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PubMed1992

Effects of cytokines, complement, and antibody on the neutrophil respiratory burst and phagocytic response to Plasmodium falciparum merozoites.

The interaction between Plasmodium falciparum merozoites and human neutrophils, as well as the role of cytokines, complement, and antimalarial antibody on this interaction, was examined in vitro by measuring luminol-dependent chemiluminescence and phagocytosis. Merozoites, in the presence of heat-inactivated (56 degrees C/30 min) normal serum, had very little effect on the neutrophil chemiluminescence. This response was significantly enhanced by the addition of normal serum (containing normal complement activity). In the presence of serum or plasma containing anti-P. falciparum antibodies (IS) with no detectable complement activity, the merozoites induced a marked response characterized by an increase in initial peak rate of chemiluminescence and a sustained increased rate of chemiluminescence. However, this response was not further increased if IS containing complement activity was used. Pretreatment of neutrophils with either tumor necrosis factor alpha, lymphotoxin, or gamma interferon significantly increased the neutrophil response to IS-treated merozoites, reflected in an increased initial peak rate and sustained increased rate of chemiluminescence. The effects of cytokine treatment of neutrophils and IS opsonization of merozoites were synergistic. In association with the changes in the chemiluminescence responses, IS was shown to promote phagocytosis of merozoites by neutrophils, and this event was further increased by treating neutrophils with the cytokines. The results emphasize the importance of antibody and cytokines in neutrophil-mediated damage of P. falciparum merozoites.

Animals↗
PubMed2000

Cleavage of DNA induced by 9-anilinoacridine inhibitors of topoisomerase II in the malaria parasite Plasmodium falciparum.

Due to resistance by Plasmodium falciparum, the most virulent strain of the four species of human malaria parasites, to most currently used antimalarial drugs, development of new effective antimalarials is urgently needed. Derivatives of 9-anilinoacridine, an antitumor drug, have been shown to inhibit P. falciparum growth in culture and to inhibit parasite DNA topoisomerase II activity in vitro. Using KCl-SDS precipitation assay to detect the presence of protein-DNA complexes within parasite cells, an indicator of DNA topoisomerase II inactivation, derivatives containing 3,6-diNH(2) substitutions with 1'-electron donating (NMe(2), CH(2)NMe(2), NHSO(2)Me, OH, OMe), and 1'-electron withdrawing (SO(2)NH(2)) groups produced protein-DNA complexes. However, the antimalarial pyronaridine, 9-anilinoazaacridine, did not generate protein-DNA complexes, although it was capable of inhibiting P. falciparum DNA topoisomerase II activity in vitro. These results should prove useful in future designs of novel antimalarial compounds directed against parasite DNA topoisomerase II.

Amsacrine↗
PubMed1987

Reduced in-vitro susceptibility to mefloquine in West African isolates of Plasmodium falciparum.

West African isolates of Plasmodium falciparum were more susceptible to chloroquine but less susceptible to mefloquine than were Southeast Asian isolates. The West African isolates were more sensitive to halofantrine than to mefloquine. Since neither mefloquine nor halofantrine has been used in West Africa, the findings suggest that P falciparum may be inherently resistant to mefloquine and that mefloquine should be introduced cautiously to West Africa. Moreover, halofantrine may be of greater value than mefloquine for controlling multidrug-resistant falciparum malaria in West Africa.

Adult↗
PubMed1992

Purification and properties of Plasmodium falciparum malate dehydrogenase.

Asexual intraerythrocytic Plasmodium falciparum were shown to have a single isoenzyme of malate dehydrogenase. This malate dehydrogenase was purified to apparent homogeneity using a three-step purification protocol. The parasite malate dehydrogenase had an apparent subunit molecular weight of 32 kDa, a pH optimum of 7.0 for the reduction of oxaloacetate, and a sharp thermal transition between 40 degrees C and 45 degrees C. These characteristics distinguish P. falciparum malate dehydrogenase from both the cytoplasmic and mitochondrial malate dehydrogenase isoenzymes of humans. In addition, the resistance of the parasite malate dehydrogenase to substrate inhibition by oxaloacetate suggests that it is the cytoplasmic malate dehydrogenase isoenzyme. The apparent absence of mitochondrial malate dehydrogenase from asexual intraerythrocytic P. falciparum contributes to evidence indicating that the mitochondrion is undeveloped at this stage of the parasite's life cycle.

Animals↗
PubMed2006

Differential expression of var gene groups is associated with morbidity caused by Plasmodium falciparum infection in Tanzanian children.

