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

Cao, Huan; Antonopoulos, Aristotelis; Henderson, Sadie; Wassall, Heather; Brewin, John; Masson, Alanna; Shepherd, Jenna; Konieczny, Gabriela; Patel, Brijesh; Williams, Maria-Louise; Davie, Adam; Forrester, Megan A; Hall, Lindsay S; Minter, Beverley; Tampakis, Dimitris; Moss, Michael; Lennon, Charlotte; Pickford, Wendy; Erwig, Lars P.; Robertson, Beverley; Dell, Anne; Brown, Gordon D.; Rees, David C.; Haslam, Stuart M.; Rowe, J. Alexandra; Barker, Robert N.; Vickers, Mark A.

doi:10.1038/s41467-021-21814-z

Cited by 19 publications

(25 citation statements)

References 56 publications

(22 reference statements)

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“…Even though most of these glycan structures are present on healthy uRBC surfaces (Bua et al, 2021), the higher abundance of complex N-glycans on PfEVs cannot be explained by increased N-glycosylation expression, as mature RBCs lack genomic DNA. Nevertheless, Pf-iRBCs were recently reported to present significantly higher levels of high mannose N-glycans on their cell surface due to oxidative stress at the late stages of the intraerythrocytic parasite cycle (Cao et al, 2021). Furthermore, although Pf parasites do not possess the genetic machinery to synthesize full length complex N-glycans (Samuelson et al, 2005), host sialylated N-glycoproteins carried or expressed on PfEV membrane are a plausible explanation for our observations.…”

Section:  Discussionmentioning

confidence: 57%

“…Moreover, current knowledge on membrane protein cargo of PfEVs is limited, and significant differences are observed even between EVs derived from substrains as NF54 (Dekel et al, 2021) and 3D7 (Mantel et al, 2013). Interestingly, RBC membrane glycoproteins as the anion transport protein (Band 3), glycophorins, or the Glucose transporter 1 Glut-1 (Cao et al, 2021;Cohen et al, 2009) are also highly abundant in PfEVs (Mantel et al, 2013). We hypothesize that our observed differences in sialylated N-glycan reflect changes in the glycosylated membrane proteins displayed on PfEVs and hEVs.…”

Section:  Discussionmentioning

confidence: 83%

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Sialylated N‐glycans mediate monocyte uptake of extracellular vesicles secreted from Plasmodium falciparum‐infected red blood cells

Pilo

Khilji

Lühle

et al. 2022

J of Extracellular Bio

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Glycoconjugates on extracellular vesicles (EVs) play a vital role in internalization and mediate interaction as well as regulation of the host immune system by viruses, bacteria, and parasites. During their intraerythrocytic life‐cycle stages, malaria parasites, Plasmodium falciparum (Pf) mediate the secretion of EVs by infected red blood cells (RBCs) that carry a diverse range of parasitic and host‐derived molecules. These molecules facilitate parasite‐parasite and parasite‐host interactions to ensure parasite survival.To date, the number of identified Pf genes associated with glycan synthesis and the repertoire of expressed glycoconjugates is relatively low. Moreover, the role of Pf glycans in pathogenesis is mostly unclear and poorly understood. As a result, the expression of glycoconjugates on Pf‐derived EVs or their involvement in the parasite life‐cycle has yet to be reported.Herein, we show that EVs secreted by Pf‐infected RBCs carry significantly higher sialylated complex N‐glycans than EVs derived from healthy RBCs. Furthermore, we reveal that EV uptake by host monocytes depends on N‐glycoproteins and demonstrate that terminal sialic acid on the N‐glycans is essential for uptake by human monocytes. Our results provide the first evidence that Pf exploits host sialylated N‐glycans to mediate EV uptake by the human immune system cells.

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Section:  Discussionmentioning

confidence: 57%

Section:  Discussionmentioning

confidence: 83%

Sialylated N‐glycans mediate monocyte uptake of extracellular vesicles secreted from Plasmodium falciparum‐infected red blood cells

Pilo

Khilji

Lühle

et al. 2022

J of Extracellular Bio

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Papadopoulos

Spourita

Mimidis

et al. 2022

Preprint

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Non-alcoholic steatohepatitis (NASH) constitutes a significant cause of deaths, liver transplantations and economic costs worldwide. Despite extended research, investigations on the role of erythrocytes are scarce. Red blood cells from experimental animals and human patients with NASH, present phosphatidylserine exposure which is then recognized by Kupffer cells. This event leads to erythrophagocytosis, and amplification of inflammation through iron disposition. In addition, it has been shown that erythrocytes from NASH patients release the chemokine MCP1, leading to increased TNF-α release from macrophages RAW 264.7. However, erythrophagocytosis can also be caused by reduced CD47 levels. In addition, increased MCP1 release could be either signal-induced, or caused by higher MCP1 levels on the erythrocyte membrane. Finally, erythrocyte efferocytosis could provide additional inflammatory metabolites. In this study, we measured the erythrocyte membrane levels of CD47 and MCP1 by ELISA, and cholesterol and sphingosine with thin-layer chromatography. 18 patients (8 men, 10 women aged 56.7+/-11.5 years) and 14 healthy controls (7 men, 7 women aged 39.3+/-15.5 years) participated in our study. The erythrocyte CD47 levels were decreased in the erythrocyte membranes of NASH patients (844+/-409 pg/ml) compared to healthy controls (2969+/-1936 pg/ml) with P(Healthy>NAFLD)=99.1%, while the levels of MCP1 were increased in NASH patients (389+/-255 pg/ml), compared to healthy controls (230+/-117 pg/ml) with P(Healthy<NAFLD)=88.9%. Moreover, in erythrocyte membranes there was a statistically significant accumulation of sphingosine and cholesterol in NASH patients, compared to healthy controls. Our results imply that erythrocytes release chemotactic (find me signals) MCP1, while containing reduced (do not eat me signals) CD47. These molecules can lead to erythrophagocytosis. Next, increased (goodbye signals) sphingosine and cholesterol could augment inflammation by metabolic reprogramming.

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“…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).…”

Section: N-glycansmentioning

confidence: 99%

“…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).…”

Section: N-glycansmentioning

confidence: 99%

Unveiling the Sugary Secrets of Plasmodium Parasites

2021

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Plasmodium parasites cause malaria disease, one of the leading global health burdens for humanity, infecting hundreds of millions of people each year. Different glycans on the parasite and the host cell surface play significant roles in both malaria pathogenesis and host defense mechanisms. So far, only small, truncated N- and O-glycans have been identified in Plasmodium species. In contrast, complex glycosylphosphatidylinositol (GPI) glycolipids are highly abundant on the parasite’s cell membrane and are essential for its survival. Moreover, the parasites express lectins that bind and exploit the host cell surface glycans for different aspects of the parasite life cycle, such as adherence, invasion, and evasion of the host immune system. In parallel, the host cell glycocalyx and lectin expression serve as the first line of defense against Plasmodium parasites and directly dictate susceptibility to Plasmodium infection. This review provides an overview of the glycobiology involved in Plasmodium-host interactions and its contribution to malaria pathogenesis. Recent findings are presented and evaluated in the context of potential therapeutic exploitation.

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

Cited by 19 publications

References 56 publications

Sialylated N‐glycans mediate monocyte uptake of extracellular vesicles secreted from Plasmodium falciparum‐infected red blood cells

Sialylated N‐glycans mediate monocyte uptake of extracellular vesicles secreted from Plasmodium falciparum‐infected red blood cells

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

Unveiling the Sugary Secrets of Plasmodium Parasites

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