PCRCR complex is essential for invasion of human erythrocytes by Plasmodium falciparum

Scally, SW; Triglia, T; Evelyn, C; Seager, BA; Pasternak, M; Lim, PS; Healer, J; Geoghegan, ND; Adair, A; Tham, WH; Dagley, LF; Rogers, KL; Cowman, AF

Author(s): Scally, SW; Triglia, T; Evelyn, C; Seager, BA; Pasternak, M; Lim, PS; Healer, J; Geoghegan, ND; Adair, A; Tham, WH; Dagley, LF; Rogers, KL; Cowman, AF;
Details: Publication Year 2022-11-17,Volume 7,Issue #12,Page 2039-2053
Journal Title: Nature Microbiology
Abstract: The most severe form of malaria is caused by Plasmodium falciparum. These parasites invade human erythrocytes, and an essential step in this process involves the ligand PfRh5, which forms a complex with cysteine-rich protective antigen (CyRPA) and PfRh5-interacting protein (PfRipr) (RCR complex) and binds basigin on the host cell. We identified a heteromeric disulfide-linked complex consisting of P. falciparum Plasmodium thrombospondin-related apical merozoite protein (PfPTRAMP) and P. falciparum cysteine-rich small secreted protein (PfCSS) and have shown that it binds RCR to form a pentameric complex, PCRCR. Using P. falciparum lines with conditional knockouts, invasion inhibitory nanobodies to both PfPTRAMP and PfCSS, and lattice light-sheet microscopy, we show that they are essential for merozoite invasion. The PCRCR complex functions to anchor the contact between merozoite and erythrocyte membranes brought together by strong parasite deformations. We solved the structure of nanobody-PfCSS complexes to identify an inhibitory epitope. Our results define the function of the PCRCR complex and identify invasion neutralizing epitopes providing a roadmap for structure-guided development of these proteins for a blood stage malaria vaccine.
Publisher: NPG
Keywords: Humans; Plasmodium falciparum/genetics; Cysteine; Erythrocytes; Malaria, Falciparum; Malaria Vaccines; Blood Group Antigens; Epitopes
Research Division(s): Infectious Diseases And Immune Defence; Advanced Technology And Biology
PubMed ID: 36396942
Publisher's Version: https://doi.org/10.1038/s41564-022-01261-2
Open Access at Publisher's Site: https://doi.org/10.1038/s41564-022-01261-2
Terms of Use/Rights Notice: Refer to copyright notice on published article.
Documents: Scally SW et al_Nature Microbiology_2022.pdf - (9.72MB, application/pdf)

Creation Date: 2022-12-13 03:13:00

Last Modified: 2022-12-14 01:06:38