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PubMed1981

Chloroquine sensitivity of isolates of Plasmodium falciparum adapted to in vitro culture.

Thirteen isolates of Plasmodium falciparum obtained from cases of malaria imported into the Netherlands and established in culture were tested for their sensitivity to chloroquine. Reproducibility of the test results depended on the exposure of a standardized number of parasites in culture to the drug. The maximum activity of chloroquine was obtained when medium with the drug was added to parasite cultures twice at 24 hour intervals. The result of drug action over a period of 48 hours was estimated best when parasites were counted 72 hours after the commencement of the test. Sensitivity to chloroquine could not provide a basis for the characterisation of strains.

Animals↗
PubMed1990

Several alleles of the multidrug-resistance gene are closely linked to chloroquine resistance in Plasmodium falciparum.

The lethal form of human malaria caused by Plasmodium falciparum is virtually uncontrollable in many areas because of the development of drug resistance, in particular chloroquine resistance (CQR). CQR is biologically similar to the multiple drug resistance phenotype (MDR) of mammalian tumour cells, as both involve expulsion of drug from the cell and both can be reversed by calcium channel antagonists. A homologue (pfmdr1) of the mammalian multidrug resistance gene has been implicated in CQR because it is amplified in some CQR isolates of P. falciparum as is an mdr gene in MDR tumour cells. We show here that the complete sequences of pfmdr1 genes from 2 CQ sensitive (CQS) P. falciparum isolates are identical. In 5 CQR isolates, 1-4 key nucleotide differences resulted in amino acid substitutions. On the basis of these substitutions, we have correctly predicted the CQS/CQR status of a further 34 out of 36 isolates. This is a paradox as CQR arises much less frequently than would be predicted if single point mutations were sufficient. We conclude that a mutated pfmdr1 gene is one of at least two mutated genes required for CQR.

Alleles↗
PubMed2006

Comparative proteomic analysis of metabolically labelled proteins from Plasmodium falciparum isolates with different adhesion properties.

The virulence of Plasmodium falciparum relates in part to the cytoadhesion characteristics of parasitized erythrocytes but the molecular basis of the different qualitative and quantitative binding phenotypes is incompletely understood. This paucity of information is due partly to the difficulty in working with membrane proteins, the variant nature of these surface antigens and their relatively low abundance. To address this two-dimensional (2D) protein profiles of closely related, but phenotypically different laboratory strains of P. falciparum have been characterized using proteomic approaches. Since the mature erythrocyte has no nucleus and no protein synthesis capability, metabolic labelling of proteins was used to selectively identify parasite proteins and increase detection sensitivity.A small number of changes (less than 10) were observed between four different P. falciparum laboratory strains with distinctive cytoadherence properties using metabolic labelling, with more parasite protein changes found in trophozoite iRBCs than ring stage. The combination of metabolic labelling and autoradiography can therefore be used to identify parasite protein differences, including quantitative ones, and in some cases to obtain protein identifications by mass spectrometry. The results support the suggestion that the membrane protein profile may be related to cytoadherent properties of the iRBCs. Most changes between parasite variants were differences in iso-electric point indicating differential protein modification rather than the presence or absence of a specific peptide.

Animals↗
PubMed2003

Evidence for the importance of genetic structuring to the structural and functional specialization of the Plasmodium falciparum var gene family.

The var gene family encodes Plasmodium falciparum erythrocyte membrane 1 (PfEMP1) proteins that act as virulence factors responsible for both antigenic variation and cytoadherence of infected erythrocytes. These proteins orchestrate infected erythrocyte sequestration from blood circulation and contribute to adhesion-based complications of P. falciparum malaria infections. For this study, we analysed the genetic organization and strain structure of var genes and present evidence for three separately evolving groups that have, in part, functionally diverged and differ between subtelomeric and central chromosomal locations. Our analyses suggest that a recombination hierarchy limits reassortment between groups and may explain why some var genes are unusually conserved between parasite strains. This recombination hierarchy, coupled with binding and immune selection, shapes the variant antigen repertoire and has structural, functional and evolutionary consequences for the PfEMP1 protein family that are directly relevant to malaria pathogenesis.

Animals↗
PubMed1992

Characterization of Plasmodium falciparum sporozoite surface protein 2.

