Hostname: page-component-586b7cd67f-r5fsc Total loading time: 0 Render date: 2024-11-23T15:14:42.609Z Has data issue: false hasContentIssue false
  • English
  • Français

VAR2CSA and protective immunity against pregnancy-associated Plasmodium falciparum malaria

Published online by Cambridge University Press:  25 October 2007

L. HVIID  and
A. SALANTI
L. HVIID*
Affiliation:
Centre for Medical Parasitology at Department of International Health, Immunology and Microbiology, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark
A. SALANTI
Affiliation:
Centre for Medical Parasitology at Department of International Health, Immunology and Microbiology, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark
*
Address for correspondence: Lars Hviid, Centre for Medical Parasitology, Department of Infectious Diseases M4701, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen Ø, Denmark. Fax +45 35 32 78 51. E-mail: [email protected]
Get access Rights & Permissions [Opens in a new window]

Summary

People living in areas with stable transmission of P. falciparum parasites acquire protective immunity to malaria over a number of years and following multiple disease episodes. Immunity acquired this way is mediated by IgG with specificity for parasite-encoded, clonally variant surface antigens (VSA) on the surface of infected erythrocytes (IEs). However, women in endemic areas become susceptible to P. falciparum infection when they become pregnant, particularly for the first time, regardless of previously acquired protective immunity. This conundrum was resolved when it was observed that the selective placental accumulation of IEs that characterizes pregnancy-associated malaria (PAM) is caused by an immunologically and functionally unique subset of VSA (VSAPAM) that is only expressed by parasites infecting pregnant women, and that protective immunity to PAM is mediated by IgG with specificity for VSAPAM. In this review we summarize the research leading to the identification of the distinctly structured PfEMP1 variant VAR2CSA as the dominant PAM-type VSA and as the clinically most important target of the protective immune response to placental P. falciparum infection.

Keywords

AntibodiesimmunitymalariaPlasmodium falciparumpregnancyVAR2CSAvariant surface antigens
Type
Research Article
Information
Parasitology , Volume 134 , Special Issue 13: PARASITES IN PREGNANCY , December 2007 , pp. 1871 - 1876
Copyright
Copyright © Cambridge University Press 2007

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

REFERENCES

Andrews, K. T., Pirrit, L. A., Przyborski, J. M., Sanchez, C. P., Sterkers, Y., Ricken, S., Wickert, H., Lepolard, C., Avril, M., Scherf, A., Gysin, J. and Lanzer, M. (2003). Recovery of adhesion to chondroitin-4-sulphate in Plasmodium falciparum var CSA disruption mutants by antigenically similar PfEMP1 variants. Molecular Microbiology 49, 655–669.Google Scholar
Badaut, C., Faure, G., Tuikue Ndam, N. G., Bertin, G., Chaffotte, A., Khattab, A., Klinkert, M.-Q., Deloron, P. and Bentley, G. A. (2007). Receptor-binding studies of the DBLγ domain of Plasmodium falciparum erythrocyte membrane protein 1 from a placental isolate. Molecular and Biochemical Parasitology 151, 89–99.Google Scholar
Barfod, L., Bernasconi, N., Dahlbäck, M., Jarrosay, D., Andersen, P. H., Salanti, A., Ofori, M. F., Turner, L., Resende, M., Nielsen, M. A., Theander, T. G., Sallusto, F., Lanzavecchia, A. and Hviid, L. (2007). Human pregnancy-associated malaria-specific B cells target polymorphic, conformational epitopes in VAR2CSA. Molecular Microbiology 63, 335–347.CrossRefGoogle ScholarPubMed
