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)

Plasmodium vivax merozoite surface protein 4 (PvMSP4) has been considered to be a promising malarial vaccine candidate. The antigenic diversity displayed by parasite populations is one of the main factors limiting the efficacy of asexual-stage anti-malarial vaccine candidates. The present study is the first characterising PvMSP4 polymorphism. P. vivax isolates were collected from endemic areas in Colombia and diversity and selection pattern studies were carried out. Overall conservation in this protein was remarkable. Changes were only found in exons I and II, the former only having single nucleotide polymorphisms (SNPs) whilst the latter showed variations in tandem repeat number caused by exon II slippage. The remaining regions (EGF-like domain, GPI anchor and intron) were completely conserved. Selection and neutrality tests carried out over variant exons indicated negative selective forces acting on them. No evidence of intragenic recombination was found. The strong conservation displayed in this molecule by isolates from geographically different regions (Colombia, Salvador and Thailand) stresses its potential importance as a candidate for a vaccine against P. vivax malaria.
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PMID:High level of conservation in Plasmodium vivax merozoite surface protein 4 (PvMSP4). 1616 42

A key issue relating to developing multi-component anti-malarial vaccines, lies in studying Plasmodium vivax surface proteins' genetic variation. The present work was aimed at amplifying, cloning and sequencing the gene encoding P. vivax merozoite surface protein 5 (PvMSP5) in samples obtained from infected patients from Colombian areas having varying malaria transmission rates. Nucleotide sequence data reported in this paper are available in the GenBank, EMBL and DDBJ databases under Accessions numbers DQ341586 to DQ341601. Our results have revealed that PvMSP5 is one of the P. vivax surface proteins having greater polymorphism, this being restricted to specific protein regions. The intron and exon II (which includes the GPI anchor and EGF-like domain) were both highly conserved when compared to exon I; exon I displayed the greatest variation and most of the recombination events occurred within it. No geographical grouping was observed. The Nei-Gojobori test revealed significant positive selection in the samples analysed here, whereas Tajima and Fu and Li tests presented a neutral selection pattern. The results reflected a localized variation pattern, recombination between PvMSP5 alleles and also functional and immune pressures, where stronger selective forces might be acting on exon I than on exon II, suggesting that the latter could be an important region to be included in an anti-malarial vaccine.
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PMID:High polymorphism in Plasmodium vivax merozoite surface protein-5 (MSP5). 1697 50

The Plasmodium falciparum merozoite surface protein-1 19 kDa fragment (MSP-1(19)) comprises two closely packed EGF-like domains (EGF=epidermal growth factor), each stabilized by three disulfide bonds. The native conformation of this protein is important for eliciting P. falciparum growth inhibitory antibodies. Here we show that the N-terminal EGF domain alone can be chemically synthesized and efficiently refolded to a native-like state, as shown by its solution structure as determined by NMR spectroscopy. In order to study its immunogenicity, the domain was coupled through its N terminus to a phospholipid and incorporated into reconstituted influenza virus-like particles (virosomes). When used to immunize mice, the peptide-loaded virosomes elicited potent humoral immune responses that were shown by Western blots and immunofluorescence assays to cross-react with native MSP-1 on the surfaces of P. falciparum blood stage parasites. This opens the way for a medicinal chemistry-oriented approach to the study and optimization of the antigenicity of the protein as a potential malaria vaccine candidate, whilst exploiting the immunopotentiating properties of influenza virosomes as a delivery vehicle.
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PMID:Synthesis, solution structure and immune recognition of an epidermal growth factor-like domain from Plasmodium falciparum merozoite surface protein-1. 1706 40

Merozoite surface protein 1 (MSP1) of the malaria parasite Plasmodium falciparum is an important vaccine candidate antigen. Antibodies specific for the C-terminal maturation product, MSP1(19), have been shown to inhibit erythrocyte invasion and parasite growth. Specific monoclonal antibodies react with conformational epitopes contained within the two EGF-like domains that constitute the antigen MSP1(19). To gain greater insight into the inhibitory process, the authors selected two strongly inhibitory antibodies (designated 12.8 and 12.10) and modeled their structures by homology. Computational docking was used to generate antigen-antibody complexes and a selection filter based on NMR data was applied to obtain plausible models. Molecular Dynamics simulations of the selected complexes were performed to evaluate the role of specific side chains in the binding. Favorable complexes were obtained that complement the NMR data in defining specific binding sites. These models can provide valuable guidelines for future experimental work that is devoted to the understanding of the action mechanism of invasion-inhibitory antibodies.
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PMID:Interaction of malaria parasite-inhibitory antibodies with the merozoite surface protein MSP1(19) by computational docking. 1717 81

