Sulphated tyrosines mediate association of chemokines and Plasmodium vivax Duffy binding protein with the Duffy antigen/receptor for chemokines (DARC)

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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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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Frequent expansion of Plasmodium vivax Duffy Binding Protein in Ethiopia and its epidemiological significance

10.1101/543959 ◽

2019 ◽

Author(s):

Eugenia Lo ◽

Jessica B. Hostetler ◽

Delenasaw Yewhalaw ◽

Richard D. Pearson ◽

Muzamil M. A. Hamid ◽

...

Keyword(s):

Plasmodium Vivax ◽

Copy Number ◽

Diagnostic Method ◽

Binding Protein ◽

Whole Genome ◽

Quantitative Real Time Pcr ◽

Pcr Assay ◽

Duffy Binding Protein ◽

Duffy Antigen ◽

Asymptomatic Infections

AbstractPlasmodium vivax invasion of human erythrocytes depends on the Duffy Binding Protein (PvDBP) which interacts with the Duffy antigen. PvDBP copy number varies between P. vivax isolates, but the prevalence of PvDBP multiplications in Sub-Saharan Africa and its impact are unknown. We determined the prevalence and type of PvDBP duplications, as well as PvDBP copy number variation among 178 Ethiopian P. vivax isolates using a PCR-based diagnostic method, a novel quantitative real-time PCR assay and whole genome sequencing. For the 145 symptomatic samples, PvDBP duplications were detected in 95 isolates, of which 81 had the Cambodian and 14 Malagasy-type PvDBP duplications. PvDBP varied from 1 to >4 copies. Isolates with multiple PvDBP copies were found to be higher in symptomatic than asymptomatic infections. For the 33 asymptomatic samples, PvDBP was detected with two copies in two of the isolates, and both were the Cambodian-type PvDBP duplication. PvDBP copy number in Duffy-negative heterozygotes was not significantly different from that in Duffy-positives, providing no support for the hypothesis that increased copy number is a specific association with Duffy-negativity, although the number of Duffy-negatives was small and further sampling is required to test this association thoroughly.Author summaryPlasmodium vivax invasion of human erythrocytes relies on interaction between the Duffy antigen and P. vivax Duffy Binding Protein (PvDBP). Whole genome sequences from P. vivax field isolates in Madagascar identified a duplication of the PvDBP gene and PvDBP duplication has also been detected in non-African P. vivax-endemic countries.Two types of PvDBP duplications have been reported, termed Cambodian and Malagasy-type duplications. Our study used a combination of PCR-based diagnostic method, a novel quantitative real-time PCR assay, and whole genome sequencing to determine the prevalence and type of PvDBP duplications, as well as PvDBP copy number on a broad number of P. vivax samples in Ethiopia. We found that over 65% of P. vivax isolated from the symptomatic infections were detected with PvDBP duplications and PvDBP varied from 1 to >4 copies. The majority of PvDBP duplications belongs to the Cambodian-type while the Malagasy-type duplications was also detected. For the asymptomatic infections, despite a small sample size, the majority of P. vivax were detected with a single-copy based on both PCR and qPCR assays. There was no significant difference in PvDBP copy number between Duffy-null heterozygote and Duffy-positive homozygote/heterozygote. Further investigation is needed with expanded Duffy-null homozygotes to examine the functional significance of PvDBP expansion.

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Fine Specificity of Plasmodium vivax Duffy Binding Protein Binding Engagement of the Duffy Antigen on Human Erythrocytes

Infection and Immunity ◽

10.1128/iai.00206-12 ◽

2012 ◽

Vol 80 (8) ◽

pp. 2920-2928 ◽

Cited By ~ 12

Author(s):

Asim A. Siddiqui ◽

Jia Xainli ◽

Jesse Schloegel ◽

Lenore Carias ◽

Francis Ntumngia ◽

...

Keyword(s):

Plasmodium Vivax ◽

Binding Protein ◽

Human Erythrocytes ◽

Full Length ◽

Laboratory Animals ◽

Duffy Binding Protein ◽

Content Type ◽

Duffy Antigen ◽

Key Residues ◽

Blocking Antibodies

ABSTRACTPlasmodium vivaxinvasion of human erythrocytes requires interaction of theP. vivaxDuffy binding protein (PvDBP) with its host receptor, the Duffy antigen (Fy) on the erythrocyte surface. Consequently, PvDBP is a leading vaccine candidate. The binding domain of PvDBP lies in a cysteine-rich portion of the molecule called region II (PvDBPII). PvDBPII contains three distinct subdomains based upon intramolecular disulfide bonding patterns. Subdomain 2 (SD2) is highly polymorphic and is thought to contain many key residues for binding to Fy, while SD1 and SD3 are comparatively conserved and their role in Fy binding is not well understood. To examine the relative contributions of the different subdomains to binding to Fy and their abilities to elicit strain-transcending binding-inhibitory antibodies, we evaluated recombinant proteins from SD1+2, SD2, SD3, and SD3+, which includes 24 residues of SD2. All of the recombinant subdomains, except for SD2, bound variably to human erythrocytes, with constructs containing SD3 showing the best binding. Antisera raised in laboratory animals against SD3, SD3+, and SD2+3 inhibited the binding of full-length PvDBPII, which is strain transcending, whereas antisera generated to SD1+2 and SD2 failed to generate blocking antibodies. All of the murine monoclonal antibodies generated to full-length PvDBPII that had significant binding-inhibitory activity recognized only SD3. Thus, SD3 binds Fy and elicits blocking antibodies, indicating that it contains residues critical to Fy binding that could be the basis of a strain-transcending candidate vaccine againstP. vivax.

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