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DOI

  • Author: Tessema, Sofonias K

    University of Melbourne, Australia

  • Author: Utama, Digjaya

    University of Melbourne, Australia

  • Author: Chesnokov, Olga

    Florida Atlantic University, United States

  • Author: Hodder, Anthony N

    University of Melbourne, Australia

  • Author: Lin, Clara S

    University of Melbourne, Australia

  • Author: Harrison, G. L. Abby

    University of Melbourne, Australia

  • Author: Jespersen, Jakob S.

    University of Copenhagen, Denmark

  • Author: Petersen, Bent

    Center for Biological Sequence Analysis, Department of Systems Biology, Metagenomics, Department of Bio and Health Informatics, Technical University of Denmark, Kemitorvet, 2800, Kgs. Lyngby, Denmark

  • Author: Tavul, Livingstone

    Papua New Guinea Institute of Medical Research, Papua New Guinea

  • Author: Siba, Peter

    Papua New Guinea Institute of Medical Research, Papua New Guinea

  • Author: Kwiatkowski, Dominic

    University of Oxford, United Kingdom

  • Author: Lavstsen, Thomas

    University of Copenhagen, Denmark

  • Author: Hansen, Diana S

    University of Melbourne, Australia

  • Author: Oleinikov, Andrew V

    Florida Atlantic University, United States

  • Author: Mueller, Ivo

    Institut Pasteur Paris, France

  • Author: Barry, Alyssa E

    University of Melbourne, Australia

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Plasmodium falciparum Erythrocyte Membrane Protein 1 (PfEMP1) mediates parasite sequestration to the cerebral microvasculature via binding of DBLβ domains to Intercellular Adhesion Molecule 1 (ICAM1) and is associated with severe cerebral malaria. In a cohort of 187 young children from Papua New Guinea (PNG), we examined baseline antibody levels to the ICAM1-binding PfEMP1 domain, DBLβ3PF11_0521, in comparison to four control antigens including NTS-DBLα and CIDR1 domains from another group A variant and a group B/C variant. Antibody levels for the group A antigens were strongly associated with age and exposure. Antibody responses to DBLβ3PF11_0521 were associated with a 37% reduced risk of high-density clinical malaria in the follow up period (adjusted incidence risk ratio, aIRR = 0.63 [95% CI: 0.45-0.88; p = 0.007]) and a 25% reduction in risk of low-density clinical malaria (aIRR = 0.75 [95% CI: 0.55-1.01; p = 0.06]), whilst there was no such association for other variants. Children who experienced severe malaria also had significantly lower antibody levels to DBLβ3PF11_0521 and the other group A domains than other children. Furthermore, a subset of PNG DBLβ sequences had ICAM1-binding motifs, formed a distinct phylogenetic cluster and were similar to sequences from other endemic areas. PfEMP1 variants associated with these DBLβ were enriched for DC4 and DC13 head-structures implicated in EPCR-binding and severe malaria, suggesting conservation of dual binding specificity. These results provide further support for the development of specific classes of PfEMP1 as vaccine candidates, and as biomarkers for protective immunity against clinical P. falciparum malaria.
Original languageEnglish
Article numbere00485-17
JournalInfection and Immunity
Volume86
Issue number8
Number of pages14
ISSN0019-9567
DOIs
Publication statusPublished - 2018
CitationsWeb of Science® Times Cited: No match on DOI

    Research areas

  • DBLβ, EPCR, ICAM1, Papua New Guinea, PfEMP1, Antibodies, Diversity, Malaria, var genes

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