Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Cytoadhesion of Plasmodium falciparum ring-stage-infected erythrocytes


A common pathological characteristic of Plasmodium falciparum infection is the cytoadhesion of mature-stage-infected erythrocytes (IE) to host endothelium and syncytiotrophoblasts. Massive accumulation of IE in the brain microvasculature or placenta is strongly correlated with severe forms of malaria1. Extensive binding of IE to placental chondroitin sulfate A (CSA) is associated with physiopathology during pregnancy2,3. The adhesive phenotype of IE correlates with the appearance of Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) at the erythrocyte surface (approximately 16 h after merozoite invasion), so that only early blood-stage (ring-stage) IE appear in the peripheral blood. Here, we describe results that challenge the existing view of blood-stage IE biology by demonstrating the specific adhesion of IE, during the early ring-stage, to endothelial cell lines from the brain and lung and to placental syncytiotrophoblasts. Later, during blood-stage development of these IE, trophozoites switch to an exclusively CSA cytoadhesion phenotype. Therefore, adhesion to an individual endothelial cell or syncytiotrophoblast may occur throughout the blood-stage cycle, indicating the presence in malaria patients of noncirculating (cryptic) parasite subpopulations. We detected two previously unknown parasite proteins on the surface of ring-stage IE. These proteins disappear shortly after the start of PfEMP1-mediated adhesion.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Ring-stage IECSA adhesion to various cells and tissues.
Figure 2: Cytoadhesion throughout the blood-stage cycle.
Figure 3: Adhesive ring-stage IE express previously unknown ring-stage-specific surface molecules that are targets of the immune response.


  1. Miller, L.H., Good, M.F. & Milon, G. Malaria pathogenesis. Science 264, 1878–1883 (1994).

    Article  CAS  Google Scholar 

  2. Fried, M. & Duffy, P.E. Adherence of Plasmodium falciparum to chondroitin sulfate A in the human placenta. Science 272, 1502–1504 ( 1996).

    Article  CAS  Google Scholar 

  3. Gysin, J., Pouvelle, B., Fievet, N., Scherf, A. & Lépolard, C. Ex vivo desequestration of Plasmodium falciparum-infected erythrocytes from human placenta by chondroitin sulfate A. Infect. Immun. 67, 6596–6602 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Watkinson, M. & Rushton, D.I. Plasmodial pigmentation of placenta and outcome of pregnancy in West African mothers. Br. Med. J. 287, 251–254 (1983).

    Article  CAS  Google Scholar 

  5. Matteelli, A. et al. Malaria and anaemia in pregnant women in urban Zanzibar, Tanzania . Ann. Trop. Med. Parasitol. 88, 475– 483 (1994).

    Article  CAS  Google Scholar 

  6. Beeson, J.G. et al. Plasmodium falciparum isolates from infected pregnant women and children are associated with distinct adhesive and antigenic properties . J. Infect. Dis. 180, 464– 472 (1999).

    Article  CAS  Google Scholar 

  7. Fusaï, T. et al. Characterisation of the chondroitin sulphate of Saimiri brain microvascular endothelial cells involved in P. falciparum cytoadhesion. Mol. Biochem. Parasitol., 108, 25–37 (2000).

    Article  Google Scholar 

  8. Buffet, P.A. et al. Plasmodium falciparum domain mediating adhesion to chondroitin sulfate A: A receptor for human placental infection. Proc. Natl. Acad. Sci. USA. 96, 12743– 12748 (1999).

    Article  CAS  Google Scholar 

  9. Silamut, K. et al. A quantitative analysis of the microvascular sequestration of malaria parasites in the human brain. Am. J. Pathol. 155, 395–410 (1999).

    Article  CAS  Google Scholar 

  10. Boffa, M.C., Jackman, R.W., Peyri, N. & George, B. Thrombomodulin in the central nervous system. Nouv. Rev. Fr. Hematol. 33, 423–429 ( 1991).

    CAS  PubMed  Google Scholar 

  11. Wong, V.L., Hofman, F.M., Ishii, H. & Fisher, M. Regional distribution of thrombomodulin in human brain. Brain Res. 556, 1–5 (1991).

