Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Spontaneous binding of uninfected erythrocytes to Plasmodium falciparum-infected erythrocytes (rosetting) has been suggested to have a critical role in the induction of cerebral malaria. We report here that rosetting can be mediated by several molecular mechanisms involving parasite polypeptides with M(r)s of 22,000 or 28,000, termed rosettins. Antibodies to either polypeptide disrupt rosettes in a strain-specific fashion. Rosettes of five of the seven isolates examined thus far are more easily disrpted by anti-22,000-M(r) rosettin antibodies than by anti-28,000-M(r) rosettin antibodies. Polyclonal anti-22,000-M(r) rosettin antibodies raised in mice or rabbits strongly and strain specifically stain the surface of nonfixed erythrocytes infected with late asexual stages of rosetting P. falciparum. Simultaneous antibody staining and rosetting are seen when the anti-22,000-M(r) rosettin antiserum is diluted so that only partial disruption of rosettes is obtained, confirming that the fluorescence-labelled infected erythrocytes are involved in rosetting. The 22,000-M(r) rosettin is accessible for surface iodination on erythrocytes infected with strains of rosetting parasites sensitive to anti-22,000-M(r) rosettin antibodies, whereas no labelling occurred on either normal erythrocytes or nonrosetting-P. falciparum-infected erythrocytes. Purified anti-22,000-M(r) rosettin serum immunoglobulin G immunoprecipitated three parasite-derived polypeptides with M(r)s of 22,000, 45,000 (doublet), and 50,000 from lysates of [35S]methionine-labelled, parasite-infected erythrocytes. Our results suggest that rosetting is mediated by strain-specific, antigenically distinct, P. falciparum-derived polypeptides.
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PMID:Rosetting Plasmodium falciparum-infected erythrocytes express unique strain-specific antigens on their surface. 767 99

The cytokine tumor necrosis factor (TNF-alpha) is a pleotrophic polypeptide that plays a significant role in brain immune and inflammatory activities. TNF-alpha is produced in the brain in response to various pathological processes such as infectious agents [e.g., human immunodeficiency virus (HIV) and malaria], ischemia, and trauma. TNF-alpha mRNA is rapidly produced in response to brain ischemia within 1 h, reaches a peak at 6-12 h post ischemia, and subsides 1-2 days later. TNF-alpha mRNA expression corresponds in a temporal fashion to other cytokines such as interleukin (IL)-6, cytokine-induced neutrophil chemoattractant (KC), and IL-1 and precedes the infiltration of inflammatory cells into the injured zone. TNF-alpha is present early in neuronal cells in and around the ischemic tissue (penumbra), yet at later time points, the peptide is found in macrophages in the infarcted tissue. TNF-alpha has been demonstrated to cause expression of proadhesive molecules on the endothelium, which results in leukocyte accumulation, adherence, and migration from capillaries into the brain. Furthermore, TNF-alpha activates glial cells, thereby regulating tissue remodeling, gliosis, and scar formation. Thus, evidence is emerging in support of a role for TNF-alpha in injury induced by infectious, immune, toxic, traumatic, and ischemic stimuli. TNF-alpha promotes inflammation by stimulation of capillary endothelial cell proinflammatory responses and thereby provides leukocyte adhesion and infiltration into the ischemic brain. The evidence generated so far suggests that agents that suppress TNF-alpha's production or actions will reduce leukocyte infiltration into ischemic brain regions and thereby diminish the extent of tissue loss.
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PMID:Cytokines, inflammation, and brain injury: role of tumor necrosis factor-alpha. 788 Jul 18

The biological activity of a new synthetic polypeptide, the MAP-1987 was proved in the rodent malaria system. The administration of 4 micrograms/kg of MAP-1987 prevents the haemolysis of the Plasmodium berghei infected erythrocytes but not the Plasmodium vinckei infected ones. The MAP-1987 given alone changes neither the survival time of the infected mice nor the rate of parasitaemia. The chloroquine given alone increases the survival time of the mice infected with P. berghei under the standardized experimental condition but later the animals die with a low rate of parasitaemia. Chloroquine administered together with MAP-1987 definitely cures the P. berghei infected animals. This activity is unique and specific and it does not apply to P. vinckei infection.
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PMID:The immunomodulating effect of a new polyamine (the MAP-1987) administered with chloroquine in plasmodia infected mice. 792 53

