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    Plasmodium vivax Reticulocyte Binding Proteins Are Key Targets of Naturally Acquired Immunity in Young Papua New Guinean Children

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    Author
    Franca, CT; He, W-Q; Gruszczyk, J; Lim, NTY; Lin, E; Kiniboro, B; Siba, PM; Tham, W-H; Mueller, I
    Date
    2016-09-01
    Source Title
    PLoS Neglected Tropical Diseases
    Publisher
    PUBLIC LIBRARY SCIENCE
    University of Melbourne Author/s
    Tham, Wai-Hong; Mueller, Ivo; Tenorio Franca, Camila
    Affiliation
    Medical Biology (W.E.H.I.)
    Metadata
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    Document Type
    Journal Article
    Citations
    Franca, C. T., He, W. -Q., Gruszczyk, J., Lim, N. T. Y., Lin, E., Kiniboro, B., Siba, P. M., Tham, W. -H. & Mueller, I. (2016). Plasmodium vivax Reticulocyte Binding Proteins Are Key Targets of Naturally Acquired Immunity in Young Papua New Guinean Children. PLOS NEGLECTED TROPICAL DISEASES, 10 (9), https://doi.org/10.1371/journal.pntd.0005014.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/256715
    DOI
    10.1371/journal.pntd.0005014
    Abstract
    BACKGROUND: Major gaps in our understanding of Plasmodium vivax biology and the acquisition of immunity to this parasite hinder vaccine development. P. vivax merozoites exclusively invade reticulocytes, making parasite proteins that mediate reticulocyte binding and/or invasion potential key vaccine or drug targets. While protein interactions that mediate invasion are still poorly understood, the P. vivax Reticulocyte-Binding Protein family (PvRBP) is thought to be involved in P. vivax restricted host-cell selectivity. METHODOLOGY/PRINCIPAL FINDINGS: We assessed the binding specificity of five members of the PvRBP family (PvRBP1a, PvRBP1b, PvRBP2a, PvRBP2b, PvRBP2-P2 and a non-binding fragment of PvRBP2c) to normocytes or reticulocytes. PvRBP2b was identified as the only reticulocyte-specific binder (P<0.001), whereas the others preferentially bound to normocytes (PvRBP1a/b P≤0.034), or showed comparable binding to both (PvRBP2a/2-P2, P = 0.38). Furthermore, we measured levels of total and IgG subclasses 1, 2, 3 and 4 to the six PvRBPs in a cohort of young Papua New Guinean children, and assessed their relationship with prospective risk of P. vivax malaria. Children had substantial, highly correlated (rho = 0.49-0.82, P<0.001) antibody levels to all six PvRBPs, with dominant IgG1 and IgG3 subclasses. Both total IgG (Incidence Rate Ratio [IRR] 0.63-0.73, P = 0.008-0.041) and IgG1 (IRR 0.56-0.69, P = 0.001-0.035) to PvRBP2b and PvRBP1a were strongly associated with reduced risk of vivax-malaria, independently of age and exposure. CONCLUSION/SIGNIFICANCE: These results demonstrate a diversity of erythrocyte-binding phenotypes of PvRBPs, indicating binding to both reticulocyte-specific and normocyte-specific ligands. Our findings provide further insights into the naturally acquired immunity to P. vivax and highlight the importance of PvRBP proteins as targets of naturally acquired humoral immunity. In-depth studies of the role of PvRBPs in P. vivax invasion and functional validation of the role of anti-PvRBP antibodies in clinical immunity against P. vivax are now required to confirm the potential of the reticulocyte-binding PvRBP2b and PvRBP1a as vaccine candidate antigens.

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