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 3D7 form of the merozoite surface protein 2 (MSP2) of Plasmodium falciparum was one of three subunits of the malaria vaccine Combination B that were tested in a phase I/IIb double-blind randomized placebo-controlled trial, which was undertaken with 120 Papua New Guinean children of 5 to 9 years of age. Because only one variant of the highly polymorphic MSP2 was used for vaccination, we examined whether the elicited response was directed against conserved or strain-specific epitopes. Postvaccination (week 12) titers of antibody against recombinantly expressed individual domains of MSP2 were measured by enzyme-linked immunosorbent assay and compared to baseline values. We found that vaccination with the 3D7 form of MSP2 induced a significant strain-specific humoral response directed against the repetitive and semiconserved family-specific part. The conserved N- and C-terminal domains were not immunogenic. Titers of antibody against the alternate FC27 family-specific domain showed a tendency to increase in vaccinated children, but there was no increase in antibodies against FC27-type 32-mer repeats. These results indicate that vaccination with one MSP2 variant mainly induced a strain-specific response, which can explain the selective effect of vaccination with combination B on the genotypes of breakthrough parasites. These findings support the inclusion of both family-specific domains (3D7 and FC27) in an improved vaccine formulation.
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PMID:Strain-specific humoral response to a polymorphic malaria vaccine. 1550 57

The circumsporozoite (CS) is the most abundant surface protein of the Plasmodium sporozoite, and is also present early in the liver stage of the infection. Following successful protective experiments in mice and monkeys, the synthetic 102-mer malaria vaccine polypeptide representing the C-terminal region of the CS of Plasmodium falciparum was tested in a clinical trial with healthy human volunteers. This vaccine induced strong CD8(+), CD4(+) T lymphocyte and antibody responses specific for the immunizing peptide. CD8(+) T lymphocyte responses elicited in HLA-A*0201 volunteers recognized two well-defined cytotoxic T lymphocyte epitopes within the CS. Here, we show that both monocyte-derived dendritic cells (Mo-DC) and Epstein-Barr virus-transformed B-lymphoblastoid cells (LCL) can present a cytotoxic T lymphocyte epitope contained within the 102-mer synthetic peptide. Paraformaldehyde and low temperature inhibited presentation, indicating that cellular processing was required. Using specific inhibitors, we show that, in both cell types, processing requires the proteasome and the MHC class I pathway, while the endosomal compartment appears to be critical only for the presentation by Mo-DC. Antigen uptake is associated with actin polymerization in both cell types. These in vitro results demonstrate the likely pathway of antigen presentation achieved via vaccination with this synthetic peptide.
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PMID:MHC class I-restricted exogenous presentation of a synthetic 102-mer malaria vaccine polypeptide. 1568 45

Several EBA-175 paralogues (EBA-140, EBA-165, EBA-175, EBA-181, and EBL-1) have been described among the Plasmodium falciparum malaria parasite proteins, which are important in the red blood cell (RBC) invasion process. EBA-181/JESEBL is a 181 kDa protein expressed in the late schizont stage and located in the micronemes; it belongs to the Plasmodium Duffy binding-like family and is able to interact with the erythrocyte surface. Here, we describe the synthesis of 78, 20-mer synthetic peptides derived from the reported EBA-181/JESEBL sequence and their ability to bind RBCs in receptor-ligand assays. Five peptides (numbered 30030, 30031, 30045, 30051, and 30060) displayed high specific binding to erythrocytes; their equilibrium binding parameters were then determined. These peptides interacted with 53 and 33 kDa receptor proteins on the erythrocyte surface, this binding being altered when RBCs were pretreated with enzymes. They were able to inhibit P. falciparum merozoite invasion of RBCs when tested in in vitro assays. According to these results, these five EBA-181/JESEBL high specific erythrocyte binding peptides, as well as the entire protein, were seen to be involved in the molecular machinery used by the parasite for invading RBCs. They are thus suggested as potential candidates in designing a multi-sub-unit vaccine able to combat the P. falciparum malaria parasite.
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PMID:Amino terminal peptides from the Plasmodium falciparum EBA-181/JESEBL protein bind specifically to erythrocytes and inhibit in vitro merozoite invasion. 1582 Jul 49

