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PubMed1984

Species- and stage-specific antigens in exoerythrocytic stages of Plasmodium falciparum.

Numerous exoerythrocytic forms of Plasmodium falciparum ( PFEEF ) were obtained from the liver of the South American monkey, Cebus apella, for analysis of the antigens on this stage. As antigen for the fluorescent assay, 5-micron sections of liver fragments collected on day 5 following sporozoite inoculation and fixed in Carnoy's solution or kept in liquid nitrogen were used. Two types of fluorescent labeling of the PFEEF were identified: diffuse and peripheral. Each of 23 sera from individuals with P. falciparum infection acquired naturally by mosquito bite showed the diffuse and peripheral patterns of fluorescence at low serum dilutions (i.e., 1:10-1:100), but only peripheral staining at higher serum dilutions (i.e., 1:200-1:1,600). All other polyclonal sera tested showed only the diffuse pattern of fluorescence whatever the serum dilution used; this was true for P. falciparum infections acquired accidentally by blood transfusion, heterologous human infections with P. vivax, P. ovale, P. malariae or P. cynomolgi, and experimental animal infections with P. berghei, P. gallinaceum, or P. cynomolgi. Fluorescent antibody titers on PFEEF were generally 1-4 dilutions lower than on blood stages. No age-dependent pattern of fluorescence titers was found in 30 sera from individuals ranging in age from 2-78 years living in a malaria-endemic area. Twenty-six monoclonal antibodies directed to P. falciparum blood stages which reacted at high titers with rings, schizonts, merozoites, and gametocytes did not react with PFEEF antigen even when using the undiluted ascitic fluid.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1991

A simple method for the purification of mitochondrial DNA from Plasmodium falciparum.

Mitochondrial DNA (mtDNA) from Plasmodium falciparum was isolated by conventional differential centrifugation in an SS34 rotor, a simpler method than CsC1 centrifugation of total DNA as employed by other workers. The nature of the sample was verified by sequencing a polymerase chain reaction (PCR) product obtained using oligonucleotide primers derived from known malarial mtDNA sequence.

Animals↗

PubMed2006

Origins of sequence diversity in the malaria vaccine candidate merozoite surface protein-2 (MSP-2) in Amazonian isolates of Plasmodium falciparum.

The recent evolution of Plasmodium falciparum is at odds with the extensive polymorphism found in most genes coding for antigens. Here, we examined the patterns and putative mechanisms of sequence diversification in the merozoite surface protein-2 (MSP-2), a major malarial repetitive surface antigen. We compared the msp-2 gene sequences from closely related clones derived from sympatric parasite isolates from Brazilian Amazonia and used microsatellite typing to examine, in these same clones, the haplotype background of chromosome 2, where msp-2 is located. We found examples of msp-2 sequence rearrangements putatively created by nonreciprocal recombinational events, such as replication slippage and gene conversion, while maintaining the chromosome haplotype. We conclude that these nonreciprocal recombination events may represent a major source of antigenic diversity in MSP-2 in P. falciparum populations with low rates of classical meiotic recombination.

Alleles↗

PubMed1993

Immunogenicity and antigenic reactivity of a carrier-free synthetic peptide complex derived from a 70-kDa Plasmodium falciparum exoantigen.

A 70-kDa Plasmodium falciparum exoantigen was purified from supernatant fluids of continuous in vitro P. falciparum cultures using sequential cation-exchange and high performance liquid chromatographic procedures. The purified protein was then digested with chymotrypsin and amino-acid sequences were determined for the resulting fragments. Four peptides (termed C2, C3, C5, and C10) were subsequently selected for synthesis based on their predictability for antigenic sites. The peptides were effectively used as a synthetic immunogen (SPf70) when they had been copolymerized with glutaraldehyde in the absence of a carrier. When given with Freund's adjuvant, the synthetic peptide complex was found to be highly immunogenic in rabbits. Serologic reactivity to the peptide complex and peptides C2 and C5 was uniformly high, followed by the responses to peptides C3 and C10. Peptide antigenicity was also assessed with human anti-P. falciparum sera from malaria-endemic regions of Uganda and Venezuela. Enzyme-linked immunosorbent assay (ELISA) data showed that anti-P. falciparum antibodies were specific for and reactive to the peptides. The specificity of the rabbit anti-SPf70 antibodies for P. falciparum antigen was shown by immunoprecipitation of metabolically labeled proteins and by immunoblotting. Herein we describe the peptide sequences of a 70-kDa P. falciparum exoantigen (Pf70) that, when synthesized and constructed as a copolymer (SPf70), are capable of inducing the formation of antibodies that are reactive with the native malarial protein. The high immunogenicity and antigenic reactivity of SPf70 indicate the potential use of this synthetic peptide polymer as an immunogen and a diagnostic reagent.