The var gene family of Plasmodium falciparum encodes the variant surface antigen Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1). PfEMP1 is considered an important pathogenicity factor in P. falciparum infection because it mediates cytoadherence to host cell endothelial receptors. var genes can be grouped into three major groups, A, B, and C, and the conserved var genes, var1-4, according to sequence similarities in coding and noncoding upstream regions. Using real-time quantitative PCR in a study conducted in Tanzania, the var transcript abundances of the different var gene groups were compared among patients with severe, uncomplicated, and asymptomatic malaria. Transcripts of var group A and B genes were more abundant in patients with severe malaria than in patients with uncomplicated malaria. In general, the transcript abundances of var group A and B genes were higher for children with clinical malaria than for children with asymptomatic infections. The var group C and var1-like transcript abundances were similar between the three sample groups. A transcript abundance pattern similar to that for var group A was observed for var2csa and var3-like genes. These results suggest that substantial and systematic differences in var gene expression exist between different clinical presentations.

Animals↗
PubMed2006

The plasma membrane permease PfNT1 is essential for purine salvage in the human malaria parasite Plasmodium falciparum.

The human malaria parasite Plasmodium falciparum relies on the acquisition of host purines for its survival within human erythrocytes. Purine salvage by the parasite requires specialized transporters at the parasite plasma membrane (PPM), but the exact mechanism of purine entry into the infected erythrocyte, and the primary purine source used by the parasite, remain unknown. Here, we report that transgenic parasites lacking the PPM transporter PfNT1 (P. falciparum nucleoside transporter 1) are auxotrophic for hypoxanthine, inosine, and adenosine under physiological conditions and are viable only if these normally essential nutrients are provided at excess concentrations. Transport measurements across the PPM revealed a severe reduction in hypoxanthine uptake in the knockout, whereas adenosine and inosine transport were only partially affected. These data provide compelling evidence for a sequential pathway for exogenous purine conversion into hypoxanthine using host enzymes followed by PfNT1-mediated transport into the parasite. The phenotype of the conditionally lethal mutant establishes PfNT1 as a critical component of purine salvage in P. falciparum and validates PfNT1 as a potential therapeutic target.

Animals↗
PubMed1987

The polymorphic 11.1 locus of Plasmodium falciparum.

Clone pPF11.1 encodes a Plasmodium falciparum antigen expressed during the intraerythrocytic cycle and containing tandem repeats of a 9 amino acid unit. We report here an analysis of the genomic region specific for 11.1, which extends over 30 kb. It contains two blocks of repeats, spanning 13 kb and 9 kb. The restriction map suggests that the locus may result from a gene duplication. The 11.1 region is present in all P. falciparum strains examined so far. Southern analysis of 8 distinct isolates indicates that the locus is highly polymorphic. Thus the pPF11.1 repeats constitute a sensitive and discriminating probe to type P. falciparum strains.

Alleles↗
PubMed2005

Reconstitution of an apicoplast-localised electron transfer pathway involved in the isoprenoid biosynthesis of Plasmodium falciparum.

In the malaria parasite Plasmodium falciparum isoprenoid precursors are synthesised inside a plastid-like organelle (apicoplast) by the mevalonate independent 1-deoxy-d-xylulose-5-phosphate (DOXP) pathway. The last reaction step of the DOXP pathway is catalysed by the LytB enzyme which contains a [4Fe-4S] cluster. In this study, LytB of P. falciparum was shown to be catalytically active in the presence of an NADPH dependent electron transfer system comprising ferredoxin and ferredoxin-NADP(+) reductase. LytB and ferredoxin were found to form a stable protein complex. These data suggest that the ferredoxin/ferredoxin-NADP(+) reductase redox system serves as the physiological electron donor for LytB in the apicoplast of P. falciparum.

Animals↗
PubMed1975

The distribution of enzyme variation in populations of Plasmodium falciparum in Africa.

Isolates of Plasmodium falciparum collected from the east and west coasts of tropical Africa and also from several inland regions have been examined for electrophoretic forms of the enzymes GPI, LDH and 6PGD. Variation within and between isolates was found in the parasite forms of all three enzymes. While not disproving the existence of genetic divisions between P. falciparum populations in Africa the distribution of this variation provides no evidence for such a hypothesis.

Africa, Eastern↗
PubMed1990

Specificity and inhibitory activity of antibodies to Plasmodium falciparum aldolase.