Barnwell, J. W., Ockenhouse, C. F. and Knowles, D. M. II. (1985). Monoclonal antibody OKM5 inhibits the in vitro binding of Plasmodium falciparum infected erythrocytes to monocytes, endothelial, and C32 melanoma cells. Journal of Immunology 135, 3494–3497.CrossRefGoogle ScholarPubMed
Baruch, D. I., Pasloske, B. L., Singh, H. B., Bi, X., Ma, X. C., Feldman, M., Taraschi, T. F. and Howard, R. J. (1995). Cloning the P. falciparum gene encoding PfEMP1, a malarial variant antigen and adherence receptor on the surface of parasitized human erythrocytes. Cell 82, 77–87.CrossRefGoogle Scholar
Beeson, J. G., Brown, G. V., Molyneux, M. E., Mhango, C., Dzinjalamala, F. and Rogerson, S. J. (1999). Plasmodium falciparum isolates from infected pregnant women and children are associated with distinct adhesive and antigenic properties. Journal of Infectious Diseases 180, 464–472.Google Scholar
Bir, N., Yazdani, S. S., Avril, M., Layez, C., Gysin, J. and Chitnis, C. E. (2006). Immunogenicity of Duffy binding-like domains that bind chondroitin sulfate A and protection against pregnancy-associated malaria. Infection and Immunity 74, 5955–5963.CrossRefGoogle ScholarPubMed
Blacklock, B. and Gordon, R. M. (1925). Malaria parasites in the placental blood. Annals of Tropical Medicine 19, 37–45.Google Scholar
Bruce-Chwatt, L. J. (1952). Malaria in African infants and children in southern Nigeria. Annals of Tropical Medicine and Parasitology 46, 173–200.Google Scholar
Buffet, P. A., Gamain, B., Scheidig, C., Baruch, D., Smith, J. D., Hernandez-Rivas, R., Pouvelle, B., Oishi, S., Fujii, N., Fusai, T., Parzy, D., Miller, L. H., Gysin, J. and Scherf, A. (1999). Plasmodium falciparum domain mediating adhesion to chondroitin sulfate A: a receptor for human placental infection. Proceedings of the National Academy of Sciences, USA 96, 12743–12748.Google Scholar
Bull, P. C., Lowe, B. S., Kortok, M., Molyneux, C. S., Newbold, C. I. and Marsh, K. (1998). Parasite antigens on the infected red cell are targets for naturally acquired immunity to malaria. Nature Medicine 4, 358–360.Google Scholar
Chia, Y.-S., Badaut, C., Tuikue Ndam, N. G., Khattab, A., Igonet, S., Fievet, N., Bentley, G. A., Deloron, P. and Klinkert, M.-Q. (2005). Functional and immunological characterization of a Duffy binding-like-γ domain from Plasmodium falciparum erythrocyte membrane protein-1 expressed by a placental isolate. Journal of Infectious Diseases 192, 1284–1293.Google Scholar
Cohen, S., McGregor, I. A. and Carrington, S. (1961). Gammaglobulin and acquired immunity to human malaria. Nature 192, 733–737.CrossRefGoogle ScholarPubMed
Dahlbäck, M., Rask, T. S., Andersen, P. H., Nielsen, M. A., Tuikue-Ndam, N. G., Resende, M., Turner, L., Deloron, P., Hviid, L., Lund, O., Pedersen, A. G., Theander, T. G. and Salanti, A. (2006). Epitope mapping and topographic analysis of VAR2CSA DBL3X involved in Plasmodium falciparum placental sequestration. PLoS Pathogens 2, e124.Google Scholar
David, P. H., Hommel, M., Miller, L. H., Udeinya, I. J. and Oligino, L. D. (1983). Parasite sequestration in Plasmodium falciparum malaria: spleen and antibody modulation of cytoadherence of infected erythrocytes. Proceedings of the National Academy of Sciences, USA 80, 5075–5079.CrossRefGoogle ScholarPubMed