Immunization of mice with Plasmodium yoelii sporozoite surface protein 2 (PySSP2) and circumsporozoite protein protects completely against P. yoelii. The amino acid sequence of PySSP2 suggested that the thrombospondin-related anonymous protein (TRAP) [Robson, K. J. H., Hall, J. R. S., Jennings, M. W., Harris, T. J. R., Marsh, K., Newbold, C. I., Tate, V. E. & Weatherall, D. J. (1988) Nature (London) 335, 79-82] is the Plasmodium falciparum homolog of PySSP2. We report data confirming that TRAP is P. falciparum SSP2 (PfSSP2). Murine antibodies against recombinant PfSSP2 identify a 90-kDa protein in extracts of P. falciparum sporozoites, recognize sporozoites and infected hepatocytes by immunofluorescence, localize PfSSP2 to the sporozoite micronemes by immunoelectron microscopy and to the surface membrane by live immunofluorescence, and inhibit sporozoite invasion and development in hepatocytes in vitro. Human volunteers immunized with irradiated sporozoites and protected against malaria develop antibody and proliferative T-cell responses to PfSSP2, suggesting that, like PySSP2, PfSSP2 is a target of protective immunity, and supporting inclusion of PfSSP2 in a multicomponent malaria vaccine.

Amino Acid Sequence↗
PubMed1992

Transcription of the gene for the merozoite surface antigen MSA2 of the human malaria parasite Plasmodium falciparum during the asexual cycle.

The transcription of the Plasmodium falciparum gene for the MSA2 antigen has been studied throughout the parasite's asexual growth cycle. For this purpose poly(A)+ RNA from different times of the cycle was tested for the presence of the mRNA encoding MSA2 by in vitro translation and subsequent analysis of the translation products by immunoprecipitation with an antibody against MSA2. The results revealed that this mRNA is present in trophozoites, reaches the highest concentration during the transition from the trophozoite into the schizont stage, and persists until the cycle end. Minute amounts of this mRNA were also detected in rings. In addition, the data confirmed that the primary translation product is not proteolytically processed at any time of the cycle.

Animals↗
PubMed1983

[Plasmodium falciparum malaria acquired in Kenya with type II or type III resistance to amino-4-quinolines].

The authors report a case of Plasmodium falciparum malaria acquired in Kenya by a French tourist under correct chloroquine prophylaxis. She recovered under quinine and a sulfadoxine-pyrimethamine association. This is a new case of high level resistance (R II or R III) of Plasmodium falciparum to amino-4-quinolines recognized in East Africa. Malarial chemoprophylaxis recommended until now for this area may need to be reviewed.

Adult↗
PubMed1989

46-53 kilodalton glycoprotein from the surface of Plasmodium falciparum merozoites.

A 46-53 kDa glycoprotein antigen of Plasmodium falciparum merozoites has been identified using a murine monoclonal antibody that inhibits infection of human erythrocytes in vitro. Immunofluorescence screening with the antibody of greater than 250 isolates of the parasite finds the inhibitory epitope expressed by only 18% of strains. The glycoprotein is metabolically labelled with methionine, cysteine, histidine and glucosamine but incorporates little lysine or leucine. It is synthesized early in schizogony and remains, without any apparent processing, on the surface of released merozoites where it is demonstrated by immuno-electronmicroscopy and also by vectorial radio-iodination.

Animals↗
PubMed1993

Stage-specific transcripts of the Plasmodium falciparum pfmdr 1 gene.

Genes have been identified in Plasmodium falciparum which belong to the ATP-binding cassette superfamily of transport systems based upon sequence and structural homology. One of these genes, the pfmdr 1 gene, is homologous to the mammalian mdr 1 gene, which encodes the P-glycoprotein product. Strong phenotypic data suggests the involvement of a P-glycoprotein-like molecule in the mediation of drug resistance in P. falciparum. The goal of this work was to characterize the expression of the pfmdr 1 messenger RNA: both the stage specific expression and the level of expression in mefloquine sensitive or resistant parasites. We identified two messenger RNA homologous to this gene, one of 8.5 kb expressed in ring and trophozoite stages, and a second messenger RNA of 7.5 kb expressed only in trophozoites. Previously we had reported an increased expression of messenger RNA for pfmdr 1 in a mefloquine-resistant clone. Here we extend this and demonstrate that overexpression of the pfmdr 1 gene is consistent with the mefloquine resistance phenotype in a panel of recent isolates from Thailand.

Animals↗
PubMed1989

Purification and identification of a neutral endopeptidase in Plasmodium falciparum schizonts and merozoites.

An endopeptidase specific to the Plasmodium falciparum erythrocytic schizont stage and to free merozoites was detected using the fluorogenic GlcA-Val-Leu-Gly-Lys(or Arg)-AEC substrate. The enzyme was purified by high performance liquid chromatography (HPLC); its optimal activity was around pH 7.5 and its isoelectric point was 4.4. The molecular weight of the enzyme was about 68,000, as demonstrated by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) under reducing conditions. The endopeptidase was strongly inhibited by thiol proteinase inhibitors, leupeptin, and antipain. The possible involvement of this neutral endopeptidase in the reinvasion process is discussed.

