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 135-kD parasite protein, a minor component of the Plasmodium knowlesi malaria radiolabeled proteins released into culture supernatant at the time of merozoite release and reinvasion, specifically bound to human erythrocytes that are invaded and carry a Duffy blood group determinant (Fya or Fyb), but did not bind to human erythrocytes that are not invaded and do not carry a Duffy determinant (FyFy). Specific anti-Duffy antibodies blocked the binding of the 135-kD protein to erythrocytes carrying that specific Duffy determinant. Purified 135-kD protein bound specifically to the 35-45-kD Duffy glycoprotein on a blot of electrophoretically separated membrane proteins from Fya and Fyb erythrocytes but not from FyFy erythrocytes. Binding of the 135-kD protein was consistently greater to Fyb than to Fya both on the blot and on intact erythrocytes. The 135-kD protein also bound to rhesus erythrocytes that are Fyb and are invaded, but not to rabbit or guinea pig erythrocytes that are Duffy-negative and are not invaded. Cleavage of the Duffy determinant by pretreating Fyb human erythrocytes with chymotrypsin greatly reduced both invasion and binding of the 135-kD protein, whereas pretreating Fyb erythrocytes with trypsin had little effect on the Duffy antigen, the 135-kD protein binding, or on invasion. However, instances of invasion of other enzyme-treated erythrocytes that are Duffy-negative and do not bind the 135-kD protein suggest that alternative pathways for invasion do exist.
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PMID:Receptor-like specificity of a Plasmodium knowlesi malarial protein that binds to Duffy antigen ligands on erythrocytes. 283 62

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.
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PMID:Immunogenicity and antigenic reactivity of a carrier-free synthetic peptide complex derived from a 70-kDa Plasmodium falciparum exoantigen. 841 67

Digestion of blood within the mosquito midgut is mediated primarily by a series of proteases, and several previous studies have described protease activity within homogenates of the midgut of the malaria vector Anopheles stephensi. We have expanded on these previous data by resolving protease isoforms from the midgut as well as the hemolymph of adult An. stephensi mosquitoes via gel electrophoresis and zymography. Using this procedure, we have been able to identify multiple isozymes of trypsin, chymotrypsin, and aminopeptidase. We were able to detect an increase in the intensity of some of these protease bands plus the appearance of new bands 24 hr after mosquitoes had taken a blood meal. Furthermore, we detected 2 endogenous trypsin isozymes within the hemolymph. There was no upregulation of these hemolymph isozymes after a blood meal, thus suggesting that they may not be involved in digestion of the blood meal by the mosquito.
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PMID:Identification of electrophoretically separated proteases from midgut and hemolymph of adult Anopheles stephensi mosquitoes. 957 12

Midgut proteases contribute to the success or failure of Plasmodium infection of the mosquito. This paper examines the reciprocal effect of Plasmodium yoelii nigeriensis on midgut trypsin, chymotrypsin, aminopeptidase and carboxypeptidase in the mosquito Anopheles stephensi. The total protein ingested and the rate of protein digestion were unaffected by the parasite, but more protein was ingested at the first than the second bloodmeal. All peptidases were unaffected by the presence of the parasite during the first gonotrophic cycle, when ookinetes were penetrating the midgut. In the second gonotrophic cycle, trypsin and chymotrypsin were unaffected by growing oocysts, but aminopeptidase activity was reduced in the midguts of infected mosquitoes. Chymotrypsin activity was depressed and aminopeptidase activity elevated during the second gonotrophic cycle. Plasmodium infection has a negligible effect on bloodmeal digestion and does not limit the availability of the protein for egg production. The significance of changes in aminopeptidase activity when oocysts are present is discussed.
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PMID:Blood digestion in the mosquito, Anopheles stephensi: the effects of Plasmodium yoelii nigeriensis on midgut enzyme activities. 1063 14

