Induction of Strain-transcendent Antibodies to Placental-type Isolates with VAR2CSA DBL3 or DBL5 Recombinant Proteins

Overview

Journal Malar J

Publisher Biomed Central

Specialty Tropical Medicine

Date 2011 Feb 15

PMID 21314945

Citations 21

Authors

Marion Avril

Megan M Cartwright

Marianne J Hathaway

Joseph D Smith

Affiliations

Soon will be listed here.

Abstract

Background: Pregnancy associated malaria is a severe clinical syndrome associated with sequestration of Plasmodium falciparum-infected erythrocytes in the placenta. Placental binding is mediated by VAR2CSA, which adheres to chondroitin sulphate A (CSA). VAR2CSA is a large and polymorphic protein that has six Duffy binding-like (DBL) domains. There is still limited understanding as to how effective individual VAR2CSA domains are at generating inhibitory antibodies or the number of domain variants needed for universal vaccine coverage.

Methods: To investigate the immunogenic properties of single domain VAR2CSA recombinant proteins, rats or rabbits were immunized with five of the six VAR2CSA domains produced in Pichia pastoris. Immune plasma was analysed against a geographically diverse panel of CSA-binding lab lines to assess antibody breadth and inhibitory activity.

Results: Of the five domains, DBL3, and to a lesser extent DBL5, induced antibodies that cross-reacted on five diverse CSA-binding parasite lines by flow cytometry. By comparison, anti-DBL6 antibodies were highly strain-specific and anti-DBL1 and anti-DBL4 antibodies were poorly reactive by flow cytometry. From this series of recombinant proteins, adhesion-blocking activity was restricted to a single rat immunized against a DBL4 recombinant protein.

Conclusions: Single domain VAR2CSA recombinant proteins produced in P. pastoris had limited efficacy in eliciting adhesion blocking antibody responses, but VAR2CSA DBL3 and DBL5 domains contain strain-transcendent epitopes that can be targeted by vaccination and may have application for vaccine development.

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References

Hommel M, Elliott S, Soma V, Kelly G, Fowkes F, Chesson J . Evaluation of the antigenic diversity of placenta-binding Plasmodium falciparum variants and the antibody repertoire among pregnant women. Infect Immun. 2010; 78(5):1963-78. PMC: 2863515. DOI: 10.1128/IAI.01365-09. View

Barfod L, Nielsen M, Turner L, Dahlback M, Jensen A, Hviid L . Baculovirus-expressed constructs induce immunoglobulin G that recognizes VAR2CSA on Plasmodium falciparum-infected erythrocytes. Infect Immun. 2006; 74(7):4357-60. PMC: 1489712. DOI: 10.1128/IAI.01617-05. View

Fernandez P, Petres S, Mecheri S, Gysin J, Scherf A . Strain-transcendent immune response to recombinant Var2CSA DBL5-ε domain block P. falciparum adhesion to placenta-derived BeWo cells under flow conditions. PLoS One. 2010; 5(9):e12558. PMC: 2933227. DOI: 10.1371/journal.pone.0012558. View

Jaworowski A, Fernandes L, Yosaatmadja F, Feng G, Mwapasa V, Molyneux M . Relationship between human immunodeficiency virus type 1 coinfection, anemia, and levels and function of antibodies to variant surface antigens in pregnancy-associated malaria. Clin Vaccine Immunol. 2009; 16(3):312-9. PMC: 2650867. DOI: 10.1128/CVI.00356-08. View

Resende M, Ditlev S, Nielsen M, Bodevin S, Bruun S, Pinto V . Chondroitin sulphate A (CSA)-binding of single recombinant Duffy-binding-like domains is not restricted to Plasmodium falciparum Erythrocyte Membrane Protein 1 expressed by CSA-binding parasites. Int J Parasitol. 2009; 39(11):1195-204. DOI: 10.1016/j.ijpara.2009.02.022. View

Staalsoe T, Shulman C, Bulmer J, Kawuondo K, Marsh K, Hviid L . Variant surface antigen-specific IgG and protection against clinical consequences of pregnancy-associated Plasmodium falciparum malaria. Lancet. 2004; 363(9405):283-9. DOI: 10.1016/S0140-6736(03)15386-X. View

Salanti A, Staalsoe T, Lavstsen T, Jensen A, Sowa M, Arnot D . Selective upregulation of a single distinctly structured var gene in chondroitin sulphate A-adhering Plasmodium falciparum involved in pregnancy-associated malaria. Mol Microbiol. 2003; 49(1):179-91. DOI: 10.1046/j.1365-2958.2003.03570.x. View

Viebig N, Gamain B, Scheidig C, Lepolard C, Przyborski J, Lanzer M . A single member of the Plasmodium falciparum var multigene family determines cytoadhesion to the placental receptor chondroitin sulphate A. EMBO Rep. 2005; 6(8):775-81. PMC: 1369142. DOI: 10.1038/sj.embor.7400466. View

Walker-Abbey A, Djokam R, Eno A, Leke R, Titanji V, Fogako J . Malaria in pregnant Cameroonian women: the effect of age and gravidity on submicroscopic and mixed-species infections and multiple parasite genotypes. Am J Trop Med Hyg. 2005; 72(3):229-35. View

10.

