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

2012 ◽  
Vol 80 (8) ◽  
pp. 2920-2928 ◽  
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.

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

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

scholarly journals Plasmodium vivax Invasion of Human Erythrocytes Inhibited by Antibodies Directed against the Duffy Binding Protein

PLoS Medicine ◽  
2007 ◽  
Vol 4 (12) ◽  
pp. e337 ◽  
Author(s):  
Brian T Grimberg ◽  
Rachanee Udomsangpetch ◽  
Jia Xainli ◽  
Amy McHenry ◽  
Tasanee Panichakul ◽  
...  
Keyword(s):  
Plasmodium Vivax ◽  
Binding Protein ◽  
Human Erythrocytes ◽  
Duffy Binding Protein

scholarly journals Conserved and Variant Epitopes of Plasmodium vivax Duffy Binding Protein as Targets of Inhibitory Monoclonal Antibodies

2012 ◽  
Vol 80 (3) ◽  
pp. 1203-1208 ◽  
Author(s):  
Francis B. Ntumngia ◽  
Jesse Schloegel ◽  
Samantha J. Barnes ◽  
Amy M. McHenry ◽  
Sanjay Singh ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Plasmodium Vivax ◽  
Vivax Malaria ◽  
Binding Protein ◽  
Blood Stage ◽  
Effective Vaccine ◽  
Enzyme Linked Immunosorbent Assay ◽  
Duffy Binding Protein ◽  
Content Type ◽  
Functional Inhibition

The Duffy binding protein (DBP) is a vital ligand forPlasmodium vivaxblood-stage merozoite invasion, making the molecule an attractive vaccine candidate against vivax malaria. Similar to other blood-stage vaccine candidates, DBP allelic variation eliciting a strain-specific immunity may be a major challenge for development of a broadly effective vaccine against vivax malaria. To understand whether conserved epitopes can be the target of neutralizing anti-DBP inhibition, we generated a set of monoclonal antibodies to DBP and functionally analyzed their reactivity to a panel of allelic variants. Quantitative analysis by enzyme-linked immunosorbent assay (ELISA) determined that some monoclonal antibodies reacted strongly with epitopes conserved on all DBP variants tested, while reactivity of others was allele specific. Qualitative analysis characterized by anti-DBP functional inhibition using anin vitroerythrocyte binding inhibition assay indicated that there was no consistent correlation between the endpoint titers and functional inhibition. Some monoclonal antibodies were broadly inhibitory while inhibition of others varied significantly by target allele. These data demonstrate a potential for vaccine-elicited immunization to target conserved epitopes but optimization of DBP epitope target specificity and immunogenicity may be necessary for protection against diverseP. vivaxstrains.

scholarly journals Plasmodium vivax Strains Use Alternative Pathways for Invasion

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.

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

2005 ◽  
Vol 144 (1) ◽  
pp. 100-103 ◽  
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

scholarly journals Design and Immunogenicity of a Novel Synthetic Antigen Based on the Ligand Domain of the Plasmodium vivax Duffy Binding Protein

2011 ◽  
Vol 19 (1) ◽  
pp. 30-36 ◽  
Author(s):  
Francis B. Ntumngia ◽  
John H. Adams
Keyword(s):  
Amino Acids ◽  
Plasmodium Vivax ◽  
Binding Protein ◽  
Cell Epitope ◽  
Binding Motif ◽  
Duffy Binding Protein ◽  
Asexual Blood Stage ◽  
Content Type ◽  
Specific Immunity ◽  
Erythrocyte Binding

ABSTRACTThe Duffy binding protein is considered a leading vaccine candidate against asexual blood-stagePlasmodium vivax. The interaction ofP. vivaxmerozoites with human reticulocytes through Duffy binding protein (DBP) and its cognate receptor is vital for parasite infection. The ligand domain of DBP (DBPII) is polymorphic, showing a diversity characteristic of selective immune pressure that tends to compromise vaccine efficacy associated with strain-specific immunity. A previous study resolved that a polymorphic region of DBPII was a dominant B-cell epitope target of human inhibitory anti-DBP antibodies, which we refer to as the DEK epitope for the amino acids in the SalI allele. We hypothesized that the polymorphic residues, which are not functionally important for erythrocyte binding but flank the receptor binding motif of DBPII, comprise variant epitopes that tend to divert the immune response away from more conserved epitopes. In this study, we designed, expressed, and evaluated the immunogenicity of a novel artificial DBPII allele, termed DEKnull, having nonpolar amino acids in the naturally occurring polymorphic charged residues of the DEK epitope. The DEKnull antigen retained erythrocyte-binding activity and elicited antibodies to shared epitopes of SalI DBPII from which it was derived. Our results confirmed that removal of the dominant variant epitope in the DEKnull vaccine lowered immunogenicity of DBPII, but inhibitory anti-DBPII antibodies were elicited against shared neutralizing epitopes on SalI. Focusing immune responses toward more conserved DBP epitopes may avoid development of a strain-specific immunity and enhance functional inhibition against broader range of DBPII variants.

