DC‐SIGN mediated internalisation of glycosylated extracellular vesicles from Schistosoma mansoni increases activation of monocyte‐derived dendritic cells

Abstract

Helminths like Schistosoma mansoni release excretory/secretory (E/S) products that modulate host immunity to enable infection. Extracellular vesicles (EVs) are among these E/S products, yet molecular mechanisms and functionality of S. mansoni EV interaction with host immune cells is unknown. Here we demonstrate that EVs released by S. mansoni schistosomula are internalised by human monocyte-derived dendritic cells (moDCs). Importantly, we show that this uptake was mainly mediated via DC-SIGN (CD209). Blocking DC-SIGN almost completely abrogated EV uptake, while blocking mannose receptor (MR, CD206) or dendritic cell immunoreceptor (DCIR, CLEC4A) had no effect on EV uptake. Mass spectrometric analysis of EV glycans revealed the presence of surface N-glycans with terminal Galβ1-4(Fucα1-3)GlcNAc (LewisX) motifs, and a wide array of fucosylated lipid-linked glycans, including LewisX, a known ligand for DC-SIGN. Stimulation of moDCs with schistosomula EVs led to increased expression of costimulatory molecules CD86 and CD80 and regulatory surface marker PD-L1. Furthermore, schistosomula EVs increased expression of IL-12 and IL-10 by moDCs, which was partly dependent on the interaction with DC-SIGN. These results provide the first evidence that glycosylation of S. mansoni EVs facilitates the interaction with host immune cells and reveals a role for DC-SIGN and EVassociated glycoconjugates in parasite-induced immune modulation.

Functional characterization of Schistosoma mansoni fucosyltransferases in Nicotiana benthamiana plants

“…Additionally, the monosaccharide fucose can be highly immunogenic and many antibodies in the human host are directed against fucose containing glycan motifs 12 . Fucose-containing glycan motifs, such as LeX and LDN-F, interact with innate immune cells via C-type lectin receptors and can influence the outcome of immunological responses 13 – 17 . For instance, the Th2 inducing capacity of the S. mansoni soluble egg antigen omega-1 is glycosylation dependent.…”

Extracellular Vesicles: Schistosomal Long-Range Precise Weapon to Manipulate the Immune Response

“…The specificity is probably imposed by membrane associated proteins or other cell surface molecules. It was shown that the uptake of the S. mansoni schistosomula-derived EVs by monocyte-derived DCs is mainly mediated via the C-type lectin receptor DC-SIGN (CD209) (Kuipers et al, 2020). DC-SIGN is an adhesion molecule that recognizes and binds highmannose-containing glycoproteins on pathogens, and is present on the surface of both macrophages and dendritic cells.…”

“…EVs are cell-derived membrane-enclosed particles that varied by their size, content, and intra-cellular origin. It was demonstrated that both S. japonicum and S. mansoni adult worms, as well as S. mansoni schistosomula and S. japonicum eggs, secrete EVs ( Wang et al., 2004 ; Nowacki et al., 2015 ; Sotillo et al., 2016 ; Zhu et al., 2016a ; Zhu et al., 2016b ; Samoil et al., 2018 ; Kuipers et al., 2020 ; Meningher et al., 2020 ). This review is focused on the current knowledge on the way by which schistosomal EVs modulate the immune response, mostly as was learned from the murine model.…”

“…Decreasing either the number of host monocytes or the TNF-α levels in the infected mice alleviate the worm and egg burden and consequently the pathology. Secreted-EVs from S. mansoni schistosomula are also internalized by human monocyte-derived dendritic cells (DCs) and increase their expression of IL-12 ( Kuipers et al., 2020 ), another hallmark cytokine of the M1 response, and a powerful inducer of the Th1 pathway (see below). These data altogether indicate that schistosomal EVs skew the innate immune response toward the M1 pathway, and this deviation is beneficial for the parasite survival.…”

Understanding the Pathophysiology of Exosomes in Schistosomiasis: A New Direction for Disease Control and Prevention

“…Determining whether they are potential vaccine antigens could help achieve schistosomiasis control. Efforts have also been made to understand how these schistosome-specific proteins are packaged within exosomes and further delivered and taken up by host cells ( 58 ). This work could provide new insights into the strategies of competently targeting exosomes applied for the antigen-presenting process.…”