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)

Structural diversity in a 45 kDa surface antigen on Plasmodium falciparum merozoites (termed GYMSSA, MSP-2 or MSA-2) and other candidate molecules for developing a malaria vaccine need to be investigated in parasites obtained directly from patients in different malaria endemic countries. A double-stranded DNA sequencing method suitable for this purpose, and also for studying diversity in genes of other haploid cells, is described. A first round polymerase chain reaction (PCR) on DNA isolated from blood was carried out with a primer containing the GCN4 binding site to amplify and subsequently purify the coding region of the MSA-2 gene on GCN4 coated tubes. A second round PCR with more internal primers incorporating M13 forward and reverse primer sequences was then performed. Cycle sequencing was done with unlabelled M13 primers and [alpha-35S]dATP by the dideoxynucleotide procedure. Two different allelic forms of MSA-2 were identified in samples of Plasmodium falciparum from patients in Sri Lanka.
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PMID:Cycle DNA sequencing with [alpha-35S]dATP demonstrates polymorphism of a surface antigen in malaria parasites from Sri Lankan patients. 791 80

The prevalence and concentration of antibodies to merozoite surface antigen-2 (MSA-2) were measured in blood samples collected during a cross-sectional survey. Antibodies were measured by enzyme-linked immunosorbent assay using two recombinant proteins that closely approximated the full-length mature MSA-2 polypeptides expressed by the Plasmodium falciparum isolate FC27 and the cloned line 3D7 and that were representative of the dimorphic forms of MSA-2. Antibodies were also measured to a form of the 3D7 MSA-2 lacking the central repetitive sequences (d3D7). High antibody prevalence was observed to all three antigens: the overall prevalence of IgG to FC27, 3D7, and d3D7 was 91%, 90%, and 90%, respectively. The majority of individuals > or = 5 years of age had antibodies to both forms of MSA-2. The geometric mean antibody units increased with age with a plateau being reached by 15-20 years of age. There was a significant positive association of antibody prevalence with both the presence of the parasite and an enlarged spleen in children. This study provides the first evidence that antibodies against nonrepeat regions of MSA-2 are associated with fewer fever episodes and less anemia, both known to be indicators of malaria morbidity.
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PMID:Relationship between humoral response to Plasmodium falciparum merozoite surface antigen-2 and malaria morbidity in a highly endemic area of Papua New Guinea. 798 52

Numerous polymorphic antigens of the asexual erythrocytic stages of P. falciparum are now well characterized. Diversity in some of these antigens, including MSA-1, MSA-2 and the S-antigen is associated with changes in the repeat sequences which are frequently a prominent structural feature of malaria antigens. It is not known whether the variation in repeats causes allelic gene products to adopt different conformations but variation in and around the repeats in SPAM, a newly characterized secreted antigen, preserve the unusual alanine-heptad repeats which we assume generate a helical bundle in this protein. Mutations in non-repetitive regions of the S-antigen and in AMA-1, an antigen lacking repeats, are strongly biased towards those which alter the amino acid sequence. This and other evidence indicates the operation of biological selection but the role of immune responses as a selection pressure operating on these diverse antigens remains to be established.
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PMID:Molecular variation in Plasmodium falciparum: polymorphic antigens of asexual erythrocytic stages. 810 Jun 73

Conserved and variant regions of two blood stage vaccine candidate antigens of Plasmodium falciparum, merozoite surface antigen (MSA-1) and ring-infected erythrocyte surface antigen (Pf155/RESA), have been shown to be immunogenic. However, the relative immunogenicity of these immunogens in different populations has not been studied. The conserved N-terminal region of MSA-1 was investigated for its immunogenicity by studying cellular (T cell) and humoral (B cell) immune responses in P. falciparum-primed individuals, living in malaria-hyperendemic areas (Orissa State, India), where malaria presents an alarming situation. MSA-1-derived synthetic peptides contained sequences that activated T cells to proliferate and release gamma interferon in vitro. There was considerable variation in the responses to different peptides. However, the highest responses (51% [18 of 35] by proliferation and 34% [12 of 35] by gamma interferon release) were obtained with a synthetic hybrid peptide containing sequences from conserved N- and C-terminal repeat regions of MSA-1 and Pf155/RESA, respectively. Antibody reactivities in an enzyme immunoassay of plasma samples from these donors to different peptides used for T-cell activation were heterogeneous. In general, there was poor correlation between DNA synthesis and either gamma interferon release or antibody responses in individual donors, underlining the importance of examining several parameters of T-cell activation to assess the total T-cell responsiveness of a study population to a given antigen. However, the results from our studies suggest that synthetic constructs containing sequences from the N- and C-terminal regions of MSA-1 and Pf155/RESA representing different erythrocytic stages of the P. falciparum parasite are more immunogenic in humans living in malaria-hyperendemic areas of India who have been primed by natural infection.
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PMID:Cellular and humoral immune responses to well-defined blood stage antigens (major merozoite surface antigen) of Plasmodium falciparum in adults from an Indian zone where malaria is endemic. 830 Feb 25

