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 EV-associated glycoconjugates in parasite-induced immune modulation.

中文翻译：

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DC-SIGN介导的曼氏血吸虫糖基化胞外囊泡的内化作用增强了单核细胞衍生树突状细胞的激活。

曼氏血吸虫等蠕虫会释放排泄/分泌（E / S）产品，从而调节宿主的免疫力以实现感染。这些E / S产品中有细胞外囊泡（EV），但尚不清楚曼氏链球菌EV与宿主免疫细胞相互作用的分子机制和功能。在这里，我们证明了曼氏血吸虫血吸虫释放的EVs是由人单核细胞衍生的树突状细胞（moDCs）内化的。重要的是，我们表明这种摄取主要是通过DC-SIGN（CD209）介导的。阻断DC-SIGN几乎完全消除了EV摄取，而阻断甘露糖受体（MR，CD206）或树突状细胞免疫受体（DCIR，CLEC4A）对EV摄取没有影响。EV聚糖的质谱分析表明，存在带有末端Galβ1-4（Fucα1-3）GlcNAc（LewisX）图案的表面N-聚糖，以及各种岩藻糖基化脂质连接的聚糖，包括LewisX，DC-SIGN的已知配体。用血吸虫EV刺激moDCs导致共刺激分子CD86和CD80以及调节性表面标志物PD-L1的表达增加。此外，血吸虫EVs通过moDCs增加IL-12和IL-10的表达，这部分取决于与DC-SIGN的相互作用。这些结果提供了第一个证据，表明曼氏链球菌EV的糖基化促进了与宿主免疫细胞的相互作用，并揭示了寄生虫诱导的免疫调节中DC-SIGN和EV相关糖缀合物的作用。血吸虫EVs通过moDCs增加IL-12和IL-10的表达，这部分取决于与DC-SIGN的相互作用。这些结果提供了第一个证据，表明曼氏链球菌EV的糖基化促进了与宿主免疫细胞的相互作用，并揭示了寄生虫诱导的免疫调节中DC-SIGN和EV相关糖缀合物的作用。血吸虫EVs通过moDCs增加IL-12和IL-10的表达，这部分取决于与DC-SIGN的相互作用。这些结果提供了第一个证据，表明曼氏链球菌EV的糖基化促进了与宿主免疫细胞的相互作用，并揭示了寄生虫诱导的免疫调节中DC-SIGN和EV相关糖缀合物的作用。