Red blood cell mannoses as phagocytic ligands mediating both sickle cell anaemia and malaria resistance

Huan Cao, Aristotelis Antonopoulos, Sadie Henderson, Heather J.h Wassall, John Brewin, Alanna Masson, Jenna Shepherd, Gabriela Konieczny, Bhinal Patel, Maria-Louise Williams, Adam Davie, Megan Amy Forrester, Lindsay Susan Hall, Beverley Minter, Dimitris Tampakis, Michael Moss, Charlotte Lennon, Wendy Pickford, Lars Erwig, Beverley RobertsonAnne Dell, Gordon Brown, Heather Wilson, David C. Rees, Stuart M Haslam, J. Alexandra Rowe, Robert Barker, Mark Vickers* (Corresponding Author)

*Corresponding author for this work

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In both sickle cell disease and malaria, red blood cells (RBCs) are phagocytosed in the spleen, but receptor-ligand pairs mediating uptake have not been identified. Here, we report that patches of high mannose N-glycans (Man5-9GlcNAc2), expressed on diseased or oxidized RBC surfaces, bind the mannose receptor (CD206) on phagocytes to mediate clearance. We find that extravascular hemolysis in sickle cell disease correlates with high mannose glycan levels on RBCs. Furthermore, Plasmodium falciparum-infected RBCs expose surface mannose N-glycans, which occur at significantly higher levels on infected RBCs from sickle cell trait subjects compared to those lacking hemoglobin S. The glycans are associated with high molecular weight complexes and protease-resistant, lower molecular weight fragments containing spectrin. Recognition of surface N-linked high mannose glycans as a response to cellular stress is a molecular mechanism common to both the pathogenesis of sickle cell disease and resistance to severe malaria in sickle cell trait
Original languageEnglish
Article number1792
Number of pages13
JournalNature Communications
Issue number1
Early online date19 Mar 2021
Publication statusPublished - 19 Mar 2021

Bibliographical note

We are grateful for the assistance provided by both the Microscopy and Histology Core Facility, and the Iain Fraser Cytometry Centre, at the University of Aberdeen. We thank Ann Wheeler and Matt Pearson from Edinburgh Super-Resolution Imaging Consortium for technical support with 3D SIM microscopy. We also thank Janet A. Willment and Bernard Kerscher, supervised by G.D.B., for providing the Fc fusion proteins, Jeanette A. Wagener, supervised by Neil A.R.G. Gow, for providing high purity chitin, Jan Westland for obtaining blood samples and Paul Crocker for useful discussions. Principal funding for this project was provided by Wellcome Trust grant 094847 (R.N.B., L.P.E., M.A.V.). In addition, support was provided by Biotechnology and Biological Sciences Research Council grants BBF0083091 (A.D. and S.M.H.) and BBK0161641 (A.D. and S.M.H.), Wellcome Trust grant 082098 (A.D.), Wellcome Trust grants 97377, 102705 (G.D.B.), and funding for the MRC Centre for Medical Mycology at the University of Aberdeen MR/N006364/1 (G.D.B.).


  • Glycobiology
  • Malaria
  • Pattern recognition receptors
  • sickle cell disease


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