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At least 217 records · Page 12Linked to original sources
PubMed1995

A synthetic tumor necrosis factor-alpha agonist peptide enhances human polymorphonuclear leukocyte-mediated killing of Plasmodium falciparum in vitro and suppresses Plasmodium chabaudi infection in mice.

A peptide corresponding to residues 70-80 of the TNF-alpha polypeptide was synthesized and shown to enhance human PMN-mediated killing of Plasmodium falciparum in vitro and reduced the Plasmodium chabaudi parasitemia in mice. Studies of the mechanism of action showed that the peptide, TNF(70-80), stimulated and primed PMN for an increased respiratory burst and release of granule constituents in response to a second agonist. The PMN-stimulatory activity of the peptide was inhibited by mAbs against the p55 and p75 TNF receptors and a TNF-neutralizing mAb. Analysis of PMN receptor expression showed that CR3 (CD18/CD11b) and Fc gamma RIII were upregulated by TNF(70-80), which was consistent with the peptide's ability to enhance parasite killing by PMN. The peptide, unlike TNF, did not increase the expression of adhesion molecules on endothelial cells and failed to promote binding of P. falciparum-infected erythrocytes to endothelial cells. TNF(70-80) also inhibited the TNF-induced increase in adhesion of P. falciparum-infected erythrocytes to endothelial cells. The results demonstrate that the host-protective effects of TNF can be retained while toxic effects are eliminated using a selected, characterized subunit of the cytokine.

Animals↗
PubMedDate not supplied

Plants as sources of antimalarial drugs, Part 4: Activity of Brucea javanica fruits against chloroquine-resistant Plasmodium falciparum in vitro and against Plasmodium berghei in vivo.

Extracts of Brucea javanica fruit have been prepared and monitored for their in vitro and in vivo antiplasmodial activities. The antimalarial activity of the fruit was found to be attributable to its quassinoid constituents. Nine of the quassinoids possessed in vitro IC50 values between 0.046-0.0008 microgram/ml against the chloroquine resistant Plasmodium falciparum strain (Kl) tested. The two quassinoid glycosides tested were considerably less active in vitro than the aglycones. Four quassinoids were found to possess activity in vivo against Plasmodium berghei infections in mice after oral dosing. All five quassinoids tested in vivo showed some toxicity.

Animals↗
PubMed1993

Plasmodium falciparum sporozoite immunization protects against Plasmodium berghei sporozoite infection.

Irradiated sporozoites are generally thought to elicit protective immune responses that are parasite stage and species specific. But immunization with Plasmodium falciparum sporozoites delivered by the bite of infected mosquitoes protects an average of 60% mice from Plasmodium berghei sporozoite infection. Protection appears to be specific as P. falciparum sporozoite-immunized mice protected against P. berghei remain susceptible to Plasmodium yoelii sporozoite infection. Passively transferred immunoglobulin from P. falciparum sporozoite-immunized mouse serum protected naive mice against challenge with P. berghei sporozoites, indicating that cross-protection is mediated, at least in part, by anti-sporozoite antibody. Antibody-mediated protection may not be due to cross-reaction between P. falciparum and P. berghei CS proteins because mice immunized with the recombinant P. falciparum CS protein repeat vaccine candidate, R32tet32, remain susceptible to P. berghei sporozoite infection.

Animals↗
PubMed2006

Induction of cross-reactive immune responses to NTS-DBL-1alpha/x of PfEMP1 and in vivo protection on challenge with Plasmodium falciparum.

The interactions of Plasmodium falciparum infected erythrocytes parasitized red blood cells (pRBC) with endothelial receptors and erythrocytes are mediated by multiple Duffy-binding like (DBL) and cysteine-rich interdomain region (CIDR) domains harboured in the Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1). The success of a subunit vaccine based on PfEMP1 depends on its ability to elicit cross-reactive responses to a substantial number of PfEMP1 variants. We have here evaluated serological PfEMP1 cross-reactivity by immunizing rats with phylogenetically diverse recombinant NTS-DBL-1alpha/x fusion domains from the 3D7 genome parasite emulsified in Montanide ISA 720. Cross-reactivity was elicited to these diverse DBL-1alpha/x domains as measured by ELISA and by immunoblotting. Employing a novel in vivo model of human infected erythrocyte sequestration, immunized animals were challenged with the FCR3S1.2 clone and cross-protection in terms of reduction in lung sequestration amounting to approximately 50% was demonstrated. Our results suggest that immunization with phylogenetically distant DBL-1alpha/x variants, can elicit partial cross-protection to challenge with the parasites harbouring a distant variant. These observations have implications for the design of multi-component vaccines against P. falciparum malaria.