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

2005 ◽  
Vol 55 (5) ◽  
pp. 1413-1422 ◽  
Author(s):  
Hyeryun Choe ◽  
Michael J. Moore ◽  
Christopher M. Owens ◽  
Paulette L. Wright ◽  
Natalya Vasilieva ◽  
...  
Keyword(s):  
Plasmodium Vivax ◽  
Binding Protein ◽  
Antigen Receptor ◽  
Duffy Binding Protein ◽  
Duffy Antigen

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

PLoS ONE ◽  
2015 ◽  
Vol 10 (6) ◽  
pp. e0131339 ◽  
Author(s):  
Daniela Camargos Costa ◽  
Gabriela Maíra Pereira de Assis ◽  
Flávia Alessandra de Souza Silva ◽  
Flávia Carolina Araújo ◽  
Júlio César de Souza Junior ◽  
...  
Keyword(s):  
Genetic Variability ◽  
Plasmodium Vivax ◽  
Malaria Parasite ◽  
Binding Protein ◽  
Antigen Receptor ◽  
Duffy Binding Protein ◽  
Duffy Antigen

scholarly journals Identification of an Immunogenic Broadly Inhibitory Surface Epitope of thePlasmodium vivaxDuffy Binding Protein Ligand Domain

mSphere ◽  
2019 ◽  
Vol 4 (3) ◽  
Author(s):  
Miriam T. George ◽  
Jesse L. Schloegel ◽  
Francis B. Ntumngia ◽  
Samantha J. Barnes ◽  
Christopher L. King ◽  
...  
Keyword(s):  
Plasmodium Vivax ◽  
Vivax Malaria ◽  
Vaccine Candidate ◽  
Allelic Variation ◽  
Binding Protein ◽  
Effective Vaccine ◽  
Inhibitory Antibody ◽  
Duffy Binding Protein ◽  
Content Type ◽  
Surface Receptor

ABSTRACTThePlasmodium vivaxDuffy binding protein region II (DBPII) is a vital ligand for the parasite’s invasion of reticulocytes, thereby making this molecule an attractive vaccine candidate against vivax malaria. However, strain-specific immunity due to DBPII allelic variation in Bc epitopes may complicate vaccine efficacy, suggesting that an effective DBPII vaccine needs to target conserved epitopes that are potential targets of strain-transcending neutralizing immunity. The minimal epitopes reactive with functionally inhibitory anti-DBPII monoclonal antibody (MAb) 3C9 and noninhibitory anti-DBPII MAb 3D10 were mapped using phage display expression libraries, since previous attempts to deduce the 3C9 epitope by cocrystallographic methods failed. Inhibitory MAb 3C9 binds to a conserved conformation-dependent epitope in subdomain 3, while noninhibitory MAb 3D10 binds to a linear epitope in subdomain 1 of DBPII, consistent with previous studies. Immunogenicity studies using synthetic linear peptides of the minimal epitopes determined that the 3C9 epitope, but not the 3D10 epitope, could induce functionally inhibitory anti-DBPII antibodies. Therefore, the highly conserved binding-inhibitory 3C9 epitope offers the potential as a component in a broadly inhibitory, strain-transcending DBP subunit vaccine.IMPORTANCEVivax malaria is the second leading cause of malaria worldwide and the major cause of non-African malaria. Unfortunately, efforts to develop antimalarial vaccines specifically targetingPlasmodium vivaxhave been largely neglected, and few candidates have progressed into clinical trials. The Duffy binding protein is considered a leading blood-stage vaccine candidate because this ligand’s recognition of the Duffy blood group reticulocyte surface receptor is considered essential for infection. This study identifies a new target epitope on the ligand’s surface that may serve as the target of vaccine-induced binding-inhibitory antibody (BIAb). Understanding the potential targets of vaccine protection will be important for development of an effective vaccine.

scholarly journals Immunogenicity of a Synthetic Vaccine Based on Plasmodium vivax Duffy Binding Protein Region II

2014 ◽  
Vol 21 (9) ◽  
pp. 1215-1223 ◽  
Author(s):  
Francis B. Ntumngia ◽  
Samantha J. Barnes ◽  
Amy M. McHenry ◽  
Miriam T. George ◽  
Jesse Schloegel ◽  
...  
Keyword(s):  
Plasmodium Vivax ◽  
Vaccine Development ◽  
Allelic Variation ◽  
Binding Protein ◽  
Blood Stage ◽  
Duffy Binding Protein ◽  
Merozoite Invasion ◽  
Content Type ◽  
Functional Antibodies ◽  
Region Ii

ABSTRACTMolecules that play a role inPlasmodiummerozoite invasion of host red blood cells represent attractive targets for blood-stage vaccine development against malaria. InPlasmodium vivax, merozoite invasion of reticulocytes is mediated by the Duffy binding protein (DBP), which interacts with its cognate receptor, the Duffy antigen receptor for chemokines, on the surface of reticulocytes. The DBP ligand domain, known as region II (DBPII), contains the critical residues for receptor recognition, making it a prime target for vaccine development against blood-stage vivax malaria. In natural infections, DBP is weakly immunogenic and DBPII allelic variation is associated with strain-specific immunity, which may compromise vaccine efficacy. In a previous study, a synthetic vaccine termed DEKnull that lacked an immunodominant variant epitope in DBPII induced functional antibodies to shared neutralizing epitopes on the native Sal1 allele. Anti-DEKnull antibody titers were lower than anti-Sal1 titers but produced more consistent, strain-transcending anti-DBPII inhibitory responses. In this study, we further characterized the immunogenicity of DEKnull, finding that immunization with recombinant DEKnull produced an immune response comparable to that obtained with native recombinant DBP alleles. Further investigation of DEKnull is necessary to enhance its immunogenicity and broaden its specificity.

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