TY - JOUR
T1 - High mannose N-glycans on red blood cells as phagocytic ligands, mediating both sickle cell anaemia and resistance to malaria
AU - Cao, Huan
AU - Antonopoulos, Aristotelis
AU - Henderson, Sadie
AU - Wassall, Heather J.h
AU - Brewin, John
AU - Masson, Alanna
AU - Shepherd, Jenna
AU - Konieczny, Gabriela
AU - Patel, Bhinal
AU - Williams, Maria-Louise
AU - Davie, Adam
AU - Forrester, Megan Amy
AU - Hall, Lindsay
AU - Minter, Beverley
AU - Tampakis, Dimitris
AU - Moss, Michael
AU - Lennon, Charlotte
AU - Pickford, Wendy
AU - Erwig, Lars
AU - Robertson, Beverley
AU - Dell, Anne
AU - Brown, Gordon Douglas
AU - Wilson, Heather
AU - Rees, David C.
AU - Haslam, Stuart M
AU - Rowe, J. Alexandra
AU - Barker, Robert
AU - Vickers, Mark
N1 - Acknowledgements
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).
PY - 2020/11/27
Y1 - 2020/11/27
N2 - In both sickle cell disease (SCD) 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. Extravascular haemolysis in SCD correlates with high mannose glycan levels on RBCs. Infection of RBCs with Plasmodium falciparum expose surface mannose N-glycans on healthy RBCs, which occurred at significantly higher levels on RBCs from subjects with sickle cell trait compared to those lacking haemoglobin S. The glycans were associated with high molecular weight complexes and protease-resistant, lower molecular weight fragments containing spectrin. Recognition of surface N-linked high mannose glycans, a novel response to cellular stress, is the first molecular mechanism common to both the pathogenesis of SCD and resistance to severe malaria in sickle cell trait.
AB - In both sickle cell disease (SCD) 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. Extravascular haemolysis in SCD correlates with high mannose glycan levels on RBCs. Infection of RBCs with Plasmodium falciparum expose surface mannose N-glycans on healthy RBCs, which occurred at significantly higher levels on RBCs from subjects with sickle cell trait compared to those lacking haemoglobin S. The glycans were associated with high molecular weight complexes and protease-resistant, lower molecular weight fragments containing spectrin. Recognition of surface N-linked high mannose glycans, a novel response to cellular stress, is the first molecular mechanism common to both the pathogenesis of SCD and resistance to severe malaria in sickle cell trait.
U2 - 10.1101/2020.11.26.399402
DO - 10.1101/2020.11.26.399402
M3 - Article
JO - bioRxiv
JF - bioRxiv
ER -
