Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A neural network approach for the prediction of mitochondrial transit peptides (mTPs) from the malaria-causing parasite Plasmodium falciparum is presented. Nuclear-encoded mitochondrial protein precursors of P. falciparum were analyzed by statistical methods, principal component analysis and supervised neural networks, and were compared to those of other eukaryotes. A distinct amino acid usage pattern has been found in protein encoding regions of P. falciparum: glycine, alanine, tryptophan and arginine are under-represented, whereas isoleucine, tyrosine, asparagine and lysine are over-represented compared to the SwissProt average. Similar patterns were observed in mTPs of P. falciparum. Using principal component analysis (PCA), mTPs from P. falciparum were shown to differ considerably from those of other organisms. A neural network system (PlasMit) for prediction of mTPs in P. falciparum sequences was developed, based on the relative amino acid frequency in the first 24 N-terminal amino acids, yielding a Matthews correlation coefficient of 0.74 (90% correct prediction) in a 20-fold cross-validation study. This system predicted 1177 (22%) mitochondrial genes, based on 5334 annotated genes in the P. falciparum genome. A second network with the same topology was trained to give more conservative estimate. This more stringent network yielded a Matthews correlation coefficient of 0.51 (84% correct prediction) in a 10-fold cross-validation study. It predicted 381 (7.1%) mitochondrial genes, based on 5334 annotated genes in the P. falciparum genome.
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PMID:Properties and prediction of mitochondrial transit peptides from Plasmodium falciparum. 1459 65

The ability of human NK cells to inhibit the growth in vitro of the asexual blood stages of Plasmodium falciparum was tested. Purified NK cells from donors with no prior exposure to malaria significantly inhibited parasite growth after 48 hours of co-culture in the presence of human immune serum. This inhibition was completely abrogated by pre-treatment of the NK cells with an anti-CD95 (anti-Fas) monoclonal antibody and human Fas-Fc soluble protein. The level of growth inhibition was also substantially reduced by pre-treatment with an anti-CD56 antibody. These two antibodies caused reductions, to varying levels, of the amounts of NK cell-derived granzyme B (GrB) and pro-inflammatory cytokines, but only the anti-CD95 antibody affected the production of soluble Fas ligand (sFasL). Direct destruction of parasite-infected red cells by NK cells, in the absence of serum, was also observed in a standard 51Cr cytotoxicity test, during which N-carboxybenzoxy-L-lysine thiobenzil ester (BLT esterase) activity, which catalyzes serine protease granule release, was detected. The results obtained are indicative of a novel mechanism of NK cell-mediated cytotoxic activity against Plasmodium falciparum-infected red cells, which is mediated in part by both Fas and by GrB.
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PMID:Natural killer (NK) cell-mediated cytolysis of Plasmodium falciparum-infected human red blood cells in vitro. 1465 86

Plasmodium falciparum-infected erythrocytes (pRBCs) adhere to the endothelium via receptors expressed on the surface of vascular endothelial cells (EC) and sequester in the microvasculature of several organs and block the blood circulation. The sequestration, which involves receptors, may be related to the severity of malaria. Here, we report that pRBCs bind to the membrane-bound form of Fractalkine/CX3CL1 (FKN), which is expressed on the surface of vascular EC in various organs. pRBCs adhered to FKN on the surface of FKN cDNA-transfected Chinese hamster ovary cells (CHO-FKN cells). Both the recombinant human FKN-chemokine domain (FKN-CD) and anti-FKN-CD antibody efficiently blocked adherence of pRBCs to CHO-FKN cells. Similar to binding between FKN and FKN receptor on blood mononuclear cells, two amino acid residues, Lys-7 and Arg-47 within FKN-CD, were critical for FKN-pRBC binding. Immunohistological analysis revealed the expression of FKN on EC at the site of sequestration in the brain of a patient with cerebral malaria. These results suggest that the membrane-bound form of FKN acts as a receptor for pRBCs, and this may contribute to furthering our present understanding of cytoadherence in the pathology of falciparum malaria.
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PMID:Binding of Plasmodium falciparum-infected erythrocytes to the membrane-bound form of Fractalkine/CX3CL1. 1466 93

