Role of Plasmodium vivax Duffy-binding protein 1 in invasion of Duffy-null Africans

Abstract

The ability of the malaria parasite Plasmodium vivax to invade erythrocytes is dependent on the expression of the Duffy blood group antigen on erythrocytes. Consequently, Africans who are null for the Duffy antigen are not susceptible to P. vivax infections. Recently, P. vivax infections in Duffy-null Africans have been documented, raising the possibility that P. vivax, a virulent pathogen in other parts of the world, may expand malarial disease in Africa. P. vivax binds the Duffy blood group antigen through its Duffy-binding protein 1 (DBP1). To determine if mutations in DBP1 resulted in the ability of P. vivax to bind Duffy-null erythrocytes, we analyzed P. vivax parasites obtained from two Duffy-null individuals living in Ethiopia where Duffy-null and -positive Africans live side-by-side. We determined that, although the DBP1s from these parasites contained unique sequences, they failed to bind Duffy-null erythrocytes, indicating that mutations in DBP1 did not account for the ability of P. vivax to infect Duffy-null Africans. However, an unusual DNA expansion of DBP1 (three and eight copies) in the two Duffy-null P. vivax infections suggests that an expansion of DBP1 may have been selected to allow low-affinity binding to another receptor on Duffy-null erythrocytes. Indeed, we show that Salvador (Sal) I P. vivax infects Squirrel monkeys independently of DBP1 binding to Squirrel monkey erythrocytes. We conclude that P. vivax Sal I and perhaps P. vivax in Duffy-null patients may have adapted to use new ligand-receptor pairs for invasion.Plasmodium vivax | Duffy blood group antigen | Duffy-binding protein | DNA expansionI n 1975 we identified the failure of Plasmodium knowlesi to invade Duffy-null erythrocytes (1). We assumed that the Duffy blood group null phenotype, a common African phenotype, conferred resistance in Africans to P. vivax, a Plasmodium closely related to P. knowlesi. Subsequent studies demonstrated that African American volunteers who were Duffy-null were resistant to mosquito-transmitted P. vivax (2). In addition, African American soldiers in Vietnam who were infected with P. vivax were all Duffypositive (3). Furthermore, African Americans in a village in Honduras who were infected with P. vivax were all Duffy-positive whereas those infected with P. falciparum were both Duffy-null and -positive (4). We concluded that Duffy null was the basis of resistance to P. vivax by Africans.The molecular basis of Duffy null was a single point mutation in the GATA1-binding sequence in the promotor region 5′ to the Duffy blood group ORF (Fig. 1B) that led to Duffy-blood-groupnull erythrocytes (5). In vitro studies with P. knowlesi demonstrated that the invasive merozoites were able to bind and reorient apically with Duffy-null erythrocytes but could not form a junction as occurred in Duffy-positive erythrocytes, indicating that the Duffy blood group was required for P. vivax invasion (6). Later, in P. knowlesi parasite culture supernatants, the parasite ligand binding to Duffy blood group antigen was identi...

A Novel Erythrocyte Binding Protein of Plasmodium vivax Suggests an Alternate Invasion Pathway into Duffy-Positive Reticulocytes

“…Similarly, a recent study also showed evidence of EBP2 binding to both Duffy-positive and Duffy-negative erythrocytes, though at low frequency (23). During receptor binding, the DBP ligand domain has been shown to form a homodimer with the N-terminal extracellular domain of DARC (24).…”

Genetic diversity in twoPlasmodium vivaxprotein ligands for reticulocyte invasion

“…Since then, this hypothesis has been challenged by Hostetler et al [18] who found that PvDBP gene duplications were widespread even in malaria endemic areas in Southeast Asia where Duffy-negativity is not present. Another recent study [19] reported evidence of PvDBP gene amplification (3 and 8 copies) in two Duffynegative Ethiopian isolates. In addition, sequence data generated from a P. vivax field isolate (C127 isolate from Cambodia), which used reconstruction of long reads without relying on the reference genome (e.g.…”

Molecular interactions governing host-specificity of blood stage malaria parasites

“…Gunalan et al . [64] recently analyzed P. vivax isolates from two DARC-negative Ethiopians and described a novel copy number expansion of the Pv DBP gene. The authors proposed that this expansion may facilitate binding to a low-affinity receptor, though experimental support through the identification of this receptor is currently lacking.…”