The multiplication of Plasmodium falciparum within RBC is energy-dependent and the glucose consumption of infected RBC is increased more than 50 times over the consumption of normal RBC. High levels of glycolytic enzymes such as fructose-1,6-diphosphate aldolase (p41) have been detected in infected RBC. Expression of the cloned aldolase gene of P. falciparum in Escherichia coli resulted in an enzymatically active polypeptide with a high sp. act. and the recombinant p41 aldolase was used for enzymatic and immunologic studies reported here. The presence of antibodies against p41 in the sera of human adults partially immune to malaria and immunization experiments in monkeys suggest that p41 is implicated in protective immune response against the parasite. Therefore, we analyzed the capacity of various antisera to inhibit P. falciparum aldolase activity. It was found that anti-p41 antibodies raised in mice, rabbits, and monkeys inhibited very efficiently aldolase activity in vitro up to dilutions higher than 10(-3). In contrast none of the human sera with high levels of anti-p41 antibodies were able to inhibit parasite aldolase activity even at a dilution of 1/2. The inability of human antisera to neutralize parasite aldolase is not related to antibody titers but is probably related to the specificity of the human antibodies. This finding is discussed in relation to homology of structure of P. falciparum and mammalian aldolase and to a possible mechanism of parasite adaptation and survival in its natural host.

Animals↗
PubMed1981

Parasite-derived mitogenic activity for human T cells in Plasmodium falciparum continuous cultures.

Supernatants from Plasmodium falciparum continuous cultures exhibited mitogenic activity against human blood lymphocytes from unsensitized donors. This effect, which was not observed with supernatants from control cultures grown in the absence of the parasites, was dependent upon (i) the concentration of supernatant added to the lymphocyte cultures and (ii) the parasite concentration in the P. falciparum continuous cultures. T cells were the predominant target cells of this mitogenic activity. We observed similar response in lymphocytes from malaria-sensitized individuals to P. falciparum continuous culture material. We also detected a mitogenic activity in parasite-infected erythrocytes from P. falciparum continuous cultures. P. falciparum continuous cultures may provide practical quantities of parasite-derived substances which, presumably, are able to manipulate the immune effector mechanisms of an infected host.

Animals↗
PubMed1985

Effects of transmission-blocking monoclonal antibodies on different isolates of Plasmodium falciparum.

The strain diversity in Plasmodium falciparum has been studied with respect to gamete surface antigens which are the targets of transmission-blocking antibodies. Of 12 isolates tested, 11 were positive by immunofluorescence with the three monoclonal antibodies studied. The exception was a Liberian isolate, two clones of which were found to react with only one of the three monoclonal antibodies. Antibodies IIC5-B10 and IA3-B8, which previously have been shown to act synergistically to block infectivity of 7G8, a Brazilian clone of P. falciparum, acted in an exactly similar way with another Brazilian isolate, It.D12, and an isolate from Thailand. In the presence of complement either IA3-B8 or a third antibody, IID2-A10, strongly suppressed infectivity of It.D12 as well as 7G8, but neither isolate was strongly suppressed by IIC5-B10. IA3-B8 and IID2-A10 did not react by immunofluorescence or immunoprecipitation with gametes of L.E5; IIC5-B10 reacted positively with L.E5 gametes in these tests. In the absence of complement, the combination of IA3-B8 and IIC5-B10 did not suppress infectivity of L.E5 to mosquitoes. In contrast to its effect on gametocytes of other isolates, IIC5-B10 in the presence of complement strongly suppressed infectivity of L.E5 to mosquitoes. These results imply that IA3-B8 and IIC5-B10 react with two structurally distinct epitopes on the surface of gametes of P. falciparum and that the properties of both epitopes on gametes of L.E5 differ from those on gametes of the other isolates tested.

Animals↗
PubMed1993

Factors affecting exflagellation of in vitro-cultivated Plasmodium falciparum gametocytes.

The environment of Plasmodium falciparum gametocytes changes when they make the transition from the vertebrate to the invertebrate host. Gametocytes of this species cultivated in vitro were used to evaluate the effect of serum, pH, pCO2 tension, bicarbonate ion, and temperature on gamete formation. Temperature was the only factor responsible for keeping P. falciparum gametocytes in the inactivated state. Mature gametocytes held at temperatures above 30 degrees C remained quiescent in 10% serum, even at low ambient pCO2 tension, alkaline pH, and in the presence of 25 mM bicarbonate ion. When the temperature of the medium was allowed to drop below 30 degrees C, gametocytes emerged from the red blood cells and microgametocytes consistently exflagellated at pH 7.4, even in the absence of bicarbonate ion. With regard to bicarbonate ion, exflagellation in P. falciparum is similar to P. berghei and different from P. gallinaceum gametocytes, which have an obligate requirement for bicarbonate ion.

