Browsing by Author "The Walter and Eliza Hall Institute for Medical Research"

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    Antibodies against a Plasmodium falciparum antigen PfMSPDBL1 inhibit merozoite invasion into human erythrocytes
    (2012-03-02) Hirokazu Sakamoto; Satoru Takeo; Alexander G. Maier; Jetsumon Sattabongkot; Alan F. Cowman; Takafumi Tsuboi; Ehime University; The Walter and Eliza Hall Institute for Medical Research; Armed Forces Research Institute of Medical Sciences, Thailand; La Trobe University; Mahidol University
    One approach to develop a malaria blood-stage vaccine is to target proteins that play critical roles in the erythrocyte invasion of merozoites. The merozoite surface proteins (MSPs) and the erythrocyte-binding antigens (EBAs) are considered promising vaccine candidates, for they are known to play important roles in erythrocyte invasion and are exposed to host immune system. Here we focused on a Plasmodium falciparum antigen, PfMSPDBL1 (encoded by PF10_0348 gene) that is a member of the MSP3 family and has both Duffy binding-like (DBL) domain and secreted polymorphic antigen associated with merozoites (SPAM) domain. Therefore, we aimed to characterize PfMSPDBL1 as a vaccine candidate. Recombinant full-length protein (rFL) of PfMSPDBL1 was synthesized by a wheat germ cell-free system, and rabbit antiserum was raised against rFL. We show that rabbit anti-PfMSPDBL1 antibodies inhibited erythrocyte invasion of wild type parasites in vitro in a dose dependent manner, and the specificity of inhibitory activity was confirmed using PfMSPDBL1 knockout parasites. Pre-incubation of the anti-PfMSPDBL1 antibodies with the recombinant SPAM domain had no effect on the inhibitory activity suggesting that antibodies to this region were not involved. In addition, antibodies to rFL were elicited by P. falciparum infection in malaria endemic area, suggesting the PfMSLDBL1 is immunogenic to humans. Our results suggest that PfMSPDBL1 is a novel blood-stage malaria vaccine candidate. © 2012 Elsevier Ltd.
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    Discovery of GAMA, a plasmodium falciparum merozoite micronemal protein, as a novel blood-stage vaccine candidate antigen
    (2011-11-01) Thangavelu U. Arumugam; Satoru Takeo; Tsutomu Yamasaki; Amporn Thonkukiatkul; Kazutoyo Miura; Hitoshi Otsuki; Hong Zhou; Carole A. Long; Jetsumon Sattabongkot; Jennifer Thompson; Danny W. Wilson; James G. Beeson; Julie Healer; Brendan S. Crabb; Alan F. Cowman; Motomi Torii; Takafumi Tsuboi; Ehime University; Burapha University; National Institute of Allergy and Infectious Diseases; Tottori University; Armed Forces Research Institute of Medical Sciences, Thailand; The Walter and Eliza Hall Institute for Medical Research; Burnet Institute; Mahidol University
    One of the solutions for reducing the global mortality and morbidity due to malaria is multivalent vaccines comprising antigens of several life cycle stages of the malarial parasite. Hence, there is a need for supplementing the current set of malaria vaccine candidate antigens. Here, we aimed to characterize glycosylphosphatidylinositol (GPI)-anchored micronemal antigen (GAMA) encoded by the PF08_0008 gene in Plasmodium falciparum. Antibodies were raised against recombinant GAMA synthesized by using a wheat germ cell-free system. Immunoelectron microscopy demonstrated for the first time that GAMA is a microneme protein of the merozoite. Erythrocyte binding assays revealed that GAMA possesses an erythrocyte binding epitope in the C-terminal region and it binds a nonsialylated protein receptor on human erythrocytes. Growth inhibition assays revealed that anti-GAMA antibodies can inhibit P. falciparum invasion in a dose-dependent manner and GAMA pl ays a role in the sialic acid (SA)-independent invasion pathway. Anti-GAMA antibodies in combination with anti-erythrocyte binding antigen 175 exhibited a significantly higher level of invasion inhibition, supporting the rationale that targeting of both SA-dependent and SA-independent ligands/pathways is better than targeting either of them alone. Human sera collected from areas of malaria endemicity in Mali and Thailand recognized GAMA. Since GAMA in P. falciparum is refractory to gene knockout attempts, it is essential to parasite invasion. Overall, our study indicates that GAMA is a novel blood-stage vaccine candidate antigen. © 2011, American Society for Microbiology.