Knob-independent cytoadherence of Plasmodium falciparum to the leukocyte differentiation antigen CD36.

Abstract

The survival of Plasmodium falciparum-infected erythrocytes is enhanced by the sequestration of mature trophozoites and schizonts from the peripheral circulation. Cytoadherence of infected erythrocytes in vivo is associated with the presence of knobs on the erythrocyte surface, but we and others have shown recently that cytoadherence to C32 melanoma cells may occur in vitro in the absence of knobs. We show here that a knobless clone of P. falciparum adheres to the leukocyte differentiation antigen, CD36, suggesting that binding to CD36 is independent of the presence of knobs on the surface of the infected erythrocyte. This clone showed little cytoadherence to immobilized thrombospondin or to endothelial cells expressing the intercellular adhesion molecule 1. Furthermore, an Mr approximately 300-kD trypsin-sensitive protein doublet was immunoprecipitated from knobless trophozoite-infected erythrocytes. Finding a P. falciparum erythrocyte membrane protein 1 (PfEMP1)-like molecule on these infected erythrocytes is consistent with a role for PfEMP1 in cytoadherence to CD36 and C32 melanoma cells.

Sequestrin, a CD36 recognition protein on Plasmodium falciparum malaria-infected erythrocytes identified by anti-idiotype antibodies.

“…The significance of an immunoprecipitated doublet migrating at 270 kDa is unclear but may represent partial proteolytic cleavage of the sequestrin molecule. A high molecular weight trypsinsensitive doublet from CD36-binding K-C+ IRBC was similarly observed (14).…”

“…Additionally, we have exploited the detergent-insoluble properties of the binding ligand within the erythrocyte membrane of K+ C+ parasites by selecting a knobless parasite line that binds to CD36. This approach described recently by Biggs et al (14) enabled the extraction of a trypsin-sensitive high molecular mass protein from erythrocytes of knobless cytoadherent parasites. In our experiments, immunoprecipitation with anti-Id antibodies and CD36 receptor affinity precipitation of soluble detergent lysates of both surface-and biosyntheticlabeled CAMP K-C+ IRBC identified an -270-kDa membrane protein of parasite origin.…”

“…Culture-adapted IRBC and IRBC from patients with uncomplicated and cerebral malaria bound to purified anti-Id antibodies but not to rabbit anti-mouse allotypic and isotypic antibodies (Fig. 1 Culture-adapted knob-negative (K-) IRBC bind to C32 melanoma cells and purified CD36 (12)(13)(14). These observations led us to select a CD36-binding parasite population from a parental knobless noncytoadherent clone, CAMP K-C-, by repeated panning of the knobless parasitized erythrocytes on purified CD36.…”

Infectivity of Plasmodium falciparum in Malaria-Naive Individuals Is Related to Knob Expression and Cytoadherence of the Parasite

“…Knobless parasites continue to express PfEMP1 (17, 18) and have been shown to cytoadhere in static assays (17,19,20). However, under physiologic flow conditions, the ability of knob-and KAHRP-negative parasites to bind to tissue receptors is significantly reduced (7).…”

“…Cytoadherence involves an interaction between parasite ligands and tissue receptors, including CD36, on the vascular endothelium (11, 12). The principal parasite adhesin is P. falciparum erythrocyte membrane protein 1 (PfEMP1) (13), an antigenically variant product of the var gene family that is expressed on the surface of late-stage PEs and is concentrated on knobs (14-16).Knobless parasites continue to express PfEMP1 (17, 18) and have been shown to cytoadhere in static assays (17,19,20). However, under physiologic flow conditions, the ability of knob-and KAHRP-negative parasites to bind to tissue receptors is significantly reduced (7).…”