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)

Vaccination with native full-length merozoite surface protein 1 (MSP1) or with recombinant C-terminal peptides protects mice against lethal challenge with virulent malaria parasites. To determine whether other regions of MSP1 can also induce protection, Plasmodium yoelii MSP1 was divided into four separate regions. Each was expressed in Escherichia coli as a fusion protein with glutathione S-transferase (GST). The N-terminal fragment began after the cleavage site for the signal sequence and ended in the region comparable to the cleavage site for the C terminus of the 82-kDa peptide of Plasmodium falciparum. This expressed protein was 30 kDa smaller than the predicted peptide. One peptide from the middle region was produced, and the C terminus consisted of a 42-kDa fragment corresponding to the analogous peptide of P. falciparum and a 19-kDa fragment that extended 37 amino acids in the amino-terminal direction beyond the probable cleavage site. To test protection of mice against lethal P. yoelii challenge, three mouse strains (CAF1, BALB/c, and A/J) were vaccinated with each of the four recombinant proteins of MSP1. Mice vaccinated with the C-terminal 19-kDa protein were highly protected (described previously), as were those vaccinated with the 42-kDa protein that contained the 19-kDa fragment. The N-terminally expressed fragment of P. yoelii was not full length because of proteolytic cleavage in E. coli. The GST-82-kDa partial fragments induced some immunity, but the surviving mice still had high parasitemias. Vaccination with the peptide from the middle region of MSP1 gave minimal to no protection. Therefore, in addition to the C-terminal 19- and 42-kDa proteins, the only other fragment to give protection was the 82-kDa protein. The protection induced by the truncated 82-kDa protein was minimal compared with that of the C-terminal fragments.
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PMID:Comparison of protection induced by immunization with recombinant proteins from different regions of merozoite surface protein 1 of Plasmodium yoelii. 923 50

Given the emerging difficulties with malaria drug resistance and vector control, as well as the persistent lack of an effective vaccine, new malaria vaccine development strategies are needed. We used a novel methodology to synthesize and fully characterize multiple antigen peptide (MAP) conjugates containing protective epitopes from Plasmodium falciparum and evaluated their immunogenicity in four different strains of mice. A di-epitope MAP (T3-T1) containing two T-cell epitopes of liver stage antigen-1 (LSA-1), a di-epitope MAP containing T-cell epitopes from LSA-1 and from merozoite surface protein-1, and a tri-epitope MAP (T3-CS-T1) containing T3-T1 and a potent B-cell epitope from the circumsporozoite protein central repeat region were tested in this study. Mice of all four strains produced peptide-specific antibodies; however, the magnitude of the humoral response indicated strong genetic restriction between the different strains of mice. Anti-MAP antibodies recognized stage-specific proteins on the malaria parasites in an immunofluorescence assay. In addition, serum from hybrid BALB/cJ x A/J CAF1 mice that had been immunized with the tri-epitope MAP T3-CS-T1 successfully inhibited the malaria sporozoite invasion of hepatoma cells in vitro. Spleen cells from immunized mice also showed a genetically restricted cellular immune response when stimulated with the immunogen in vitro. This study indicates that well-characterized MAPs combining solid-phase synthesis and conjugation chemistries are potent immunogens and that this approach can be utilized for the development of subunit vaccines.
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PMID:Immunogenicity of well-characterized synthetic Plasmodium falciparum multiple antigen peptide conjugates. 1144 64

CEL-1000 (DGQEEKAGVVSTGLIGGG) is a novel potential preventative and therapeutic agent. We report that CEL-1000 confers a high degree of protection against Plasmodium sporozoite challenge in a murine model of malaria, as shown by the total absence of blood stage infection following challenge with 100 sporozoites (100% protection) and by a substantial reduction (400-fold) of liver stage parasite RNA following challenge with 50,000 sporozoites. CEL-1000 protection was demonstrated in A/J (H-2(a)) and C3H/HeJ (H-2(k)) mice but not in BALB/c (H-2(d)) or CAF1 (A/J x BALB/c F(1) hybrid) mice. In CEL-1000-treated and protected mice, high levels of gamma interferon (IFN-gamma) in serum and elevated frequencies of hepatic and splenic CD4+ IFN-gamma-positive T cells were detected 24 h after administration of an additional dose of CEL-1000. Treatment of A/J mice that received CEL-1000 with antibodies against IFN-gamma just prior to challenge abolished the protection, and a similar treatment with antibodies against CD4+ T cells partially reduced the level of protection, while treatment with control antibodies or antibodies specific for interleukin-12 (IL-12), CD8+ T cells, or NK cells had no effect. Our data establish that the protection induced by CEL-1000 is dependent on IFN-gamma and is partially dependent on CD4+ T cells but is independent of CD8+ T cells, NK cells, and IL-12 at the effector phase and does not induce a detectable antibody response.
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PMID:A small peptide (CEL-1000) derived from the beta-chain of the human major histocompatibility complex class II molecule induces complete protection against malaria in an antigen-independent manner. 1521 94

Synthetic linear peptide chimeras (LPCs(cys+)) show promise as delivery platforms for malaria subunit vaccines. Maximal immune response to LPCs(cys+) in rodent malaria models depends upon formation of cross-linkages to generate homopolymers, presenting challenges for vaccine production. To replicate the immunogenicity of LPCs(cys+) using a recombinant approach, we designed a recombinant LPC (rLPC) based on Plasmodium yoelii circumsporozoite protein-specific sequences of 208 amino acids consisting of four LPC subunits in series. BALB/c or CAF1/J mice were immunized with synthetic or recombinant LPCs. Antibody concentrations, cytokine production and protection against challenge were compared. Recombinant peptide replicated the robust, high avidity antibody responses obtained with the synthetic linear peptide chimera. After in vitro stimulation spleen cells from mice immunized with rLPC or synthetic LPC(cys+) produced gamma interferon and IL-4 suggesting the efficient priming of T cells. Immunization of mice with either recombinant or synthetic LPC(cys+) provided comparable protection against experimental challenge with P. yoelii sporozoites. Recombinant LPCs reproduced the immunogenicity of synthetic LPC(cys+) without requiring polymerization, improving prospects for use as malaria vaccines.
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PMID:Recombinant peptide replicates immunogenicity of synthetic linear peptide chimera for use as pre-erythrocytic stage malaria vaccine. 1901 42

Coordinated regulation of gene expression is a hallmark of the Plasmodium falciparum asexual blood-stage development cycle. We report that carbon catabolite repressor protein 4 (CCR4)-associated factor 1 (CAF1) is critical in regulating more than 1,000 genes during malaria parasites' intraerythrocytic stages, especially egress and invasion proteins. CAF1 knockout results in mistimed expression, aberrant accumulation and localization of proteins involved in parasite egress, and invasion of new host cells, leading to premature release of predominantly half-finished merozoites, drastically reducing the intraerythrocytic growth rate of the parasite. This study demonstrates that CAF1 of the CCR4-Not complex is a significant gene regulatory mechanism needed for Plasmodium development within the human host.
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PMID:CCR4-associated factor 1 coordinates the expression of Plasmodium falciparum egress and invasion proteins. 2180 64