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)

The immunogenicity and efficacy of a hybrid recombinant protein derived from the N-terminal end of the glutamate-rich protein (GLURP) and the C-terminal portion of the merozoite surface protein 3 (MSP3) of Plasmodium falciparum was evaluated in Saimiri sciureus monkeys. The GLURP/MSP3 hybrid protein, expressed in Lactococcus lactis, was administered in association with alum, Montanide ISA720, or complete or incomplete Freund adjuvant (CFA/IFA) in groups of five animals each. The three formulations were shown to be immunogenic, but the one with alum was shown to be weak compared to the other two, particularly CFA/IFA, which provided very high antibody titers (enzyme-linked immunosorbent assay titers of >3,000,000 and immunofluorescence antibody test titers of 6,400). After a challenge infection with P. falciparum FUP strain, all five monkeys from the GLURP/MSP3-alum group showed a rapid increase in parasitemia, reaching 10% and were treated early. The two monkeys with the highest antibody titers in group GLURP/MSP3-Montanide ISA720 had a delay in the course of parasitemia and were treated late due to a low hematocrit. In the GLURP/MSP3-CFA/IFA group, parasitemia remained below this threshold in four of the five animals and, after it reached a peak, parasitemia started to decrease and monkeys were treated late. When all animals were grouped according to the outcome, a statistically significant association between high antibody titers and partial protection was observed. The challenge infection boosted the antibody titers, and the importance of this event for vaccine efficacy in areas where this parasite is endemic is discussed. In conclusion, these data suggest that GLURP and MSP3 can induce protection against malaria infection if antibodies are induced at properly high titers.
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PMID:Immunization of Saimiri sciureus monkeys with a recombinant hybrid protein derived from the Plasmodium falciparum antigen glutamate-rich protein and merozoite surface protein 3 can induce partial protection with Freund and Montanide ISA720 adjuvants. 1569 17

A cross-sectional study was conducted in a malaria hyperendemic state of India to ascertain the distribution of Plasmodium falciparum genotypes in patients with mild (n=40) and severe (n=35) malaria. PCR and nested PCR were used to determine the glutamate-rich protein (GLURP), merozoite surface proteins 1 and 2 (MSP1 and MSP2) and knob-associated histidine-rich protein (KAHRP) for characterization of the parasite. The results indicate that (i) the 200bp allele of the MAD20 family of MSP1 and the 550bp allele of the 3D7 family of MSP2 show over-representation in severe malaria cases; (ii) the multiplicity of infection with respect to MSP2 alleles is significantly higher (P<0.001) in severe cases than in mild cases; and (iii) comparison with the findings of other studies leads to the conclusion that the distribution of P. falciparum genotypes between different clinical groups differs geographically.
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PMID:Distribution of Plasmodium falciparum genotypes in clinically mild and severe malaria cases in Orissa, India. 1578 Mar 46

Haemoglobin C, which carries a glutamate-to-lysine mutation in the beta-globin chain, protects West African children against Plasmodium falciparum malaria. Mechanisms of protection are not established for the heterozygous (haemoglobin AC) or homozygous (haemoglobin CC) states. Here we report a marked effect of haemoglobin C on the cell-surface properties of P. falciparum-infected erythrocytes involved in pathogenesis. Relative to parasite-infected normal erythrocytes (haemoglobin AA), parasitized AC and CC erythrocytes show reduced adhesion to endothelial monolayers expressing CD36 and intercellular adhesion molecule-1 (ICAM-1). They also show impaired rosetting interactions with non-parasitized erythrocytes, and reduced agglutination in the presence of pooled sera from malaria-immune adults. Abnormal cell-surface display of the main variable cytoadherence ligand, PfEMP-1 (P. falciparum erythrocyte membrane protein-1), correlates with these findings. The abnormalities in PfEMP-1 display are associated with markers of erythrocyte senescence, and are greater in CC than in AC erythrocytes. Haemoglobin C might protect against malaria by reducing PfEMP-1-mediated adherence of parasitized erythrocytes, thereby mitigating the effects of their sequestration in the microvasculature.
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PMID:Abnormal display of PfEMP-1 on erythrocytes carrying haemoglobin C may protect against malaria. 1597 12