Animals↗
PubMed1994

Serum levels of adhesion molecules and thrombomodulin as indicators of vascular injury in severe Plasmodium falciparum malaria.

Severe Plasmodium falciparum malaria is characterized by multiple organ involvement due to sequestration of infected erythrocytes in small vessels. Endothelial cell adhesion molecules play an important role in this interaction. During the course of a severe cerebral P. falciparum malaria infection we found very markedly elevated levels of the soluble adhesion molecules intercellular adhesion molecule-1, E-selectin, and vascular cell adhesion molecule-1, with a maximum increase of nine, seven, and eight times, respectively. These very high levels of soluble adhesion molecules point to an endothelial cell injury as an additional cause to physiological release or shedding due to receptor interactions. Soluble thrombomodulin (sTM) levels showed an extremely marked elevation up to 332 ng/ml (up to 13 times the normal value) as well. Malaria patients without severe organ involvement/cerebral manifestation showed only a mild elevation of sTM levels. TM is a parameter independent of the immunological system. It is regarded as a marker of vasculitis and endothelial cell destruction. Therefore, markedly elevated sTM levels document a substantial endothelial cell injury in severe malarial infection and may be of diagnostic and prognostic importance.

Adult↗
PubMed2003

[Influence of deleting 9 amino acid residues at N-terminus on immunogenicity of a Plasmodium falciparum chimeric protein].

Plasmodium falciparum chimeric protein 2 (PfCP-2), fused by erythrocytic stage antigens, AMA-1(III) and MSP1-19, is a potential vaccine candidate against malaria. However, the two-band pattern of this protein product in SDS-PAGE has some negative influence for the application of it for clinical tests. N-terminal sequence analysis of the product showed that the doublet had different N-terminus, with 9 amino acid deletion in the band with low molecular weight. Therefore, the gene was modified to generate a new construct, named PfCP-2.9, which was lack of these 9 residues at its N-terminus. Expression of PfCP-2.9 produced only one band. Moreover, the new construct was as same as the original product in the level of expression, conformation dependence on the disulfide bond, immunogenicity and inhibitory effect on the parasite growth in vitro.

Amino Acid Sequence↗
PubMed2002

Genome sequence of the human malaria parasite Plasmodium falciparum.

The parasite Plasmodium falciparum is responsible for hundreds of millions of cases of malaria, and kills more than one million African children annually. Here we report an analysis of the genome sequence of P. falciparum clone 3D7. The 23-megabase nuclear genome consists of 14 chromosomes, encodes about 5,300 genes, and is the most (A + T)-rich genome sequenced to date. Genes involved in antigenic variation are concentrated in the subtelomeric regions of the chromosomes. Compared to the genomes of free-living eukaryotic microbes, the genome of this intracellular parasite encodes fewer enzymes and transporters, but a large proportion of genes are devoted to immune evasion and host-parasite interactions. Many nuclear-encoded proteins are targeted to the apicoplast, an organelle involved in fatty-acid and isoprenoid metabolism. The genome sequence provides the foundation for future studies of this organism, and is being exploited in the search for new drugs and vaccines to fight malaria.

Animals↗
PubMed2006

Quinoline resistance associated polymorphisms in the pfcrt, pfmdr1 and pfmrp genes of Plasmodium falciparum in Iran.