Erythrocyte invasion by malaria parasites is a multi-step process requiring specific molecular interactions between merozoites and erythrocyte surface receptors. Human Duffy blood group protein is the receptor for Plasmodium vivax merozoite invasion to red blood cells. The cognate parasite ligand for Duffy protein is a 135 kDa Duffy binding protein (DBP). Previously, we defined the domain on the N-terminus of human Duffy protein required for DBP binding and showed that a 35-mer N-terminal peptide inhibited DBP binding to Duffy positive red cells in vitro. There is no efficient in vitro culture system or small animal model to study P. vivax ligand binding and invasion to red blood cells. Plasmodium yoelii is frequently used to study the interaction between host receptors and parasite ligands. Similar to human parasite P. vivax, rodent malaria parasite P. yoelii also uses Duffy protein on mouse RBCs for invasion. However, the domain on the mouse Duffy for P. yoelii binding is not known. In this communication, using a mouse model, we show that an antibody against the N-terminus of mouse Duffy protein inhibited P. yoelii invasion in the mouse. In addition, by using small peptides from the N-terminal exocellular domain, we defined the domain on the Duffy protein for P. yoelii binding and invasion to mouse erythrocytes. Our results also indicated that small peptides from the host receptor could act as decoy receptors and may be utilized as potential antimalarial drugs.
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PMID:The domain on the mouse Duffy protein for Plasmodium yoelii binding and invasion to mouse erythrocytes. 1638 20

The stability of anti-malarial immunity will influence the interpretation of immunologic endpoints during malaria vaccine trials conducted in endemic areas. Therefore, we evaluated cytokine responses to Plasmodium falciparum liver stage antigen-1 (LSA-1) and thrombospondin-related adhesive protein (TRAP) by Kenyans from a holoendemic area at a 9-month interval. The proportion of adults with interferon-gamma (IFN-gamma) responses to 9-mer LSA-1 peptides was similar at both time-points, whereas responses from children decreased (P < 0.05). Response to the longer, 23-mer LSA-1 peptide was variable, decreasing in adults and children over time (P < 0.02 and P < 0.001, respectively). The proportion of children with IFN-gamma responses to either antigen at the second time-point was significantly lower than that of adults, yet more adults responded to 9-mer TRAP peptides (P < 0.02). In contrast, the proportion of interleukin-10 responses to LSA-1 and TRAP was similar at both time-points for both age groups. Most noteworthy was that even when the repeat cross-sectional frequency of cytokine responses was the same, these responses were not generated by the same individuals. This suggests that cytokine responses to LSA-1 and TRAP are transient under natural exposure conditions.
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PMID:Stability of interferon-gamma and interleukin-10 responses to Plasmodium falciparum liver stage antigen-1 and thrombospondin-related adhesive protein in residents of a malaria holoendemic area. 1660 88

On 21st November 1916, the Royal Navy Hospital ship 'Britannic' (the sister ship of the 'Titanic') was torpedoed near the island of Kea in the Aegean Sea. Captain Dr. John Cropper, aged 52, was one of 30 people who drowned of the 1100 on board. Dr. Cropper was born in 1864, at Guisborough, England. He obtained his medical degree from Cambridge University in 1891. After his marriage to Anne Ellen Walker in 1895, the Church Missionary Society sent him on a medical mission to Palestine. Dr. Cropper stayed in Palestine for about 10 years working in Acre, Nablus, Ramallah and Jerusalem. He published his experiences in 35 articles and letters in English medical periodicals, more than anyone else did in Palestine at that time. In those publications, he described various operations that he carried out and observations on infectious diseases, most of which were the first descriptions from that remote and unhealthy country. His prominent research was in the field of malaria - the most common and important disease in Palestine during that period. It was less than two years after Grassi's discovery of the role of Anopheles mosquitoes as the vector of human malaria that Dr. Cropper carried out surveys of larval and adult mosquitoes in correlation with malarial distribution in Palestine. Dr. Cropper was the first who routinely examined slides microscopically in Palestine and correctly diagnosed the type of malaria. Dr. Cropper was also the first in Palestine to suggest antimalarial measures aimed directly at the mosquito vector and paid attention to ecological aspects such as breeding places and the daily behavior of adult mosquitoes. Dr. Cropper noted the common antimalarial measurements of that time, such as covering of wells, planting of Eucalyptus trees to drain swamps and the routine use of quinine as a preventive medicine, but he wrote that those measures were not effective under the local conditions. He suggested that the only effective measures must be aimed against the larval mosquitoes and he recommended the use of a sulphur compound in order to destroy the larvae. Only many years later were those observations recognized as being correct. In our local public scientific memory, we remember early researchers such as Dr. Hillel Jaffe, Prof. Peter Muehlens, Prof. Israel Kligler, Prof. Gideon Mer, Dr. Zvi Saliternik and many others. Dr. Cropper preceded all of them. The comprehensive contributions of this English doctor to the medical research in Palestine should not be forgotten.
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PMID:[What is the link between the sister of the "Titanic" and the history of medicine in Palestine?]. 1683 4

