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)

Several cellular and humoral mechanisms probably play a role in natural immunity to Plasmodium falciparum malaria, but the development of an effective vaccine has been impeded by uncertainty as to which antigens are targeted by protective immune responses. Experimental models of malaria have shown that cytotoxic T lymphocytes (CTL) which kill parasite-infected hepatocytes can provide complete protective immunity against certain species of Plasmodium in mice, and studies in The Gambia have provided indirect evidence that CTL play a protective role against P falciparum in humans. By using an HLA-based approach, termed reverse immunogenetics, we have previously identified peptide epitopes for CTL in liver-stage antigen-1 and the circumsporozoite protein of P falciparum. We have extended this work to identify CTL epitopes for HLA class I antigens that are found in most individuals from Caucasian and African populations. Most of these epitopes are in conserved regions of P falciparum. CTL peptide epitopes were found in a further two antigens, thrombospondin-related anonymous protein and sporozoite threonine and asparagine rich protein, indicating that a subunit vaccine designed to induce a protective CTL response may need to include parts of several parasite antigens. However, CTL levels in both children with malaria and in semi-immune adults from an endemic area were low suggesting that boosting these low levels by immunisation might provide substantial or even complete protection against infection and disease.
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PMID:Identification of conserved antigenic components for a cytotoxic T lymphocyte-inducing vaccine against malaria. 753 70

A novel Plasmodium falciparum sporozoite antigen, STARP (Sporozoite Threonine and Asparagine-Rich Protein), detected consistently on the surface of sporozoites obtained from laboratory strains and field isolates, has been identified and cloned, following a systematic approach aimed at isolating novel non-CS sporozoite surface antigens. The 2.0-kb STARP gene has a 5' miniexon/large central exon structure and contains a complex repetitive region encoding multiple dispersed motifs and tandem 45- and 10-amino acid repeats. In sporozoites, transcription of the STARP gene has been conclusively demonstrated by reverse PCR and Northern blot hybridisation and the 78-kDa protein has been localized by immunofluorescence and immunoelectron microscopy to the sporozoite surface. STARP is also expressed in liver stages, as revealed by immunofluorescence assays using antisera raised either to the central repetitive region or the C-terminal non-repetitive region. Expression is also detected in early ring stages, though not in mature erythrocytic or sexual stages. Identification and elucidation of this novel antigen is a step forward in current efforts aimed at developing an effective preerythrocytic-stage malaria vaccine.
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PMID:Cloning and characterization of a novel Plasmodium falciparum sporozoite surface antigen, STARP. 793

Thrombospondin related anonymous protein (TRAP) of Plasmodium falciparum is characterized by the presence of an amino acid motif based on the sequence Trp-Ser-Pro-Cys-Ser-Val-Thr-Cys-Gly (WSPCSVTCG) that is found in a growing family of proteins. The sequence WSPCSVTCG is considered to confer sulpho-galactosyl-cerebroside (sulphatide) binding properties to antistasin, TSP, CS protein and properdin. The observation that TRAP is localized both on the micronemes and on the surface of P. falciparum sporozoites would suggest a role played by TRAP, and its putative sulphated glycoconjugates binding motif, in the recognition and/or entry of hepatocytes by the sporozoite. Our results indicated that TRAP constructs, expressed in E. coli, bind to sulpho-galactosyl-cerebrosides (sulphatides) and to the surface of HepG2 cells using the conserved amino acid motif WSPCSVTCG. Antisera raised against TRAP constructs inhibited sporozoite invasion of HepG2 cells thus suggesting, thus, that TRAP may be one of the parasite-encoded molecules implicated in the sporozoite invasion of hepatocytes. Moreover, the possibility that TRAP antibodies may be relevant in malaria immunity is supported by the results obtained in a prospective study conducted in a malaria endemic area. In adolescents, the presence of TRAP antibodies, before malaria transmission, correlated positively with the control of parasite density.
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PMID:Thrombospondin related anonymous protein (TRAP) of Plasmodium falciparum in parasite-host cell interactions. 823 17