Duffy, M. F., Byrne, T. J., Elliott, S. R., Wilson, D. W., Rogerson, S. J., Beeson, J. G., Noviyanti, R. and Brown, G. V. (2005). Broad analysis reveals a consistent pattern of var gene transcription in Plasmodium falciparum repeatedly selected for a defined adhesion phenotype. Molecular Microbiology 56, 774–788.Google Scholar
Duffy, M. F., Maier, A. G., Byrne, T. J., Marty, A. J., Elliott, S. R., O'Neill, M. T., Payne, P. D., Rogerson, S. J., Cowman, A. F., Crabb, B. S. and Brown, G. V. (2006). VAR2CSA is the principal ligand for chondroitin sulfate A in two allogeneic isolates of Plasmodium falciparum. Molecular and Biochemical Parasitology 148, 117–124.Google Scholar
Duffy, P. E. and Desowitz, R. S. (2001). Pregnancy malaria throughout history: dangerous labors. In Malaria in Pregnancy. Deadly Parasite, Susceptible Host. (ed. Duffy, P. E. and Fried, M.), pp. 1–25. Taylor & Francis, London.Google Scholar
Duffy, P. E. and Fried, M. (2003). Antibodies that inhibit Plasmodium falciparum adhesion to chondroitin sulfate A are associated with increased birth weight and the gestational age of newborns. Infection and Immunity 71, 6620–6623.CrossRefGoogle ScholarPubMed
Elliott, S. R., Brennan, A. K., Beeson, J. G., Tadesse, E., Molyneux, M. E., Brown, G. V. and Rogerson, S. J. (2005). Placental malaria induces variant-specific antibodies of the cytophilic subtypes immunoglobulin G1 (IgG1) and IgG3 that correlate with adhesion inhibitory activity. Infection and Immunity 73, 5903–5907.CrossRefGoogle ScholarPubMed
Fried, M. and Duffy, P. E. (1996). Adherence of Plasmodium falciparum to chondroitin sulphate A in the human placenta. Science 272, 1502–1504.CrossRefGoogle ScholarPubMed
Fried, M. and Duffy, P. E. (2002). Two DBLγ subtypes are commonly expressed by placental isolates of Plasmodium falciparum. Molecular and Biochemical Parasitology 122, 201–210.Google Scholar
Fried, M., Nosten, F., Brockman, A., Brabin, B. T. and Duffy, P. E. (1998). Maternal antibodies block malaria. Nature 395, 851–852.CrossRefGoogle ScholarPubMed
Gamain, B., Smith, J. D., Avril, M., Baruch, D. I., Scherf, A., Gysin, J. and Miller, L. H. (2004). Identification of a 67-amino-acid region of the Plasmodium falciparum variant surface antigen that binds chondroitin sulphate A and elicits antibodies reactive with the surface of placental isolates. Molecular Microbiology 53, 445–455.Google Scholar
Gamain, B., Trimnell, A. R., Scheidig, C., Scherf, A., Miller, L. H. and Smith, J. D. (2005). Identification of multiple chondroitin sulfate A (CSA)-binding domains in the var2CSA gene transcribed in CSA-binding parasites. Journal of Infectious Diseases 191, 1010–1013.Google Scholar
Gardner, M. J., Hall, N., Fung, E., White, O., Berriman, M., Hyman, R. W., Carlton, J. M., Pain, A., Nelson, K. E., Bowman, S., Paulsen, I. T., James, K., Eisen, J. A., Rutherford, K., Salzberg, S. L., Craig, A., Kyes, S., Chan, M. S., Nene, V., Shallom, S. J., Suh, B., Peterson, J., Angiuoli, S., Pertea, M., Allen, J., Selengut, J., Haft, D., Mather, M. W., Vaidya, A. B., Martin, D. M., Fairlamb, A. H., Fraunholz, M. J., Roos, D. S., Ralph, S. A., McFadden, G. I., Cummings, L. M., Subramanian, G. M., Mungall, C., Venter, J. C., Carucci, D. J., Hoffman, S. L., Newbold, C., Davis, R. W., Fraser, C. M. and Barrell, B. (2002). Genome sequence of the human malaria parasite Plasmodium falciparum. Nature 419, 498–511.Google Scholar
Greenwood, B. and Mutabingwa, T. (2002). Malaria in 2002. Nature 415, 670–672.CrossRefGoogle ScholarPubMed