An effective malaria vaccine is needed to address the public health tragedy resulting from the high levels of morbidity and mortality caused by Plasmodium parasites. The first protective immune mechanism identified in the irradiated sporozoite vaccine, the "gold standard" for malaria preerythrocytic vaccines, was sporozoite-neutralizing antibody specific for the repeat region of the surface circumsporozoite (CS) protein. Previous phase I studies demonstrated that a branched peptide containing minimal T- and B-cell epitopes of Plasmodium falciparum CS protein elicited antirepeat antibody and CD4(+)-T-cell responses comparable to those observed in volunteers immunized with irradiated P. falciparum sporozoites. The current study compares the immunogenicity of linear versus tetrabranched peptides containing the same minimal T- and B-cell epitopes, T1BT*, comprised of a CS-derived universal Th epitope (T*) synthesized in tandem with the T1 and B repeats of P. falciparum CS protein. A simple 48-mer linear synthetic peptide was found to elicit antisporozoite antibody and gamma interferon-secreting T-cell responses comparable to the more complex tetrabranched peptides in inbred strains of mice. The linear peptide was also immunogenic in outbred nonhuman primates (Aotus nancymaae), eliciting antibody titers equivalent to those induced by tetrabranched peptides. Importantly, the 48-mer linear peptide administered in adjuvants suitable for human use elicited antibody-mediated protection against challenge with rodent malaria transgenic sporozoites expressing P. falciparum CS repeats. These findings support further evaluation of linear peptides as economical, safe, and readily produced malaria vaccines for the one-third of the world's population at risk of malaria infection.
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PMID:A linear peptide containing minimal T- and B-cell epitopes of Plasmodium falciparum circumsporozoite protein elicits protection against transgenic sporozoite challenge. 1703 May 84

Antigenic variation is a survival mechanism developed by the malaria parasite Plasmodium falciparum in order to allow for the establishment of a chronic infection. Here we have studied clonal differences in the transcriptomes of two isogenic P. falciparum clones (3D7S8.4 and 3D7AH1S2) of distinct adhesive and antigenic phenotypes employing a P. falciparum 70-mer oligonucleotide microarray. Fifteen transcripts were highly differentially expressed (greater than a 5-fold change) with five transcripts upregulated in 3D7AH1S2 compared to 3D7S8.4, and ten downregulated. Identified genes encode apical organellar (Gbph2, GBP-related antigen), cell cycle and DNA/RNA processing (SERA-5, RNA-methylase), cell-rescue, defense/virulence (RESA-2, RIFIN, PfEMP1) and hypothetical proteins (PFB0115w, PFI1445w, MAL13P1.121). A number of short and full-length var transcripts were differentially expressed between the clones but one full-length transcript was dominant in both rings and trophozoites (PFD0630c versus PFF0845c). Distinct members of two other variant gene families (phist-a and rif-like), scattered over the subtelomeric areas of the 14 chromosomes, were also found to be clonally and developmentally expressed. Three sibling-clones of 3D7AH1S2 (3D7AH1S1, -S3, -S4) were further studied for the expression of transcripts upregulated in 3D7AH1S2 compared to 3D7S8.4. Individual var and phist-a genes were found expressed in all of the clones while the expression of a rif-like gene and gbph2 varied in-between the clones. The present data provides evidence for complex transcriptional differences between closely related isogenic P. falciparum of distinct adhesive and antigenic characteristics.
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PMID:Comparative transcriptomal analysis of isogenic Plasmodium falciparum clones of distinct antigenic and adhesive phenotypes. 1719 75