Glycophorin A is a major receptor on human erythrocytes for Plasmodium falciparum, the human malaria parasite. In this work, we have produced four glycophorin A-specific mAb: 2B10, 1E4, 3H12, and 3H2. 2B10 was mapped to the amino terminal region of glycophorin (amino acids 1-31), and its binding to erythrocytes was fully dependent on sialic acid residues. 3H2 bound to the region close to the cell membrane, and its binding to Wr (b-) erythrocytes was significantly decreased, compared with its binding to Wr (b+) erythrocytes. 1E4 and 3H12 recognized sites between those identified by 2B10 and 3H2. Pf200 (MSA-1) is a surface protein on the P. falciparum merozoite which has been shown to bind to erythrocytes. By reciprocal inhibition assays, 2B10 and MSA-1 could be shown to share the same determinant on erythrocytes. Using an in vitro assay, we have shown that 2B10 was the most efficient inhibitor of the invasion of human erythrocytes by P. falciparum merozoites. We conclude that the binding site for MSA-1 is primarily located on the amino terminal region, amino acids 1-31, of glycophorin A, and that 2B10 is valuable for additional study of the interactions between P. falciparum merozoites and human erythrocytes.
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PMID:A monoclonal antibody capable of blocking the binding of Pf200 (MSA-1) to human erythrocytes and inhibiting the invasion of Plasmodium falciparum merozoites into human erythrocytes. 839

Seven monoclonal antibodies (mAbs) were produced to the precursor of the merozoite surface antigens (MSA-1 or gp195) using the Plasmodium falciparum Uganda-Palo Alto isolate. Three mAbs (CE2, DB8, and EB2) reacted with epitopes on the 83-kDa N-terminal processing fragment by immunoprecipitation of radiolabeled proteins and in immunoblots of native and recombinant proteins. Three other mAbs (BC9, AG5, and AD9) reacted with epitopes on the 42- and 19-kDa C-terminal processing fragments while one remaining mAb (24A1.7) reacted with only 150- and 110-kDa intermediate processing fragments. Epitopes were mapped to either conserved or dimorphic regions of the expressed protein when parasite isolates with known MSA-1 alleles were examined by indirect immunofluorescence. Moreover, one mAb (CE2), specific for the variable tripeptide repeat region SAQ(SGT)5, was growth inhibitory for P. falciparum in vitro. Growth inhibition by the mAb was concentration dependent and its parasite-neutralizing properties were not enhanced when used in combination with other gp195-specific mAbs. These results may be useful in the elucidation of biological variation of field isolates and in the definition of immunologically relevant epitopes in a gp195-based malaria vaccine.
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PMID:Plasmodium falciparum: gp195 tripeptide repeat-specific monoclonal antibody inhibits parasite growth in vitro. 888 34

The prevalence and concentration of IgG antibodies to defined Plasmodium falciparum antigens were assessed in serum samples of 97 children with cerebral malaria and 146 children with uncomplicated malaria. The antigens used included the schizont extract, ring-infected erythrocyte surface antigen, the C-terminal region of merozoite surface antigen-1 (MSA-1) (BVp42), and three recombinant proteins of MSA-2 (FC27, 3D7, and d3D7). Parasite isolates from 24 children with cerebral malaria and 22 children with uncomplicated malaria were genotyped for MSA-1 and MSA-2. The distribution of parasite genotypes belonging to the different allelic families was similar in both the cerebral and uncomplicated malaria groups. There were higher antibody levels to antigens derived from the infecting parasite genotype than to heterologous genotypes, but this difference was only statistically significant for antibody against the d3D7 antigen among children infected with the 3D7 parasite genotype (mean log = 4.72 versus 3.45 antibody units [AU]; P = 0.029). Those who died were more likely to be infected with the FC27 genotype and had lower antibody levels to MSA-2 of the 3D7 type than had cerebral malaria patients who survived (mean log = 2.94 versus 3.79 AU; P = 0.049). Antibodies against parasites of the 3D7 genotype are associated with a better prognosis among children with cerebral malaria partly because these children are more likely to be infected with parasites of this genotype rather than the FC27 genotype, which appears to be more virulent.
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PMID:Humoral response to defined Plasmodium falciparum antigens in cerebral and uncomplicated malaria and their relationship to parasite genotype. 915 53

