified from infected and uninfected variant RBCs associated with severe G6PD deficiency. G6PD from infected RBCs contained two components separable by starch gel electrophoresis: a major component (approximately 90% activity) with a very slow anodal electrophoretic mobility and a minor component (approximately 10% activity) with the same mobility as the host G6PD. Parasite G6PD exhibited much higher affinity (low Km) to G6P and nicotinamide-adenine dinucleotide phosphate (NADP) than did human G6PD. Southern blot hybridization indicated that the parasite genome contained nucleotide sequences that were hybridizable with the human G6PD cDNA. These data indicate that the parasite is capable of adapting to G6PD-deficient RBCs by producing its own G6PD.

Collodion↗

PubMed1993

Evidence for two-stage binding by the 175-kD erythrocyte binding antigen of Plasmodium falciparum.

Plasmodium falciparum malaria merozoites invade human erythrocytes bearing sialic acid in a multistage process involving the sialic acid-dependent binding of a malaria molecule, the 175-kD erythrocyte binding antigen (EBA-175). We show here that after the initial interaction of EBA-175 with its sialic acid-containing erythrocyte determinant, endogenous proteases can cleave EBA-175 to 65-kD fragment(s), whose binding to erythrocytes is sialic acid independent. A 65-kD fragment was immunoprecipitated by antibodies against peptides between residues 354 and 1061 but not beyond residue 1062. Binding experiments utilizing combinations of native protein, expression-PCR-synthesized EBA-175 polypeptides, peptide synthesis, and antibodies, demonstrated that sialic acid-independent binding could be further mapped to a small (about 40-amino acid) homologous part of the dimorphic allelic region of EBA-175, residues 898-938 (Camp strain numbering). These data support a two-step binding hypothesis and are discussed in relation to the formation of a junction between the merozoite and the erythrocyte, and the finding that after the interaction of some viruses with specific cellular receptors, they undergo conformational changes or cleavage permitting membrane fusion with the host cell.

Amino Acid Sequence↗

PubMedDate not supplied

Variability in schizonticidal drug susceptibility amongst clones and isolates of Plasmodium falciparum.

Plasmodium falciparum isolates from Malaysia, Africa and Thailand were cultured in vitro following the method of Trager and Jensen and subsequently cloned using the limiting dilution method of Rosario. These clones were presently characterized against three schizonticidal drugs, chloroquine, mefloquine and quinine, using the modified in vitro microtechnique. Results showed that all the clones derived from Gombak A isolate were chloroquine-resistant with average IC50 values ranging at 0.1377-1.0420 microM (0.007-0.058 mefloquine activity), sensitive to mefloquine at 0.0032-0.0103 microM and quinine at 0.0025-0.0428 microM (0.075-3.080 mefloquine activity). Similarly, the TGR clone displayed resistance to chloroquine at 0.1715-0.5875 microM (0.002-0.029 mefloquine activity) but were also sensitive to mefloquine at 0.0008-0.0058 microM and quinine at 0.0055-0.0700 microM (0.055-0.202 mefloquine activity). In contrast, four out of six Gambian clones were sensitive to chloroquine at 0.0047-0.0172 microM (0.122-0.617 mefloquine activity) but all were sensitive to mefloquine at 0.0008-0.0029 and 0.0016-0.0102 microM (0.096-1.813 mefloquine activity). In general, most of the clones displayed susceptibility patterns similar to that of their parent isolates against the three schizonticidal drugs except Gm/B2 and Gm/H5 Gambian clones were chloroquine-resistant at 0.3427 microM (0.006 mefloquine activity) and 0.2260 microM (0.004 mefloquine activity), respectively. Further results indicated that they were pure clones compared to their parent isolates as their schizonticidal drug susceptibilities were statistically different (p < 0.05) except Gm/C6 and TGR/B7 clones against mefloquine (p < 0.05).

Animals↗

PubMed2005

Process development and analysis of liver-stage antigen 1, a preerythrocyte-stage protein-based vaccine for Plasmodium falciparum.