Plasmodium falciparum resistance to chloroquine (CQ) has been documented in Iran since the early 1980s and has since gradually increased. Iran is therefore reviewing its national drug policy for malaria control. We describe the prevalence of single nucleotide polymorphisms (SNP) associated with quinoline drug resistance in south eastern Iran. Pre-treatment blood from patients with uncomplicated but symptomatic P. falciparum infection was analysed. Polymorphisms at codons 76, 152, 163 and 220 of the pfcrt gene (chloroquine resistance transporter) and at codons 86, 184, 1034, 1042 and 1246 of the pfmdr1 gene (multidrug resistance) were determined by PCR-RFLP and sequencing. In addition, SNPs on a recently described multidrug resistance protein (pfmrp) and a microsatellite (MS-4760) in the pfnhe-1 (sodium hydrogen exchanger) gene associated with quinoline and quinine resistance, respectively, were investigated for the first time in field samples not from Thailand. pfcrt 76T was found in 99% and pfmdr1 86Y in 72% of the samples. pfmrp 191H and 437S associated with decreased quinoline response were found to be absolutely linked at a frequency of 13.6%. The pfnhe-1 MS-4760 one repeat allele associated to quinine response in vitro was also detected. Sequencing of the pfcrt 72-76 haplotype revealed that SVMNT was the most common allele as previously observed in India. This suggests that pfcrt found in the Iranian P. falciparum population may have the same origin as in the P. falciparum populations in India but different from that normally found in south east Asia. In conclusion, the frequencies of quinoline resistance associated gene polymorphisms in this region suggest a population that has been significantly selected for by the long use of CQ.

Adolescent↗
PubMed2002

A new reporter gene for transient transfection of Plasmodium falciparum.

Transfection of Plasmodium falciparum has remained difficult and laborious due to a lack of suitable reporter genes and low transfection efficiency. Therefore, the luciferase gene of Renilla reniformis, a sensitive mammalian reporter gene, was evaluated as a reporter gene in this system. Our studies indicate that the R. reniformis luciferase gene can be expressed in P. falciparum and is easily detected by luminometry. P. falciparum extracts do not contain endogenous R. reniformis luciferase activity, which is essential for its use as a reporter gene in this organism. Moreover, both firefly and R. reniformis luciferase genes can be co-expressed in P. falciparum and their respective enzyme activities can be measured from the same sample. Thus, the R. reniformis luciferase gene can be used as an experimental reporter gene and/or used in conjunction with the firefly luciferase gene where one gene would be used to control transfection efficiency. The R. reniformis luciferase gene thus provides a valuable tool to facilitate transient transfection analysis in P. falciparum.

Animals↗
PubMed2000

Chemoresistance of Plasmodium falciparum in the urban region of Yaounde, Cameroon. Part 2: Evaluation of the efficacy of amodiaquine and sulfadoxine-pyrimethamine combination in the treatment of uncomplicated Plasmodium falciparum malaria in Yaounde, Cameroon.

The spread of chloroquine resistance or its stabilization at a high level calls for a change in the therapeutic strategy, including a possible replacement of chloroquine. We assessed and compared the efficacy of amodiaquine and sulfadoxine-pyrimethamine in Yaoundé. Of 140 adults and children > 5 years enrolled in the study, 59 in the amodiaquine and 58 in the sulfadoxine-pyrimethamine treatment group were followed until day 14. The efficacy of amodiaquine was 100%, whereas 12.1% of the patients treated with sulfadoxine-pyrimethamine responded with an early treatment failure. Side effects in both treatment groups were mild and did not require any specific treatment. We did in vitro drug assays for monodesethylamodiaquine (active metabolite of amodiaquine) and pyrimethamine and measured plasma levels of monodesethylamodiaquine, sulfadoxine, and pyrimethamine. Unlike amodiaquine, the results of the in vitro drug sensitivity test for pyrimethamine were not concordant with the clinical response. A wide inter-individual variation in the plasma drug levels was observed. Unlike chloroquine, the mean plasma concentrations did not vary with age. There was no significant difference in the plasma concentrations of sulfadoxine and pyrimethamine between patients responding with an adequate clinical response and those responding with treatment failure. Amodiaquine has several advantages over sulfadoxine-pyrimethamine combination and may be considered to be an effective drug in an endemic zone with a moderate level of chloroquine resistance.

Adolescent↗
PubMed1989

Structure and expression of the Plasmodium falciparum SERA gene.