Animals↗
PubMed1983

Requirement of malarial protease in the invasion of human red cells by merozoites of Plasmodium falciparum.

Highly synchronous cultures of the erythrocyte stages of Plasmodium falciparum were used to determine the effects of a number of protease inhibitors on parasite development and merozoite invasion. Leupeptin, N-tosyl-L-lysyl chloromethylketone and pepstatin at a concentration greater than 0.05 mM were deleterious to both parasite development and merozoite invasion whereas aprotinin, antipain, alpha-1-antitrypsin and soybean trypsin inhibitor had no effect at a concentration of 0.5 mM. On the other hand, N-tosyl-L-phenylalanyl chloromethylketone and phenylmethylsulfonylfluoride at a concentration of 1 mM and chymostatin at a concentration of 0.15 mM inhibited merozoite invasion but were not deleterious to parasite development. Pretreatment of red cells with these three inhibitors did not block merozoite invasion. These results suggested that a chymotrypsin-like activity of the merozoite is important in the invasion process.

Erythrocytes↗
PubMed2003

Drug-induced alterations in gene expression of the asexual blood forms of Plasmodium falciparum.

The complete genome sequence of the malarial parasite, Plasmodium falciparum [Gardner, M.J., Hall, N., Fung, E., White, O., Berriman, M., and Hyman, R.W. (2002) Nature 419: 498-510; Hyman, R.W., Fung, E., Conway, A., Kurdi, O., Mao, J., Miranda, M. et al. (2002) Nature 419: 534-537], has provided researchers with the informational base for establishing genomic [Volkman, S.K., Hartl, D.L., Wirth, D.F., Nielsen, K.M., Choi, M., Batalov, S., et al. (2002) Science 298: 216-218], proteomic [Florens, L., Washburn, M.P.J.D.R., Anthony, R.M., Grainger, M., Haynes, J.D., et al. (2002) Nature 419: 520-526; Lasonder, E., Ishihama, Y., Anderson, J.S., Vermunt, A.M.W., Pain, A., Sauerwein, R.W., et al. (2002) Nature 419: 537-542] and genome-wide RNA expression [Ben Mamoun, C., Gluzman, I.Y., Hott, C., MacMillan, S.K., Amarakone, A.S., Anderson, D.L., et al. (2001) Mol Microbiol 39: 26-36; Hayward, R.E., Derisi, J.L., Alfadhli, S., Kaslow, D.C., Brown, P.O., and Rathod, P.K. (2000) Mol Microbiol 35: 6-14] analyses in this system. In fact, we have previously utilized SAGE (serial analysis of gene expression) to identify abundant loci that probably constitute part of the active metabolome [Patankar, S., Munasinghe, A., Shoaibi, A., Cummings, L.M., and Wirth, D.F. (2001) Mol Biol Cell 12: 3114-3125], as well as to characterize antisense transcription on a global scale in Plasmodium. In the present study, the comprehensive annotation of SAGE libraries derived from an asexual stage population exposed to drug and its matched control was used to assess the modulation of gene expression by chloroquine. Here, we observed a constellation of changes, with the differential regulation of over 100 transcripts, and have confirmed the data by alternate methods. A few responsive loci, including PfMDR1, have previously been implicated in the mechanism of chloroquine action/resistance. Several others, however, were derived from unexpected categories, including a large number of unknown open reading frames (ORFs), whose induction after drug exposure may provide first hints to their possible function.

Animals↗
PubMed2000

Receptor-mediated targeting of toxins to intraerythrocytic parasite Plasmodium falciparum. surolia@jncasr.ac.in.

The increasing prevalence of drug-resistant Plasmodium falciparum malaria and the absence of effective vaccines or of vector control measures makes the development of new antimalarial drugs and other approaches for treating malaria, an urgent priority. The development of immunotoxins for targeted cytotoxic effects to kill the parasite is an attractive alternative therapeutic concept. The cytocidal effect of such hybrid molecules is highly specific and requires only minute doses. Cell surface receptor-directed targeting of toxins (hybrid toxins or immunotoxins) to human malaria parasite could eventually be developed as an effective therapy for malaria. Hybrid toxins may provide means of controlling this dreadful disease and counter morbidity as well as mortality. Our results suggests that hybrid toxins are potent and efficacious in killing the parasite and that these agents should be examined in an appropriate in vivo model of malaria.

Animals↗
PubMed1997

[Serum HRP-2 antigens and imported Plasmodium falciparum malaria: comparison of ParaSight-F and ICT malaria P.f].

