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Syndecan 4 Upregulation on Activated Langerhans Cells Counteracts Langerin Restriction to Facilitate Hepatitis C Virus Transmission.
Frontiers in Immunology ( IF 5.7 ) Pub Date : 2020-03-27 , DOI: 10.3389/fimmu.2020.00503
Bernadien M Nijmeijer 1 , Julia Eder 1 , Catharina J M Langedijk 1 , Tanja M Kaptein 1 , Sofie Meeussen 2 , Pascale Zimmermann 2, 3 , Carla M S Ribeiro 1 , Teunis B H Geijtenbeek 1
Affiliation  

Sexually transmitted Hepatitis C virus (HCV) infections and high reinfections are a major concern amongst men who have sex with men (MSM) living with HIV-1 and HIV-negative MSM. Immune activation and/or HIV-1 coinfection enhance HCV susceptibility via sexual contact, suggesting that changes in immune cells or external factors are involved in increased susceptibility. Activation of anal mucosal Langerhans cells (LCs) has been implicated in increased HCV susceptibility as activated but not immature LCs efficiently retain and transmit HCV to other cells. However, the underlying molecular mechanism of transmission remains unclear. Here we identified the Heparan Sulfate Proteoglycan Syndecan 4 as the molecular switch, controlling HCV transmission by LCs. Syndecan 4 was highly upregulated upon activation of LCs and interference with Heparan Sulfate Proteoglycans or silencing of Syndecan 4 abrogated HCV transmission. These data strongly suggest that Syndecan 4 mediates HCV transmission by activated LCs. Notably, our data also identified the C-type lectin receptor langerin as a restriction factor for HCV infection and transmission. Langerin expression abrogated HCV infection in HCV permissive cells, whereas langerin expression on the Syndecan 4 expressing cell line strongly decreased HCV transmission to a target hepatoma cell line. These data suggest that the balanced interplay between langerin restriction and Syndecan 4 transmission determines HCV dissemination. Silencing of langerin enhanced HCV transmission whereas silencing Syndecan 4 on activated LCs decreased transmission. Blocking Heparan Sulfate Proteoglycans abrogated HCV transmission by LCs ex vivo identifying Heparan Sulfate Proteoglycans and Syndecan 4 as potential targets to prevent sexual transmission of HCV. Thus, our data strongly suggest that the interplay between receptors promotes or restricts transmission and further indicate that Syndecan 4 is the molecular switch controlling HCV susceptibility after sexual contact.

中文翻译:


激活的 Langerhans 细胞上的 Syndecan 4 上调可抵消 Langerin 限制,从而促进丙型肝炎病毒传播。



性传播丙型肝炎病毒 (HCV) 感染和高再感染率是感染 HIV-1 的男男性接触者 (MSM) 和 HIV 阴性 MSM 的主要关注点。免疫激活和/或 HIV-1 合并感染通过性接触增强 HCV 易感性,这表明免疫细胞的变化或外部因素与易感性增加有关。肛门粘膜朗格汉斯细胞 (LC) 的激活与 HCV 易感性增加有关,因为激活但不成熟的 LC 可以有效保留 HCV 并将其传递给其他细胞。然而,传播的潜在分子机制仍不清楚。在这里,我们将硫酸乙酰肝素蛋白聚糖 Syndecan 4 确定为分子开关,通过 LC 控制 HCV 传播。在激活 LC 并干扰硫酸乙酰肝素蛋白聚糖或沉默 Syndecan 4 后,Syndecan 4 会高度上调,从而消除 HCV 传播。这些数据强烈表明 Syndecan 4 通过激活的 LC 介导 HCV 传播。值得注意的是,我们的数据还确定了 C 型凝集素受体 langerin 是 HCV 感染和传播的限制因素。 Langerin 表达消除了 HCV 允许细胞中的 HCV 感染,而 Langerin 在 Syndecan 4 表达细胞系上的表达强烈减少了 HCV 向靶肝癌细胞系的传播。这些数据表明,langerin 限制和 Syndecan 4 传播之间的平衡相互作用决定了 HCV 传播。沉默 langerin 会增强 HCV 传播,而沉默活化 LC 上的 Syndecan 4 则会减少传播。阻断硫酸乙酰肝素蛋白多糖可消除体外 LC 的 HCV 传播,将硫酸乙酰肝素蛋白多糖和 Syndecan 4 识别为预防 HCV 性传播的潜在目标。 因此,我们的数据强烈表明受体之间的相互作用促进或限制传播,并进一步表明 Syndecan 4 是控制性接触后 HCV 易感性的分子开关。
更新日期:2020-03-30
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