Synthetic peptides were used to probe O- and N-glycosylation reactions in cell-free systems of the parasitic protozoa Plasmodium falciparum, Toxoplasma gondii, and Trypanosoma brucei brucei. O-Glycosylation of the peptide Pro-Tyr-Thr-Val-Val was observed with lysates from all organisms. However, the spectrum of sugars transferred from their respective nucleotide or dolichol-phosphate derivatives to the peptide varied greatly according to the parasite. N-glycosylation of the peptides N-Bz-Asn-Gly-ThrNH2 and DNP-Arg-Asn-Ala-Thr-Ala-ValNH2 by exogenous radioactive dolichol-pyrophosphate linked oligosaccharide donors was observed only when lysates of T. gondii or T. b. brucei were used, but not in P. falciparum. To assay for endogenous N-glycosylation donors, the radiolabeled tripeptide [3H]Ac-Asn-Gly-ThrNHMe was used as acceptor. The peptide was N-glycosylated only by T. gondii and T. b. brucei preparations. Only in these latter two parasites dolichol-cycle mannosyltransferase activity was demonstrated by the elongation of exogenous radiolabeled dolichol-PP-chitobiose. The data substantiate the occurrence of protein O-glycosylation in parasitic protozoa and the exceptional absence of protein N-glycosylation in the asexual intraerythrocytic stage of the malaria parasite, P. falciparum.
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PMID:Glycosylation reactions in Plasmodium falciparum, Toxoplasma gondii, and Trypanosoma brucei brucei probed by the use of synthetic peptides. 828 Jul 51

Following infection by the malaria parasite, human erythrocytes show increased uptake of a wide variety of low molecular weight solutes via pathways with functional characteristics different from those of the transporters of normal erythrocytes. In this study glibenclamide and meglitinide were shown to inhibit the induced transport of a sugar alcohol (sorbitol), an amino acid (threonine), an inorganic anion (Cl-) and an organic cation (choline) into human erythrocytes infected in vitro with Plasmodium falciparum. The results are consistent with the hypothesis that a diverse range of substrates enter malaria-infected cells via common pathways which have features in common with Cl- channels in other cell types. glibenclamide and meglitinide were also shown to inhibit the in vitro growth of the intracellular parasite which would suggest that these pathways may be a viable chemotherapeutic target.
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PMID:Glibenclamide and meglitinide block the transport of low molecular weight solutes into malaria-infected erythrocytes. 849 24

Phospholipid-containing antigens of malaria parasites stimulate macrophages to secrete tumour necrosis factor (TNF), induce hypoglycaemia and are toxic to mice. This TNF induction is inhibited by antisera made against the antigens, the inhibitory activity of which can be removed specifically by adsorption to phosphatidylinositol (PI) liposomes. Although the same was true of antisera made against PI, the inhibitory activity of antisera made against some other phospholipids appeared to be directed against a common determinant, probably the phosphate ester head group. We have shown previously that the activity of all the antisera was associated mainly with IgM and was not boosted by repeated injections of the antigens. To try and induce a secondary response against the parasite antigens using non-toxic molecules, mice were immunized with various phosphorylated compounds coupled to keyhole limpet haemocyanin (KLH). Three injections of PI-KLH or of phosphatidylserine (PS) coupled to KLH induced significantly higher titres of inhibitory antibody than one; furthermore, the inhibitory activity was mainly in the IgG fraction. The antisera did not inhibit TNF induction by lipopolysaccharide (LPS) or lipoteichoic acid. However, antisera against PS-KLH, though not PI-KLH, inhibited the induction of TNF by the phospholipid, platelet-activating factor (PAF). These antisera, and antisera from mice immunized with phospho-threonine or galactosamine-1-phosphate conjugated to KLH, contained inhibitory antibodies of differing specificities. Mice immunized with PI-KLH, PS-KLH or phospho-threonine-KLH did not develop hypoglycaemia when challenged with the parasite toxic antigens. These results indicate that the antigenicity of non-toxic analogues can be dramatically enhanced by coupling to a protein carrier.
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PMID:Phospholipids coupled to a carrier induce IgG antibody that blocks tumour necrosis factor induction by toxic malaria antigens. 850 34

We have examined the effects of seven protein kinase inhibitors (staurosporine, genistein, methyl 2,5-dihydroxycinnamate, tyrphostins B44 and B46, lavendustin A and R03) on the erythrocytic cycle of the malaria parasite, Plasmodium falciparum. One (staurosporine) strongly inhibits serine/threonine kinases, but the remainder all exhibit a strong preference for tyrosine kinases. We have been able to discriminate between effects on invasion and on intraerythrocytic development. All reagents impeded development of intraerythrocytic parasites, though at widely differing concentrations, from the sub-micromolar to the millimolar. Several inhibitors, including staurosporine, also reduced invasion. The phosphatase inhibitor, okadaic acid, had a strong inhibitory effect both on invasion and development. The regulation of malaria development by phosphorylation or dephosphorylation reactions at several points in the blood-stage cycle is implied.
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PMID:Inhibition of invasion and intraerythrocytic development of Plasmodium falciparum by kinase inhibitors. 869 1

