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

Melissa N. Hart, Franziska Mohring, Sophia M. DonVito, James A. Thomas, Nicole Muller-Sienerth, Gavin J. Wright, Ellen Knuepfer, Helen R. Saibil and Robert W. Moon ()
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Melissa N. Hart: Faculty of Infectious and Tropical Disease, London School of Hygiene and Tropical Medicine
Franziska Mohring: Faculty of Infectious and Tropical Disease, London School of Hygiene and Tropical Medicine
Sophia M. DonVito: Faculty of Infectious and Tropical Disease, London School of Hygiene and Tropical Medicine
James A. Thomas: Faculty of Infectious and Tropical Disease, London School of Hygiene and Tropical Medicine
Nicole Muller-Sienerth: Wellcome Sanger Institute
Gavin J. Wright: Wellcome Sanger Institute
Ellen Knuepfer: Royal Veterinary College
Helen R. Saibil: ISMB, Biological Sciences, Birkbeck, University of London
Robert W. Moon: Faculty of Infectious and Tropical Disease, London School of Hygiene and Tropical Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: 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. One DBP (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.

Date: 2023
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DOI: 10.1038/s41467-023-40357-z

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