Animals↗
PubMed1988

New approaches to the serotypic analysis of the epidemiology of Plasmodium falciparum.

Considerable antigenic heterogeneity of Plasmodium falciparum has been demonstrated in natural parasite populations. However, very little is known about the relative virulence, transmission efficiency and prevalence over space and time of parasites expressing different serotypes of variant antigens. The recent application of recombinant DNA techniques to express a wide range of P. falciparum antigens in Escherichia coli has led to a better understanding of the molecular basis of antigenic diversity of a number of parasite proteins including the precursor to the major merozoite surface antigen (PMMSA) and the heat-stable S-antigens. Highly specific reagents such as DNA probes, monoclonal antibodies and polyclonal antisera to either cloned antigens or synthetic peptides have become available for serotypic analysis of natural parasite populations. With these reagents important epidemiological questions can now be asked concerning the population biology of different serotypes of P. falciparum. The use of the polymorphic S-antigen system as a serotypic marker to analyse the transmission dynamics of P. falciparum in Madang, Papua New Guinea (PNG) is discussed. Results of serotyping studies with the S-antigen system highlight the complexities of malaria transmission, which require consideration in the design of malaria vaccine trials.

Animals↗
PubMed2001

Glycobiology of Plasmodium falciparum.

The human malaria parasite, Plasmodium falciparum, has as its only glycoconjugate GPI anchors. These structures, present in essentially all parasite surface proteins, are associated with disease pathology. In contrast, the parasite depends for essential recognition events on saccharides associated with host cell glycoproteins and proteoglycans.

Animals↗
PubMed1991

Detection of antigens and antibodies in the urine of humans with Plasmodium falciparum malaria.

Humans infected with Plasmodium falciparum frequently have elevated levels of proteins in their urine, but it is unclear if any of these proteins are parasite antigens or antimalarial antibodies. To resolve this question, urine samples from malaria patients and controls living in Thailand and Ghana were evaluated. Urine samples from 85% of the patients had elevated protein levels and contained proteins with Mrs ranging from less than 29,000 to greater than 224,000 as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Antisera were produced against urine from infected and control subjects. Antisera raised against infected, but not control, urine were positive by indirect immunofluorescence on P. falciparum parasites and immunoprecipitated approximately 12 unique bands from extracts of parasites metabolically labeled with 35S-methionine. These data suggest that a variety of P. falciparum antigens are released into urine during acute infection. It is also likely that anti-P. falciparum antibodies are present in the urine of malaria patients because samples from these patients, but not controls, were positive in indirect immunofluorescence assays and immunoprecipitated at least 19 P. falciparum antigens from extracts of metabolically labeled parasites. The detection of malarial antigens and antibodies in urine may lead to a new approach for the diagnosis of malaria.

Adult↗
PubMed2003

Purification and partial characterization of PfHRP-II protein of Plasmodium falciparum.

The human malarial parasite Plasmodium falciparum secretes various intra-and extra-cellular proteins during its asexual life cycle in human RBC. Histidine rich protein-II (HRP-II) is one of the most prominent proteins, found to be secreted by P. falciparum throughout the asexual cycle with the peak during mature schizont stage of the parasite development in human IRBC. The high histidine content (35% of the total amino acids in protein) of this protein suggested the potential to bind divalent metal ions. We have demonstrated by metal chelate chromatography, an extraordinary capacity of HRP-II to bind nickel ions (Ni++) and employed this characteristic to purify the extra-cellular HRP-II protein secreted by P. falciparum from culture supernatant. The identity of the purified protein was verified by the relative molecular weight on SDS-PAGE, by reacting with polyclonal antibodies directed against it using Western blot technique.

Animals↗
PubMedDate not supplied

Cloning and expression of genomic DNA sequences coding for putative erythrocyte membrane-associated antigens of Plasmodium falciparum.

Genomic DNA fragments of Plasmodium falciparum generated by mung bean nuclease digestion were cloned in the lambda expression vector lambda JK2. The resulting library was screened with a rabbit antiserum raised against purified membranes of P. falciparum-infected erythrocytes and with a serum pool from immune humans from an endemic area of Liberia. Positive clones were rescreened with a series of human and monkey sera. Twelve selected clones were analysed in detail. Four of them corresponded to already described membrane-associated P. falciparum antigens. The other positive clones contained inserts which, according to the nucleotide sequence, Southern blot analysis and immunological characteristics, correspond to so far unknown antigens.

Amino Acid Sequence↗