A 175-kilodalton erythrocyte binding protein, EBA-175, of the parasite Plasmodium falciparum mediates the invasion of erythrocytes. The erythrocyte receptor for EBA-175 is dependent on sialic acid. The domain of EBA-175 that binds erythrocytes was identified as region II with the use of truncated portions of EBA-175 expressed on COS cells. Region II, which contains a cysteine-rich motif, and native EBA-175 bind specifically to glycophorin A, but not to glycophorin B, on the erythrocyte membrane. Erythrocyte recognition of EBA-175 requires both sialic acid and the peptide backbone of glycophorin A. The identification of both the receptor and ligand domains may suggest rational designs for receptor blockade and vaccines.

Plasmodium vivax and P. falciparum are the major causes of human malaria, except in sub-Saharan Africa where people lack the Duffy blood group antigen, the erythrocyte receptor for P. vivax. Duffy negative human erythrocytes are resistant to invasion by P. vivaxand the related monkey malaria, P. knowlesi. Several lines of evidence in the present study indicate that the Duffy blood group antigen is the erythrocyte receptor for the chemokines interleukin-8 (IL-8) and melanoma growth stimulatory activity (MGSA). First, IL-8 binds minimally to Duffy negative erythrocytes. Second, a monoclonal antibody to the Duffy blood group antigen blocked binding of IL-8 and other chemokines to Duffy positive erythrocytes. Third, both MGSA and IL-8 blocked the binding of the parasite ligand and the invasion of human erythrocytes by P. knowlesi, suggesting the possibility of receptor blockade for anti-malarial therapy.

Antigens that bind to erythrocytes were identified in the supernatant fluids of a cultured human malaria parasite (Plasmodium falciparum). A 175-kilodalton (175K) antigen bound only to erythrocytes susceptible to invasion. The 175K antigen from the Camp or the FCR-3 strain also bound to merozoites. However, the antigen did not bind to merozoites when merozoites and supernatant antigens were from different strains unless proteinase inhibitors were present. Moreover, erythrocytes coated with supernatant antigens from the Camp or FCR-3 strain were invaded normally by merozoites of the homologous strain but were partially resistant to invasion by merozoites of the heterologous strain. The 175K antigen may be a receptor acting as a "bridge" between erythrocytes and merozoites.

SummaryThe Duffy antigen/receptor for chemokines (DARC), first identified on erythrocytes, functions not only as a promiscuous chemokine receptor but also as a receptor for the malarial parasite, Plasmodium vivax. The recent finding that DARC is ubiquitously expressed by endothelial cells lining postcapillary venules provides a possible insight into the function of this receptor because this anatomic site is an active interface for leukocyte trafficking. However, the biological significance of DARC is questionable since it has not yet been determined whether individuals lacking the expression of this protein on their erythrocytes (Duffy negative individuals), who are apparently immunologicaUy normal, express the receptor on endothelial cells. However, we report here that DARC is indeed expressed in endothelial cells lining postcapillary venules and splenic sinusoids in individuals who lack the erythrocyte receptor. These findings are based on immunohistochemical, biochemical, and molecular biological analysis of tissues from Duff-y negative individuals. We also present data showing that, in contrast to erythrocyte DAILC, cells transfected with DARC internalize radiolabeled ligand. We conclude that the DARC may play a critical role in mediating the effects of proinflammatory chemokines on the interactions between leukocyte and endothelial cells since the molecular pathology of the Duffy negative genotype maintains expression on the latter cell type.

phenotype and denoted as Fy(a0b0). When Duffy-negative individuals of African descent develop anti-Duffy alloanti-NE OF THE MOST notable achievements of biomedical research in the first half of this century was the identification of red blood cell (RBC) antigens and the recog-bodies, they are almost always anti-Fy a rather than anti-Fy b . 19,20 The genotype designated FY/FY, which gives rise nition of their importance to transfusion medicine and hemolytic disease of the newborn. 1,2 These discoveries gave rise to the Fy(a0b0) erythroid phenotype, contains a coding sequence identical to that of FY*B. 21 In individuals of the to an era of descriptive RBC serology during which a complex array of RBC membrane antigens were defined by their Fy(a0b0) phenotype, this sequence remains silent in erythroid cells but is transcribed and expressed on endothelial reactivity with specific alloantibodies. 3,4 In recent years, RBC immunohematology has progressed from descriptive cells of postcapillary venules. 22 Reactivity with anti-Fy a and anti-Fy b alloantibodies is serology into an era of structural and functional analysis of blood group antigens, many of which are expressed in both abolished after chymotrypsin or papain treatment of intact RBCs. 23,24 Albrey et al 25 described an anti-Duffy alloanti-erythroid and nonerythroid tissue. [5][6][7][8] Here we will focus on the Duffy blood group antigen, a structure that has been of body, denoted anti-Fy3, that reacts with chymotrypsinand papain-treated RBCs. Anti-Fy3 reacts with both particular interest because it serves as a receptor on the RBC for the malarial parasite, Plasmodium vivax (P vivax). [8][9][10] Fy(a/b0) and Fy(a0b/) RBCs, but not Fy(a0b0) RBCs. Adsorption and elution experiments showed that anti-Fy3 We will attempt to highlight recent advances in our understanding of the molecular basis for the interaction of the P reacts with a site common to both Fy(a/b0) and Fy(a0b/) RBCs. Although initially described in the se-vivax malaria parasite with the Duffy blood group antigen and indicate how this information also contributed to the rum of a rare Fy(a0b0) white woman (AZ) with a history of pregnancy and blood transfusions, anti-Fy3 can also identification of an important gene family for cytoadherence proteins of P falciparum. In the context of normal physiol-occur in Duffy-negative individuals of African descent, often in conjunction with anti-Fy a . 18 Other Duffy-related ogy, the Duffy blood group antigen has been shown to be receptor for chemoattractant cytokines, or chemokines, and epitopes have been defined by rare antisera, anti-Fy4 and anti-Fy5. 26,27 Anti-Fy4 reacts only with Fy(a0b0) RBCs to be expressed by endothelial cells of postcapillary venules and by Purkinje cells of the cerebellum. 11,12 We will attempt from individuals of African descent. 26 Anti-Fy5 reacts with all human RBCs except those that are Fy(a0b0) and to review this important area of chemokine receptor research and discuss the potential relevance of the Duffy chemokine Rh null or expre...