Skip to main content

Thank you for visiting nature.com. 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.

Basigin is a receptor essential for erythrocyte invasion by Plasmodium falciparum

Nature volume 480, pages 534–537 (2011)Cite this article

Subjects

This article has been updated

Abstract

Erythrocyte invasion by Plasmodium falciparum is central to the pathogenesis of malaria. Invasion requires a series of extracellular recognition events between erythrocyte receptors and ligands on the merozoite, the invasive form of the parasite. None of the few known receptor–ligand interactions involved1,2,3,4 are required in all parasite strains, indicating that the parasite is able to access multiple redundant invasion pathways5. Here, we show that we have identified a receptor–ligand pair that is essential for erythrocyte invasion in all tested P. falciparum strains. By systematically screening a library of erythrocyte proteins, we have found that the Ok blood group antigen, basigin, is a receptor for PfRh5, a parasite ligand that is essential for blood stage growth6. Erythrocyte invasion was potently inhibited by soluble basigin or by basigin knockdown, and invasion could be completely blocked using low concentrations of anti-basigin antibodies; importantly, these effects were observed across all laboratory-adapted and field strains tested. Furthermore, Oka− erythrocytes, which express a basigin variant that has a weaker binding affinity for PfRh5, had reduced invasion efficiencies. Our discovery of a cross-strain dependency on a single extracellular receptor–ligand pair for erythrocyte invasion by P. falciparum provides a focus for new anti-malarial therapies.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: BSG is an erythrocyte receptor for PfRh5.
Figure 2: Soluble BSG, anti-BSG antibodies and BSG knockdown potently block erythrocyte invasion.
Figure 3: The Ok a− BSG variant has reduced binding affinity for PfRh5 and Ok a− erythrocytes have reduced merozoite invasion frequencies.

Change history

  • 21 December 2011

    The Competing Financial Interests statement appeared incorrectly in the AOP PDF version. This has been corrected.

References

  1. Maier, A. G. et al. Plasmodium falciparum erythrocyte invasion through glycophorin C and selection for Gerbich negativity in human populations. Nature Med. 9, 87–92 (2003)

    Article  CAS  Google Scholar 

  2. Mayer, D. C. et al. Glycophorin B is the erythrocyte receptor of Plasmodium falciparum erythrocyte-binding ligand, EBL-1. Proc. Natl Acad. Sci. USA 106, 5348–5352 (2009)

    Article  ADS  CAS  Google Scholar 

  3. Sim, B. K. et al. Receptor and ligand domains for invasion of erythrocytes by Plasmodium falciparum. Science 264, 1941–1944 (1994)

    Article  ADS  CAS  Google Scholar 

  4. Tham, W. H. et al. Complement receptor 1 is the host erythrocyte receptor for Plasmodium falciparum PfRh4 invasion ligand. Proc. Natl Acad. Sci. USA 107, 17327–17332 (2010)

    Article  ADS  CAS  Google Scholar 

  5. Cowman, A. F. & Crabb, B. S. Invasion of red blood cells by malaria parasites. Cell 124, 755–766 (2006)

    Article  CAS  Google Scholar 

  6. Baum, J. et al. Reticulocyte-binding protein homologue 5 – an essential adhesin involved in invasion of human erythrocytes by Plasmodium falciparum. Int. J. Parasitol. 39, 371–380 (2009)

    Article  CAS  Google Scholar 

  7. Iyer, J. et al. Invasion of host cells by malaria parasites: a tale of two protein families. Mol. Microbiol. 65, 231–249 (2007)

    Article  CAS  Google Scholar 

  8. Hayton, K. et al. Erythrocyte binding protein PfRH5 polymorphisms determine species-specific pathways of Plasmodium falciparum invasion. Cell Host Microbe 4, 40–51 (2008)

    Article  CAS  Google Scholar 

  9. Rodriguez, M. et al. PfRH5: a novel reticulocyte-binding family homolog of Plasmodium falciparum that binds to the erythrocyte, and an investigation of its receptor. PLoS ONE 3, e3300 (2008)