Plasmodium falciparum isolates from 24 Papua New Guinean patients with symptomatic malaria were tested for susceptibility to pyrimethamine and cycloguanil. Thirteen isolates were sensitive to both agents and the remainder exhibited varying degrees of resistance. No isolates were found to be resistant to one agent yet sensitive to the other and a positive correlation suggesting cross-resistance was found. Parasite DNA extracted from the patients' stained blood slides was amplified and sequenced to examine point mutations in the dihydrofolate reductase (DHFR) and dihydropteroate synthetase genes (DHPS) associated with antifolate resistance. All resistant isolates possessed mutations in the DHFR gene at codon 108, the majority changing from Ser to Asn, but one isolate from Ser to Thr, a change not previously reported in field isolates. A second mutation of the DHFR gene at Cys-59 to Arg was present in isolates with higher level resistance, but not exclusively so. Sequencing the DHPS gene, as a predictor of sulfadoxine resistance, revealed only one example that was different from DHPS alleles of sensitive isolates.
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PMID:Point mutations in the dihydrofolate reductase and dihydropteroate synthetase genes and in vitro susceptibility to pyrimethamine and cycloguanil of Plasmodium falciparum isolates from Papua New Guinea. 878 Apr 62

Pyrimethamine and cycloguanil resistance of Plasmodium falciparum has been linked to mutations in the dihydrofolate reductase (dhfr) portion of the dhfr-ts gene. In this paper, the DNA sequence of the dhfr-ts gene of 50 isolates from Vietnam and 2 clones (T9/94 and T9/96) isolated from a malaria patient from Thailand have been analyzed. A comparison between these isolates and clones showed differential mutation patterns. Forty-eight isolates were found to consist of mutations associated with Pyr. A novel leucine mutation at position 140 was found in the isolate VP8 and in clone T9/94. The isolate VP8 and the clone T9/94 were found to also have the characteristic changes at positions 16 (Val) and 108 (Thr) that have been found in cycloguanil-resistant isolates. The isolate VP35 was shown to be resistant to both antifolates, while the clone T9/96 was found to be sensitive to both antifolates and to have a sequence identical to that of wild-type dhfr-ts. The two clones from a single patient showed the coexistence of resistant and sensitive clones in the absence of treatment by antifolates. Since cycloguanil resistance seems to be rare in Vietnam, cycloguanil alone or in combination with other antimalarial agents might be an alternative for treatment and prophylaxis, even in areas with high resistance to pyrimethamine.
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PMID:Plasmodium falciparum: mutation pattern in the dihydrofolate reductase-thymidylate synthase genes of Vietnamese isolates, a novel mutation, and coexistence of two clones in a Thai patient. 888 32

Infection of human erythrocytes with the malaria parasite Plasmodium falciparum induces many morphological and biochemical changes in the host cell. Host serine/threonine protein kinases could be involved in some of these processes. The aim of this study was to determine the effect of infection on red blood cell protein kinase C (PKC) and establish the importance of this enzyme in parasite growth and sexual stage differentiation. Phorbol myristate acetate (PMA)-induced translocation of erythrocyte PKC activity is impaired in erythrocytes enriched for mature asexual stage infected cells. Western blotting shows that this is due to a relative reduction in membrane PKC protein levels rather than inhibition of enzyme activity and analysis of PKC activity isolated from whole cell lysates by DE52 chromatography suggests that total activatable PKC levels are lower in infected erythrocytes. A reduction in PMA-induced activation is also observed in PKC assays performed in situ. Downregulation of erythrocyte PKC by overnight incubation with PMA before infection causes a significant decrease in the rate of the asexual growth, suggesting that the enzyme, although lost later in infection, may be important in the earlier development of the parasite. By contrast, the lack of PKC had no effect on the production of sexual stage parasites.
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PMID:Modulation of protein kinase C activity in Plasmodium falciparum-infected erythrocytes. 905 62


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