The yeast transcriptional coactivator GCN5 (yGCN5), a histone acetyltransferase (HAT), is part of large multimeric complexes that are required for chromatin remodeling and transcriptional activation. Like other eukaryotes, the malaria parasite DNA is organized into nucleosomes and the genome encodes components of chromatin-remodeling complexes. Here we show that GCN5 is conserved in Plasmodium species and that the most homologous regions are within the HAT domain and the bromodomain. The Plasmodium falciparum GCN5 homologue (PfGCN5) is spliced with three introns, encoding a protein of 1,464 residues. Mapping of the ends of the PfGCN5 transcript suggests that the mRNA is 5.2 to 5.4 kb, consistent with the result from Northern analysis. Using free core histones, we determined that recombinant PfGCN5 proteins have conserved HAT activity with a substrate preference for histone H3. Using substrate-specific antibodies, we determined that both Lys-8 and -14 of H3 were acetylated by the recombinant PfGCN5. In eukaryotes, GCN5 homologues interact with yeast ADA2 homologues and form large multiprotein HAT complexes. We have identified an ADA2 homologue in P. falciparum, PfADA2. Yeast two-hybrid and in vitro binding assays verified the interactions between PfGCN5 and PfADA2, suggesting that they may be associated with each other in vivo. The conserved function of the HAT domain in PfGCN5 was further illustrated with yeast complementation experiments, which showed that the PfGCN5 region corresponding to the full-length yGCN5 could partially complement the yGCN5 deletion mutation. Furthermore, a chimera comprising the PfGCN5 HAT domain fused to the remainder of yeast GCN5 (yGCN5) fully rescued the yGCN5 deletion mutant. These data demonstrate that PfGCN5 is an authentic GCN5 family member and may exist in chromatin-remodeling complexes to regulate gene expression in P. falciparum.
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PMID:Plasmodium falciparum histone acetyltransferase, a yeast GCN5 homologue involved in chromatin remodeling. 1507 57

Band 3 proteins, members of the anion exchange family of proteins (AE 0-3), are involved in a number of physiological activities such as cell volume and osmotic homeostasis, HCO3-/Cl- exchange, red cell aging, IgG binding and cellular removal, and the maintenance of the structural integrity of cells. They are present in the membranes of all cells and cellular organelles examined including Golgi, mitochondria and nuclei. The first polymorphisms of band 3 discovered were the asymptomatic band 3 Memphis variants carrying the Lys --> Gly substitution at position 56 in the cytoplasmic tail, and band 3 Texas (high transport band 3 Texas) with a mutation in the critical transmembrane, anion transport domain (Pro --> Leu substitution at position 868). The rate at which band 3 mutations were discovered accelerated in the mid 1990s and there are now over 50 known. The most common polymorphisms of band 3 are the Diego blood group antigens which reside on extracellular loops of the protein. Southeast Asia ovalocytosis (SAO; a nine amino acid deletion of residues 400-408) is a band 3 mutation known only in the heterozygous state in which it does not cause disease. It is thought to confer resistance to malaria by altering red cell deformability. Band 3 mutations are responsible for a subset of the heterogeneous group of disorders known as hereditary spherocytosis (HS). HS is a relatively common congenital or inherited group of anemias characterized by chronic hemolysis and abnormal red cell morphology. Red cells in the subset of HS with band 3 mutations behave like they are band 3 deficient either because the mutant protein is not incorporated into the membrane or because it is not functional. HS can be caused by mutations in any of at least 5 proteins involved in membrane stability. Band 3 mutations are associated with diseases in cells besides erythrocytes. For example, 2 types of distal renal tubular acidosis are the result of band 3 mutations either alone or combined with SAO. Band 3 alterations are implicated in neurological diseases such as familial paroxysmal dyskinesia, idiopathic generalized epilepsies, and neuro- or choreoacanthocytosis although they have not been demonstrated to be causative. Mutations in other genes can cause changes in band 3. An example is sickle cell anemia where the increased oxidation causes accelerated aging of band 3 and increased IgG binding and cellular removal.
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PMID:Band 3 and its alterations in health and disease. 1509 83

The hemoglobin E variant (HbE; ( beta )26Glu-->Lys) is concentrated in parts of Southeast Asia where malaria is endemic, and HbE carrier status has been shown to confer some protection against Plasmodium falciparum malaria. To examine the effect of natural selection on the pattern of linkage disequilibrium (LD) and to infer the evolutionary history of the HbE variant, we analyzed biallelic markers surrounding the HbE variant in a Thai population. Pairwise LD analysis of HbE and 43 surrounding biallelic markers revealed LD of HbE extending beyond 100 kb, whereas no LD was observed between non-HbE variants and the same markers. The inferred haplotype network suggests a single origin of the HbE variant in the Thai population. Forward-in-time computer simulations under a variety of selection models indicate that the HbE variant arose 1,240-4,440 years ago. These results support the conjecture that the HbE mutation occurred recently, and the allele frequency has increased rapidly. Our study provides another clear demonstration that a high-resolution LD map across the human genome can detect recent variants that have been subjected to positive selection.
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PMID:Extended linkage disequilibrium surrounding the hemoglobin E variant due to malarial selection. 1511 32