Immunization of mice with subunit vaccines based on the Plasmodium yoelii 17kDa hepatocyte erythrocyte protein (PyHEP17), orthologue of Plasmodium falciparum exported protein 1 (PfExp1), induces antigen-specific immune responses and protects against sporozoite challenge. To aid in the characterization of candidate subunit vaccines based on this antigen, we have mapped the immunodominant and subdominant CD8+ and CD4+ T cell epitopes on PyHEP17. Using a panel of 29 15-mer synthetic peptides representing the complete sequence of PyHEP17 (amino acids 1-153), and overlapping each other by 10 residues, we identified an immunogenic region between amino acids 61-85. To define the minimal CD4+ and CD8+ T cell epitopes within this region, we synthesized 25 9-mer peptides overlapping each other by one residue. We screened the capacity of the 15-mer and 9-mer peptides to be recognized by splenocytes and lymph node cells from mice immunized with PyHEP17 plasmid DNA or peptides in Freund's adjuvant, as assessed by cytokine secretion, lymphoproliferation, and cytotoxicity. The profile of response to the T cell epitopes varied depending upon the immunization regimen. Antigen-specific T cell responses were detected to three 15-mer peptides (residues 61-75, 66-80 and 71-85) representing two 10-mer epitopes mapping to residues 66-75 (LTKNKKSLRK) and 71-80 (KSLRKINVAL). IFN-gamma responses after DNA immunization predominantly mapped to two overlapping 9-mer peptides (residues 73-81 and 74-82) sharing an eight amino acid overlap (residues 74-81, RKINVALA), whereas CTL responses predominantly mapped to four 9-mer peptides (residues 61-69, 70-78, 76-84, and 84-92). In addition, a subdominant 10-mer CD8+ T cell epitope recognized by peptide immunization but not DNA immunization mapped to residues 31-40 (GKYGSQNVIK). The identification of these epitopes will allow the evaluation of delivery systems for malaria vaccine candidates as well as the delineation of protective immune mechanisms.
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PMID:Identification of minimal CD8+ and CD4+ T cell epitopes in the Plasmodium yoelii hepatocyte erythrocyte protein 17kDa. 1730 42

Merozoite surface protein 2 (MSP2) is a GPI-anchored protein on the surface of the merozoite stage of the malaria parasite Plasmodium falciparum. It is largely disordered in solution, but has a propensity to form amyloid-like fibrils under physiological conditions. The N-terminal conserved region (MSP2(1-25)) is part of the protease-resistant core of these fibrils. To investigate the structure and dynamics of this region, its ability to form fibrils, and the role of individual residues in these properties, we have developed a bacterial expression system that yields > or =10 mg of unlabeled or (15)N-labeled peptide per litre of culture. Two recombinant versions of MSP2(1-25), wild-type and a Y7A/Y16A mutant, have been produced. Detailed conformational analysis of the wild-type peptide and backbone (15)N relaxation data indicated that it contains beta-turn and nascent helical structures in the central and C-terminal regions. Residues 6-21 represent the most ordered region of the structure, although there is some flexibility around residues 8 and 9. The 10-residue sequence (MSP2(7-16)) (with two Tyr residues) was predicted to have a higher propensity for beta-aggregation than the 8-mer sequence (MSP2(8-15)), but there was no significant difference in conformation between MSP2(1-25) and [Y7A,Y16A]MSP2(1-25) and the rate of fibril formation was only slightly slower in the mutant. The peptide expression system described here will facilitate further mutational analyses to define the roles of individual residues in transient structural elements and fibril formation, and thus contribute to the further development of MSP2 as a malaria vaccine candidate.
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PMID:Merozoite surface protein 2 of Plasmodium falciparum: expression, structure, dynamics, and fibril formation of the conserved N-terminal domain. 1751 3


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