Plasmodium vivax infection is the second most common cause of malaria throughout the world. Like other Plasmodium species, P. vivax has a large protein complex, MSP-1, located on the merozoite surface. The C-terminal MSP-1 sub-unit, MSP-1(42), is cleaved during red blood cell invasion, causing the majority of the complex to be shed and leaving only a small 15kDa sub-unit, MSP-1(19), on the merozite surface. MSP-1(19) is considered a strong vaccine candidate. We have determined the solution structure of MSP-1(19) from P. vivax using nuclear magnetic resonance (NMR) and show that, like in other Plasmodium species, it consists of two EGF-like domains that are oriented head-to-tail. The protein has a flat, disk-like shape with a highly charged surface. When MSP-1(19) is part of the larger MSP-1(42) precursor it exists as an independent domain with no stable contacts to the rest of the sub-unit. Gel filtration and analytical ultracentrifugation experiments indicate that P. vivax MSP-1(42) exists as a dimer in solution. MSP-1(19) itself is a monomer, however, 35 amino-acids immediately upstream of its N-terminus are sufficient to cause dimerization. Our data suggest that if MSP-1(42) exists as a dimer in vivo, secondary processing would cause the dissociation of two tightly linked MSP-1(19) proteins on the merozoite surface just prior to invasion.
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PMID:Structural studies on Plasmodium vivax merozoite surface protein-1. 1734 30

Malaria is caused by the protozoan Plasmodium. The parasite Plasmodium completes its life cycle inside two hosts, i. e. human and mosquito. Among all known Plasmodium species, Plasmodium falciparum is known to cause maximum mortality. Various studies done on the mosquito stages of the parasite suggest that the proteins present on the parasite's surface are responsible for its survival under the adverse conditions prevailing in the mosquito midgut. When human blood containing Plasmodium gametocytes enters the mosquito gut, the gametocytes form gametes which then fuse to form zygotes. At this stage two closely related proteins, Pfs25 and Pfs28 are expressed on the surface of the parasite which continue to express up to the young oocyst stage. These proteins present on zygotes, ookinetes and young oocysts of Plasmodium are categorized in P25 and P28 families and are well known malaria vaccine candidate proteins. In this study, we have done sequence analysis, homology modeling and docking studies of a typical member of the P25 family of ookinete surface protein, i.e. Pfs25 from Plasmodium falciparum. We have built a 3D model of Pfs25 based on the X-ray crystallographic structure of Pvs25 from Plasmodium vivax. Also we have modeled the Fv region of the malaria transmission blocking monoclonal antibody 4B7. This antibody is the transmission blocking monoclonal antibody for Pfs25 protein. Pfs25 and 4B7 scFv (single chain variable fragment only) docking results indicate that EGF domain III of the Pfs25 protein interacts with the scFv region of modeled 4B7 antibody forming seven hydrogen bonds out of which six are formed with heavy chain of scFv region. Docking results of Pfs25 with gamma chain of laminin also suggest a possible role of Pfs25 protein in host parasite interaction.
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PMID:Structure and mechanism of a transmission blocking vaccine candidate protein Pfs25 from P. falciparum: a molecular modeling and docking study. 1903 56

The P28 family of proteins are 28 kDa proteins expressed on the surface of sexual stages--zygote, ookinete and young oocyst stages--of Plasmodium species when the parasite resides inside the mosquito midgut. Together with P25 proteins, P28 proteins protect the parasite from the harsh proteolytic environment prevailing inside the mosquito midgut. Vaccines against these proteins induce antibodies in vertebrate hosts that are capable of inhibiting parasite development in the mosquito midgut, thus preventing transmission of the parasite from the mosquito to another human host. These transmission-blocking vaccines are helpful in reducing the burden caused by malaria, which affects 300-600 million, and kills 1-3 million, people annually. The purpose of this study was to structurally characterise six members of the P28 family of ookinete surface proteins with the help of homology modelling, to compare these proteins in terms of transmission blocking and host parasite interactions, and to analyse phylogenetic relationships within the P28 family and with the P25 family. Our results indicate that all the members of the P28 family studied have four EGF domains arranged in triangular fashion with a very big C loop present in EGF domain IV, which could serve as a diagnostic feature of the P28 family as this loop is absent in the P25 family of ookinete surface proteins. The models of the P28 family of ookinete surface proteins obtained may help in understanding the biology of the parasite inside the mosquito midgut, and in designing transmission-blocking vaccines against malaria in the absence of experimentally determined structures of these important surface proteins.
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PMID:A very large C-loop in EGF domain IV is characteristic of the P28 family of ookinete surface proteins. 1905 32