    Article  ADS  Google Scholar 

  10. Pasini, E. M. et al. In-depth analysis of the membrane and cytosolic proteome of red blood cells. Blood 108, 791–801 (2006)

    Article  CAS  Google Scholar 

  11. Bushell, K. M. et al. Large-scale screening for novel low-affinity extracellular protein interactions. Genome Res. 18, 622–630 (2008)

    Article  CAS  Google Scholar 

  12. Martin, S. et al. Construction of a large extracellular protein interaction network and its resolution by spatiotemporal expression profiling. Mol. Cell. Proteomics 9, 2654–2665 (2010)

    Article  CAS  Google Scholar 

  13. Söllner, C. & Wright, G. J. A cell surface interaction network of neural leucine-rich repeat receptors. Genome Biol. 10, R99 (2009)

    Article  Google Scholar 

  14. Spring, F. A. et al. The Oka blood group antigen is a marker for the M6 leukocyte activation antigen, the human homolog of OX-47 antigen, basigin and neurothelin, an immunoglobulin superfamily molecule that is widely expressed in human cells and tissues. Eur. J. Immunol. 27, 891–897 (1997)

    Article  CAS  Google Scholar 

  15. Igakura, T. et al. A null mutation in basigin, an immunoglobulin superfamily member, indicates its important roles in peri-implantation development and spermatogenesis. Dev. Biol. 194, 152–165 (1998)

    Article  CAS  Google Scholar 

  16. Fadool, J. M. & Linser, P. J. 5A11 antigen is a cell recognition molecule which is involved in neuronal-glial interactions in avian neural retina. Dev. Dyn. 196, 252–262 (1993)

    Article  CAS  Google Scholar 

  17. Wright, G. J. Signal initiation in biological systems: the properties and detection of transient extracellular protein interactions. Mol. Biosyst. 5, 1405–1412 (2009)

    Article  CAS  Google Scholar 

  18. Williams, B. P. et al. Biochemical and genetic analysis of the Oka blood group antigen. Immunogenetics 27, 322–329 (1988)

    Article  CAS  Google Scholar 

  19. Guo, H. et al. Stimulation of matrix metalloproteinase production by recombinant extracellular matrix metalloproteinase inducer from transfected Chinese hamster ovary cells. J. Biol. Chem. 272, 24–27 (1997)

    Article  CAS  Google Scholar 

  20. Anstee, D. J. The nature and abundance of human red cell surface glycoproteins. J. Immunogenet. 17, 219–225 (1990)

    Article  CAS  Google Scholar 

  21. Theron, M., Hesketh, R. L., Subramanian, S. & Rayner, J. C. An adaptable two-color flow cytometric assay to quantitate the invasion of erythrocytes by Plasmodium falciparum parasites. Cytometry A 77A, 1067–1074 (2010)

    Article  CAS  Google Scholar 

  22. Neafsey, D. E. et al. Genome-wide SNP genotyping highlights the role of natural selection in Plasmodium falciparum population divergence. Genome Biol. 9, R171 (2008)

    Article  Google Scholar 

  23. Bei, A. K., Brugnara, C. & Duraisingh, M. T. In vitro genetic analysis of an erythrocyte determinant of malaria infection. J. Infect. Dis. 202, 1722–1727 (2010)

    Article  Google Scholar 

  24. Durbin, R. M. et al. A map of human genome variation from population-scale sequencing. Nature 467, 1061–1073 (2010)

    Article  ADS  CAS  Google Scholar 

  25. Jallow, M. et al. Genome-wide and fine-resolution association analysis of malaria in West Africa. Nature Genet. 41, 657–665 (2009)

    Article  CAS  Google Scholar 

  26. Teo, Y. Y., Small, K. S. & Kwiatkowski, D. P. Methodological challenges of genome-wide association analysis in Africa. Nature Rev. Genet. 11, 149–160 (2010)

    Article  CAS  Google Scholar 

  27. Sabeti, P. C. et al. Genome-wide detection and characterization of positive selection in human populations. Nature 449, 913–918 (2007)

    Article  ADS  CAS  Google Scholar 

  28. Schlegel, J. et al. Solution characterization of the extracellular region of CD147 and its interaction with its enzyme ligand cyclophilin A. J. Mol. Biol. 391, 518–535 (2009)

