High mannose N-glycans on red blood cells as phagocytic ligands, mediating both sickle cell anaemia and resistance to malaria

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 Hall; Beverley Minter; Dimitris  Tampakis; Michael Moss; Charlotte Lennon; Wendy Pickford; Lars Erwig; Beverley  Robertson; Anne  Dell; Gordon Douglas Brown; Heather Wilson; David C.  Rees; Stuart M Haslam; J. Alexandra Rowe; Robert Barker; Mark Vickers

doi:10.1101/2020.11.26.399402

High mannose N-glycans on red blood cells as phagocytic ligands, mediating both sickle cell anaemia and resistance to malaria

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 Hall, Beverley Minter, Dimitris Tampakis, Michael Moss, Charlotte Lennon, Wendy Pickford, Lars Erwig, Beverley RobertsonAnne Dell, Gordon Douglas Brown, Heather Wilson, David C. Rees, Stuart M Haslam, J. Alexandra Rowe^* (Corresponding Author), Robert Barker, Mark Vickers^* (Corresponding Author)

^*Corresponding author for this work

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Abstract

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.

Original language	English
Journal	bioRxiv
Early online date	27 Nov 2020
DOIs	https://doi.org/10.1101/2020.11.26.399402
Publication status	E-pub ahead of print - 27 Nov 2020

Bibliographical note

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).

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Cao, H., Antonopoulos, A., Henderson, S., Wassall, H. J. H., Brewin, J., Masson, A., Shepherd, J., Konieczny, G., Patel, B., Williams, M.-L., Davie, A., Forrester, M. A., Hall, L., Minter, B., Tampakis, D., Moss, M., Lennon, C., Pickford, W., Erwig, L., ... Vickers, M. (2020). High mannose N-glycans on red blood cells as phagocytic ligands, mediating both sickle cell anaemia and resistance to malaria. bioRxiv. Advance online publication. https://doi.org/10.1101/2020.11.26.399402

Cao, H, Antonopoulos, A, Henderson, S, Wassall, HJH, Brewin, J, Masson, A, Shepherd, J, Konieczny, G, Patel, B, Williams, M-L, Davie, A, Forrester, MA, Hall, L, Minter, B, Tampakis, D, Moss, M, Lennon, C, Pickford, W, Erwig, L, Robertson, B, Dell, A, Brown, GD, Wilson, H, Rees, DC, Haslam, SM, Rowe, JA, Barker, R & Vickers, M 2020, 'High mannose N-glycans on red blood cells as phagocytic ligands, mediating both sickle cell anaemia and resistance to malaria', bioRxiv. https://doi.org/10.1101/2020.11.26.399402

@article{7b6c79751e064e1fad743b0fa37f83a0,

title = "High mannose N-glycans on red blood cells as phagocytic ligands, mediating both sickle cell anaemia and resistance to malaria",

abstract = "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.",

author = "Huan Cao and Aristotelis Antonopoulos and Sadie Henderson and Wassall, {Heather J.h} and John Brewin and Alanna Masson and Jenna Shepherd and Gabriela Konieczny and Bhinal Patel and Maria-Louise Williams and Adam Davie and Forrester, {Megan Amy} and Lindsay Hall and Beverley Minter and Dimitris Tampakis and Michael Moss and Charlotte Lennon and Wendy Pickford and Lars Erwig and Beverley Robertson and Anne Dell and Brown, {Gordon Douglas} and Heather Wilson and Rees, {David C.} and Haslam, {Stuart M} and Rowe, {J. Alexandra} and Robert Barker and Mark Vickers",

note = "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).",

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doi = "10.1101/2020.11.26.399402",

language = "English",

journal = "bioRxiv",

publisher = "Cold Spring Harbor Laboratory Press",

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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 -

High mannose N-glycans on red blood cells as phagocytic ligands, mediating both sickle cell anaemia and resistance to malaria

Abstract

Bibliographical note

UN SDGs

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Iain Fraser Cytometry Centre

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