Plasmodium falciparum liver-stage antigen 1 (LSA-1) is expressed solely in infected hepatocytes and is thought to have a role in liver schizogony and merozoite release. Specific humoral, cellular, and cytokine immune responses to LSA-1 are well documented, with epitopes identified that correlate with antibody production, proliferative T-cell responses, or cytokine induction. With the goal of developing a vaccine against this preerythrocyte-stage protein, we undertook the good manufacturing practices (GMP) manufacture of a recombinant LSA-1 construct, LSA-NRC, incorporating the N- and C-terminal regions of the protein and two of the centrally placed 17-amino-acid repeats. To improve the protein yield, a method of codon harmonization was employed to reengineer the gene sequence for expression in Escherichia coli. A 300-liter GMP fermentation produced 8 kg of bacterial cell paste, and a three-step column chromatographic method yielded 8 mg of purified antigen per g of paste. The final bulk protein was >98% pure, demonstrated long-term stability, and contained <0.005 endotoxin units per 50 microg of protein. To accomplish the initial stages of evaluation of this protein as a human-use vaccine against malaria, we immunized rabbits and mice with LSA-NRC in Montanide ISA 720. New Zealand White rabbits and A/J (H-2K) mice produced high-titer antibodies that recognized liver-stage parasites in infected cultured human hepatocytes. Gamma interferon-producing cells, which have been associated with LSA-1-mediated protection, were detected in splenocytes harvested from immunized mice. Finally, sera taken from people living in a region where malaria is holoendemic recognized LSA-NRC by Western blotting.

Amino Acid Sequence↗

PubMed2003

The transcriptome of the intraerythrocytic developmental cycle of Plasmodium falciparum.

Plasmodium falciparum is the causative agent of the most burdensome form of human malaria, affecting 200-300 million individuals per year worldwide. The recently sequenced genome of P. falciparum revealed over 5,400 genes, of which 60% encode proteins of unknown function. Insights into the biochemical function and regulation of these genes will provide the foundation for future drug and vaccine development efforts toward eradication of this disease. By analyzing the complete asexual intraerythrocytic developmental cycle (IDC) transcriptome of the HB3 strain of P. falciparum, we demonstrate that at least 60% of the genome is transcriptionally active during this stage. Our data demonstrate that this parasite has evolved an extremely specialized mode of transcriptional regulation that produces a continuous cascade of gene expression, beginning with genes corresponding to general cellular processes, such as protein synthesis, and ending with Plasmodium-specific functionalities, such as genes involved in erythrocyte invasion. The data reveal that genes contiguous along the chromosomes are rarely coregulated, while transcription from the plastid genome is highly coregulated and likely polycistronic. Comparative genomic hybridization between HB3 and the reference genome strain (3D7) was used to distinguish between genes not expressed during the IDC and genes not detected because of possible sequence variations. Genomic differences between these strains were found almost exclusively in the highly antigenic subtelomeric regions of chromosomes. The simple cascade of gene regulation that directs the asexual development of P. falciparum is unprecedented in eukaryotic biology. The transcriptome of the IDC resembles a "just-in-time" manufacturing process whereby induction of any given gene occurs once per cycle and only at a time when it is required. These data provide to our knowledge the first comprehensive view of the timing of transcription throughout the intraerythrocytic development of P. falciparum and provide a resource for the identification of new chemotherapeutic and vaccine candidates.

Animals↗

PubMedDate not supplied

Mixed Plasmodium falciparum-Plasmodium malariae infection and hemoglobin SC disease: a case report.

In today's society, immigration and travel has resulted in large-scale population movements. This poses an additional challenge to the clinician when he or she takes the patient's history. The differential diagnosis of any presentation would need to include any diseases endemic to the area where the patient had been in. Ghana is considered a holoendemic high-risk area for the transmission of malaria. Moreover, compound heterozygous inheritance of hemoglobin (Hb) S and HbC often occurs in this area. We present a case of mixed Plasmodium falciparum-Plasmodium malariae infection complicating HbSC disease in a 34-year-old Ghanaian immigrant. We postulate that the malaria infection has transformed the patient's silent combined hemoglobinopathies (HbS/HbC) into a syndrome resembling a sickle cell crisis.

Adult↗

PubMed2000

[Congenital malaria due to Plasmodium falciparum and Plasmodium malariae].

Increasing tourism and growing numbers of immigrants from malaria-endemic countries are leading to a higher importation rate of rare tropical disorders in European countries. We describe, to the best of our knowledge, the first case of connatal malaria in Austria. The patient is the first child of a 24 year old mother who was born in Ghana and immigrated to Austria one and a half years before delivery. She did not stay in an endemic region during this period and did not show fever or any other signs of malaria. The boy was healthy for the first six weeks of his life. In the 8th week of life he was admitted to our hospital due to persistent fever of unknown origin. On physical examination he showed only mild splenomegaly. Routine laboratory testing revealed mild hemolytic anemia with a hemoglobin value of 8.3 g/l. In the blood smear Plasmodium falciparum and Plasmodium malariae were detected. Oral therapy with quinine hydrochloride was successful and blood smears became negative for Plasmodia within 6 days. This case shows that congenital malaria can occur in children of clinically healthy women who were born in malaria-endemic areas even one and a half year after they have immigrated to non-endemic regions.