    Article  CAS  Google Scholar 

  29. Yu, X. L. et al. Crystal structure of HAb18G/CD147: implications for immunoglobulin superfamily homophilic adhesion. J. Biol. Chem. 283, 18056–18065 (2008)

    Article  CAS  Google Scholar 

  30. Snounou, G. & Beck, H. P. The use of PCR genotyping in the assessment of recrudescence or reinfection after antimalarial drug treatment. Parasitol. Today 14, 462–467 (1998)

    Article  CAS  Google Scholar 

  31. Crosnier, C., Staudt, N. & Wright, G. J. A rapid and scalable method for selecting recombinant mouse monoclonal antibodies. BMC Biol. 8, 76 (2010)

    Article  Google Scholar 

  32. van der Merwe, P. A. & Barclay, A. N. Analysis of cell-adhesion molecule interactions using surface plasmon resonance. Curr. Opin. Immunol. 8, 257–261 (1996)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to the Oka− blood donors. We thank V. Horejsi for monoclonal antibodies and D. Ahr for technical assistance. This work was supported by the Wellcome Trust grant numbers 077108 (G.J.W.) and 089084 (J.C.R.) and National Institutes of Health R01AI057919 (M.T.D.). A.K.B. is supported by a Center for Disease Control grant R36 CK000119-01 and an Epidemiology of Infectious Disease and Biodefense Training Grant 2T32 AI007535-12.

Author information

Author notes

  1. Cécile Crosnier, Leyla Y. Bustamante and S. Josefin Bartholdson: These authors contributed equally to this work.

Authors and Affiliations

  1. Cell Surface Signalling Laboratory, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, UK

    Cécile Crosnier, S. Josefin Bartholdson & Gavin J. Wright

  2. Malaria Programme, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK

    Leyla Y. Bustamante, Michel Theron, Dominic P. Kwiatkowski, Julian C. Rayner & Gavin J. Wright

  3. Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, 02115, Massachusetts, USA

    Amy K. Bei & Manoj T. Duraisingh

  4. Tokyo Red Cross Blood Center, Tokyo 135-8639, Japan

    Makoto Uchikawa

  5. Laboratory of Bacteriology and Virology, Le Dantec Hospital and Laboratory of Parasitology, Cheikh Anta Diop University, BP: 7325, Dakar, Senegal

    Souleymane Mboup & Omar Ndir

  6. Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, UK

    Dominic P. Kwiatkowski

Authors
  1. Cécile Crosnier
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Leyla Y. Bustamante
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S. Josefin Bartholdson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Amy K. Bei
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Michel Theron
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Makoto Uchikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Souleymane Mboup
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Omar Ndir
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Dominic P. Kwiatkowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Manoj T. Duraisingh
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Julian C. Rayner
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Gavin J. Wright
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

C.C. compiled the erythrocyte protein library and identified the PfRh5–BSG interaction. L.Y.B. led the P. falciparum functional validation, with support from M.T. S.J.B. performed the biochemical and biophysical characterization of the interaction. A.K.B. performed the lentiviral knockdown and parasite invasion experiments under the direction of M.T.D. M.U. provided the Oka− blood samples and matching controls. O.N. and S.M. supervised the collection and culturing of field strains. D.P.K. performed genetic analysis on the BSG and PfRh5 loci. G.J.W. and J.C.R. conceived and supervised the project, and wrote the manuscript.

Corresponding authors

Correspondence to Julian C. Rayner or Gavin J. Wright.

Ethics declarations

Competing interests

C.C., L.Y.B., S.J.B., J.C.R. and G.J.W. are named on a patent application relating to this work.

Supplementary information

Supplementary Information

The file contains Supplementary Figures 1-9 with legends and Supplementary Tables 1-4. (PDF 1634 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Crosnier, C., Bustamante, L., Bartholdson, S. et al. Basigin is a receptor essential for erythrocyte invasion by Plasmodium falciparum. Nature 480, 534–537 (2011). https://doi.org/10.1038/nature10606

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature10606

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

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