TY - JOUR T1 - High mannose N-glycans on red blood cells as phagocytic ligands, mediating both sickle cell anaemia and resistance to malaria JF - bioRxiv DO - 10.1101/2020.11.26.399402 SP - 2020.11.26.399402 AU - Huan Cao AU - Aristotelis Antonopoulos AU - Sadie Henderson AU - Heather Wassall AU - John Brewin AU - Alanna Masson AU - Jenna Shepherd AU - Gabriela Konieczny AU - Bhinal Patel AU - Maria-Louise Williams AU - Adam Davie AU - Megan A Forrester AU - Lindsay Hall AU - Beverley Minter AU - Dimitris Tampakis AU - Michael Moss AU - Charlotte Lennon AU - Wendy Pickford AU - Lars Erwig AU - Beverley Robertson AU - Anne Dell AU - Gordon D. Brown AU - Heather M. Wilson AU - David C. Rees AU - Stuart M. Haslam AU - J. Alexandra Rowe AU - Robert N. Barker AU - Mark A. Vickers Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/11/27/2020.11.26.399402.abstract 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.Competing Interest StatementThe University of Aberdeen has applied for a patent arising from this work ER -