Amino Acid Sequence↗

PubMed1986

Plaque antibody selection: rapid immunological analysis of a large number of recombinant phage clones positive to sera raised against Plasmodium falciparum antigens.

A library of Plasmodium falciparum genomic DNA on the lambda gt11 phage vector was screened for clones positive to a rabbit serum raised against a purified fraction of P. falciparum proteins and a pool of sera from malaria patients. The positive clones were characterized with antibodies purified by the plaque antibody selection technique. This technique consist of purifying specific antibodies on a nitrocellulose filter blotted directly on a lawn of plaques of an antigen-producing phage clone. The purified antibodies are then used as a probe in a Western blot of parasite protein extract, for preliminary characterization of the clones. Using this method, two different clones coding for P. falciparum antigens were identified with the rabbit serum and about 20 with the human sera. This method can be of general use, i.e. it is not limited to parasite systems, and facilitates the immunological analysis and identification of a large number of clones.

Adult↗

PubMed1984

[Obtaining hepatic stages of Plasmodium falciparum in vitro].

Sporozoites of Plasmodium falciparum, obtained by membrane feeding of Anopheles freeborni or A. stephensi with cultured gametocytes, were used to infect monolayers of human hepatocytes. Fluorescent labelling with an African serum as well as Giemsa staining performed from day one to day 7 of cultures, demonstrated the presence of numerous hepatic schizonts measuring up to 40 micron.

Animals↗

PubMed2005

Biochemical characterization of the two nucleosome assembly proteins from Plasmodium falciparum.

The human malaria parasite Plasmodium falciparum contains two nucleosome assembly proteins, which we have termed PfNAPS and PfNAPL. We have over-expressed, purified and characterized these proteins using biochemical and biophysical techniques. PfNAPS and PfNAPL exist as dimers in solution and circular dichroism studies suggest that they may have different three-dimensional protein structures. ELISA-based binding data also suggest that PfNAPS and PfNAPL preferentially interact with the H3-H4 tetramer histones over H2A and H2B histones. We show that the parasite lysate phosphorylates only PfNAPL and this phosphorylation can be inhibited by heparin suggesting a potential role of casein kinase II in this process. Immuno-fluorescence experiments revealed that both PfNAPS and PfNAPL were expressed in all erythrocytic stages of the parasite. PfNAPL was predominantly localised in the cytoplasm in asexual and sexual stages of the parasite. PfNAPS did not co-localise with PfNAPL and was more intimately associated with the parasite nucleus, most strikingly in P. falciparum gametocytes. Taken together, our data show that although PfNAPS and PfNAPL share histone chaperone acitivities, they are regulated differently by phosphorylation and are spatially segregated within the parasite. These proteins are therefore likely to play non-redundant roles as nucleosome assembly motors in the parasite.

Animals↗

PubMed1995

[Role of modulators in Plasmodium falciparum resistance to antimalarials].

Modulating agents that circumvent the Plasmodium falciparum resistance to antimalarials are components without any intrinsic antimalarial activity but able, in association with a standard antimalarial drug, to restore the sensitivity of Plasmodium falciparum to this drug. Two hypotheses are forwarded about their possible mechanisms of action : the mechanisms involving the inhibition of the drug efflux and the mechanisms involving the inhibition of antimalarial drug metabolic degradation. None of these mechanisms is able to alone explain the effect of all modulating agents. The future use prospects of these compounds are limited by their in vivo toxicity. That relevant to the calcium channels blockers seems to be circumvented by the use of dextro-enantiomers. A toxicity relevant to a possible accumulation of the antimalarial in healthy, non target cells must be also suspected. Moreover the use of these agents evidences a socio-economic problem : a complete new development of the association (antimalaria plus modulatin drugs) is needed and that, in developing countries. Nevertheless, the agents modulating the Plasmodium falciparum resistance are a new approach for the treatment of resistant malaria which might give a recrudescence of activity to the old antimalarials as chloroquine.

Animals↗

PubMed1996

Electrophoretic variations of enzyme, GDH (NADP-dependent glutamate dehydrogenase)(EC. 1.4.1.4) in characterizing clones and isolates of Malaysian Plasmodium falciparum.