The acidic basic repeat antigen (ABRA) of Plasmodium falciparum has been localised on the merozoite surface and in the parasitophorous vacuole. It is one of the antigens enriched in the clusters of merozoites formed with growth inhibitory immune serum and possesses chymotrypsin-like activity. Chymostatin, an inhibitor of chymotrypsin, inhibits malaria invasion as well as autoproteolysis of ABRA. Based on these characteristics of ABRA, it seems important for invasion and should be investigated as a target for vaccine and drug design. For the functional characterisation of this protein, the full-length mature ABRA protein and its fragments with/without the putative protease active site were cloned, expressed and purified from Escherichia coli. The polyclonal serum raised against recombinant ABRA fragment recognised a parasite protein with a mobility of 101 kDa in an immunoblot assay and showed immunofluorescence activity with a schizont-rich preparation of P. falciparum. Using a partially purified fragment containing the putative active site and fluorogenic and chromogenic substrates, we established that the protease activity of ABRA resides in the N-terminal portion of the protein and the highly charged C-terminal part of the protein is not required for this activity. The protease activity of ABRA was inhibited with serine protease inhibitors like chymostatin and phenyl methyl sulfonyl fluoride (PMSF) whereas leupeptin was not able to inhibit this enzyme activity. These results clearly indicated that ABRA is a protease with chymotrypsin-like specificity. This is the first report describing the expression and characterisation of recombinant ABRA protein.
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PMID:Expression and characterisation of Plasmodium falciparum acidic basic repeat antigen expressed in Escherichia coli. 1069 51

Plasmodium falciparum merozoite membrane surface antigen 2 (MSA2) has been associated with the development of protective immunity against malaria. MSA2 antibodies were able to inhibit in vitro merozoite invasion. In our search for experimental evidence concerning the participation of MSA2 in merozoite invasion, 40 peptides were synthesized according to sequences reported for the CAMP and FC27 prototype Plasmodium strains. These peptides were purified, 125I-radiolabeled and tested for their ability to bind to erythrocytes. Two MSA2 synthetic peptides with high specific binding to human erythrocytes were found. The peptide coded 4044 (KNESKYSNTFINNAYNMSIR), located in the MSA2 N-terminal conserved region, has an affinity coefficient of 72 nM and showed a positive cooperativity for the receptor-ligand interaction. The other peptide, coded 4053 (NPNHKNAETNPKGKGEVQKP) and located in the central variable region of MSA2, has an affinity coefficient of 49nM and also showed a positive cooperativity for the receptor-ligand interaction. The binding capacity of these peptides is affected by erythrocytes treated with neuraminidase and trypsin, but it is not affected by chymotrypsin. Both of these sequences inhibit in vitro erythrocyte parasite invasion by up to 95% suggesting that they have an important role in the parasite's invasion process. Furthermore, as published previously [A. Saul et al. (1992) J. Immunol., 148, 208-211], a protective B epitope is included in the 4044 peptide sequence.
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PMID:Two MSA 2 peptides that bind to human red blood cells are relevant to Plasmodium falciparum merozoite invasion. 1072 3

The 235-kDa rhoptry protein of the rodent malaria parasite Plasmodium yoelii yoelii was shown to bind to the surface of mouse red blood cells in a calcium-independent process, using a erythrocyte-binding assay. This binding is affected by modification of the surface of the red blood cells by enzymatic treatment. Chymotrypsin and trypsin but not neuraminidase treatment of the erythrocytes significantly reduced the binding of the 235-kDa proteins. The binding of an unrelated 135-kDa protein was abolished by treatment with chymotrypsin. Although the 235-kDa proteins bind to both reticulocytes and mature red blood cells, the binding to mature cells was more pronounced. In the presence of hyperimmune infection serum or specific polyclonal antibodies to the 235-kDa protein its binding to erythrocytes was reduced, further demonstrating the specificity of this ligand-receptor interaction.
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PMID:Plasmodium yoelii: effects of red blood cell modification and antibodies on the binding characteristics of the 235-kDa rhoptry protein. 1096 46