Guilbert, L. J., Abbasi, M. and Mosmann, T. R. (2001). The immunology of pregnancy: maternal defenses against infectious diseases. In Malaria in Pregnancy. Deadly Parasite, Susceptible Host. (ed. Duffy, P. E. and Fried, M.), pp. 53–70. Taylor & Francis, London.CrossRefGoogle Scholar
Hviid, L. (2005). Naturally acquired immunity to Plasmodium falciparum malaria in Africa. Acta Tropica 95, 270–275.CrossRefGoogle ScholarPubMed
Jensen, A. T. R., Zornig, H. D., Buhmann, C., Salanti, A., Koram, K. A., Riley, E. M., Theander, T. G., Hviid, L. and Staalsoe, T. (2003). Lack of gender-specific antibody recognition of products from domains of a var gene implicated in pregnancy-associated Plasmodium falciparum malaria. Infection and Immunity 71, 4193–4196.CrossRefGoogle ScholarPubMed
Keen, J., Serghides, L., Ayi, K., Patel, S. N., Ayisi, J., van Eijk, A., Steketee, R., Udhayakumar, V. and Kain, K. C. (2007). HIV impairs phagocytic clearance of pregnancy-associated malaria parasites. PLoS Medicine (in press).Google Scholar
Kraemer, S. M. and Smith, J. D. (2003). Evidence for the importance of genetic structuring to the structural and functional specialization of the Plasmodium falciparum var gene family. Molecular Microbiology 50, 1527–1538.CrossRefGoogle Scholar
Kyes, S. A., Christodoulou, Z., Raza, A., Horrocks, P., Pinches, R., Rowe, J. A. and Newbold, C. I. (2003). A well-conserved Plasmodium falciparum var gene shows an unusual stage-specific transcript pattern. Molecular Microbiology 48, 1339–1348.Google Scholar
Lavstsen, T., Salanti, A., Jensen, A. T. R., Arnot, D. E. and Theander, T. G. (2003). Sub-grouping of Plasmodium falciparum 3D7 var genes based on sequence analysis of coding and non-coding regions. Malaria Journal 2, 27.Google Scholar
Leech, J. H., Barnwell, J. W., Miller, L. H. and Howard, R. J. (1984). Identification of a strain-specific malarial antigen exposed on the surface of Plasmodium falciparum-infected erythrocytes. Journal of Experimental Medicine 159, 1567–1575.Google Scholar
Marsh, K. and Howard, R. J. (1986). Antigens induced on erythrocytes by P. falciparum: expression of diverse and conserved determinants. Science 231, 150–153.CrossRefGoogle ScholarPubMed
Marsh, K., Otoo, L., Hayes, R. J., Carson, D. C. and Greenwood, B. M. (1989). Antibodies to blood stage antigens of Plasmodium falciparum in rural Gambians and their relation to protection against infection. Transactions of the Royal Society of Tropical Medicine and Hygiene 83, 293–303.CrossRefGoogle ScholarPubMed
McGregor, I. A. (1984). Epidemiology, malaria and pregnancy. American Journal of Tropical Medicine and Hygiene 33, 517–525.CrossRefGoogle ScholarPubMed
McGregor, I. A., Carrington, S. P. and Cohen, S. (1963). Treatment of East African P. falciparum malaria with West African human γ-globulin. Transactions of the Royal Society of Tropical Medicine and Hygiene 57, 170–175.Google Scholar
Megnekou, R., Staalsoe, T., Taylor, D. W., Leke, R. and Hviid, L. (2005). Effects of pregnancy and intensity of Plasmodium falciparum transmission on immunoglobulin G subclass responses to variant surface antigens. Infection and Immunity 73, 4112–4118.CrossRefGoogle ScholarPubMed
Menendez, C. (1995). Malaria during pregnancy: a priority area of malaria research and control. Parasitology Today 11, 178–183.Google Scholar
Miller, L. H., Baruch, D. I., Marsh, K. and Doumbo, O. K. (2002). The pathogenic basis of malaria. Nature 415, 673–679.Google Scholar