Plasmodium falciparum, strain FCR3, genomic DNA that encodes the SERA gene of P. falciparum was isolated and sequenced. The SERA gene coding region was interrupted by 3 introns, the largest number observed, so far, in any Plasmodium gene. Two SERA gene alleles, allele I and allele II, were identified in the FCR3 strain, while only allele I was found in the Honduras-1 strain. Allele I mRNA was abundant in vivo during the late trophozoite and schizont stages. Allele II mRNA was either not expressed, or it was labile.

Alleles↗
PubMed1997

The novel oxygenated chalcone, 2,4-dimethoxy-4'-butoxychalcone, exhibits potent activity against human malaria parasite Plasmodium falciparum in vitro and rodent parasites Plasmodium berghei and Plasmodium yoelii in vivo.

Previous studies have shown that licochalcone A, an oxygenated chalcone, exhibits antileishmanial and antimalarial activities. The present study was designed to examine the antimalarial activity of an analog of licochalcone A, 2,4-dimethoxy-4'-butoxychalcone (2,4mbc). 2,4mbc inhibited the in vitro growth of both a chloroquine-susceptible (3D7) and a chloroquine-resistant (Dd2) strain of Plasmodium falciparum in a [3H]hypoxanthine uptake assay. The in vivo activity of 2,4mbc was tested in mice infected with Plasmodium berghei or Plasmodium yoelii and in rats infected with P. berghei. 2,4mbc administered either orally, intraperitoneally, or subcutaneously for 5 days protected the mice from otherwise lethal infections of these parasites. 2,4mbc administered orally for 5 days reduced parasitemia in the rats infected with P. berghei. These results demonstrate that 2,4mbc exhibits potent antimalarial activity and might be developed into a new antimalarial drug.

Animals↗
PubMed2005

An iron regulatory-like protein expressed in Plasmodium falciparum displays aconitase activity.

Plasmodium falciparum iron regulatory-like protein (PfIRPa) has homology to both mammalian iron regulatory proteins and aconitases and is capable of binding RNA iron response elements. We examined the subcellular localization of PfIRPa and its enzymatic properties at low oxygen tension. Differential digitonin permeabilization of isolated trophozoites with subsequent Western blot analysis suggests that the localization of PfIRPa is predominantly in the membranous compartments of the parasite, such as the mitochondrion. Immunofluorescence analysis showed that PfIRPa colocalizes with heat shock protein 60 (Hsp60), a mitochondrial marker, and is also present in the parasitic cytosol/food vacuole. Under conditions favoring the formation of an iron-sulfur cluster, recombinant PfIRPa (rPfIRPa) had aconitase activity as detected by a colorimetric NADPH-MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide) assay. As assessed by the hydration of cis-aconitate spectrophotometrically at 240 nm, rPfIRPa had high affinity for cis-aconitate (Km=3.5 microM) but a low turnover number (Kcat= 3.3 s(-1)). The overall catalytic efficiency (Kcat/Km) of rPfIRPa was similar in magnitude to human cytosolic IRP1/aconitase and human mitochondrial aconitase. PfIRPa immunoprecipitated from parasite lysates also had aconitase activity, as assessed by an MTT-based assay. Our results provide evidence that PfIRPa localizes in the mitochondrion and in the cytosol/food vacuole and is able to demonstrate aconitase activity. Further understanding of the role of PfIRPa/aconitase in the regulation of P. falciparum homeostasis may contribute towards the development of novel antimalarial strategies against plasmodial species.

Aconitate Hydratase↗
PubMed1999

[Molecular analysis of Plasmodium falciparum infections in man].

Plasmodium falciparum diversity has been analysed in two Senegalese villages with different transmission conditions and distinct kinetics of immunity acquisition. A very large allelic polymorphism was observed in both villages, with a similar number of alleles but quite distinct allelic frequencies, indicating a substantial micro-geographical heterogeneity of malaria parasite populations. In addition, the molecular characteristics of the infections differed in both villages. As in most endemic areas, many infected subjects carry multiple parasite clones. In Dielmo, the number of distinct clones hosted decreases at the age of acquisition of an efficient immunity. There was no influence of age on the number of clones hosted in Ndiop where adults experience clinical attacks. This indicates that complexity reflects acquired immunity. The precise longitudinal follow-up of parasitaemia, clinical signs and parasite genetic characteristics showed a rapid turn over of parasite populations in the peripheral blood during the transmission season, suggesting that immunity does not prevent infection but restricts multiplication of numerous genotypes at the erythrocytic stage. Clinical malaria occurs after a rapid, apparently unrestricted growth of recently inoculated parasites. The successive clinical attacks experienced by children are associated with genotypes different for each attack and different from those that the child carried during preceding asymptomatic phases. These data indicate that parasite diversity contributes to the pathology of infection and that control of parasite density, which is at least in part strain-specific, is an essential element of protection against malaria clinical attacks.