Malaria merozoite surface and apical organellar molecules facilitate invasion into the host erythrocyte. The underlying molecular mechanisms of invasion are poorly understood, and there are few data to delineate roles for individual merozoite proteins. Apical membrane antigen-1 (AMA-1) is a conserved apicomplexan protein present in the apical organelle complex and at times on the surface of Plasmodium and Toxoplasma zoites. AMA-1 domains 1/2 are conserved between Plasmodium and Toxoplasma and have similarity to the defined ligand domains of MAEBL, an erythrocyte-binding protein identified from Plasmodium yoelii. We expressed selected portions of the AMA-1 extracellular domain on the surface of COS-7 cells to assay for erythrocyte-binding activity. The P. yoelii AMA-1 domains 1/2 mediated adhesion to mouse and rat erythrocytes, but not to human erythrocytes. Adhesion to rodent erythrocytes was sensitive to trypsin and chymotrypsin, but not to neuraminidase. Other parts of the AMA-1 ectodomain, including the full-length extracellular domain, mediated significantly less erythrocyte adhesion activity than the contiguous domains 1/2. The results support the role of AMA-1 as an adhesion molecule during merozoite invasion of erythrocytes and identify highly conserved domains 1/2 as the principal ligand of the Plasmodium AMA-1 and possibly the Toxoplasma AMA-1. Identification of the AMA-1 ligand domains involved in interaction between the parasite and host cell should help target the development of new therapies to block growth of the blood-stage malaria parasites.
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PMID:Erythrocyte-binding activity of Plasmodium yoelii apical membrane antigen-1 expressed on the surface of transfected COS-7 cells. 1155 31

The recognition and invasion of human erythrocytes by the most lethal malaria parasite Plasmodium falciparum is dependent on multiple ligand-receptor interactions. Members of the erythrocyte binding-like (ebl) family, including the erythrocyte binding antigen-175 (EBA-175), are responsible for high affinity binding to glycoproteins on the surface of the erythrocyte. Here we describe a paralogue of EBA-175 and show that this protein (EBA-181/JESEBL) binds in a sialic acid-dependent manner to erythrocytes. EBA-181 is expressed at the same time as EBA-175 and co-localizes with this protein in the microneme organelles of asexual stage parasites. The receptor binding specificity of EBA-181 to erythrocytes differs from other members of the ebl family and is trypsin-resistant and chymotrypsin-sensitive. Furthermore, using glycophorin B-deficient erythrocytes we show that binding of EBA-181 is not dependent on this sialoglycoprotein. The level of expression of EBA-181 differs among parasite lines, and the importance of this ligand for invasion appears to be strain-dependent as the EBA-181 gene can be disrupted in W2mef parasites, without affecting the invasion phenotype, but cannot be targeted in 3D7 parasites.
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PMID:A novel erythrocyte binding antigen-175 paralogue from Plasmodium falciparum defines a new trypsin-resistant receptor on human erythrocytes. 1255 70

The Plasmodium falciparum erythrocyte-binding antigen 175 (EBA-175) is a ligand for merozoite invasion into human erythrocytes that binds to glycophorin A in a sialic acid-dependent manner. P. falciparum strain W2mef depends on sialic acid for invasion of erythrocytes, whereas 3D7 is sialic acid-independent. We generated parasites that lack expression or express truncated forms of EBA-175 in W2mef and 3D7. Lack of EBA-175 expression in W2mef parasites was associated with a switch to sialic acid-independent invasion. 3D7 parasites lacking expression of EBA-175 showed no alteration in their ability to utilize sialic acid-independent pathways. Strikingly, both W2mef and 3D7 parasites lacking EBA-175 expression invaded chymotrypsin-treated erythrocytes inefficiently compared with the parental lines. This loss of function suggests that the EBA-175/glycophorin A ligand-receptor interaction is the major chymotrypsin-resistant invasion pathway. Parasite lines with truncated EBA-175 had invasion phenotypes equivalent to parasites lacking expression of EBA-175. The EBA-175 ligand is functional in erythrocyte invasion by merozoites that utilize either sialic acid-dependent or -independent invasion pathways. This finding suggests a model where a minimal affinity supplied by multiple ligand-receptor interactions is required for successful invasion and has implications for EBA-175 as a malaria vaccine candidate.
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PMID:Erythrocyte-binding antigen 175 mediates invasion in Plasmodium falciparum utilizing sialic acid-dependent and -independent pathways. 1267 57


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