Erythrocyte invasion-neutralising antibodies prevent Plasmodium falciparum RH5 from binding to basigin-containing membrane protein complexes

• Published in: eLife Vol. 12
• Main Authors: Jamwal, Abhishek, Constantin, Cristina F, Hirschi, Stephan, Henrich, Sebastian, Bildl, Wolfgang, Fakler, Bernd, Draper, Simon J, Schulte, Uwe, Higgins, Matthew K
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 05.10.2023; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: Adenosine triphosphatase; Antibodies; Antibodies, Neutralizing; Antigens, Protozoan; Basigin; Ca2+-transporting ATPase; CD147 antigen; Cholesterol; Chromatography; Erythrocytes; Erythrocytes - parasitology; Ethylenediaminetetraacetic acid; Homeostasis; Humans; International economic relations; Macromolecules; Malaria; Malaria vaccine; Malaria, Falciparum - parasitology; MCT1; Membrane proteins; Membranes; Microbiology and Infectious Disease; Molecular weight; monoclonal antibody; Parasites; Parasitic diseases; PfRH5; Physiological aspects; Plasma; Plasmodium falciparum; Plasmodium falciparum - physiology; PMCA; Prevention; Protein Binding; Proteins; Protozoan Proteins - metabolism; Scientific equipment and supplies industry; Vaccines; Viral antibodies; United States; infectious disease; P. falciparum; MCT1; microbiology; basigin; malaria; monoclonal antibody; PMCA; PfRH5
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.83681

Basigin is an essential host receptor for invasion of into human erythrocytes, interacting with parasite surface protein PfRH5. PfRH5 is a leading blood-stage malaria vaccine candidate and a target of growth-inhibitory antibodies. Here, we show that erythrocyte basigin is exclusively found in one of two macromolecular complexes, bound either to plasma membrane Ca -ATPase 1/4 (PMCA1/4) or to monocarboxylate transporter 1 (MCT1). PfRH5 binds to each of these complexes with a higher affinity than to isolated basigin ectodomain, making it likely that these are the physiological targets of PfRH5. PMCA-mediated Ca export is not affected by PfRH5, making it unlikely that this is the mechanism underlying changes in calcium flux at the interface between an erythrocyte and the invading parasite. However, our studies rationalise the function of the most effective growth-inhibitory antibodies targeting PfRH5. While these antibodies do not reduce the binding of PfRH5 to monomeric basigin, they do reduce its binding to basigin-PMCA and basigin-MCT complexes. This indicates that the most effective PfRH5-targeting antibodies inhibit growth by sterically blocking the essential interaction of PfRH5 with basigin in its physiological context.