We report in this paper that glycophorin C (GPC) is the receptor for PfEBP-2 (baebl, EBA-140), the newly identified erythrocyte binding ligand of Plasmodium falciparum. PfEBP-2 is a member of the Duffy bindinglike erythrocyte binding protein (DBL-EBP) family. Although several reports have been published characterizing PfEBP-2, the identity of its erythrocytic receptor was still unknown. Using a combination of enzymatically treated red blood cells (RBCs) and rare, variant RBCs lacking different surface proteins, we have shown that PfEBP-2 does not bind to cells lacking GPC. Additionally, we found that PfEBP-2 binds differentially to variants of GPC lacking exon 2 or exon 3, and determined that the binding domain on GPC is potentially restricted to amino acid residues 14 through 22 within exon 2. Thus PfEBP-2 is involved in a sialic acid-dependent pathway of invasion, which does not involve glycophorin A or glycophorin B and represents a novel route of entry into the

The invasion of red blood cells (RBCs) by Plasmodium falciparum is dependent on multiple molecular interactions between erythrocyte receptors and parasite ligands. Invasion studies using culture-adapted parasite strains have indicated significant receptor heterogeneity. It is not known whether this heterogeneity reflects the parasite invasion arsenal in the field. We have studied the invasion phenotypes of 14 distinct field isolates from the Legal Amazon areas of Brazil by using erythrocyte invasion assays to investigate invasion into normal, enzyme-treated, and clinical-mutant RBCs. Analysis of these isolates revealed four distinct invasion profiles. Using En(a؊) cells to get an unequivocal estimate of the use of glycophorin A (GPA) as a receptor, we found that the 175-kDa erythrocyte-binding antigen (EBA-175)/GPA pathway was used by a minority of the parasite isolates studied. Although polymorphism of region II domains at specific amino acid positions in both EBA-140 and EBA-181 was found in these field isolates, this did not correlate with invasion profiles and thus receptor selectivity. These studies have further confirmed the existence of a significant diversity of invasion pathways in nature and suggest that additional parasite ligands will have to be targeted to devise global vaccines that will work in the field.The human red blood cell (RBC) serves as the host vehicle for the malaria parasite Plasmodium falciparum for the entire erythrocytic phase of the parasite's life cycle. Invasion of erythrocytes by malaria parasites is a multistep process involving several specific interactions between receptors on the RBCs and parasite ligands. As invasion is the central point in the erythrocytic life cycle of the malaria parasite, the presence of multiple invasion pathways is believed to be a survival strategy of the malaria parasite. In P. falciparum, five major invasion pathways have been identified. Of these, only two have been well characterized, one involving glycophorin A (GPA) and the 175-kDa erythrocyte-binding antigen (EBA-175) (5, 24) and the second utilizing glycophorin C (GPC) and a 140-kDa paralogue of EBA-175, EBA-140 (also called PfEBP-2 and baebl) (13,14,15,19,27). At least five additional receptors on the erythrocyte surface, including glycophorin B (GPB) and four as yet unidentified receptors, X, Y, E, and Z, have been postulated to play a role in GPA-independent pathways of invasion, termed alternative pathways (7,8). Receptor X is neuraminidase resistant but trypsin sensitive (11), Y and E are trypsin resistant and neuraminidase and chymotrypsin sensitive (8,22), and receptor Z is resistant to neuraminidase and trypsin but sensitive to chymotrypsin (9). In addition to EBA-175 and EBA-140, three other merozoite ligands, EBA-181 (jesebl), PfNBP1, and PfNBP2b, have been characterized (9, 10, 22); however, the identities of their RBC receptors remain unknown. Thus, although parasite invasion has attracted considerable study, the molecules and the basic mechanisms responsible for the GPA-independen...

Babesiosis has long been recognized as an economically important disease of cattle, but only in the last 30 years has Babesia been recognized as an important pathogen in humans. Invasion of erythrocytes is an integral part of the Babesia life cycle. However, very little information is available on the molecules involved in this process, in contrast to another hemoparasite, Plasmodium falciparum. Using invasion assays into normal red blood cells (RBCs), enzyme-treated cells, and clinically mutant cells, we showed that Babesia divergens uses neuraminidase-and trypsin-sensitive receptors to enter the RBCs, of which glycophorins A and B are the prominent ones. These results could have broad implications relating to evolutionarily conserved mechanisms of host cell entry in these related Apicomplexan parasites and pave the way toward a detailed molecular analysis of erythrocyte invasion in B. divergens.Babesiosis, caused by infection with intraerythrocytic parasites of the genus Babesia, is one of the most common infections of free-living animals worldwide and is gaining increasing interest as an emerging zoonosis, a disease that is communicable from animals to humans (17,26). The rodent parasite Babesia microti and the bovine pathogen Babesia divergens are responsible for most of the ϳ500 human infections that have been reported so far (26). Parasites that live in red blood cells (RBCs) have rather ingenious ways of gaining entry into these cells, thus escaping the dangers of the host immune system. Although there are many erythrocyte-seeking protozoa, most data regarding erythrocyte invasion have come from studies on Plasmodium, a related Apicomplexan parasite. In both parasites, invasion has been shown to be composed of an initial phase of random cell-cell contact, subsequent reorientation, and specific receptor-ligand interactions (6,14,15,25). However, in contrast to Plasmodium falciparum, little is known about the molecules used by Babesia to attach and invade erythrocytes, and yet this is one of the most critical factors in the life cycle of the parasite.The Babesia blood stage merozoite is designed for one major role: to locate, bind to, and invade host RBCs. This is a very specific interaction; Babesia does not invade other host cells (15,26). This specificity implies the presence of a receptor(s) on the erythrocyte, which is recognized by a complementary ligand(s) on the parasite. Several Babesia molecules have been shown to bind RBCs in vitro and may thus play a role in invasion. In Babesia bovis, a merozoite surface antigen (MSA-2) (21) and a rhoptry-associated antigen (RAP-1) (22) have been shown to bind erythrocytes. In Babesia equi, two other merozoite antigens, EMA-1 and EMA-2, have also been shown to interact with the RBC membrane skeleton (18). The cognate RBC receptors for these molecules remain unknown, as has the identity of any erythrocytic receptor used by the invading Babesia merozoite.The work presented in this report is based on the hypothesis that erythrocyte invasion by B. divergens and P. ...

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