Herein we describe an assay that was developed to quantitate the binding of normal red blood cells (RBC), labeled with carboxy fluorescein diacetate (C-FDA), to rosetting Plasmodium falciparum-infected RBC. The binding of RBC obtained from various animal species or humans to different strains or clones of rosetting P. falciparum-infected RBC was studied. A strain-specific preference of rosetting was observed for either blood group A/AB or B/AB RBC for all parasites tested. The higher affinity of rosette binding of blood group A, B, or AB vs. O RBC was reflected in larger rosettes when a given parasite was grown in RBC of the preferred blood group. The small size of the rosettes formed when P. falciparum was grown in blood group O RBC may be the in vitro correlate of the relative protection against cerebral malaria afforded by belonging to blood group O rather than to blood group A or B. Rosettes of a blood group A-preferring parasite could be completely disrupted by heparin only when grown in blood group O or B RBC, but not when grown in blood group A RBC. Similarly, the rosettes of a blood group B-preferring parasite could be more easily disrupted by heparin when grown in blood group O or A RBC than when grown in blood group B RBC. Several different saccharides inhibited rosetting of group O RBC, including two monosaccharides that are basic components of heparin. The rosetting of the same parasites grown in blood group A or B RBC was less sensitive to heparin and was specifically inhibited only by the terminal mono- and trisaccharides of the A and the B blood group antigens, the H disaccharide, and fucose. Our results suggest that rosetting is mediated by multiple lectin-like interactions, the usage of which rely on the parasite phenotype and whether the receptors are present on the host cell or not.

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