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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Laminin is a major constituent of the basal lamina surrounding the midgut of the malaria vectors that has been implicated in the development of the Plasmodium oocyst. In this report we describe the cloning of the Anopheles gambiae gene encoding the laminin gamma 1 polypeptide and follow its expression during mosquito development. To further investigate the putative role of laminin in the transmission of the malaria parasite we studied the potential binding of the P25 surface protein of Plasmodium berghei using a yeast two-hybrid system. Heterodimer formation was observed and does not require any additional protein factors since purified fusion proteins can also bind each other in vitro. Laminin gamma 1 also interacts with the paralogue of P25, namely P28, albeit more weakly, possibly explaining why the two parasite proteins can substitute for each other in deletion mutants. This represents the first direct evidence for molecular interactions between a surface protein of the Plasmodium parasite with an Anopheles protein; the strong interplay between laminin gamma 1 and P25 suggests that this pair of proteins may function as a receptor/ligand complex regulating parasite development in the mosquito vector.
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PMID:Anopheles gambiae laminin interacts with the P25 surface protein of Plasmodium berghei ookinetes. 1122 30

The malaria parasite invades the midgut tissue of its mosquito host as a motile form called the ookinete. We have examined the pellicle of the ookinete of Plasmodium gallinaceum by freeze-fracture and quick-freeze, deep-etch electron microscopy. The general organization is analogous to that of invasive stages of other members of Apicomplexa. The pellicle is composed of three membranes: the plasma membrane, and the two linked intermediate and inner membranes, which in the ookinete form one flattened vacuole that is located beneath the plasma membrane. The edges of this vacuole form a longitudinal suture. Beneath the vacuole is found an array of microtubules that are connected to the inner membrane by intramembranous particles. During freeze-fracture, the membranes can split along their hydrophobic planes, thus yielding six fracture faces, each of which displays a characteristic pattern of intramembranous particles. Additionally, we find that the ookinete pellicle differs from all other apicomplexan motile stages by the presence of large pores. These pores are of unknown function, but clearly might constitute a novel pathway for the transport of molecules to and from the cortex, which is independent of the well-described route through the apical micronemal/rhoptry complex. The pores may be the route by which motor proteins or other non micronemal surface proteins are trafficked, such as P25/P28 and SOAP, some of which are implicated in transmission blocking immunity.
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PMID:Cryofracture electron microscopy of the ookinete pellicle of Plasmodium gallinaceum reveals the existence of novel pores in the alveolar membranes. 1156 65

The design of effective, vector-based malaria transmission blocking strategies relies on a thorough understanding of the molecular and cellular interactions that occur during the parasite sporogonic cycle in the mosquito. During Plasmodium berghei invasion, transcription from the SRPN10 locus, encoding four serine protease inhibitors of the ovalbumin family, is strongly induced in the mosquito midgut. Herein we demonstrate that intense induction as well as redistribution of SRPN10 occurs specifically in the parasite-invaded midgut epithelial cells. Quantitative analysis establishes that in response to epithelial invasion, SRPN10 translocates from the nucleus to the cytoplasm and this is followed by strong SRPN10 overexpression. The invaded cells exhibit signs of apoptosis, suggesting a link between this type of intracellular serpin and epithelial damage. The SRPN10 gene products constitute a novel, robust and cell-autonomous marker of midgut invasion by ookinetes. The SRPN10 dynamics at the subcellular level confirm and further elaborate the 'time bomb' model of P. berghei invasion in both Anopheles stephensi and Anopheles gambiae. In contrast, this syndrome of responses is not elicited by mutant P. berghei ookinetes lacking the major ookinete surface proteins, P28 and P25. Molecular markers with defined expression patterns, in combination with mutant parasite strains, will facilitate dissection of the molecular mechanisms underlying vector competence and development of effective transmission blocking strategies.
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PMID:Overexpression and altered nucleocytoplasmic distribution of Anopheles ovalbumin-like SRPN10 serpins in Plasmodium-infected midgut cells. 1565 62

P25 and P28 proteins are essential for Plasmodium parasites to infect mosquitoes and are leading candidates for a transmission-blocking malaria vaccine. The Plasmodium vivax P25 is a triangular prism that could tile the parasite surface. The residues forming the triangle are conserved in P25 and P28 from all Plasmodium species. A cocrystal structure shows that a transmission-blocking antibody uses only its heavy chain to bind Pvs25 at a vertex of the triangle.
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PMID:The essential mosquito-stage P25 and P28 proteins from Plasmodium form tile-like triangular prisms. 1632 7

Development of sexual stage parasites within the mosquito vector is a crucial step in the transmission of Plasmodium parasites. The expression of the P25 and P28 proteins on the surface of Plasmodium parasites in the mosquito midgut is required for development and hence disease transmission. 3' gene-flanking sequences are essential for expression of these critical proteins but the nucleotide elements required are poorly defined. Transient gene transfection experiments using constructs containing deletions of the 3' gene-flanking region of the Plasmodium falciparum P25 homologue, pfs25, reveal that elements necessary for protein expression are within 315 nucleotides (nt) of the stop codon. A T-rich region 137-231 nt from the stop codon is required for expression. The nonamer AATAAAATG, 360 nt downstream from the stop codon, enhances expression by 51 percent. Using 3' RACE analysis, multiple polyadenylation sites from endogenous and plasmid-derived pfs25 transcripts were identified. Dissimilarities between the identified elements and those of metazoans support the hypothesis that definition of P25/28 3' gene regulatory processes may eventually permit the development of agents which block malaria transmission but are non-toxic to humans.
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PMID:3' gene regulatory elements required for expression of the Plasmodiumfalciparum developmental protein, Pfs25. 1643 31

Malaria parasite transmission-blocking control strategies within the mosquito vector require an adequate understanding of the parasite mosquito interaction at the molecular level. The ookinete P25-P28 surface proteins are required for the transition from ookinete to oocyst in the mosquito midgut; however, their respective molecular interactions in the mosquito are largely unknown. We used recombinant Pvs25 and Pvs28 as probes for identification of potential Anopheles albimanus midgut ligands. A 50 kDa protein interacted with Pvs25 but not with Pvs28 in blot overlay assays. This protein was identified as calreticulin by LS MS and was detected in membrane, but not in soluble midgut protein extracts. Calreticulin was detected in An. albimanus midgut microvilli by immunofluorescence analysis. The An. albimanus calreticulin cDNA was cloned and recombinant calreticulin was shown to interact with recombinant Pvs25 in overlay and co-immunoprecipitation assays, confirming the interaction of the two proteins. The Pvs25-calreticulin interaction in vivo could represent a potential target for developing transmission blocking strategies based on interfering the parasite-midgut interaction.
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PMID:The surface protein Pvs25 of Plasmodium vivax ookinetes interacts with calreticulin on the midgut apical surface of the malaria vector Anopheles albimanus. 1744 13

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