Department of Biochemistry, University of Oxford, Oxford, OX1 3QU, UK; Department of Medicine, Faculty of Medical Sciences, University of Sri Jayewardenepura, Nugegoda, Sri Lanka.
Department of Biochemistry, University of Oxford, Oxford, OX1 3QU, UK.
Antiviral Res. 2022 Mar;199:105269. doi: 10.1016/j.antiviral.2022.105269. Epub 2022 Feb 25.
Dendritic cells (DCs) are important targets for dengue virus (DENV) infection and play a significant role in the early immune response. Antiviral effects of iminosugars against DENV in primary cells have been demonstrated previously in monocyte-derived macrophages (MDMΦs). Given the important role played by DCs in innate immune defense against DENV, the antiviral effects of three deoxynojirimycin (DNJ) derivatives (NN-DNJ, EOO-DNJ and 2THO-DNJ) and a deoxygalactonojirimycin (DGJ) negative control were evaluated in DENV-infected primary human monocyte-derived immature DCs (imDCs). DNJ- but not DGJ-derivatives elicited antiviral activity in DENV-infected imDCs, similar to that observed in MDMΦs. The DNJ-derivatives inhibited DENV secretion in a dose-dependent manner. Endoplasmic reticulum (ER) α-glucosidase I inhibition by DNJ-derived iminosugars, at concentrations of 3.16 μM, correlated with a reduction in the specific infectivity of virions that were still secreted, as well as a reduction in DENV-induced tumour necrosis factor alpha secretion. This suggests iminosugar-mediated ER α-glucosidase I inhibition may give rise to further benefits during DENV infection, beyond the reduction in viral secretion associated with ER α-glucosidase II inhibition.
树突状细胞（DCs）是登革热病毒（DENV）感染的重要靶标，在早期免疫反应中发挥重要作用。先前已经在单核细胞衍生的巨噬细胞（MDMΦs）中证明了亚胺糖对 DENV 的抗病毒作用。鉴于 DCs 在先天免疫防御 DENV 中的重要作用，评估了三种去氧野尻霉素（DNJ）衍生物（NN-DNJ、EOO-DNJ 和 2THO-DNJ）和去氧半乳糖基野尻霉素（DGJ）阴性对照物在 DENV 感染的原代人单核细胞衍生未成熟 DCs（imDCs）中的抗病毒作用。DNJ-但不是 DGJ-衍生物在 DENV 感染的 imDCs 中引发抗病毒活性，与在 MDMΦs 中观察到的相似。DNJ 衍生物以剂量依赖性方式抑制 DENV 的分泌。DNJ 衍生的亚胺糖对 ER α-葡萄糖苷酶 I 的抑制作用，在 3.16 μM 的浓度下，与仍分泌的病毒粒子的特异性感染力降低以及 DENV 诱导的肿瘤坏死因子 α 分泌减少相关。这表明亚胺糖介导的 ER α-葡萄糖苷酶 I 抑制可能会在 DENV 感染期间带来额外的益处，而不仅仅是与 ER α-葡萄糖苷酶 II 抑制相关的病毒分泌减少。