Singh K, Gittis A, Nguyen P, Gowda D, Miller L, Garboczi D . Structure of the DBL3x domain of pregnancy-associated malaria protein VAR2CSA complexed with chondroitin sulfate A. Nat Struct Mol Biol. 2009; 15(9):932-8. PMC: 2658892. DOI: 10.1038/nsmb.1479. View

11.

Nielsen M, Pinto V, Resende M, Dahlback M, Ditlev S, Theander T . Induction of adhesion-inhibitory antibodies against placental Plasmodium falciparum parasites by using single domains of VAR2CSA. Infect Immun. 2009; 77(6):2482-7. PMC: 2687338. DOI: 10.1128/IAI.00159-09. View

12.

Elliott S, Brennan A, Beeson J, Tadesse E, Molyneux M, Brown G . Placental malaria induces variant-specific antibodies of the cytophilic subtypes immunoglobulin G1 (IgG1) and IgG3 that correlate with adhesion inhibitory activity. Infect Immun. 2005; 73(9):5903-7. PMC: 1231106. DOI: 10.1128/IAI.73.9.5903-5907.2005. View

13.

Leke R, Bioga J, Zhou J, Fouda G, Leke R, Tchinda V . Longitudinal studies of Plasmodium falciparum malaria in pregnant women living in a rural Cameroonian village with high perennial transmission. Am J Trop Med Hyg. 2010; 83(5):996-1004. PMC: 2963958. DOI: 10.4269/ajtmh.2010.10-0249. View

14.

Magistrado P, Minja D, Doritchamou J, Ndam N, John D, Schmiegelow C . High efficacy of anti DBL4ɛ-VAR2CSA antibodies in inhibition of CSA-binding Plasmodium falciparum-infected erythrocytes from pregnant women. Vaccine. 2010; 29(3):437-43. DOI: 10.1016/j.vaccine.2010.10.080. View

15.

Tolia N, Enemark E, Sim B, Joshua-Tor L . Structural basis for the EBA-175 erythrocyte invasion pathway of the malaria parasite Plasmodium falciparum. Cell. 2005; 122(2):183-93. DOI: 10.1016/j.cell.2005.05.033. View

16.

Duffy M, Maier A, Byrne T, Marty A, Elliott S, ONeill M . VAR2CSA is the principal ligand for chondroitin sulfate A in two allogeneic isolates of Plasmodium falciparum. Mol Biochem Parasitol. 2006; 148(2):117-24. DOI: 10.1016/j.molbiopara.2006.03.006. View

17.

Mount A, Mwapasa V, Elliott S, Beeson J, Tadesse E, Lema V . Impairment of humoral immunity to Plasmodium falciparum malaria in pregnancy by HIV infection. Lancet. 2004; 363(9424):1860-7. DOI: 10.1016/S0140-6736(04)16354-X. View

18.

Harrington W, Mutabingwa T, Muehlenbachs A, Sorensen B, Bolla M, Fried M . Competitive facilitation of drug-resistant Plasmodium falciparum malaria parasites in pregnant women who receive preventive treatment. Proc Natl Acad Sci U S A. 2009; 106(22):9027-32. PMC: 2690058. DOI: 10.1073/pnas.0901415106. View

19.

Fernandez P, Viebig N, Dechavanne S, Lepolard C, Gysin J, Scherf A . Var2CSA DBL6-epsilon domain expressed in HEK293 induces limited cross-reactive and blocking antibodies to CSA binding parasites. Malar J. 2008; 7:170. PMC: 2543044. DOI: 10.1186/1475-2875-7-170. View

20.

Scherf A, Hernandez-Rivas R, Buffet P, Bottius E, Benatar C, Pouvelle B . Antigenic variation in malaria: in situ switching, relaxed and mutually exclusive transcription of var genes during intra-erythrocytic development in Plasmodium falciparum. EMBO J. 1998; 17(18):5418-26. PMC: 1170867. DOI: 10.1093/emboj/17.18.5418. View