Plasmodium simium, a Plasmodium vivax-Related Malaria Parasite: Genetic Variability of Duffy Binding Protein II and the Duffy Antigen/Receptor for Chemokines

The ability of the malaria parasitePlasmodium vivaxto 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 toP. vivaxinfections. Recently,P. vivaxinfections in Duffy-null Africans have been documented, raising the possibility thatP. vivax, a virulent pathogen in other parts of the world, may expand malarial disease in Africa.P. vivaxbinds the Duffy blood group antigen through its Duffy-binding protein 1 (DBP1). To determine if mutations in DBP1 resulted in the ability ofP. vivaxto bind Duffy-null erythrocytes, we analyzedP. vivaxparasites 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 ofP. vivaxto infect Duffy-null Africans. However, an unusual DNA expansion of DBP1 (three and eight copies) in the two Duffy-nullP. vivaxinfections 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) IP. vivaxinfects Squirrel monkeys independently of DBP1 binding to Squirrel monkey erythrocytes. We conclude thatP. vivaxSal I and perhapsP. vivaxin Duffy-null patients may have adapted to use new ligand–receptor pairs for invasion.

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Plasmodium vivax Strains Use Alternative Pathways for Invasion

The Journal of Infectious Diseases ◽

10.1093/infdis/jiaa592 ◽

2020 ◽

Author(s):

Usheer Kanjee ◽

Christof Grüring ◽

Prasad Babar ◽

Anosha Meyers ◽

Rashmi Dash ◽

...

Keyword(s):

Plasmodium Vivax ◽

Transferrin Receptor ◽

Significant Variation ◽

Vaccine Development ◽

Binding Protein ◽

Invasion Pathways ◽

Duffy Binding Protein ◽

Alternative Pathways ◽

Duffy Antigen ◽

Invasion Assays

Abstract Plasmodium vivax has 2 invasion ligand/host receptor pathways (P. vivax Duffy-binding protein/Duffy antigen receptor for chemokines [DARC] and P. vivax reticulocyte binding protein 2b/transferrin receptor [TfR1]) that are promising targets for therapeutic intervention. We optimized invasion assays with isogenic cultured reticulocytes. Using a receptor blockade approach with multiple P. vivax isolates, we found that all strains utilized both DARC and TfR1, but with significant variation in receptor usage. This suggests that P. vivax, like Plasmodium falciparum, uses alternative invasion pathways, with implications for pathogenesis and vaccine development.

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Fine mapping of the Duffy antigen binding site for the Plasmodium vivax Duffy-binding protein

Molecular and Biochemical Parasitology ◽

10.1016/j.molbiopara.2005.04.016 ◽

2005 ◽

Vol 144 (1) ◽

pp. 100-103 ◽

Cited By ~ 20

Author(s):

Christophe Tournamille ◽

Anne Filipe ◽

Cyril Badaut ◽

Marie-Madeleine Riottot ◽

Shirley Longacre ◽

...

Keyword(s):

Binding Site ◽

Plasmodium Vivax ◽

Fine Mapping ◽

Binding Protein ◽

Antigen Binding ◽

Antigen Binding Site ◽

Duffy Binding Protein ◽

Duffy Antigen

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Worldwide Genetic Variability of the Duffy Binding Protein: Insights into Plasmodium vivax Vaccine Development

PLoS ONE ◽

10.1371/journal.pone.0022944 ◽

2011 ◽

Vol 6 (8) ◽

pp. e22944 ◽

Cited By ~ 25

Author(s):

Taís Nóbrega de Sousa ◽

Luzia Helena Carvalho ◽

Cristiana Ferreira Alves de Brito

Keyword(s):

Genetic Variability ◽

Plasmodium Vivax ◽

Vaccine Development ◽

Binding Protein ◽

Duffy Binding Protein

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Retraction for Siddiqui et al., Fine Specificity of Plasmodium vivax Duffy Binding Protein Binding Engagement of the Duffy Antigen on Human Erythrocytes

Infection and Immunity ◽

10.1128/iai.00338-15 ◽

2015 ◽

Vol 83 (6) ◽

pp. 2593-2593

Author(s):

Asim A. Siddiqui ◽

Jia Xainli ◽

Jesse Schloegel ◽

Lenore Carias ◽

Francis Ntumngia ◽

...

Keyword(s):

Protein Binding ◽

Plasmodium Vivax ◽

Binding Protein ◽

Human Erythrocytes ◽

Duffy Binding Protein ◽

Fine Specificity ◽

Duffy Antigen

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Sequence similarity between the erythrocyte binding domain 1 of the Plasmodium vivax Duffy binding protein and the V3 loop of HIV-1 strain MN reveals binding residues for the Duffy Antigen Receptor for Chemokines

Virology Journal ◽

10.1186/1743-422x-8-45 ◽

2011 ◽

Vol 8 (1) ◽

Cited By ~ 4

Author(s):

Michael J Bolton ◽

Robert F Garry

Keyword(s):

Plasmodium Vivax ◽

Sequence Similarity ◽

Antigen Receptor ◽

Binding Domain ◽

V3 Loop ◽

Duffy Binding Protein ◽

Duffy Antigen ◽

Erythrocyte Binding ◽

Binding Residues ◽

Hiv 1

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

mBio ◽

10.1128/mbio.01261-16 ◽

2016 ◽

Vol 7 (4) ◽

Cited By ~ 38

Author(s):

Francis B. Ntumngia ◽

Richard Thomson-Luque ◽

Letícia de Menezes Torres ◽

Karthigayan Gunalan ◽

Luzia H. Carvalho ◽

...

Keyword(s):

Plasmodium Vivax ◽

Blood Group ◽

Binding Protein ◽

Antigen Receptor ◽

Blood Stage ◽

Duffy Binding Protein ◽

Duffy Blood Group ◽

Erythrocyte Binding ◽

Invasion Pathway ◽

Duffy Negative

ABSTRACT 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. IMPORTANCE 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.

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