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      Plasmodium vivax GPI-anchored micronemal antigen (PvGAMA) binds human erythrocytes independent of Duffy antigen status

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          Abstract

          Plasmodium vivax, a major agent of malaria in both temperate and tropical climates, has been thought to be unable to infect humans lacking the Duffy (Fy) blood group antigen because this receptor is critical for erythrocyte invasion. Recent surveys in various endemic regions, however, have reported P. vivax infections in Duffy-negative individuals, suggesting that the parasite may utilize alternative receptor-ligand pairs to complete the erythrocyte invasion. Here, we identified and characterized a novel parasite ligand, Plasmodium vivax GPI-anchored micronemal antigen (PvGAMA), that bound human erythrocytes regardless of Duffy antigen status. PvGAMA was localized at the microneme in the mature schizont-stage parasites. The antibodies against PvGAMA fragments inhibited PvGAMA binding to erythrocytes in a dose-dependent manner. The erythrocyte-specific binding activities of PvGAMA were significantly reduced by chymotrypsin treatment. Thus, PvGAMA may be an adhesion molecule for the invasion of Duffy-positive and -negative human erythrocytes.

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          Most cited references 36

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          Comparative genomics of the neglected human malaria parasite Plasmodium vivax.

          The human malaria parasite Plasmodium vivax is responsible for 25-40% of the approximately 515 million annual cases of malaria worldwide. Although seldom fatal, the parasite elicits severe and incapacitating clinical symptoms and often causes relapses months after a primary infection has cleared. Despite its importance as a major human pathogen, P. vivax is little studied because it cannot be propagated continuously in the laboratory except in non-human primates. We sequenced the genome of P. vivax to shed light on its distinctive biological features, and as a means to drive development of new drugs and vaccines. Here we describe the synteny and isochore structure of P. vivax chromosomes, and show that the parasite resembles other malaria parasites in gene content and metabolic potential, but possesses novel gene families and potential alternative invasion pathways not recognized previously. Completion of the P. vivax genome provides the scientific community with a valuable resource that can be used to advance investigation into this neglected species.
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            A receptor for the malarial parasite Plasmodium vivax: the erythrocyte chemokine receptor.

            Plasmodium vivax and P. falciparum are the major causes of human malaria, except in sub-Saharan Africa where people lack the Duffy blood group antigen, the erythrocyte receptor for P. vivax. Duffy negative human erythrocytes are resistant to invasion by P. vivax and the related monkey malaria, P. knowlesi. Several lines of evidence in the present study indicate that the Duffy blood group antigen is the erythrocyte receptor for the chemokines interleukin-8 (IL-8) and melanoma growth stimulatory activity (MGSA). First, IL-8 binds minimally to Duffy negative erythrocytes. Second, a monoclonal antibody to the Duffy blood group antigen blocked binding of IL-8 and other chemokines to Duffy positive erythrocytes. Third, both MGSA and IL-8 blocked the binding of the parasite ligand and the invasion of human erythrocytes by P. knowlesi, suggesting the possibility of receptor blockade for anti-malarial therapy.
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              Identification and prioritization of merozoite antigens as targets of protective human immunity to Plasmodium falciparum malaria for vaccine and biomarker development.

              The development of effective malaria vaccines and immune biomarkers of malaria is a high priority for malaria control and elimination. Ags expressed by merozoites of Plasmodium falciparum are likely to be important targets of human immunity and are promising vaccine candidates, but very few Ags have been studied. We developed an approach to assess Ab responses to a comprehensive repertoire of merozoite proteins and investigate whether they are targets of protective Abs. We expressed 91 recombinant proteins, located on the merozoite surface or within invasion organelles, and screened them for quality and reactivity to human Abs. Subsequently, Abs to 46 proteins were studied in a longitudinal cohort of 206 Papua New Guinean children to define Ab acquisition and associations with protective immunity. Ab responses were higher among older children and those with active parasitemia. High-level Ab responses to rhoptry and microneme proteins that function in erythrocyte invasion were identified as being most strongly associated with protective immunity compared with other Ags. Additionally, Abs to new or understudied Ags were more strongly associated with protection than were Abs to current vaccine candidates that have progressed to phase 1 or 2 vaccine trials. Combinations of Ab responses were identified that were more strongly associated with protective immunity than responses to their single-Ag components. This study identifies Ags that are likely to be key targets of protective human immunity and facilitates the prioritization of Ags for further evaluation as vaccine candidates and/or for use as biomarkers of immunity in malaria surveillance and control.
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                Author and article information

                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group
                2045-2322
                19 October 2016
                2016
                : 6
                Affiliations
                [1 ]Department of Medical Environmental Biology and Tropical Medicine, School of Medicine, Kangwon National University , Chuncheon, Gangwon-do 200-701, Republic of Korea
                [2 ]Department of Parasitology, Wuxi Medical School, Jiangnan University , Wuxi, Jiangsu 214122, China
                [3 ]Laboratory of Malaria and Vector Research (LMVR), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) , Rockville, MD 20852, USA
                [4 ]Jiangsu Institute of Parasitic Diseases , Wuxi, Jiangsu, People’s China
                [5 ]Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University , Hefei, Anhui, China
                [6 ]Department of Parasitology, College of Basic Medicine, Hubei University of Medicine , Shiyan, Hubei, China
                [7 ]Division of Malaria Research, Proteo-Science Center, Ehime University , Matsuyama, Ehime 790-8577, Japan
                [8 ]Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University , Chuncheon, Gangwon-do 200-701, Republic of Korea
                [9 ]Key Laboratory of Molecular Virology and Immunology, Unit of Human Parasite Molecular and Cell Biology, Institut Pasteur of Shanghai , Shanghai 200031, China
                [10 ]Mahidol Vivax Research Unit, Faculty of Tropical Medicine, Mahidol University , Bangkok 10400, Thailand
                [11 ]Department of Medical Research , Yangon, Myanmar
                Author notes
                Article
                srep35581
                10.1038/srep35581
                5069673
                27759110
                Copyright © 2016, The Author(s)

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

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