Malaysian, African and Thai Plasmodium falciparum isolates were cultured in vitro by the Trager and Jensen method (1976; 1977) and were later cloned by the limiting dilution method (Rosario, 1981). Forty-eight clones were obtained and were characterized by electrophoretic variations of GDH (NADP-dependent glutamate dehydrogenase)(EC. 1.4.1.4). It was found that they were pure clones because they possessed either GDH-1 or GDH-2 unlike their parent isolates which exhibited both GDH-1 and GDH-2.

Animals↗

PubMed1988

DNA synthesis in gametocytes of Plasmodium falciparum.

The DNA content of Plasmodium falciparum gametocytes during intra-erythrocytic development and during gametogenesis was established by cytophotometric methods. Intraerythrocytic micro- and macrogametocytes (Stage I-Stage VB) contain about twice the amount of DNA of haploid sporozoites and ringstages, indicating that DNA is synthesized during transformation of ringforms into Stage I gametocytes. Microgametocytes, after activation at pH 8, rapidly duplicate their genome several times, while the DNA content of macrogametocytes remains constant during gametogenesis.

Animals↗

PubMed1990

[In vitro cultivation of Plasmodium falciparum with umbilical cord erythrocyte].

Plasmodium falciparum was cultivated with umbilical cord erythrocytes or with erythrocytes from human adults for 33 days and 50 days respectively. The erythrocyte infection rate increased eightfold to eighteenfold at intervals of three to four days, the highest erythrocyte infection rate being more than 20%. Furthermore, the infection rate of umbilical cord erythrocytes was higher than that of adult erythrocytes at 48, 72 and 96 hours of cultivation, respectively (P less than 0.01). The results suggested that human umbilical cord blood might be a good source of erythrocytes for in vitro cultivation of malaria parasite.

Animals↗

PubMedDate not supplied

Field applications of agglutination and cytoadherence assays with Plasmodium falciparum from Papua New Guinea.

Plasmodium falciparum isolates obtained directly from patients in Papua New Guinea were tested in their first cycle of growth in vitro for adherence to melanoma cells and for susceptibility to agglutination by immune serum. Binding varied among isolates and, in many cases, increased with further rounds of replication under optimal culture conditions. Binding inhibition assays and agglutination assays demonstrated extreme heterogeneity of surface antigens; apparently none of the sera from adult patients recognized all of the variants presented.

Adult↗

PubMed2001

Diamidine compounds: selective uptake and targeting in Plasmodium falciparum.

Extensive drug resistance in Plasmodium falciparum emphasizes the urgent requirement for novel antimalarial agents. Here we report potent antimalarial activity of a number of diamidine compounds. The lead compound pentamidine is concentrated 500-fold by erythrocytes infected with P. falciparum. Pentamidine accumulation can be blocked by inhibitors of hemoglobin digestion, suggesting that the drug binds to ferriprotoporphyrin IX (FPIX). All of the compounds bound to FPIX in vitro and inhibited the formation of hemozoin. Furthermore, inhibitors of hemoglobin digestion markedly antagonized the antimalarial activity of the diamidines, indicating that binding to FPIX is crucial for the activity of diamidine drugs. Pentamidine was not accumulated into uninfected erythrocytes. Pentamidine transport into infected cells exhibits an initial rapid phase, nonsaturable in the micromolar range and sensitive to inhibition by furosemide and glibenclamide. Changing the counter-ion in the order Cl(-) < Br(-) < NO(2)(-) < I(-) <SCN(-) markedly stimulated pentamidine transport. These data suggest that pentamidine is transported although a pore or ion channel with properties similar to those of the recently characterized 'induced permeability pathway' on the infected red cell membrane. In summary, the diamidines exhibit two levels of selectivity against P. falciparum. The route of entry and molecular target are both specific to malaria-infected cells and are distinct from targets in other protozoa. Drugs that target the hemoglobin degradation pathway of malaria parasites have a proven record of accomplishment. The employment of induced permeability pathways to access this target represents a novel approach to antiparasite chemotherapy and offers an additional level of selectivity.

Animals↗

PubMed1994

Partial purification and characterization of DNA topoisomerase II from Plasmodium falciparum.