Mount, A. M., Mwapasa, V., Elliott, S. R., Beeson, J. G., Tadesse, E., Lema, V. M., Molyneux, M. E., Meshnick, S. R. and Rogerson, S. J. (2004). Impairment of humoral immunity to Plasmodium falciparum malaria in pregnancy by HIV infection. Lancet 363, 1860–1867.Google Scholar
Nguyen-Dinh, P., Steketee, R. W., Greenberg, A. E., Wirima, J. J., Mulenda, O. and Williams, S. B. (1988). Rapid spontaneous postpartum clearance of Plasmodium falciparum parasitaemia in African women. Lancet 2, 751–752.Google Scholar
Ockenhouse, C. F., Tandon, N. N., Magowan, C., Jamieson, G. A. and Chulay, J. D. (1989). Identification of a platelet membrane glycoprotein as a falciparum malaria sequestration receptor. Science 243, 1469–1471.CrossRefGoogle ScholarPubMed
Ricke, C. H., Staalsoe, T., Koram, K., Akanmori, B. D., Riley, E. M., Theander, T. G. and Hviid, L. (2000). Plasma antibodies from malaria-exposed pregnant women recognize variant surface antigens on Plasmodium falciparum-infected erythrocytes in a parity-dependent manner and block parasite adhesion to chondroitin sulphate A. Journal of Immunology 165, 3309–3316.Google Scholar
Robert, C., Pouvelle, B., Meyer, P., Muanza, K., Fujioka, H., Aikawa, M., Scherf, A. and Gysin, J. (1995). Chondroitin-4-sulphate (proteoglycan), a receptor for Plasmodium falciparum-infected erythrocyte adherence on brain microvascular endothelial cells. Research in Immunology 146, 383–393.CrossRefGoogle ScholarPubMed
Rogerson, S. J., Chaiyaroj, S. C., Ng, K., Reeder, J. C. and Brown, G. V. (1995). Chondroitin sulfate A is a cell surface receptor for Plasmodium falciparum-infected erythrocytes. Journal of Experimental Medicine 182, 15–20.CrossRefGoogle ScholarPubMed
Rowe, J. A., Kyes, S. A., Rogerson, S. J., Babiker, H. A. and Raza, A. (2002). Identification of a conserved Plasmodium falciparum var gene implicated in malaria in pregnancy. Journal of Infectious Diseases 185, 1207–1211.Google Scholar
Sabchareon, A., Burnouf, T., Ouattara, D., Attanath, P., Bouharoun, T. H., Chantavanich, P., Foucault, C., Chongsuphajaisiddhi, T. and Druilhe, P. (1991). Parasitologic and clinical human response to immunoglobulin administration in falciparum malaria. American Journal of Tropical Medicine and Hygiene 45, 297–308.CrossRefGoogle ScholarPubMed
Sachs, J. and Malaney, P. (2002). The economic and social burden of malaria. Nature 415, 680–685.CrossRefGoogle ScholarPubMed
Salanti, A., Dahlbäck, M., Turner, L., Nielsen, M. A., Barfod, L., Magistrado, P., Jensen, A. T. R., Lavstsen, T., Ofori, M. F., Marsh, K., Hviid, L. and Theander, T. G. (2004). Evidence for the involvement of VAR2CSA in pregnancy-associated malaria. Journal of Experimental Medicine 200, 1197–1203.Google Scholar
Salanti, A., Jensen, A. T. R., Zornig, H. D., Staalsoe, T., Joergensen, L., Nielsen, M. A., Khattab, A., Arnot, D. E., Klinkert, M. Q., Hviid, L. and Theander, T. G. (2002). A sub-family of common and highly conserved var genes expressed by CSA-adhering Plasmodium falciparum. Molecular and Biochemical Parasitology 122, 111–115.CrossRefGoogle Scholar
Salanti, A., Staalsoe, T., Lavstsen, T., Jensen, A. T. R., Sowa, M. P. K., Arnot, D. E., Hviid, L. and Theander, T. G. (2003). Selective upregulation of a single distinctly structured var gene in CSA-adhering Plasmodium falciparum involved in pregnancy-associated malaria. Molecular Microbiology 49, 179–191.Google Scholar