We assessed the efficacy of trimethoprim/sulfamethoxazole (TRM/SMX) in vivo in relation to the frequency of dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) alleles in 45 Sudanese malaria patients. Plasma levels of TRM, SMX, and acetylsulfamethoxazole (AcSMX) were measured before treatment and at days 3, 7, and 14 or upon recrudescence to ascertain drug absorption. Forty patients (89%) had an adequate clinical response, one patient (2%) had an early treatment failure response, while four patients (8%) showed late treatment failure responses. Genotyping of merozoite surface protein 1, MSP-1, MSP-2, and glutamate-rich protein before treatment and upon recrudescence showed that all recurring parasites were recrudescences. The plasma levels of TRM, AcSMX, and SMX indicated adequate drug absorption in all patients. This suggests parasite resistance as a cause of treatment failure. The presence of dhfr Ile 51 and Asn 108 alone or coupled with dhps Ala-436 among parasites that were cleared after treatment indicates that these alleles alone are insufficient to cause in vivo resistance. However, the presence of the triple mutant dhfr (Ile-51/Arg-59/Asn-108) with the dhps Gly-437 genotype in all recurring infections, suggests the importance of codon 59 and 437 alleles in susceptibility to TRM/SMX. However, the number is too little to make firm conclusions.
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PMID:Response of Plasmodium falciparum to cotrimoxazole therapy: relationship with plasma drug concentrations and dihydrofolate reductase and dihydropteroate synthase genotypes. 1601 54

The informative value of genotyping Plasmodium falciparum populations in single blood samples was studied before and during treatment in 13 patients with P. falciparum malaria. Genotyping of the two merozoite surface proteins (msp1 [block 2] and msp2) and the glutamate-rich protein showed multiple genotypes in seven patients, and single genotypes in the remaining six patients. The same genotype profiles were detected in consecutive samples obtained every 12 hours during treatment from the respective patients, although some genotypes were cleared earlier than others. These patterns are in contrast to the extensive daily dynamics previously described in asymptomatic infections. The genotypes detected in one pre-treatment sample thus appear to reflect the parasite subpopulations of the clinical malaria infection during the following days, and additional sampling does not provide any additional information.
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PMID:Limited advantage of multiple consecutive samples for genotyping Plasmodium falciparum populations during the first days of treatment. 1601 59

Plasmodium falciparum in Suriname was studied for the presence of drug resistance and genetic variation in blood samples of 86 patients with symptomatic malaria. Drug resistance was predicted by determining point mutations in the chloroquine resistance marker of the P. falciparum chloroquine resistance transporter (pfcrt) gene (codon 76) and the pyrimethamine-sulfadoxine resistance markers in the dihydrofolate reductase (dhfr) gene (codons 16, 51, 59, 108, and 164) and dihydropteroate synthase (dhps) gene (codons 436, 437, 540, 581, and 613). Genetic variability was determined by sequence analysis of the polymorphic segments of the merozoite surface protein 2 (msp-2) and glutamate-rich protein (glurp) genes. Mutations in the pfcrt, dhps, and dhfr genes were found in all samples tested, suggesting that resistance to chloroquine and antifolate drugs is present at a high frequency. A low number of alleles was found for the msp-2 and glurp genes. This indicates limited genetic diversity and, based on geographic data, a genetically homogeneous P. falciparum population in Suriname.
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PMID:Drug resistance and genetic diversity of Plasmodium falciparum parasites from suriname. 1628 89

Vacuolar H(+)-ATPase (V-ATPase), an electrogenic proton pump, is highly expressed in Plasmodium falciparum, the human malaria parasite. Although V-ATPase-driven proton transport is involved in various physiological processes in the parasite, the overall features of the V-ATPase of P. falciparum, including the gene organization and biogenesis, are far less known. Here, we report cDNA cloning of proteolipid subunit c of P. falciparum, the smallest and most highly hydrophobic subunit of V-ATPase. RT-PCR analysis as well as Northern blotting indicated expression of the proteolipid gene in the parasite cells. cDNA, which encodes a complete reading frame comprising 165 amino acids, was obtained, and its deduced amino acid sequence exhibits 52 and 57% similarity to the yeast and human counterparts, respectively. Southern blot analysis suggested the presence of a single copy of the proteolipid gene, with 5 exons and 4 introns. Upon transfection of the cDNA into a yeast null mutant, the cells became able to grow at neutral pH, accompanied by vesicular accumulation of quinacrine. In contrast, a mutated proteolipid with replacement of glutamate residue 138 with glutamine did not lead to recovery of the growth ability or vesicular accumulation of quinacrine. These results indicated that the cDNA actually encodes the proteolipid of P. falciparum and that the proteolipid is functional in yeast.
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PMID:Proteolipid of vacuolar H(+)-ATPase of Plasmodium falciparum: cDNA cloning, gene organization and complementation of a yeast null mutant. 1629 23

