Complement Receptor 1 Is a Sialic Acid-Independent Erythrocyte Receptor of Plasmodium falciparum

Abstract

Plasmodium falciparum is a highly lethal malaria parasite of humans. A major portion of its life cycle is dedicated to invading and multiplying inside erythrocytes. The molecular mechanisms of erythrocyte invasion are incompletely understood. P. falciparum depends heavily on sialic acid present on glycophorins to invade erythrocytes. However, a significant proportion of laboratory and field isolates are also able to invade erythrocytes in a sialic acid-independent manner. The identity of the erythrocyte sialic acid-independent receptor has been a mystery for decades. We report here that the complement receptor 1 (CR1) is a sialic acid-independent receptor for the invasion of erythrocytes by P. falciparum. We show that soluble CR1 (sCR1) as well as polyclonal and monoclonal antibodies against CR1 inhibit sialic acid-independent invasion in a variety of laboratory strains and wild isolates, and that merozoites interact directly with CR1 on the erythrocyte surface and with sCR1-coated microspheres. Also, the invasion of neuraminidase-treated erythrocytes correlates with the level of CR1 expression. Finally, both sialic acid-independent and dependent strains invade CR1 transgenic mouse erythrocytes preferentially over wild-type erythrocytes but invasion by the latter is more sensitive to neuraminidase. These results suggest that both sialic acid-dependent and independent strains interact with CR1 in the normal red cell during the invasion process. However, only sialic acid-independent strains can do so without the presence of glycophorin sialic acid. Our results close a longstanding and important gap in the understanding of the mechanism of erythrocyte invasion by P. falciparum that will eventually make possible the development of an effective blood stage vaccine.

Complement receptor 1 is the host erythrocyte receptor for Plasmodium falciparum PfRh4 invasion ligand

“…As a result, parasite invasion into neuraminidase-treated erythrocytes was increasingly reliant on the PfRh4-CR1 pathway, as demonstrated by the strong inhibition of invasion by the addition of sCR1. This result is consistent with data reported by Spadafora et al (9) showing that the addition of sCR1 inhibited parasite invasion into neuraminidase-treated erythrocytes in sialic acid-independent strains, such as 7G8 and 3D7. sCR1 was not able to inhibit invasion in strains that either lack PfRh4 expression (W2mef) or possess a genetic knockout of the PfRh4 gene (W2mefΔRh4), providing convincing evidence that the reduction in invasion was due to the sCR1-PfRh4 interaction.…”

“…Anti-CR1 monoclonal antibodies that map to those regions (1B4, 3D9, and 4D6) do not inhibit either PfRh4 erythrocyte binding or the CR1-PfRh4 interaction, suggesting that the regions of binding to PfEMP-1 and PfRh4 might be distinct sites within CR1 (20). However, anti-CR1 monoclonal antibody J3B11 has been shown to inhibit parasite invasion into neuraminidasetreated erythrocytes and also to interfere with PfEMP-1 binding (9,20). A major caveat with all of these experiments is that anti-CR1 monoclonal antibodies that recognize the same epitopes show contrasting results in terms of inhibition of rosetting, PfRh4 erythrocyte binding, and invasion assays (9,20).…”

“…However, anti-CR1 monoclonal antibody J3B11 has been shown to inhibit parasite invasion into neuraminidasetreated erythrocytes and also to interfere with PfEMP-1 binding (9,20). A major caveat with all of these experiments is that anti-CR1 monoclonal antibodies that recognize the same epitopes show contrasting results in terms of inhibition of rosetting, PfRh4 erythrocyte binding, and invasion assays (9,20). In addition, it has been shown that binding of anti-CR1 antibodies to SCRs adjacent to (rather than within) ligand-binding sites can perturb function (16).…”

“…All three of these interactions are sensitive to neuraminidase treatment of erythrocytes and thus are involved in sialic acid-dependent invasion pathways. Complement receptor 1 (CR1) was recently identified as a receptor for the sialic acid-independent invasion pathways in multiple laboratory strains and wild isolates, although the parasite ligand with which it interacts has not yet been identified (9). CR1 also mediates rosetting through its interaction with PfEMP-1, a parasite-derived variant erythrocyte membrane protein (10).…”

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

“…Interestingly, RBC invasion involves the human complement receptor CR‐1, which is recognized by the reticulocyte‐binding‐like protein Rh4 located on the apical pole of the MZ (Spadafora et al , 2010; Tham et al , 2010). Approximately 1000 CR‐1 receptors cover the RBC surface, recognize C3b‐opsonized immune complexes and transport these to the liver‐resident Kupffer cells for phagocytosis (Taylor et al , 1997; van Lookeren Campagne et al , 2007).…”