Stage-dependent Localization of a Novel Gene Product of the Malaria Parasite, Plasmodium falciparum

Nguyên, Thành Vinh; Fujioka, Hisashi; Kang, Angray S.; Rogers, William O.; Fidock, David A.; James, Anthony A.

doi:10.1074/jbc.m103375200

Cited by 24 publications

(33 citation statements)

References 39 publications

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“…This suggests that the same malarial protein, expressed during different parasite stages, can recognize different receptors present on eukaryotic cells of both insect and mammalian origin. Another multistage antigen called MB2, a 120-kDa protein, has been found to be present on the sporozoite surface and is imported into the nucleus of erythrocytic-stage parasites as a 66-kDa processed fragment (26). Although the receptor for MB2 protein is yet unknown, its differential processing and localizations at different stages of parasite development indicate that MB2 is capable of interacting with host receptors on both liver cells and erythrocytes.…”

Section: Discussionmentioning

confidence: 99%

Identification, Cloning, Expression, and Characterization of the Gene for Plasmodium knowlesi Surface Protein Containing an Altered Thrombospondin Repeat Domain

et al. 2005

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Proteins present on the surface of malaria parasites that participate in the process of invasion and adhesion to host cells are considered attractive vaccine targets. Aided by the availability of the partially completed genome sequence of the simian malaria parasite Plasmodium knowlesi, we have identified a 786-bp DNA sequence that encodes a 262-amino-acid-long protein, containing an altered version of the thrombospondin type I repeat domain (SPATR). Thrombospondin type 1 repeat domains participate in biologically diverse functions, such as cell attachment, mobility, proliferation, and extracellular protease activities. The SPATR from P. knowlesi (PkSPATR) shares 61% and 58% sequence identity with its Plasmodium falciparum and Plasmodium yoelii orthologs, respectively. By immunofluorescence analysis, we determined that PkSPATR is a multistage antigen that is expressed on the surface of P. knowlesi sporozoite and erythrocytic stage parasites. Recombinant PkSPATR produced in Escherichia coli binds to a human hepatoma cell line, HepG2, suggesting that PkSPATR is a parasite ligand that could be involved in sporozoite invasion of liver cells. Furthermore, recombinant PkSPATR reacted with pooled sera from P. knowlesi-infected rhesus monkeys, indicating that native PkSPATR is immunogenic during infection. Further efficacy evaluation studies in the P. knowlesi-rhesus monkey sporozoite challenge model will help to decide whether the SPATR molecule should be developed as a vaccine against human malarias.An effective vaccine that reduces malaria-related mortality and morbidity would indeed alleviate the suffering of millions of people around the world (17). The onset and progression of malaria infection require a complex sequence of recognition, adhesion, and invasion events between the parasite and host cells. To accomplish this, the parasite expresses a multitude of proteins on its surface that serve as ligands that interact with the receptors present on the host cells. For example, circumsporozoite protein and thrombospondin-related anonymous protein (two sporozoite-stage proteins) participate in the binding of malaria sporozoites to liver cells (6, 30). In the erythrocytic-stage cycle, erythrocyte-binding antigen 175 is recognized as a merozoite ligand that binds to glycophorin A on erythrocytes to initiate the process of merozoite invasion (33). Likewise, the products of the var genes expressed on the surface of infected erythrocytes facilitate the adherence of mature forms of parasites to deep venules of endothelial cells and thus shield them from clearance by the host immune system.The standard steps in preclinical vaccine development prior to phase I clinical trials in humans are antigen identification, its biochemical/biological characterization, and efficacy evaluation in animal models. For malaria, animal studies are generally performed using pertinent orthologs of Plasmodium falciparum (the most lethal form of human malaria) in the mouse (Plasmodium yoelii/Plasmodium berghei) and monkey (Plasmodium knowlesi) mo...