Serum levels of HRP-2 antigens against Plasmodium falciparum in 568 venous blood samples collected at two general hospitals were evaluated using the ParaSight-F (Becton-Dickinson) alone (568/568 samples) or in combination (156/568 samples) with the new ICT-Malaria P.f. (ICT-diagnostic). Comparison with the reference method (thin and thick blood smears assessed by two experienced parasitologists) showed that both tests were highly sensitive (93% and 96% respectively) and specific (98% and 98% respectively). The positive predictive values of the two tests were equal (96%) and the negative predicative values were close (96% and 98% respectively). Although both tests provided results within 10 minutes and required no special equipment for interpretation, the ICT-Malaria P.f. test seemed simpler and easier to use than the ParaSight-F test. The ParaSight-F test alone was used to monitor serum antigen levels after treatment in 24 patients. Antigen levels remained positive for at least three days after disappearance of circulating parasites (range: 3 to 28 days). Evaluation of serum levels of HRP-2 antigens can be useful for emergency diagnosis, especially in patients with low circulating parasite levels. The ICT-Malaria P.f. test seems especially suited for in-field use.

Animals↗
PubMed1989

Ion exchange paper adsorption and thin-layer chromatography for detection of chloroquine in urine for the study of chemosensitivity of Plasmodium falciparum.

With a view to determining the chemosensitivity of Plasmodium falciparum to chloroquine, two qualitative tests for the detection of this antimalarial agent in urine were compared in Central African schoolchildren: the test of Dill and Glazko and a thin-layer chromatography technique involving ion exchange and extraction. Results obtained with 149 subjects showed the marked superiority in specificity and sensitivity of the chromatography test. This is of particular interest when selecting subjects before a therapeutic trial is undertaken. After administration of a single dose of chloroquine (10 mg kg-1) to 14 schoolchildren, both urinary detection tests gave positive results at 24 and 48 hours. However, on day 7 all results with the chromatography test were positive, while 57% of false negatives were recorded by the Dill and Glazko test.

Animals↗
PubMed1983

Cloning and characterisation of the rRNA genes from the human malaria parasite Plasmodium falciparum.

Ribosomal DNA fragments from the human malaria parasite Plasmodium falciparum have been cloned and analysed in detail. Restriction mapping shows that the cloned fragments are different. However, they do have some similarities, in particular a small stretch of A+T-rich DNA located between the small and large subunit rRNA genes. A small rRNA gene has been mapped to this A+T-rich region. Copy number analysis reveals that each fragment is represented approximately 4 times in the genome, and implies that there are a total of 8 rRNA genes organised into at least two classes of transcription unit. Analysis of a third overlapping rDNA fragment indicates that the large subunit rRNA gene of at least one transcription unit contains an intervening sequence.

Animals↗
PubMed1983

The synthesis and fate of stage-specific proteins in Plasmodium falciparum cultures.

Cultured ring, trophozoite and schizont stages of Plasmodium falciparum were metabolically labeled with [35S]methionine. After labeling, cultures were incubated for varying times in the presence of non-radioactive methionine. Triton-soluble proteins from different stages of growth were analysed by sodium dodecylsulfate-polyacrylamide gel electrophoresis. Most proteins were synthesized by every stage of growth and remained unchanged throughout the cycle through to the ring stage following merozoite invasion of erythrocytes. At least 15 proteins, most of high molecular weight, were synthesized solely or predominantly by schizonts. Eight proteins (approx. 177, 170, 158, 87, 83, 47, 41 and 24 kDa) appeared in schizonts but not merozoites. Eight proteins (approx. 240, 203, 106, 80, 35, 19, 15 and 14 kDa) appeared in merozoites, but not in rings following merozoite invasion. Some proteins appeared to be modified after synthesis.

Amino Acids↗
PubMed1986

Plasmodium falciparum polypeptides associated with the infected erythrocyte plasma membrane.

Plasmodium falciparum proteins associated with plasma membranes of infected erythrocytes were identified by using three techniques: isolated plasma membranes from infected and uninfected erythrocytes were compared by gel electrophoresis and silver staining; isolated plasma membranes from cells metabolically labeled with [35S]methionine were assayed by gel electrophoresis; and uninfected and infected intact erythrocytes were surface-labeled by lactoperoxidase iodination, and the labeled polypeptides were compared by gel electrophoresis. The results from these experiments indicate that at least six parasite-derived polypeptides (Mr = greater than 240,000, 150,000, 55,000, 45,000, 35,000, and 20,000) are associated with the infected erythrocyte plasma membrane. At least four of these peptides (Mr = 55,000, 45,000, 35,000, and 20,000) may be exposed on the surface of the infected erythrocytes.

Animals↗