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

Abstract

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.

Non-alcoholic steatohepatitis patients exhibit reduced CD47, and increased sphingosine, cholesterol and MCP1 levels in the erythrocyte membranes

“…The decline of the CD47 levels could be attributed to oxidative stress 26 and erythrocyte’s TLR9 activation 28 . It is also of interest that recently, mannose was also found to represent an important signal for erythrophagocytosis 29 . This mechanism also merits further investigation in the future.…”

Decreased in vitro dihydroartemisinin sensitivity in malaria parasites infecting sickle cell disease patients

“…This low parasite density could be an element explaining a protective effect against severe malaria. It could be due i) to dehydration of red blood cells which could inhibit the invasion and growth of P. falciparum parasites (57, 59, 60); or ii) to inhibition of osmotic shock in SS phenotype erythrocytes (61) resulting in reduced merozoite release (62, 63).…”

Unveiling the Sugary Secrets of Plasmodium Parasites

“…However, Plasmodium infects healthy and sickle-cell RBCs equally well with no apparent differences in invasion or release (Friedman, 1978), suggesting that resistance arises from more efficient immune clearance of infected RBCs. RBCs with sickle-cell trait were recently found to express highmannose N-glycans on their surface that are recognized by the macrophage receptor CD206 followed by phagocytosis (Cao et al, 2021). High-mannose N-glycan surface levels in sicklecell RBCs correlated with the parasite's life stage, being elevated at trophozoite and schizont stage (see Table 1).…”

“…High-mannose N-glycan surface levels in sicklecell RBCs correlated with the parasite's life stage, being elevated at trophozoite and schizont stage (see Table 1). Phagocytosis through macrophages can be inhibited by the addition of mannan, a yeast-derived high-mannose glycan, and oxidative stress can induce expression of high-mannose surface N-glycans in healthy RBCs (Cao et al, 2021). Improved immune clearance presumably arises from the increased susceptibility of sicklecell RBCs to oxidative stress caused by the parasite, mediated through an elevated high-mannose N-glycan level recognized by macrophages (Cao et al, 2021).…”