A full-length recombinant Plasmodium falciparum PfRH5 protein induces inhibitory antibodies that are effective across common PfRH5 genetic variants

Bustamante, Leyla Y.; Bartholdson, S. Josefin; Crosnier, Cécile; Campos, Marta G.; Wanaguru, Madushi; Nguon, Chea; Kwiatkowski, Dominic P.; Wright, Gavin J.; Rayner, Julian C.

doi:10.1016/j.vaccine.2012.10.106

Cited by 124 publications

(182 citation statements)

References 30 publications

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“…The CyRPA gene could not be genetically knocked out, and its indispensible nature suggests that its interaction with PfRH5 and PfRipr is imperative for erythrocyte invasion. CyRPA-FL antibodies potently blocked erythrocyte invasion of multiple P. falciparum strains, which is a characteristic that has been shown previously only for PfRH5 antibodies (9)(10)(11)(12). Thus, like PfRH5, CyRPA poses to be a leading blood-stage vaccine candidate that elicits potent strain-transcending parasite-neutralizing antibodies.…”

Section: Discussionsupporting

confidence: 55%

“…We also demonstrated that the three proteins are colocalized on the apical surface of the invading merozoite, of which only CyRPA was shown to be GPI-linked. Importantly, antibodies against full-length CyRPA potently blocked erythrocyte invasion by multiple P. falciparum strains, as observed previously only for PfRH5 antibodies (9)(10)(11)(12). Because CyRPA does not bind with the erythrocyte surface, it…”

supporting

confidence: 72%

“…We have recently raised specific antibodies against full-length recombinant PfRH5 generated in Escherichia coli that exhibited potent invasion inhibition (12), similar to that observed with PfRH5 antibodies raised against either the adenoviral vector (9) or mammalian PfRH5-CD4 fusion protein (11). Using these specific antibodies we performed coimmunoprecipitation experiments in which the PfRH5 antibodies, in comparison with its preimmune control antibodies, pulled down PfRipr as well as another previously unidentified interacting partner, CyRPA (15).…”

Section: Discussionmentioning

confidence: 84%

“…Several groups further demonstrated that specific antibodies raised against recombinant forms of PfRH5 potently blocked erythrocyte invasion by multiple worldwide P. falciparum strains that were known to exhibit diverse invasion phenotypes (9)(10)(11)(12). This definitely was a great advancement, because previously such potent strain-transcending inhibition against multiple P. falciparum strains could not be demonstrated with leading essential blood-stage vaccine candidates (AMA-1, MSP-1).…”

Section: Discussionmentioning

confidence: 99%

“…The quest to develop successful blood-stage malaria vaccines that efficiently block this process have focused on essential parasite proteins like merozoite surface protein 1 (MSP-1) and apical membrane antigen 1 (AMA-1); however, these are highly polymorphic, unable to elicit strain-transcending neutralizing antibodies, and have thus failed in field trials (4). Among the large repertoire of invasionrelated proteins, the family of P. falciparum reticulocyte bindinglike homologous (PfRH) proteins have emerged as key determinants of different invasion pathways (2,3), of which PfRH5 is the only essential conserved parasite ligand (5)(6)(7)(8) that elicits potent strain-transcending neutralizing antibodies (9)(10)(11)(12). It is localized in the rhoptry and secreted to the merozoite surface during erythrocyte invasion (6).…”

mentioning

confidence: 99%

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Multiprotein complex between the GPI-anchored CyRPA with PfRH5 and PfRipr is crucial for Plasmodium falciparum erythrocyte invasion

Reddy

Amlabu

Pandey

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

146

206

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Erythrocyte invasion by Plasmodium falciparum merozoites is a highly intricate process in which Plasmodium falciparum reticulocyte binding-like homologous protein 5 (PfRH5) is an indispensable parasite ligand that binds with its erythrocyte receptor, Basigin. PfRH5 is a leading blood-stage vaccine candidate because it exhibits limited polymorphisms and elicits potent strain-transcending parasite neutralizing antibodies. However, the mechanism by which it is anchored to the merozoite surface remains unknown because both PfRH5 and the PfRH5-interacting protein (PfRipr) lack transmembrane domains and GPI anchors. Here we have identified a conserved GPI-linked parasite protein, Cysteine-rich protective antigen (CyRPA) as an interacting partner of PfRH5-PfRipr that tethers the PfRH5/ PfRipr/CyRPA multiprotein complex on the merozoite surface. CyRPA was demonstrated to be GPI-linked, localized in the micronemes, and essential for erythrocyte invasion. Specific antibodies against the three proteins successfully detected the intact complex in the parasite and coimmunoprecipitated the three interacting partners. Importantly, full-length CyRPA antibodies displayed potent straintranscending invasion inhibition, as observed for PfRH5. CyRPA does not bind with erythrocytes, suggesting that its parasite neutralizing antibodies likely block its critical interaction with PfRH5-PfRipr, leading to a blockade of erythrocyte invasion. Further, CyRPA and PfRH5 antibody combinations produced synergistic invasion inhibition, suggesting that simultaneous blockade of the PfRH5-Basigin and PfRH5/PfRipr/CyRPA interactions produced an enhanced inhibitory effect. Our discovery of the critical interactions between PfRH5, PfRipr, and the GPI-anchored CyRPA clearly defines the components of the essential PfRH5 adhesion complex for P. falciparum erythrocyte invasion and offers it as a previously unidentified potent target for antimalarial strategies that could abrogate formation of the crucial multiprotein complex. malaria | erythrocyte invasion | protein-protein interactions | blood-stage vaccines | PfRH5

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Section: Discussionsupporting

confidence: 55%

supporting

confidence: 72%