    Article  CAS  Google Scholar 

  12. Gysin, J., Pouvelle, B., Le Tonqueze, M., Edelman, L. & Boffa, M.C. Chondroitin sulfate of thrombomodulin is an adhesion receptor for Plasmodium falciparum-infected erythrocytes. Mol. Biochem. Parasitol. 88, 267–271 (1997).

    Article  CAS  Google Scholar 

  13. Fernandez, V., Hommel, M., Chen, Q., Hagblom, P. & Wahlgren, M. Small, clonally variant antigens expressed on the surface of the Plasmodium falciparum-infected erythrocyte are encoded by the rif gene family and are the target of human immune responses. J. Exp. Med. 190, 1393–1404 (1999).

    Article  CAS  Google Scholar 

  14. Gysin, J. & Fandeur, T. Saimiri sciureus (Karyotype 14-7) an alternative experimental model of Plasmodium falciparum infection. Am. J. Trop. Med. Hyg. 32, 461–467 (1983).

    Article  CAS  Google Scholar 

  15. Robert, C. et al. Chondroitin-4-sulphate (proteoglycan), a receptor for Plasmodium falciparum-infected erythrocyte adherence on brain microvascular endothelial cells. Res. Immunol. 146, 383 –393 (1995).

    Article  CAS  Google Scholar 

  16. Pouvelle, B., Fusaï, T., Lépolard, C. & Gysin, J. Biological and biochemical characteristics of cytoadhesion of Plasmodium falciparum-infected erythrocytes to chondroitin-4-sulfate. Infect. Immun. 66, 4950–4956 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Gay, F. et al. Isolation and characterization of brain microvascular endothelial cells from Saimiri monkeys. An in vitro model for sequestration of Plasmodium falciparum-infected erythrocytes. J. Immunol. Methods 184, 15–28 ( 1995).

    Article  CAS  Google Scholar 

  18. Lou, J. et al. Modulation of soluble and membrane-bound TNF-induced phenotypic and functional changes of human brain microvascular endothelial cells by recombinant TNF binding protein I. J. Neuroimmunol. 77, 107–115 (1997).

    Article  CAS  Google Scholar 

  19. Muanza, K., Gay, F., Behr, C. & Scherf, A. Primary culture of human lung microvessel endothelial cells: a useful in vitro model for studying Plasmodium falciparum-infected erythrocyte cytoadherence . Res. Immunol. 147, 149– 163 (1996).

    Article  CAS  Google Scholar 

  20. Ades, E.W. et al. HMEC-1: establishment of an immortalized human microvascular endothelial cell line. J. Invest. Dermatol. 99, 683–690 (1992).

    Article  CAS  Google Scholar 

  21. Carter, K.C. et al. A three-dimensional view of precursor messenger RNA metabolism within the mammalian nucleus. Science 259, 1330–1335 (1993).

    Article  CAS  Google Scholar 

  22. Scherf, A. et al. Antigenic variation in malaria: in situ switching, relaxed and mutually exclusive transcription of var genes during intra-erythrocytic development in Plasmodium falciparum. EMBO J. 17, 5418–5426 (1998).

    Article  CAS  Google Scholar 

Download references


Acknowledgments We thank C. Roth for critically reading the manuscript, C. Scheidig for technical assistance, G.E. Grau, J. Sampol, and K. Muanza for human endothelial cells, and L. Edelman for the anti-CD36 FA6-152 antibody. This work was supported by grants from the Commission of the European Union for research and technical development (Contract Number CT98-0362 and QLRT-PL1999-30109), groupement de recherche and a French Army grant (Contract Number DSP/STTC-97/070). P. Buffet was supported by Fondation Mérieux and Fond d'Etudes de l'Assistance Publique/Hopitaux de Paris.

Author information

Authors and Affiliations


Corresponding author

Correspondence to J. Gysin.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Pouvelle, B., Buffet, P., Lépolard, C. et al. Cytoadhesion of Plasmodium falciparum ring-stage-infected erythrocytes . Nat Med 6, 1264–1268 (2000).

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing