Neutralization of Plasmodium falciparum merozoites by antibodies against PfRH5
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Alexander D Douglas Andrew R Williams Ellen Knuepfer Joseph J Illingworth Julie M Furze Cécile Crosnier Prateek Choudhary Leyla Y Bustamante Sara E Zakutansky Dennis K Awuah Daniel GW Alanine Michel Theron Andrew Worth Richard Shimkets Julian C Rayner Anthony Holder Gavin J Wright Simon J DraperAbstract
There is intense interest in induction and characterization of strain-transcending neutralizing Ab against antigenically variable human pathogens. We have recently identified the human malaria parasite Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) as a target of broadly neutralizing Abs, but there is little information regarding the functional mechanism(s) of Ab-mediated neutralization. In this study, we report that vaccine-induced polyclonal anti-PfRH5 Abs inhibit the tight attachment of merozoites to erythrocytes and are capable of blocking the interaction of PfRH5 with its receptor basigin. Furthermore, by developing anti-PfRH5 mAbs, we provide evidence of the following: 1) the ability to block the PfRH5–basigin interaction in vitro is predictive of functional activity, but absence of blockade does not predict absence of functional activity; 2) neutralizing mAbs bind spatially related epitopes on the folded protein, involving at least two defined regions of the PfRH5 primary sequence; 3) a brief exposure window of PfRH5 is likely to necessitate rapid binding of Ab to neutralize parasites; and 4) intact bivalent IgG contributes to but is not necessary for parasite neutralization. These data provide important insight into the mechanisms of broadly neutralizing anti-malaria Abs and further encourage anti-PfRH5–based malaria prevention efforts.
Journal details
Journal Journal of Immunology
Volume 192
Issue number 1
Pages 245-258
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Publisher website (DOI) 10.4049/jimmunol.1302045
Europe PubMed Central 24293631
Pubmed 24293631
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