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Severe malaria is associated with parasite binding to endothelial protein C receptor

Nature volume 498, pages 502–505 (2013)Cite this article

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Abstract

Sequestration of Plasmodium falciparum-infected erythrocytes in host blood vessels is a key triggering event in the pathogenesis of severe childhood malaria, which is responsible for about one million deaths every year1. Sequestration is mediated by specific interactions between members of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family and receptors on the endothelial lining2. Severe childhood malaria is associated with expression of specific PfEMP1 subtypes containing domain cassettes (DCs) 8 and 13 (ref. 3), but the endothelial receptor for parasites expressing these proteins was unknown4,5. Here we identify endothelial protein C receptor (EPCR), which mediates the cytoprotective effects of activated protein C6, as the endothelial receptor for DC8 and DC13 PfEMP1. We show that EPCR binding is mediated through the amino-terminal cysteine-rich interdomain region (CIDRα1) of DC8 and group A PfEMP1 subfamilies, and that CIDRα1 interferes with protein C binding to EPCR. This PfEMP1 adhesive property links P. falciparum cytoadhesion to a host receptor involved in anticoagulation and endothelial cytoprotective pathways, and has implications for understanding malaria pathology and the development of new malaria interventions.

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Figure 1: Binding between recombinant PfEMP1 and EPCR.
Figure 2: Binding of DC8-expressing parasites to human brain microvascular endothelial cells.

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Acknowledgements

We thank A. Salanti for supplying the full-length VAR2CSA protein and S. Lücking Nielsen for technical assistance. The work was supported by the University of Copenhagen Program of Excellence, Lundbeck Foundation, Danish International Development Agency, Augustinus Fonden, Malaria Capacity Development Consortium and The Danish Medical Research Council, as well as the National Institutes of Health (R01 AI47953 and U19 AI089688 to J.D.S.). M.K.H. was funded by a research grant from the Medical Research Council.

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Author notes

  1. Louise Turner and Thomas Lavstsen: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of International Health, University of Copenhagen and Department of Infectious Diseases, Centre for Medical Parasitology, Immunology & Microbiology, Rigshospitalet, Copenhagen, Denmark,

    Louise Turner, Thomas Lavstsen, Sanne S. Berger, Christian W. Wang, Jens E. V. Petersen, Jakob S. Jespersen, Morten A. Nielsen & Thor G. Theander

  2. Seattle Biomedical Research Institute, Seattle, 98109-5219, Washington, USA

    Marion Avril, Andrew J. Brazier & Joseph D. Smith

  3. Retrogenix, Crown House, Bingswood Estate, Whaley Bridge, High Peak SK23 7LY, UK,

    Jim Freeth

  4. National Institute of Medical Research, Tanga Centre, Tanga, Tanzania,

    Pamela Magistrado & John Lusingu

  5. Department of Global Health, University of Washington, Seattle, 98195, Washington, USA

    Joseph D. Smith

  6. Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK,

    Matthew K. Higgins

Authors
  1. Louise Turner
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Contributions

L.T., T.L., J.D.S. and A.J.B. produced recombinant proteins; J.F. performed the cell microarray experiments; S.S.B., C.W.W., J.E.V.P., M.A.N., M.A. and J.S.J. performed the work with malaria parasites; P.M., J.L. and T.G.T. organized clinical work and processed clinical samples; M.K.H. performed the SPR studies; L.T. performed the ELISA studies. The study was conceived and planned by L.T., T.L. and T.G.T. The manuscript was written by T.L., T.G.T., L.T., J.D.S. and M.K.H. All authors read and commented on the manuscript. L.T. and T.L. contributed equally to this work.

Corresponding authors

Correspondence to Louise Turner or Thomas Lavstsen.

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The authors declare no competing financial interests.

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Turner, L., Lavstsen, T., Berger, S. et al. Severe malaria is associated with parasite binding to endothelial protein C receptor. Nature 498, 502–505 (2013). https://doi.org/10.1038/nature12216

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