Basigin is a receptor essential for erythrocyte invasion by Plasmodium falciparum (original) (raw)

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

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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.

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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

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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
  2. Leyla Y. Bustamante
  3. S. Josefin Bartholdson
  4. Amy K. Bei
  5. Michel Theron
  6. Makoto Uchikawa
  7. Souleymane Mboup
  8. Omar Ndir
  9. Dominic P. Kwiatkowski
  10. Manoj T. Duraisingh
  11. Julian C. Rayner
  12. Gavin J. Wright

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 toJulian C. Rayner or Gavin J. Wright.

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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.

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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

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Editorial Summary

No entry for malaria parasites

The ability to prevent or impair the invasion of erythrocytes by the Plasmodium falciparum merozoite, the initial blood stage of malaria infection, has long been an ambition for those working on antimalarial therapeutics. It has proved elusive, but comes a step closer with the identification of a specific interaction between the parasite ligand PfRh5 and the erythrocyte receptor basigin, which is essential for parasite invasion of erythrocytes. Invasion can be inhibited by anti-basigin antibodies in all laboratory-adapted and field strains of P. falciparum tested, providing a promising starting point for the development of invasion-blocking drugs and vaccines.