Authors

Discussion

P. falciparum rosetting, the binding of two or more uninfected erythrocytes to an infected erythrocyte, is a key virulence factor associated with severe malaria. Rosette formation is mediated by P. falciparum erythrocyte membrane protein 1 (PfEMP1) expressed on the surface of infected erythrocytes. Several molecules have been proposed as host rosetting receptors (such as Blood Group A antigen and Complement Receptor 1), but none of these can account for rosetting interactions across all parasite strains, suggesting that major host receptors remain unidentified. The Wright^b blood group antigen, which is formed by a physical interaction between Band 3 and Glycophorin A, has been identified by the Rowe lab as a potential novel rosetting receptor. Antibody fragments targeting Wright^b, disrupt rosettes in several P. falciparum strains, but the mechanism of action of this antibody is largely unknown. This study aimed to characterise this key receptor-ligand interaction implicated in rosetting and determine if a rosette-disrupting antibody to Wright^b is active against a range of P. falciparum strains, suggesting therapeutic potential.

To determine whether the Wright^b antigen or Band 3 is a rosetting receptor, we tested the ability of Band 3-transfected K562 cells and naturally occurring Glycophorin null cells to form rosettes with purified P. falciparum-infected erythrocytes. Our results showed that Band 3-transfected cells (expressing the Wright^b antigen) form rosettes with two parasite strains, whereas wild type K562 cells (expressing Glycophorin A alone) do not. Rosette frequency and rosette size did not vary across the glycophorin genotypes examined, showing that Glycophorin A is not essential for rosetting for the parasite strains tested. Further, we revealed that anti-Wright^b antibody fragments show variable activity against a panel of rosetting culture-adapted P. falciparum strains and clinical isolates. Thus, our data suggest that Wright^b could be a potential anti-rosetting therapeutic target, but that, due to the complexity of rosetting mechanisms, multiple host receptors may need to be targeted to obtain an intervention effective against all P. falciparum strains.