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. (Blood. 2011; 118(7): [1923][1924][1925][1926][1927][1928][1929][1930][1931][1932][1933] IntroductionThe complement system is a first line of defense against invasion by infectious agents. On pathogen entry into the host and detection of a pathogen-associated or danger-associated molecular pattern, the complement cascade is activated in seconds and results in the production of anaphylatoxins, deposition of opsonic C3 and C4 fragments, and assembly of the potentially cytolytic membrane attack complex. By ensuring that the complement system acts in a directed manner, the regulators of complement activation (RCA) protein family protect self-tissue from complement-mediated attack. 1 Interestingly, RCA family members also contribute to cell attachment or invasion strategies of disparate pathogens, including multiple viruses and bacteria. [2][3][4][5][6] Recently, complement receptor type-1 (CR1), an erythroid membrane-bound RCA protein, was shown to be a receptor used by the malaria parasite Plasmodium falciparum for invasion of human erythrocytes. 7,8 Invasion of human erythrocytes by malaria parasites depends on specific interactions between parasite adhesins and host receptors. In P falciparum, 2 gene families encode important parasite proteins that engage with erythrocyte receptors: the erythrocyte binding-like antigens (PfEBAs; these include EBA-140/BAEBL, EBA-175, EBA-181/JESEBL, and EBL-1); and reticulocyte binding-like homolog proteins (RBPs or PfRhs; these include PfRh1, PfRh2a, PfRh2b, PfRh4 and PfRh5). 9-12 During invasion these adhesins localize to the apical tip of the merozoite and interact with specific host receptors to initiate parasite entry. Invasion pat...

Recruitment of Factor H as a Novel Complement Evasion Strategy for Blood-Stage Plasmodium falciparum Infection

“…P. falciparum uses CR1 as an entry receptor into RBCs through binding to a parasite adhesin called PfRh4 (51,52). It has been suggested that merozoites may play a dangerous game of allowing C3 fragment deposition to occur to more readily allow PfRh4 engagement with the CR1 molecules dispersed across the RBC surface (52).…”

“…P. falciparum uses CR1 as an entry receptor into RBCs through binding to a parasite adhesin called PfRh4 (51,52). It has been suggested that merozoites may play a dangerous game of allowing C3 fragment deposition to occur to more readily allow PfRh4 engagement with the CR1 molecules dispersed across the RBC surface (52). Although iC3b cannot participate in the generation of MAC, it is still a ligand for CR1 (5), and the aforementioned ability of merozoite-recruited FH and FHL-1to convert C3b to iC3b would remove some of the danger associated with such an approach.…”

ThePlasmodium falciparumblood stages acquire factor H family proteins to evade destruction by human complement

“…The binding site of Rh4 was mapped to CCP1 of CR‐1, and this region is known to be involved in binding C3b and C4b to accelerate decay of the C3 and C5 convertases (Park et al , 2014). In consequence, Rh4 binding specifically inhibits the convertase decay‐accelerating activity of CR‐1 (Tham et al , 2011). …”

Deciphering Complement Receptor Type 1 Interactions with Recognition Proteins of the Lectin Complement Pathway

“…However, contradictory results have been obtained regarding their association with malarial severity in different African populations (52)(53)(54)(55). CR1 interacts with two P. falciparum proteins, the malarial adhesin PfEMP1 (14) and the PfRh4 invasion ligand (15), but the binding sites have been located to the C3b and C4b binding sites of CR1, respectively (20,21). Consistent with these locations, Tetteh-Quarcoo et al (56) observed no difference between the Knops blood group variants McC a/b and Sl1/2 in the ability of the CR1 fragment CCP15-25 to interact with PfRh4 or to disrupt PfEMP1-dependent P. falciparum rosetting (56).…”

“…LHR-A contains the major C4b binding site located in CCPs 1-3, also involved in PfRh4 binding, whereas LHR-B and LHR-C contain homologous C4b/C3b binding sites in CCPs 8-10 and 15-17, which are also candidates for interaction with PfEMP1 (19)(20)(21). C1q and MBL have been proposed to bind LHR-D, but the localization of their interaction sites to particular CCP modules has not been described so far (12,13).…”