Plasmodium falciparum uses a key functional site in complement receptor type-1 for invasion of human erythrocytes

Wai Hong Tham, Christoph Q. Schmidt, Richard E. Hauhart, Mara Guariento, Patience B. Tetteh-Quarcoo, Sash Lopaticki, John P. Atkinson, Paul N. Barlow, Alan F. Cowman

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36 Scopus citations

Abstract

The Plasmodium falciparum adhesin PfRh4 binds to complement receptor type-1 (CR1) on human erythrocytes and mediates a glycophorin-independent invasion pathway. CR1 is a complement regulator and immune-adherence receptor on erythrocytes required for shuttling of C3b/C4b-opsonized particles to liver and spleen for phagocytosis. Using recombinant CR1 constructs, we mapped the recognition site for PfRh4 to complement control protein modules 1 to 3 (CCP1-3) at the membrane-distal amino terminus of CR1. This region of CR1 binds to C4b and C3b and accelerates decay of both classic pathway and alternative pathway C3 and C5 convertases. CCP1-3 competed for PfRh4 binding to erythroid CR1 and inhibited the PfRh4-CR1 invasion pathways across a wide range of P falciparum strains. PfRh4 did not bind significantly to other CR1 constructs, including CCP15-17, which is 85% identical to CCP1-3. PfRh4 binding to CR1 did not affect its C3b/C4b binding capability, and we show evidence for a ternary complex between CCP1-3, C4b, and PfRh4. PfRh4 binding specifically inhibited CR1's convertase decay-accelerating activity, whereas there was no effect on factor H-mediated decay-accelerating activity. These results increase our understanding of the functional implications of CR1 engagement with PfRh4 and highlight the interplay between complement regulation and infection.

Original languageEnglish
Pages (from-to)1923-1933
Number of pages11
JournalBlood
Volume118
Issue number7
DOIs
StatePublished - Aug 18 2011

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    Tham, W. H., Schmidt, C. Q., Hauhart, R. E., Guariento, M., Tetteh-Quarcoo, P. B., Lopaticki, S., Atkinson, J. P., Barlow, P. N., & Cowman, A. F. (2011). Plasmodium falciparum uses a key functional site in complement receptor type-1 for invasion of human erythrocytes. Blood, 118(7), 1923-1933. https://doi.org/10.1182/blood-2011-03-341305