Sequential roles for red blood cell binding proteins enable phased commitment to invasion for malaria parasites

Hart, Melissa N.; Mohring, Franziska; DonVito, Sophia M.; Thomas, James A.; Muller-Sienerth, Nicole; Wright, Gavin J.; Knuepfer, Ellen; Saibil, Helen R.; Moon, Robert W.

Abstract

Invasion of red blood cells (RBCs) by Plasmodium merozoites is critical to their continued survival within the host. Two major protein families, the Duffy binding-like proteins (DBPs/EBAs) and the reticulocyte binding like proteins (RBLs/RHs) have been studied extensively in P. falciparum and are hypothesized to have overlapping, but critical roles just prior to host cell entry. The zoonotic malaria parasite, P. knowlesi, has larger invasive merozoites and contains a smaller, less redundant, DBP and RBL repertoire than P. falciparum.OneDBP (DBPα) and one RBL, normocyte binding protein Xa (NBPXa) are essential for invasion of human RBCs. Taking advantage of the unique biological features of P. knowlesi and iterative CRISPR-Cas9 genome editing, we determine the precise order of key invasion milestones and demonstrate distinct roles for each family. These distinct roles support a mechanism for phased commitment to invasion and can be targeted synergistically with invasion inhibitory antibodies.

Citation

Hart, M. N., Mohring, F., DonVito, S. M., Thomas, J. A., Muller-Sienerth, N., Wright, G. J., …Moon, R. W. (in press). Sequential roles for red blood cell binding proteins enable phased commitment to invasion for malaria parasites. Nature Communications, 14(1), 4619. https://doi.org/10.1038/s41467-023-40357-z

• Journal Article Type: Article
• Acceptance Date: Jul 20, 2023
• Online Publication Date: Aug 1, 2023
• Deposit Date: Sep 5, 2023
• Publicly Available Date: Sep 6, 2023
• Journal: Nature Communications
• Electronic ISSN: 2041-1723
• Publisher: Nature Research
• Peer Reviewed: Peer Reviewed
• Volume: 14
• Issue: 1
• Pages: 4619
• DOI: https://doi.org/10.1038/s41467-023-40357-z
• Keywords: Malaria; host pathogen interaction; Red blood cells; Genetics and Molecular Biology; vaccine target; Multidisciplinary