The goal of this study was to evaluate the antibody response induced by Plasmodium falciparum glutamate-rich protein (GLURP) in naturally exposed individuals from the Brazilian Amazon region (Rondonia State). The results showed that most individuals had IgG against two well-defined regions within P. falciparum GLURP, the relatively conserved N-terminal nonrepeat region (R0) and the immunodominant repeat region (R2), 67% and 79%, respectively. The peptides S4 from R2 (53%) and P11 from R0 (49%) were identified as immunodominant B cell epitopes and induced higher levels of antibodies. The number of GLURP peptides recognized and the levels of IgG against S4 and P11 peptides showed a positive correlation with age and time of exposure in the malaria-endemic area studied. The antibody responses against GLURP epitopes appear to be modulated by HLA class II antigens. Interestingly, the GLURP immunodominant B cell epitopes in individuals from a Brazilian malaria-endemic area are distinguishable from those of the African malaria-endemic area. Considering the importance of GLURP as a malaria vaccine candidate and the increasing focus on the use of subunit vaccines in the control of infectious diseases, the concern of the influence of class II allele frequencies in ethnically diverse populations may be important before vaccine trials are conducted among people naturally exposed to malaria parasites.
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PMID:Antibody response profiles induced by Plasmodium falciparum glutamate-rich protein in naturally exposed individuals from a Brazilian area endemic for malaria. 1635 19

Polymorphism in the beta-globin gene (hemoglobin S) has been associated with protection against severe forms of malaria. In a cross-sectional study, 180 young Gabonese children with and without sickle cell trait and harboring asymptomatic Plasmodium falciparum infections, were assessed for the responses to recombinant protein containing the conserved region of glutamate-rich protein (GLURP). We reported increased age-dependence of antibody prevalence and levels of total IgG (p<0.0001), IgG1 (p=0.009), and IgG3 (p<0.03) antibodies to GLURP with a cut-off at 5 years of age. Whatever the hemoglobin type, cytophilic antibodies (IgG1 and IgG3) were prevalent, but GLURP-specific IgG4 antibodies were detected at significantly (p<0.05) lower levels in HbAS children. We showed that the distribution of non-cytophilic IgG antibodies differs according to the hemoglobin type and to the malaria antigens tested. This may have possible implication for the clearance of malaria parasites and for protection against severe malaria.
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PMID:Distribution of IgG subclass antibodies specific for Plasmodium falciparum glutamate-rich-protein molecule in sickle cell trait children with asymptomatic infections. 1635 97

The glutamate-rich protein (GLURP) of P. falciparum is the target of cytophilic antibodies which are significantly associated with protection against clinical malaria. A phase 1 clinical trial was conducted in healthy adult volunteers with the long synthetic peptide (LSP) GLURP(85-213) combined with either Aluminum Hydroxide (Alum, 18 volunteers) or Montanide ISA 720 (ISA, 18 volunteers) as adjuvants. Immunizations with 10, 30 or 100 microg GLURP(85-213) were administered subcutaneously at days 0, 30, and 120. Adverse events occurred more frequently with increasing dosage of GLURP(85-213) LSP and were more prevalent in the ISA group. Serious vaccine-related adverse events were not observed. The vaccine induced dose-dependent cellular and humoral immune responses, with high levels of (mainly cytophilic IgG1) antibodies that recognize parasites by immunofluorescence (IFA). Plasma samples collected 30 days after the last immunization induced a dose-dependent inhibition of parasite growth in vitro in the presence of monocytes. In conclusion, immunizations with GLURP(85-213) LSP formulations induce adverse events but can be administered safely, generating antibodies with capacity to mediate growth-inhibitory activity against P. falciparum in vitro.
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PMID:Glutamate-rich protein (GLURP) induces antibodies that inhibit in vitro growth of Plasmodium falciparum in a phase 1 malaria vaccine trial. 1691 40


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