Adult↗

PubMed1999

[Evaluation of immunochromatographic test in the diagnosis of Plasmodium falciparum and Plasmodium vivax].

AIM: To evaluate the effectiveness of immunochromatographic test(ICT) in detecting Plasmodium falciparum and Plasmodium vivax in malaria endemic areas. METHODS: ICT was used to detect P. falciparum and P. vivax among patients with fever in the outpatient clinics by comparason with thick blood smear method. RESULTS: The sensitivity of ICT to detect P. falciparum and P. vivax was 96.7% and 90.4%, respectively. The specificity of ICT was 98.6%, and the coincidence rate was 94.7%. There is no cross reaction between P. falciparum and P. vivax. CONCLUSION: ICT could detect P. falciparum and P. vivax simutaneously, being more rapid and simple than blood smear method.

Animals↗

PubMed2006

High prevalence of drug-resistance mutations in Plasmodium falciparum and Plasmodium vivax in southern Ethiopia.

BACKGROUND: In Ethiopia, malaria is caused by both Plasmodium falciparum and Plasmodium vivax. Drug resistance of P. falciparum to sulfadoxine-pyrimethamine (SP) and chloroquine (CQ) is frequent and intense in some areas. METHODS: In 100 patients with uncomplicated malaria from Dilla, southern Ethiopia, P. falciparum dhfr and dhps mutations as well as P. vivax dhfr polymorphisms associated with resistance to SP and P. falciparum pfcrt and pfmdr1 mutations conferring CQ resistance were assessed. RESULTS: P. falciparum and P. vivax were observed in 69% and 31% of the patients, respectively. Pfdhfr triple mutations and pfdhfr/pfdhps quintuple mutations occurred in 87% and 86% of P. falciparum isolates, respectively. Pfcrt T76 was seen in all and pfmdr1 Y86 in 81% of P. falciparum. The P. vivax dhfr core mutations N117 and R58 were present in 94% and 74%, respectively. CONCLUSION: These data point to an extraordinarily high frequency of drug-resistance mutations in both P. falciparum and P. vivax in southern Ethiopia, and strongly support that both SP and CQ are inadequate drugs for this region.

Adolescent↗

PubMed1999

Field evaluation of the ICT malaria P.f/P.v immunochromatographic test for detection of Plasmodium falciparum and Plasmodium vivax in patients with a presumptive clinical diagnosis of malaria in eastern Indonesia.

In areas such as eastern Indonesia where both Plasmodium falciparum and Plasmodium vivax occur, rapid antigen detection tests for malaria need to be able to detect both species. We evaluated the new combined P. falciparum-P. vivax immunochromatographic test (ICT Malaria P.f/P.v.) in Radamata Primary Health Centre, Sumba, Indonesia, from February to May 1998 with 560 symptomatic adults and children with a presumptive clinical diagnosis of malaria. Blinded microscopy was used as the "gold standard," with all discordant and 20% of concordant results cross-checked blindly. Only 50% of those with a presumptive clinical diagnosis of malaria were parasitemic. The ICT Malaria P.f/P.v immunochromatographic test was sensitive (95. 5%) and specific (89.8%) for the diagnosis of falciparum malaria, with a positive predictive value (PPV) and a negative predictive value (NPV) of 88.1 and 96.2%, respectively. HRP2 and panmalarial antigen line intensities were associated with parasitemia density for both species. Although the specificity and NPV for the diagnosis of vivax malaria were 94.8 and 98.2%, respectively, the overall sensitivity (75%) and PPV (50%) for the diagnosis of vivax malaria were less than the desirable levels. The sensitivity for the diagnosis of P. vivax malaria was 96% with parasitemias of >500/microl but only 29% with parasitemias of <500/microl. Nevertheless, compared with the test with HRP2 alone, use of the combined antigen detection test would reduce the rate of undertreatment from 14.7 to 3.6% for microscopy-positive patients, and this would be at the expense of only a modest increase in the rate of overtreatment of microscopy-negative patients from 7.1 to 15. 4%. Cost remains a major obstacle to widespread use in areas of endemicity.

Adolescent↗