Effective, safe antimalarial vaccines have proved elusive. The synthetic polypeptide SPf66 vaccine is based on preerythrocytic and asexual blood-stage proteins of Plasmodium falciparum. We report here a randomised double-blind placebo-controlled trial of the efficacy of the SPf66 vaccine against clinical P falciparum malaria in idete, southern Tanzania, an area of intense perennial malaria transmission. 586 children aged 1-5 years received three doses of vaccine (n = 274) or placebo (n = 312). The incidence and density of parasitaemia were assessed through repeated cross-sectional surveys on subgroups of children. Morbidity was monitored over a 1 year period through passive case detection in all children plus active case detection in a subgroup of 191. An episode of clinical malaria was defined as measured fever (> or = 37.5 degrees C) and parasite density > 20,000/microL. No severe side-effects were seen and the frequency of mild side-effects after the third dose was less than 6%. The vaccine was highly immunogenic and after three doses all vaccine recipients had detectable anti-SPf66 antibodies: the geometric mean index of response was 8.3 in the vaccine group and 0.7 in the placebo group. The incidence of parasitaemia was similar in both groups. 123 children had at least one episode of clinical malaria during the follow-up period after the third dose and annual incidence rates were 0.25 in the vaccine group and 0.35 in the placebo group. Estimated vaccine efficacy was 31% (95% confidence interval 0-52%; p = 0.046). After the third dose there were 6 deaths among the study cohort (1 vaccine, 5 placebo). This study confirms that SPf66 is safe, immunogenic and reduces the risk of clinical malaria among children exposed to intense P falciparum transmission.
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PMID:Randomised trial of efficacy of SPf66 vaccine against Plasmodium falciparum malaria in children in southern Tanzania. 793 34

Antibodies to Pfs25, a cysteine-rich 25-kDa protein present on the surface of Plasmodium falciparum zygotes, can completely block the transmission of malaria parasites when mixed with infectious blood and fed to mosquitoes through a membrane feeding apparatus. Recently, a polypeptide analog, Pfs25-B, secreted from recombinant Saccharomyces cerevisiae was found to react with conformation-dependent, transmission-blocking monoclonal antibodies and to elicit transmission-blocking antibodies in experimental animals when emulsified in either Freund's or muramyl tripeptide adjuvant. In this study, Pfs25-B adsorbed to alum induced transmission-blocking antibodies in both rodents and primates. Bacterially produced Pfs25, however, did not elicit complete transmission-blocking antibodies in rodents. Furthermore, unlike monoclonal antibodies to Pfs25, which block transmission only after ookinete development, antisera to Pfs25-B adsorbed to alum appeared to block the in vivo development of zygotes to ookinetes as well.
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PMID:Saccharomyces cerevisiae recombinant Pfs25 adsorbed to alum elicits antibodies that block transmission of Plasmodium falciparum. 796 Jan 39

SPf66 is a chemically synthesized 45 amino acid peptide derived from fractions of four different proteins of Plasmodium falciparum (83, 55 and 35 kDa and CS, the circumsporozoite protein) that elicits a protective immune response against malaria. In this paper we show the characterization of the SPf(66)n in batch 9 to be used in a field trial in young children at Ifakara in Tanzania. The analysis of SPf(66)n indicates that it is highly soluble in water and that the amino acid composition and sequence corresponds to that designed for the synthesis of the polypeptide. The packed product has a molecular weight ranging from 10 to 25 kDa. It is pure, free of metallic contaminants, atoxic and stable at 4 degrees C. The antibodies raised against this product in rabbits recognize the individual antigenic determinants of the molecule and the native epitopes of merozoites.
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PMID:Characterization of SPf(66)n: a chimeric molecule used as a malaria vaccine. 808 74

The structure of the parasite-encoded G6PD (PfG6PD) may provide clues about the relative protection against malaria in humans with glucose-6-phosphate dehydrogenase (G6PD) deficiency. We have cloned Pfg6pd cDNA encoding a predicted 856 amino acid residues polypeptide with a calculated molecular mass of > 94 kDa. The predicted amino acid sequence is highly homologous to G6PD from other organisms. Pfg6pd maps as a single or low copy number gene to chromosome 14. The unusually large N-terminus and the distance between the NADP-binding site and G6PD-binding site is novel for the parasite G6PD. The differences between parasite and human G6PD proteins could potentially be exploited for designing new chemotherapeutic agents.
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PMID:A novel glucose-6-phosphate dehydrogenase in Plasmodium falciparum: cDNA and primary protein structure. 808 63

