From malaria to chemokine receptor: The emerging physiologic role of the Duffy blood group antigen

Abstract

The glycoprotein expressed on surface of erythrocytes initially known as the Duffy blood group antigen has been shown to be a receptor for the invasion of these cells by P vivax parasites. The parasite ligand that binds to the Duffy antigen has now been cloned and characterized. The region on the Duffy binding ligand of the parasite responsible for interaction with the Duffy antigen has also been identified. It is hoped that this molecule will useful as an immunogen to induce antibodies capable of blocking invasion of the parasite into the erythrocyte. Research on the Duffy binding ligand also provided a clue (a shared motif) to the identification of the long-sought family of variant endothelial binding ligands that mediate attachment of P falciparum - infected erythrocytes to endothelial cells of postcapillary venules. If this attachment could be disrupted during the course of a malarial infection, it might lead to spleen-mediated parasite death. It might also lead to amelioration of cerebral malaria, a condition which in part is due to the blockade of cerebral venules by sequestered adherent parasites. Recently, research on the Duffy antigen has taken on a new dimension. The Duffy antigen has been shown to be a multispecific heptahelical receptor for chemokines, expressed on RBCs, endothelial cells of postcapillary venules, and Purkinje cells of the cerebellum. The challenge now is to determine its function, both in immunobiology and neurobiology. Its capacity to bind chemoattractant cytokines and its expression on endothelial cells lining postcapillary venules are highly conserved across species, suggesting that this receptor subserves a critical function. This is supported by nature's experiment, the Duffy blood group negative phenotype, in which the genetic mechanism selected to remove expression on erythroid cells to protect against malarial infection, preserved expression on endothelial cells of postcapillary venules and splenic sinusoids. Although we have significant insight into structure-function relationships for the Duffy antigen/receptor for chemokines, its mechanism of signaling and its biologic function remain to be elucidated.