DNA topoisomerase II from Plasmodium falciparum was partially purified by FPLC using three columns: Econo-Pac Q, heparin-agarose and Mono Q. The enzyme showed ATP- and Mg2 +/- dependent activities in a decatenation assay, with optimum concentrations of 0.5 and 10 mM, respectively. Furthermore, highest activity was detected in the presence of 100 mM KCI. Enzyme decatenation activity was not inhibited by the DNA topoisomerase I inhibitor, camptothecin, but was sensitive to both prokaryotic and eukaryotic DNA topoisomerase II inhibitors.

Animals↗

PubMed1984

Longitudinal study on the in vitro immune response to Plasmodium falciparum in Sudan.

Inhibition of Plasmodium falciparum in vitro by human immune serum provides needed information in understanding antimalarial immune mechanisms. Longitudinal, dry season-to-wet season changes in antimalarial activities were studied in sera isolated from 62 individuals living in an area of hyperendemic but unstable malaria. Highly synchronous cultures of P. falciparum were used to distinguish and quantitate two antimalarial activities, merozoite invasion inhibition, and intraerythrocytic parasite retardation. In 54% of the individuals, intraerythrocytic parasite retardation activity increased significantly, nearly threefold, in wet-season sera as compared with dry-season sera. Merozoite invasion inhibition activity was moderate and did not change seasonally. Merozoite invasion inhibition was, however, correlated to parasite-specific immunoglobulin G titers and total serum immunoglobulin G concentrations. These results confirm earlier studies which demonstrate two antimalarial activities in Sudanese sera and provide evidence that intraerythrocytic parasite retardation activity plays a role in antimalarial immunity.

Adult↗

PubMed1990

VH and VL region structure of antibodies that recognize the (NANP)3 dodecapeptide sequence in the circumsporozoite protein of Plasmodium falciparum.

The sporozoite form of Plasmodium falciparum displays on its surface the circumsporozoite (CS) protein. The central domain of this protein possesses a reiterated tetrapeptide sequence Asn-Ala-Asn-Pro (NANP), and greater than 90% of the sporozoite-specific antibodies obtained from individuals living in malaria endemic areas recognize epitopes within this repeat sequence. Considering the highly repetitive structure of this naturally occurring antigen and its immunodominance, we were interested in analyzing the structural diversity of antibodies that bind to the (NANP)3 sequence. Molecular characterization of immunoglobulin heavy and light chain mRNA was performed for five hybridomas that produce antibodies with binding specificity for the dodecapeptide (NANP)3. These hybridomas were produced in BALB/c mice by inoculation with whole P. falciparum sporozoites. Sequence analysis and Northern blotting showed that for heavy chain, three hybridomas used VH elements that belong to the VHIX family and two to the VHJ558 family. Four different V kappa subgroups were represented among the light chains. Different D and J kappa segments are also utilized, while four heavy chain gene rearrangements involved the JH4 segment. These results indicated that multiple VH-VL gene combinations can code for reactivity to the (NANP)3 sequence, demonstrating that the murine antibody response to this immunodominant region is structurally heterogeneous.

Amino Acid Sequence↗

PubMed1993

Morphologic effects of artemisinin in Plasmodium falciparum.

Ultrastructural changes induced in Plasmodium falciparum by artemisinin were studied in vitro. Electron microscopic autoradiography was performed on infected erythrocytes that were exposed in vitro to 3H-dihydroartemisinin and 14C-artemisinin. These drugs consistently were located in food vacuoles and mitochondria. Two hours after administration, changes were observed in parasite mitochondria, rough endoplasmic reticulum, and nuclear envelope. At four hours, in addition to the earlier changes, nuclear membranes and, to a lesser extent, some plasma membranes formed myelin figures. In addition, there was a disappearance of ribosomes, and a destruction of food vacuole membranes. These changes may lead to the total disorganization of the parasites. Approximately 30% of the parasites manifested these alterations.

Animals↗

PubMed2003

The effects of glucose concentration on the reciprocal regulation of rRNA promoters in Plasmodium falciparum.

The developmental progression of Plasmodium falciparum is remarkably sensitive to glucose concentration. We have investigated the effects of glucose concentration on the parasite development cycle as reflected by changes of ribosomal RNA (rRNA) transcription. We showed that glucose starvation differentially affects transcriptional control of the rRNA genes by sharply repressing transcription from those loci involved with asexual development of the parasite while up-regulating transcription at those loci involved with sexual development of the parasite. Temperature change also effects regulation of transcription. We found that the effects of temperature and glucose were synergistic. We identified and compared the upstream region of the transcription start sites of each gene. These putative promoter structures are considerably different from one another and contain structures remarkably similar to rRNA control elements in other organisms.

Animals↗