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Targeting a Reticulocyte Binding Protein and Duffy Binding Protein to Inhibit Reticulocyte Invasion by Plasmodium vivax.

ABSTRACT: Plasmodium vivax merozoite invasion is restricted to Duffy positive reticulocytes. Merozoite interaction with the Duffy antigen is mediated by the P. vivax Duffy binding protein (PvDBP). The receptor-binding domain of PvDBP maps to an N-terminal cysteine-rich region referred to as region II (PvDBPII). In addition, a family of P. vivax reticulocyte binding proteins (PvRBPs) mediates interactions with reticulocyte receptors. The receptor binding domain of P. vivax reticulocyte binding protein 1a (PvRBP1a) maps to a 30 kD region (PvRBP1a₃₀). Antibodies raised against recombinant PvRBP1a₃₀ and PvDBPII recognize the native P. vivax antigens and inhibit their binding to host receptors. Rabbit IgG purified from sera raised against PvRBP1a₃₀ and PvDBPII were tested individually and in combination for inhibition of reticulocyte invasion by P. vivax field isolates. While anti-PvDBPII rabbit IgG inhibits invasion, anti-PvRBP1a₃₀ rabbit IgG does not show significant invasion inhibitory activity. Combining antibodies against PvDBPII and PvRBP1a₃₀ also does not increase invasion inhibitory activity. These studies suggest that although PvRBP1a mediates reticulocyte invasion by P. vivax merozoites, it may not be useful to include PvRBP1a₃₀ in a blood stage vaccine for P. vivax malaria. In contrast, these studies validate PvDBPII as a promising blood stage vaccine candidate for P. vivax malaria.

SUBMITTER: Gupta S

PROVIDER: S-EPMC6043553 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Targeting a Reticulocyte Binding Protein and Duffy Binding Protein to Inhibit Reticulocyte Invasion by Plasmodium vivax.

Gupta Sonal S Singh Shailja S Popovici Jean J Roesch Camille C Shakri Ahmed Rushdi AR Guillotte-Blisnick Micheline M Huon Christèle C Menard Didier D Chitnis Chetan E CE

Scientific reports 20180712 1

Plasmodium vivax merozoite invasion is restricted to Duffy positive reticulocytes. Merozoite interaction with the Duffy antigen is mediated by the P. vivax Duffy binding protein (PvDBP). The receptor-binding domain of PvDBP maps to an N-terminal cysteine-rich region referred to as region II (PvDBPII). In addition, a family of P. vivax reticulocyte binding proteins (PvRBPs) mediates interactions with reticulocyte receptors. The receptor binding domain of P. vivax reticulocyte binding protein 1a ( ...[more]

PMID: 30002416

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Project description:Erythrocyte invasion by malaria parasites is essential for blood-stage development and an important determinant of host range. In Plasmodium vivax, the interaction between the Duffy binding protein (DBP) and its cognate receptor, the Duffy antigen receptor for chemokines (DARC), on human erythrocytes is central to blood-stage infection. Contrary to this established pathway of invasion, there is growing evidence of P. vivax infections occurring in Duffy blood group-negative individuals, suggesting that the parasite might have gained an alternative pathway to infect this group of individuals. Supporting this concept, a second distinct erythrocyte binding protein (EBP2), representing a new member of the DBP family, was discovered in P. vivax and may be the ligand in an alternate invasion pathway. Our study characterizes this novel ligand and determines its potential role in reticulocyte invasion by P. vivax merozoites. EBP2 binds preferentially to young (CD71(high)) Duffy-positive (Fy(+)) reticulocytes and has minimal binding capacity for Duffy-negative reticulocytes. Importantly, EBP2 is antigenically distinct from DBP and cannot be functionally inhibited by anti-DBP antibodies. Consequently, our results do not support EBP2 as a ligand for invasion of Duffy-negative blood cells, but instead, EBP2 may represent a novel ligand for an alternate invasion pathway of Duffy-positive reticulocytes. For decades, P. vivax infections in humans have been defined by a unique requirement for the interaction between the Duffy binding protein ligand of the parasite and the Duffy blood group antigen receptor (DARC). Recent reports of P. vivax infections in Duffy-negative individuals challenge this paradigm and suggest an alternate pathway of infection, potentially using the recently discovered EBP2. However, we demonstrate that EBP2 host cell specificity is more restricted than DBP binding and that EBP2 binds preferentially to Duffy-positive, young reticulocytes. This finding indicates that this DBP paralog does mediate a Duffy-independent pathway of infection.

Project description:BackgroundThe Duffy-binding protein II of Plasmodium vivax (PvDBPII) has been considered as an attractive target for vaccine-mediated immunity despite a possible highly polymorphic nature. Among seven PvDBP domains, domain II has been shown to exhibit a high rate of nonsynonymous polymorphism, which has been suggested to be a potential immune (antibody binding) evasion mechanism. This study aimed to determine the extent of genetic polymorphisms and positive natural selection at domain II of the PvDBP gene among a sampling of Thai P. vivax isolates.MethodsThe PvDBPII gene was PCR amplified and the patterns of polymorphisms were characterized from 30 Thai P. vivax isolates using DNA cloning and sequencing. Phylogenetic analysis of the sequences and positive selection were done using DnaSP ver 4.0 and MEGA ver 4.0 packages.ResultsThis study demonstrated a high rate of nonsynonymous polymorphism. Using Sal I as the reference strain, a total of 30 point-mutations were observed in the PvDBPII gene among the set of Thai P. vivax isolates, of which 25 nonsynonymous and five synonymous were found. The highest frequency of polymorphism was found in five variant amino acids (residues D384G, R390H, L424I, W437R, I503K) with the variant L424I having the highest frequency. The difference between the rates of nonsynonymous and synonymous mutations estimated by the Nei and Gojobori's method suggested that PvDBPII antigen appears to be under selective pressure. Phylogenetic analysis of PvDBPII Thai P. vivax isolates to others found internationally demonstrated six distinct allele groups. Allele groups 4 and 6 were unique to Thailand.ConclusionPolymorphisms within PvDBPII indicated that Thai vivax malaria parasites are genetically diverse. Phylogenetic analysis of DNA sequences using the Neighbour-Joining method demonstrated that Thai isolates shared distinct alleles with P. vivax isolates from different geographical areas. The study reported here will be valuable for the development of PvDBPII-based malaria vaccine.

Dataset Information

Targeting a Reticulocyte Binding Protein and Duffy Binding Protein to Inhibit Reticulocyte Invasion by Plasmodium vivax.

Publications

Targeting a Reticulocyte Binding Protein and Duffy Binding Protein to Inhibit Reticulocyte Invasion by Plasmodium vivax.

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