Animals↗
PubMed1997

Activation of gammadelta T cells in malaria: interaction of cytokines and a schizont-associated Plasmodium falciparum antigen.

A soluble Plasmodium falciparum antigen that specifically stimulates gammadelta T cells has been found associated predominantly with schizonts rather than ring forms, trophozoites, or gametocytes. This schizont-associated antigen (SAA) is resistant to protease digestion, is anionic at pH 8.5, is heat- and pH-resistant, and contains a phosphate group(s) that is crucial for biologic activity. Partially purified SAA induced proliferative responses and interferon-gamma production by gammadelta T cells. These stimulatory effects were greatly enhanced by monocyte-derived cytokines, interleukin (IL)-10, IL-12, and IL-1beta, but not by tumor necrosis factor-alpha. Taken together, these results suggest that concurrent stimulation of gammadelta T cells by SAA and by cytokines released from activated monocytes (IL-10, IL-12, IL-1beta) may represent the major mechanism underlying the selective activation of gammadelta T cells that is consistently observed in clinical cases of P. falciparum infection.

Adult↗
PubMed2005

PfEMP1 expression is reduced on the surface of knobless Plasmodium falciparum infected erythrocytes.

The Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is a key virulence factor for this species of human malarial parasite. PfEMP1 is expressed on the surface of infected erythrocytes (IEs) and directly mediates adhesion to a variety of host cells. A number of other parasite-encoded proteins are similarly exported to the IE plasma membrane and play an indirect role in this adhesion process through the modification of the erythrocyte cytoskeleton and the formation of electron dense knobs into which PfEMP1 is anchored. Analysis of the specific contribution of knob-associated proteins to adhesion is difficult due to rapid PfEMP1 switching during in vitro culture. Furthermore, these studies typically assume that the level and distribution of PfEMP1 exposed in knobby (K(+)) and knobless (K(-)) IEs is unaltered, an assumption not yet supported with data. We describe here the preparation and characterisation of a panel of isogenic K(+) and K(-) parasite clones that express one of two defined PfEMP1 variants. Analysis of the cytoadhesive properties of these clones shows that both static and flow adhesion is reduced in all the K(-) clones and, further, that this correlates with an approximately 50% reduction in PfEMP1 displayed on the IE surface. However, despite this reduction, the gross distribution of PfEMP1 in K(-) IEs appears unaltered. These data impact on our current interpretation of the role of knobs in adhesion and the mechanism of trafficking PfEMP1 to the IE surface.

Animals↗
PubMed2006

An epidemiologic model of severe morbidity and mortality caused by Plasmodium falciparum.

The intensity of Plasmodium falciparum transmission has multifarious and sometimes counter-intuitive effects on age-specific rates of severe morbidity and mortality in endemic areas. This has led to conflicting speculations about the likely impact of malaria control interventions. We propose a quantitative framework to reconcile the various apparently contradictory observations relating morbidity and mortality rates to malaria transmission. Our model considers two sub-categories of severe malaria episodes. These comprise episodes with extremely high parasite densities in hosts with little previous exposure, and acute malaria episodes accompanied by co-morbidity or other risk factors enhancing susceptibility. In addition to direct malaria mortality from severe malaria episodes, the model also considers the enhanced risk of indirect mortality following acute episodes accompanied by co-morbidity after the parasites have been cleared. We fit this model to summaries of field data from endemic areas of Africa, and show that it can account for the observed age- and exposure-specific patterns of pediatric severe malaria and malaria-associated mortality in children. This model will allow us to make predictions of the long-term impact of potential malaria interventions. Predictions for children will be more reliable than those for older people because there is a paucity of epidemiologic studies of adults and adolescents.

Animals↗