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Title: The Plasmodium falciparum Erythrocyte Invasion Ligand Pfrh4 as a Target of Functional and Protective Human Antibodies against Malaria
Authors: Linda Reiling
Jack S. Richards
Freya J.I. Fowkes
Danny W. Wilson
Watcharee Chokejindachai
Alyssa E. Barry
Wai Hong Tham
Janine Stubbs
Christine Langer
John Donelson
Pascal Michon
Livingstone Tavul
Brendan S. Crabb
Peter M. Siba
Alan F. Cowman
Ivo Mueller
James G. Beeson
Burnet Institute
Walter and Eliza Hall Institute of Medical Research
Mahidol University
University of Melbourne
University of Iowa
Papua New Guinea Institute of Medical Research
Barcelona Center for International Health Research
Keywords: Agricultural and Biological Sciences;Biochemistry, Genetics and Molecular Biology
Issue Date: 20-Sep-2012
Citation: PLoS ONE. Vol.7, No.9 (2012)
Abstract: Background: Acquired antibodies are important in human immunity to malaria, but key targets remain largely unknown. Plasmodium falciparum reticulocyte-binding-homologue-4 (PfRh4) is important for invasion of human erythrocytes and may therefore be a target of protective immunity. Methods: IgG and IgG subclass-specific responses against different regions of PfRh4 were determined in a longitudinal cohort of 206 children in Papua New Guinea (PNG). Human PfRh4 antibodies were tested for functional invasion-inhibitory activity, and expression of PfRh4 by P. falciparum isolates and sequence polymorphisms were determined. Results: Antibodies to PfRh4 were acquired by children exposed to P. falciparum malaria, were predominantly comprised of IgG1 and IgG3 subclasses, and were associated with increasing age and active parasitemia. High levels of antibodies, particularly IgG3, were strongly predictive of protection against clinical malaria and high-density parasitemia. Human affinity-purified antibodies to the binding region of PfRh4 effectively inhibited erythrocyte invasion by P. falciparum merozoites and antibody levels in protected children were at functionally-active concentrations. Although expression of PfRh4 can vary, PfRh4 protein was expressed by most isolates derived from the cohort and showed limited sequence polymorphism. Conclusions: Evidence suggests that PfRh4 is a target of antibodies that contribute to protective immunity to malaria by inhibiting erythrocyte invasion and preventing high density parasitemia. These findings advance our understanding of the targets and mechanisms of human immunity and evaluating the potential of PfRh4 as a component of candidate malaria vaccines. © 2012 Reiling et al.
ISSN: 19326203
Appears in Collections:Scopus 2011-2015

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