We have previously reported strategies for Escherichia coli production of recombinant immunogens fused to hydrophobic peptide or lipid tags to improve their capacity to be incorporated into an adjuvant formulation. In the present study, we have explored the strong interaction between biotin and SA (streptavidin) (K(D) approximately 10(-15) M) to couple recombinant immunogens to iscoms (immunostimulating complexes). Two different concepts were evaluated. In the first concept, a His(6)-tagged SA fusion protein (His(6)-SA) was bound to Ni(2+)-loaded iscom matrix (iscom without associated protein), and biotinylated immunogens were thereafter associated with the SA-coated iscoms. The immunogens were either biotinylated in vivo on E. coli expression or double biotinylated in vivo and in vitro. In the second concept, the recombinant immunogens were expressed as SA fusion proteins, which were directly bound to a biotinylated iscom matrix. A 53-amino-acid malaria peptide (M5), derived from the central repeat region of the Plasmodium falciparum blood-stage antigen Pf155/RESA, and a 232-amino-acid segment (SRS2') from the central region (from Pro-97 to Lys-328) of the major surface antigen NcSRS2 of the protozoan parasite Neospora caninum, served as model immunogens in the present study. All fusion proteins generated were found to be efficiently expressed and could be recovered to high purity using affinity chromatography. The association between the different immunogen-containing fusion proteins and the corresponding iscom matrix was demonstrated by analytical ultracentrifugation in a sucrose density gradient. However, some fusion proteins were, to a certain extent, also found to associate unspecifically with a regular iscom matrix. Furthermore, selected iscom fractions were demonstrated to induce high-titre antigen-specific antibody responses on immunization of mice. For the particular target immunogen SRS2', the induced antibodies demonstrated reactivity to the native antigen NcSRS2. We believe that the presented concepts offer convenient methods to achieve efficient adjuvant association of recombinant immunogens, and the advantages and disadvantages of the two concepts are discussed.
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PMID:Applying biotin-streptavidin binding for iscom (immunostimulating complex) association of recombinant immunogens. 1529 88

Over 3 years (1999-2002), 305 cases of falciparum malaria were diagnosed in Toulouse, France. After retrospective analysis, only 131 patients entered the study. The diagnosis of malaria was ensured by optical methods (QBC then thin smear examination), the results of which were checked from 1999 to mid-2001 by a conventional PCR method, replaced at that time by a real-time PCR using LightCycler. To detect Pfcrt K(lysine)76T(threonine) mutation, a real-time PCR assay was developed, the sensitivity of which was one mutated parasite per microliter, or 2% mutant asexual forms in a mixed population. Eighty-one patients harbored only mutant parasites, and 11 had a K76K/T76-mixed infection. The distribution of K76T mutation was significantly affected by the use of a chloroquine + proguanil (CQ + P) prophylaxis (P = 0.00037). Among 96 subjects who had no exposure to chloroquine or any history of CQ + P prophylaxis, the mean parasitemia was higher in K76-infected patients (P = 0.038), which suggested a lack of virulence in the falciparum mutant population.
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PMID:Pfcrt K76T mutation and its associations in imported Plasmodium falciparum malaria cases. 1537 34

The role of the erythrocyte anion exchanger, band 3 protein (AE1), in the adhesion of Plasmodium falciparum-infected erythrocytes to CD36 and thrombospondin (TSP) was studied. Two specific anion exchange inhibitors that bind covalently to different regions of the band 3 molecule affected cytoadherence in dissimilar ways. Modification of lysine 539 by diisothiocyanostilbene sulfonic acid (DIDS) resulted in a significant reduction in the adhesive properties of parasitized erythrocytes for CD36, but not TSP, whereas treatment with fluorescein-5-maleimide, which modifies lysine 430, was without effect on both TSP and CD36 binding. The adhesive properties of the DIDS binding region (DBR) was demonstrated by competition experiments using synthetic peptides and by direct interaction of such peptides with CD36 transfected CHO cells. The results suggest that host membrane proteins such as AE1 contribute to the adhesion of malaria-infected erythrocytes to CD36.
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PMID:Chemical modifications of band 3 protein affect the adhesion of Plasmodium falciparum-infected erythrocytes to CD36. 1547 2

Hb E [beta26(B8)Glu-->Lys], is the most common abnormal hemoglobin (Hb) in Southeast Asian populations. The hitherto highest frequencies of the Hb E gene (HBB*E) in large population samples, approximately 0.3, were observed in the southern part of northeastern Thailand. The finding of even higher frequencies in a small, isolated Austroasiatic group in Northeast Thailand prompted us to examine samples of three Austroasiatic populations in southern Laos (official designation: Lao Theung), an area inhabited by numerous ethnic groups belonging to the Mon-Khmer branch. Blood samples were collected from a total of 603 adult subjects. The HBB*E frequencies were 0.426 in the So of Khammuan Province, 0.433 in the Alak/Ngeh of Sekong Province and 0.253 in the Oy of Attapeu Province. The HBB*E frequencies in the So and Alak/Ngeh are the highest observed in Southeast Asia in representative population samples. None of the common Southeast Asian beta-thalassemia (thal) mutations were found. The results are discussed with respect to natural selection by malaria, selection time, effects of beta-thal and the ethnic history of the population of Southeast Asia.
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PMID:The 'hot-spot' of Hb E [beta26(B8)Glu-->Lys] in Southeast Asia: beta-globin anomalies in the Lao Theung population of southern Laos. 1548 86


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