Various formulations of the Plasmodium falciparum merozoite surface antigen, MSA-2, were made and tested in animals in order to select one for use in human vaccine trials. Recombinant constructs representing both major allelic forms of MSA-2 were formulated with a range of adjuvants and used to immunize rabbits, mice and sheep. After immunization, antibody responses obtained with the most potent adjuvants were at least tenfold greater than responses obtained with the least potent adjuvant Alhydrogel, which was used as the reference standard, although its lower potency indicated against its further use in clinical trials. Based on broadly similar results obtained with the three animal species, several adjuvants, including the water-in-oil adjuvant Montanide ISA 720, the oil-in-water adjuvant SAF-1, and liposomes containing lipid A formulated with Alhydrogel were demonstrated to be potent and potentially suitable for the clinical evaluation of MSA-2 as a candidate malaria vaccine antigen. Of these, ISA 720 was selected for further trial.
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PMID:Selection of an adjuvant for vaccination with the malaria antigen, MSA-2. 926 51

The prevalence and severity of drug-resistant malaria is emerging rapidly in the Amazon basin of Brazil. In support of clinical trials using the new antimalarial drug combination of atovaquone and proguanil, we performed in vitro drug sensitivities, molecular characterization of parasite populations using the circumsporozoite protein, merozoite surface antigen-1 (MSA-1), and MSA-2 markers, and an analysis of the Plasmodium falciparum multidrug resistance (pfmdr1) gene sequence and copy number in 26 isolates of P. falciparum obtained in a gold-mining endemic area in Peixoto de Azevedo, Mato Grosso State. All 26 isolates were found to be resistant to chloroquine (50% inhibitory concentration [IC50] = 100-620 nM) and sensitive to mefloquine (IC50 < 23 nM) and halofantrine (IC50 < 6 nM). The isolates also show reduced susceptibility to quinine (IC50 = 48-280 nM). Sequence analysis of the pfmdr1 gene revealed Asn, Phe, Cys, Asp, and Tyr in positions 86, 184, 1034, 1042, and 1246, respectively. These point mutations were similar to that previously described in other Brazilian isolates. Southern blot analysis revealed no amplification of the pfmdr1 gene. These results suggest that three different mechanisms for drug resistance exist for chloroquine, mefloquine, and quinine.
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PMID:Characterization of Plasmodium falciparum isolated from the Amazon region of Brazil: evidence for quinine resistance. 959 53

The gene for a 45 kDa merozoite surface protein (MSA-2) of the human malaria parasite Plasmodium falciparum was PCR amplified and cloned into eukaryotic expression vectors VR1012 and pcDNA3 to yield plasmids P1 and P2, respectively. The coding sequences for two N-terminal fragments of the 185 kDa merozoite surface protein (MSA-1) gene were similarly PCR amplified and cloned into vectors VR1020 and VR1012 to yield plasmids P3 and P4, respectively. The MSA-1 signal peptide sequence, present in P4, was replaced with the human tissue plasminogen activator signal sequence in P3. The four plasmids expressed the cloned genes under the control of the cytomegalovirus promoter and carried 3' bovine growth hormone termination/poly A signals. P1, P3 and P4 also contained the cytomegalovirus intron A enhancer sequence. MSA-1 expression was more readily detected than MSA-2 in Cos cells transfected with P3/P4 and P1/P2 respectively. The MSA-2 gene was also cloned into the phagemid pBluescript IISK+ with and without a 3' poly A tail composed of 35 A residues. MSA-2 was synthesised in HeLa cells infected with a recombinant vaccinia virus carrying T7 RNA polymerase when MSA-2 recombinant pBluescript was transfected into the cells. Inoculation with P1 intramuscularly or intradermally and with P2 intradermally into rabbits led to the production of antibodies to MSA-2 detectable by immunofluorescence and Western blotting. Antibodies were also produced against MSA-1 after intramuscular/intradermal inoculation with P3 and P4. Inoculation of rabbits with MSA-2 mRNA yielded better antibody titres when a poly A tail was present. Antibody levels were maintained for > 9 weeks after the final immunisation. However the immune sera failed to inhibit in vitro parasite growth.
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PMID:Mammalian cell expression of malaria merozoite surface proteins and experimental DNA and RNA immunisation. 998 40


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