title: Plasmodium falciparum uses a key functional site in complement receptor type-1 for invasion of human erythrocytes.
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.
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
authors.forename: Wai-Hong
authors.initials: WH
authors.lastname: Tham
authors.forename: Christoph Q
authors.initials: CQ
authors.lastname: Schmidt
authors.forename: Richard E
authors.initials: RE
authors.lastname: Hauhart
authors.forename: Mara
authors.initials: M
authors.lastname: Guariento
authors.forename: Patience B
authors.initials: PB
authors.lastname: Tetteh-Quarcoo
authors.forename: Sash
authors.initials: S
authors.lastname: Lopaticki
authors.forename: John P
authors.initials: JP
authors.lastname: Atkinson
authors.forename: Paul N
authors.initials: PN
authors.lastname: Barlow
authors.forename: Alan F
authors.initials: AF
authors.lastname: Cowman
mesh_terms: D004912:Erythrocytes / Q000469:parasitology*; D006790:Host-Parasite Interactions; D006801:Humans; D016778:Malaria, Falciparum / Q000469:parasitology*; D008565:Membrane Proteins / Q000378:metabolism*; D010963:Plasmodium falciparum / Q000502:physiology*; D011485:Protein Binding; D015800:Protozoan Proteins / Q000378:metabolism*; D011951:Receptors, Complement / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D015800:Protozoan Proteins; C464927:RH4 protein, Plasmodium falciparum; D011951:Receptors, Complement; D011994:Recombinant Proteins