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

Abstract

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.

Sialylation on vesicular integrin β1 determined endocytic entry of small extracellular vesicles into recipient cells

“…Hypersialylation of integrin β1 enhanced cell migration, and promoted colonic tumor progression by altering cell preference for certain types of ECM [ 40 ]. A 2022 study by O. Moscovitz’s group indicated that the terminal sialic acid on sEV is essential for their uptake by human monocytes [ 41 ]. By constructing different integrin β1 mutants, we observed a significant reduction in the overall sialic acid levels within the Δ7–8 mutant (Fig.…”

Surface Engineering of HEK293 Cell-Derived Extracellular Vesicles for Improved Pharmacokinetic Profile and Targeted Delivery of IL-12 for the Treatment of Hepatocellular Carcinoma

“…Even within the group of hepatic cell lines, the deglycosylation led to an increase of internalization in Hepa1-6 cells, while the effect was marginal in AML12 and HepG2 cells, resembling the observation reported previously. 22 , 27 …”

“…Our observation of extended plasma half-life after N-deglycosylation corroborated with previous reports that the alteration in EV glycosylation had a direct impact on the adhesion and uptake by lectin-expressing immune cells. 27–29 …”

Biogenesis of extracellular vesicles in protozoan parasites: The ESCRT complex in the trafficking fast lane?

“…Studies have identified a wide range of active cargo components, such as genomic DNA [ 19 , 20 ], RNA [ 18 , 57 , 59 , 61 ], host and parasitic proteins [ 58 , 63 ], glycans [ 64 ], and lipids [ 65 , 66 ], in P . falciparum -derived EVs.…”

“…Studies have identified a wide range of active cargo components, such as genomic DNA [19,20], RNA [18,57,59,61], host and parasitic proteins [58,63], glycans [64], and lipids [65,66], in P. falciparum-derived EVs. Moreover, the cargo composition in the EVs changes with the parasite's developmental stage, suggesting active cargo sorting into the EVs [20].…”