Development of a vaccine against malaria is a major global health concern. The P28 proteins expressed on the surface of ookinetes of Plasmodium are the targets of transmission blocking antibodies. Injection of P28 proteins in vertebrate hosts induces antibodies that inhibit oocyst formation, blocking transmission of the parasite from mosquitos to human hosts. P28 proteins are crucial for parasite protection inside the mosquito midgut. Despite their importance, structural details of P28 family members have not been available to date. The purpose of this study was to structurally characterise a member of the P28 family, viz. Pb28 protein from Plasmodium berghei, and to study the interaction of Pb28 protein with the scFv (single chain variable fragment) of TBmAb (transmission blocking monoclonal antibody) 13.1 which blocks malaria transmission effectively. Pb28 protein and the TBmAb 13.1 scFv were modelled separately. To decipher the antigen-antibody interaction, ZDOCK and RDOCK programs were used. Our results suggest that, as compared to the template Pvs25, Pb28 protein has four EGF (epidermal growth factor)-like domains arranged in a triangular form with maximum root mean square deviations (RMSDs) present in the loop regions of EGF domains II and III. With the help of docking we were able to show that the B loop of EGF domain II of Pb28 protein interacts with the scFv of TBmAb 13.1. The predicted probable complex of Pb28 protein and 13.1 TBmAb suggests a mechanism for transmission blocking and may help in designing vaccine candidates in the absence of experimentally determined structures of these proteins.
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PMID:EGF domain II of protein Pb28 from Plasmodium berghei interacts with monoclonal transmission blocking antibody 13.1. 1906 95

The spleen plays a crucial role in the development of immunity to malaria, but the role of pattern recognition receptors (PRRs) in splenic effector cells during malaria infection is poorly understood. In the present study, we analysed the expression of selected PRRs in splenic effector cells from BALB/c mice infected with the lethal and non-lethal Plasmodium yoelii strains 17XL and 17X, respectively, and the non-lethal Plasmodium chabaudi chabaudi AS strain. The results of these experiments showed fewer significant changes in the expression of PRRs in AS-infected mice than in 17X and 17XL-infected mice. Mannose receptor C type 2 (MRC2) expression increased with parasitemia, whereas Toll-like receptors and sialoadhesin (Sn) decreased in mice infected with P. chabaudi AS. In contrast, MRC type 1 (MRC1), MRC2 and EGF-like module containing mucin-like hormone receptor-like sequence 1 (F4/80) expression decreased with parasitemia in mice infected with 17X, whereas MRC1 an MRC2 increased and F4/80 decreased in mice infected with 17XL. Furthermore, macrophage receptor with collagenous structure and CD68 declined rapidly after initial parasitemia. SIGNR1 and Sn expression demonstrated minor variations in the spleens of mice infected with either strain. Notably, macrophage scavenger receptor (Msr1) and dendritic cell-associated C-type lectin 2 expression increased at both the transcript and protein levels in 17XL-infected mice with 50% parasitemia. Furthermore, the increased lethality of 17X infection in Msr1 -/- mice demonstrated a protective role for Msr1. Our results suggest a dual role for these receptors in parasite clearance and protection in 17X infection and lethality in 17XL infection.
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PMID:Expression of non-TLR pattern recognition receptors in the spleen of BALB/c mice infected with Plasmodium yoelii and Plasmodium chabaudi chabaudi AS. 2251 Aug 38

Malaria transmission-blocking vaccines (TBV) targeting sexual stages of the parasite represent an ideal intervention to reduce the burden of the disease and eventual elimination at the population level in endemic regions. Immune responses against sexual stage antigens impair the development of parasite inside the mosquitoes. Target antigens identified in Plasmodium falciparum include surface proteins Pfs230 and Pfs48/45 in male and female gametocytes and Pfs25 expressed in zygotes and ookinetes. The latter has undergone extensive evaluation in pre-clinical and phase I clinical trials and remains one of the leading target antigens for the development of TBV. Pfs25 has a complex tertiary structure characterized by four EGF-like repeat motifs formed by 11 disulfide bonds, and it has been rather difficult to obtain Pfs25 as a homogenous product in native conformation in any heterologous expression system. Recently, we have reported expression of codon-harmonized recombinant Pfs25 in Escherichia coli (CHrPfs25) and which elicited highly potent malaria transmission-blocking antibodies in mice. In the current study, we investigated CHrPfs25 along with gold nanoparticles of different shapes, size and physicochemical properties as adjuvants for induction of transmission blocking immunity. The results revealed that CHrPfs25 delivered with various gold nanoparticles elicited strong transmission blocking antibodies and suggested that gold nanoparticles based formulations can be developed as nanovaccines to enhance the immunogenicity of vaccine antigens.
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PMID:Nanovaccines for malaria using Plasmodium falciparum antigen Pfs25 attached gold nanoparticles. 2629 50


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