Structure of the malaria vaccine candidate antigen CyRPA and its complex with a parasite invasion inhibitory antibody.

Paola Favuzza,Arne C Rufer,Elena Guffart,Ralf Thoma,Joerg Hoernschemeyer,Anita M Dreyer,Hugues Matile,Araceli Lamelas,Markus G Rudolph,Gerd Pluschke,Bernard Gsell,Marco Tamborrini,Bianca Scherer,Georg Schmid,Joerg Benz,Johannes Erny,Catherine Joseph

doi:10.7554/elife.20383

Paola Favuzza, Arne C Rufer + Show 15 more

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https://doi.org/10.7554/elife.20383

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Abstract

Invasion of erythrocytes by Plasmodial merozoites is a composite process involving the interplay of several proteins. Among them, the Plasmodium falciparum Cysteine-Rich Protective Antigen (PfCyRPA) is a crucial component of a ternary complex, including Reticulocyte binding-like Homologous protein 5 (PfRH5) and the RH5-interacting protein (PfRipr), essential for erythrocyte invasion. Here, we present the crystal structures of PfCyRPA and its complex with the antigen-binding fragment of a parasite growth inhibitory antibody. PfCyRPA adopts a 6-bladed β-propeller structure with similarity to the classic sialidase fold, but it has no sialidase activity and fulfills a purely non-enzymatic function. Characterization of the epitope recognized by protective antibodies may facilitate design of peptidomimetics to focus vaccine responses on protective epitopes. Both in vitro and in vivo anti-PfCyRPA and anti-PfRH5 antibodies showed more potent parasite growth inhibitory activity in combination than on their own, supporting a combined delivery of PfCyRPA and PfRH5 in vaccines.

Highlights

According to the World Health Organization 2015 Malaria Report, malaria is estimated to have caused 214 million clinical cases and 438,000 deaths in 2015
All monoclonal antibodies (mAb) bound to the full-length Plasmodium falciparum Cysteine-Rich Protective Antigen (PfCyRPA). mAbs belonging to epitope group A exclusively bound this fragment, indicating that they recognize conformational epitopes not present in any of the shorter PfCyRPA sequence stretches
PfCyRPA has been identified as a novel malaria blood-stage vaccine target in an endeavor to test predicted P. falciparum open reading frames for the capacity to elicit parasite-inhibitory mAbs (Dreyer et al, 2010)

Summary

Introduction

According to the World Health Organization 2015 Malaria Report (who.int/malaria/publications/ world_malaria_report/en), malaria is estimated to have caused 214 million clinical cases and 438,000 deaths in 2015. The disease is transmitted by female Anopheles mosquitoes and caused by parasitic protozoans of the genus Plasmodium, of which P. falciparum and P. vivax are the most prevalent and P. falciparum is causing the most often fatal and medically most severe form of malaria. Debilitating clinical symptoms associated with the infection are caused by the multiplication of the asexual blood-stage parasites in erythrocytes. Invasion of host erythrocytes by merozoites is a complex process, conceptually divisible into four phases: (1) initial recognition of and reversible attachment to the erythrocyte membrane by the merozoite; (2) junction formation leading to irreversible attachment of the merozoite, parasitophorous vacuole formation, and release of the Plasmodium rhoptry-microneme secretory organelles; (3) invagination of the erythrocyte membrane around the merozoite, accompanied by the shedding of the merozoite’s surface coat; (4) closing of the parasitophorous vacuole and resealing of the erythrocyte membrane mark the completion of merozoite invasion (Pinder et al, 2000). The initial recognition and the active invasion of erythrocytes depend on specific molecular interactions between

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