During its asexual life cycle, the human malaria parasite Plasmodium falciparum exports numerous proteins beyond its surface to its host erythrocyte. We have studied the biosynthesis, processing and export of a 45 kDa parasite protein resident in membrane clefts in the erythrocyte cytoplasm. Our results indicate that this cleft protein is made as a single tightly membrane-bound 45 kDa polypeptide in ring- and trophozoite-infected erythrocytes (0-36 h in the life cycle). Using ring/trophozoite parasites released from erythrocytes, the 45 kDa protein is shown to be efficiently transported to the cell surface. This export is specifically blocked by the drug brefeldin A, and at 15 and 20 degrees C. These results indicate that transport blocks seen in the Golgi of mammalian cells are conserved in P. falciparum. Further, the newly synthesized 45 kDa protein passes through parasite Golgi compartments before its export to clefts in the erythrocyte. In mid-to-late-ring-infected erythrocytes, a fraction of the newly synthesized 45 kDa protein is processed to a second membrane-bound phosphorylated 47 kDa protein. The t1/2 of this processing step is about 4 h, suggesting that it occurs subsequent to protein export from the parasite. Evidence is presented that, in later trophozoite stages (24-36 h), the exported 45 and 47 kDa proteins are partially converted into soluble molecules in the intraerythrocytic space. Taken together, the results indicate that the lower eukaryote P. falciparum modulates a classical secretory pathway to support membrane export beyond its plasma membrane to clefts in the erythrocyte. Subsequent to export, phosphorylation and/or conversion into a soluble form may regulate the interactions of the 45 kDa protein with the clefts during parasite development.
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PMID:Biosynthesis, export and processing of a 45 kDa protein detected in membrane clefts of erythrocytes infected with Plasmodium falciparum. 809 1

A longitudinal study on the naturally acquired humoral immune responses against the merozoite surface protein 1 of Plasmodium vivax (PvMSP-1) was performed in malaria patients from the Brazilian Amazon region of Rondonia. We have previously cloned and expressed a recombinant protein, ICB2-5, that encodes 508 amino acids from the N-terminal portion of the PvMSP-1 protein. This affinity-purified polypeptide was tested by an enzyme-linked immunosorbent assay in a one-year longitudinal study using sera from 34 patients who had at least one malaria infection during the study period. The results demonstrated that more than 90% of the sera from patients having experienced more than three previous malaria infections contained antibodies to ICB2-5 at the time of a new clinical episode. Unexpectedly, more than half of these multiple-infected patients had an antibody response to ICB2-5 in which the predominant isotype was IgM. In contrast, more than 83% of the sera from these same patients contained predominantly IgG antibodies against total blood-stage antigen preparations. To determine if these results were due to the lack of boosting against this portion of the PvMSP-1 molecule, the presence of IgG antibodies to ICB2-5 in the sera from 11 patients who had consecutive malarial episodes during the study year was investigated. Five of these eleven patients failed to produce IgG antibodies to ICB2-5 even after 1-3 infections. Thus, these results suggest that no boosting against this region of the PvMSP-1 molecule was achieved by natural infections among these patients.
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PMID:Longitudinal study of naturally acquired humoral immune responses against the merozoite surface protein 1 of Plasmodium vivax in patients from Rondonia, Brazil. 837 60

The immunogenicity and protective efficacy of baculovirus recombinant polypeptide based on the Plasmodium falciparum merozoite surface protein 1 (MSP-1) has been evaluated in Aotus lemurinus griseimembra monkeys. The MSP-1-based polypeptide, BVp42, corresponds to the 42-kDa C-terminal processing fragment of the precursor molecule. Immunization of Aotus monkeys with BVp42 in complete Freund's adjuvant resulted in high antibody titers against the immunogen as well as parasite MSP-1. Fine specificity studies indicated that major epitopes recognized by these antibodies localize to conserved determinants of the 19-kDa C-terminal fragment derived from cleavage of the 42-kDa processing fragment. Effective priming of MSP-1-specific T cells was also demonstrated in lymphocyte proliferation assays. All three Aotus monkeys immunized with BVp42 in complete Freund's adjuvant showed evidence of protection of protection against blood-stage challenge with P. falciparum. Two animals were completely protected, with only one parasite being detected in thick blood films on a single days after injection. The third animal had a modified course of infection, controlling its parasite infection to levels below detection by thick blood smears for an extended period in comparison with adjuvant control animals. All vaccinated, protected Aotus monkeys produced antibodies which inhibited in vitro parasite growth, indicating that this assay may be a useful correlate of protective immunity and that immunity induced by BVp42 immunization is mediated, at least in part, by a direct effect of antibodies against the MSP-1 C-terminal region. The high level of protection obtained in these studies supports further development of BVp42 as a candidate malaria vaccine.
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PMID:A recombinant baculovirus 42-kilodalton C-terminal fragment of Plasmodium falciparum merozoite surface protein 1 protects Aotus monkeys against malaria. 855 48


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