Scherf, A., Hernandez-Rivas, R., Buffet, P., Bottius, E., Benatar, C., Pouvelle, B., Gysin, J. and Lanzer, M. (1998). Antigenic variation in malaria: in situ switching, relaxed and mutually exclusive transcription of var genes during intra-erythrocytic development in Plasmodium falciparum. EMBO Journal 17, 5418–5428.CrossRefGoogle ScholarPubMed
Smith, J. D., Chitnis, C. E., Craig, A. G., Roberts, D. J., Hudson-Taylor, D. E., Peterson, D. S., Pinches, R., Newbold, C. I. and Miller, L. H. (1995). Switches in expression of Plasmodium falciparum var genes correlate with changes in antigenic and cytoadherent phenotypes of infected erythrocytes. Cell 82, 101–110.Google Scholar
Staalsoe, T., Megnekou, R., Fievet, N., Ricke, C. H., Zornig, H. D., Leke, R., Taylor, D. W., Deloron, P. and Hviid, L. (2001). Acquisition and decay of antibodies to pregnancy-associated variant antigens on the surface of Plasmodium falciparum infected erythrocytes that are associated with protection against placental parasitemia. Journal of Infectious Diseases 184, 618–626.CrossRefGoogle ScholarPubMed
Staalsoe, T., Shulman, C. E., Bulmer, J. N., Kawuondo, K., Marsh, K. and Hviid, L. (2004). Variant surface antigen-specific IgG and protection against the clinical consequences of pregnancy-associated Plasmodium falciparum malaria. Lancet 363, 283–289.Google Scholar
Su, X., Heatwole, V. M., Wertheimer, S. P., Guinet, F., Herrfeldt, J. A., Peterson, D. S., Ravetch, J. A. and Wellems, T. E. (1995). The large diverse gene family var encodes proteins involved in cytoadherence and antigenic variation of Plasmodium falciparum-infected erythrocytes. Cell 82, 89–100.Google Scholar
Taylor, H. M., Kyes, S. A., Harris, D., Kriek, N. and Newbold, C. I. (2000). A study of var gene transcription in vitro using universal var gene primers. Molecular and Biochemical Parasitology 105, 13–23.Google Scholar
Traggiai, E., Becker, S., Subbarao, K., Kolesnikova, L., Uematsu, Y., Gismondo, M. R., Murphy, B. R., Rappuoli, R. and Lanzavecchia, A. (2004). An efficient method to make human monoclonal antibodies from memory B cells: potent neutralization of SARS coronavirus. Nature Medicine 10, 871–875.Google Scholar
Trimnell, A. R., Kraemer, S. M., Mukherjee, S., Phippard, D. J., Janes, J. H., Flamoe, E., Su, X. Z., Awadalla, P. and Smith, J. D. (2006). Global genetic diversity and evolution of var genes associated with placental and severe childhood malaria. Molecular and Biochemical Parasitology 148, 169–180.CrossRefGoogle ScholarPubMed
Tuikue Ndam, N. G., Salanti, A., Bertin, G., Dahlbäck, M., Fievet, N., Turner, L., Gaye, A., Theander, T. G. and Deloron, P. (2005). High level of var2csa transcription by Plasmodium falciparum isolated from the placenta. Journal of Infectious Diseases 192, 331–335.Google Scholar
Udeinya, I. J., Miller, L. H., McGregor, I. A. and Jensen, J. B. (1983). Plasmodium falciparum strain-specific antibody blocks binding of infected erythrocytes to amelanotic melanoma cells. Nature 303, 429–431.Google Scholar
Viebig, N. K., Gamain, B., Scheidig, C., Lepolard, C., Przyborski, J., Lanzer, M., Gysin, J. and Scherf, A. (2005). A single member of the Plasmodium falciparum var multigene family determines cytoadhesion to the placental receptor chondroitin sulphate A. EMBO Reports 6, 775–781.Google Scholar
Walton, G. A. (1949). On the control of malaria in Freetown, Sierra Leone. II – control methods and the effects upon the transmission of Plasmodium falciparum resulting from the reduced abundance of Anopheles gambiae. Annals of Tropical Medicine and Parasitology 43, 117–139.CrossRefGoogle Scholar