IDENTIFICATION OF PLASMODIUM-FALCIPARUM ERYTHROCYTE-MEMBRANE PROTEIN-1 (PFEMP1) AS THE ROSETTING LIGAND OF THE MALARIA PARASITE P-FALCIPARUM

Severe Plasmodium falciparum malaria is characterized by excessive seq uestration of infected and uninfected erythrocytes in the microvascula ture of the affected organ. Resetting, the adhesion of P. falciparum-i nfected erythrocytes to uninfected erythrocytes is a virulent parasite phenotype associated with the occurrence of severe malaria. Here we r eport on the identification by single-cell reverse transcriptase PCR a nd cDNA cloning of the adhesive ligand P. falciparum erythrocyte membr ane protein 1 (PfEMP1). Resetting PfEMP1 contains clusters of glycosam inoglycan-binding motifs. A recombinant fusion protein (Duffy binding- like 1-glutathione S transferase; Duffy binding-like-1-GST) was found to adhere directly to normal erythrocytes, disrupt naturally formed ro settes, block rosette reformation, and bind to a heparin-Sepharose mat rix. The adhesive interactions could be inhibited with heparan sulfate or enzymes that remove heparan sulfate from the cell surface whereas other enzymes or similar glycosaminoglycans of a like negative charge did not affect the binding. PfEMP1 is suggested to be the resetting Li gand and heparan sulfate, or a heparan sulfate-like molecule, the rece ptor both for PfEMP1 binding and naturally formed erythrocyte rosette.