Neutralization of Plasmodium falciparum merozoites by antibodies against PfRH5.

Abstract

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.

• Authors: 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 G W Alanine, Michel Theron, Andrew Worth, Richard Shimkets, Julian C Rayner, Anthony A Holder, Gavin J Wright, Simon J Draper
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 192 Issue 1 Pg. 245-58 (Jan 01 2014) ISSN: 1550-6606 [Electronic] United States
• PMID: 24293631 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Neutralizing
• Antibodies, Protozoan
• Carrier Proteins
• Epitopes
• Malaria Vaccines
• RH5 protein, Plasmodium falciparum

Topics

• Amino Acid Sequence
• Animals
• Antibodies, Monoclonal (chemistry, immunology, metabolism)
• Antibodies, Neutralizing (immunology, metabolism)
• Antibodies, Protozoan (immunology, metabolism)
• Carrier Proteins (immunology, metabolism)
• Epitope Mapping
• Epitopes (chemistry, immunology)
• Erythrocytes (immunology, parasitology)
• Humans
• Kinetics
• Malaria Vaccines (immunology)
• Malaria, Falciparum (immunology)
• Merozoites (immunology)
• Mice
• Neutralization Tests
• Plasmodium falciparum (growth & development, immunology)
• Protein Binding (immunology)
• Rabbits