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Section: Discussionmentioning

confidence: 99%

Identification, Cloning, Expression, and Characterization of the Gene for Plasmodium knowlesi Surface Protein Containing an Altered Thrombospondin Repeat Domain

et al. 2005

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“…Immunoelectron Microscopy-Immunoelectron microscopy was carried out on sporozoites isolated from infected mosquito salivary glands and in vitro cultured blood stages of P. falciparum (Clone 3D7) using 1:40 anti-PfSPATR antiserum as described (21). Pre-immune sera were used as control.…”

Section: Methodsmentioning

confidence: 99%

PfSPATR, a Plasmodium falciparum Protein Containing an Altered Thrombospondin Type I Repeat Domain Is Expressed at Several Stages of the Parasite Life Cycle and Is the Target of Inhibitory Antibodies

Chattopadhyay¹,

Rathore

Fujioka

et al. 2003

Journal of Biological Chemistry

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The annotated sequence of chromosome 2 of Plasmodium falciparum was examined for genes encoding proteins that may be of interest for vaccine development. We describe here the characterization of a protein with an altered thrombospondin Type I repeat domain (PfSPATR) that is expressed in the sporozoite, asexual, and sexual erythrocytic stages of the parasite life cycle. Immunoelectron microscopy indicated that this protein was expressed on the surface of the sporozoites and around the rhoptries in the asexual erythrocytic stage. An Escherichia coli-produced recombinant form of the protein bound to HepG2 cells in a dose-dependent manner and antibodies raised against this protein blocked the invasion of sporozoites into a transformed hepatoma cell line. Sera from Ghanaian adults and from a volunteer who had been immunized with radiation-attenuated P. falciparum sporozoites specifically recognized the expression of this protein on transfected COS-7 cells. These data support the evaluation of this protein as a vaccine candidate.

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“…Immunoelectron microscopy was carried out on in vitro cultured blood stage schizonts of P. falciparum and sporozoites isolated from infected mosquito salivary glands using 1:40 anti-PfCEN2 antibody by using a procedure described earlier (30).…”

Section: Immunoelectron Microscopymentioning

confidence: 99%

Centrins, Cell Cycle Regulation Proteins in Human Malaria Parasite Plasmodium falciparum

Mahajan

Selvapandiyan

Gerald

et al. 2008

Journal of Biological Chemistry

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Molecules and cellular mechanisms that regulate the process of cell division in malaria parasites remain poorly understood. In this study we isolate and characterize the four Plasmodium falciparum centrins (PfCENs) and, by growth complementation studies, provide evidence for their involvement in cell division. Centrins are cytoskeleton proteins with key roles in cell division, including centrosome duplication, and possess four Ca 2؉ -binding EF hand domains. By means of phylogenetic analysis, we were able to decipher the evolutionary history of centrins in eukaryotes with particular emphasis on the situation in apicomplexans and other alveolates. Plasmodium possesses orthologs of four distinct centrin paralogs traceable to the ancestral alveolate, including two that are unique to alveolates. By real time PCR and/or immunofluorescence, we determined the expression of PfCEN mRNA or protein in sporozoites, asexual blood forms, gametocytes, and in the oocysts developing inside mosquito mid-gut. Immunoelectron microscopy studies showed that centrin is expressed in close proximity with the nucleus of sporozoites and asexual schizonts. Furthermore, confocal and widefield microscopy using the double staining with ␣-tubulin and centrin antibodies strongly suggested that centrin is associated with the parasite centrosome. Following the episomal expression of the four PfCENs in a centrin knock-out Leishmania donovani parasite line that exhibited a severe growth defect, one of the PfCENs was able to partially restore Leishmania growth rate and overcome the defect in cytokinesis in such mutant cell line. To our knowledge, this study is the first characterization of a Plasmodium molecule that is involved in the process of cell division. These results provide the opportunity to further explore the role of centrins in cell division in malaria parasites and suggest novel targets to construct genetically modified, live attenuated malaria vaccines.

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Stage-dependent Localization of a Novel Gene Product of the Malaria Parasite, Plasmodium falciparum

Cited by 24 publications

References 39 publications

Identification, Cloning, Expression, and Characterization of the Gene for Plasmodium knowlesi Surface Protein Containing an Altered Thrombospondin Repeat Domain

Identification, Cloning, Expression, and Characterization of the Gene for Plasmodium knowlesi Surface Protein Containing an Altered Thrombospondin Repeat Domain

PfSPATR, a Plasmodium falciparum Protein Containing an Altered Thrombospondin Type I Repeat Domain Is Expressed at Several Stages of the Parasite Life Cycle and Is the Target of Inhibitory Antibodies

Centrins, Cell Cycle Regulation Proteins in Human Malaria Parasite Plasmodium falciparum

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