Activated macrophages promote hepatitis C virus entry in a tumor necrosis factor-dependent manner.
Activated macrophages promote hepatitis C virus entry in a tumor necrosis factor-dependent manner.
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DOI：
10.1002/hep.26911
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发表时间：
2014-04
期刊：
影响因子：
13.5
通讯作者：
McKeating, Jane A.
中科院分区：
文献类型：
--
作者：
Fletcher, Nicola F.;Sutaria, Rupesh;Jo, Juandy;Barnes, Amy;Blahova, Miroslava;Meredith, Luke W.;Cosset, Francois-Loic;Curbishley, Stuart M.;Adams, David H.;Bertoletti, Antonio;McKeating, Jane A.
巨噬细胞是肝脏先天免疫反应的重要组成部分。慢性丙型肝炎与免疫浸润有关，感染肝脏巨噬细胞总数显著增加；然而，人们对它们在病毒生命周期中的作用知之甚少。用一组toll样受体激动剂激活血源性和肝内巨噬细胞诱导可溶性介质，促进丙型肝炎病毒（HCV）进入极化肝癌细胞。我们发现肿瘤坏死因子α (TNF-α)是参与这一过程的主要细胞因子。重要的是，这种效应并不局限于HCV；TNF-α增加了肝癌细胞对拉沙病毒、麻疹病毒和水泡性口炎假病毒感染的容忍度。TNF-α诱导了紧密连接蛋白occludin的重新定位，并增加了极化HepG2细胞中HCV受体tetraspanin CD81的横向扩散速度，为其增加允许度以支持HCV进入提供了机制。高浓度HCV颗粒可刺激巨噬细胞表达TNF-α，为病毒促进感染提供了直接机制。结论：本研究显示了TNF-α增加病毒进入的新作用，并强调了HCV利用肝脏中现有的先天免疫反应促进新生感染事件的潜力。(肝脏病学59:1320 2014;1330)
Macrophages are critical components of the innate immune response in the liver. Chronic hepatitis C is associated with immune infiltration and the infected liver shows a significant increase in total macrophage numbers; however, their role in the viral life cycle is poorly understood. Activation of blood-derived and intrahepatic macrophages with a panel of Toll-like receptor agonists induce soluble mediators that promote hepatitis C virus (HCV) entry into polarized hepatoma cells. We identified tumor necrosis factor α (TNF-α) as the major cytokine involved in this process. Importantly, this effect was not limited to HCV; TNF-α increased the permissivity of hepatoma cells to infection by Lassa, measles and vesicular stomatitis pseudoviruses. TNF-α induced a relocalization of tight junction protein occludin and increased the lateral diffusion speed of HCV receptor tetraspanin CD81 in polarized HepG2 cells, providing a mechanism for their increased permissivity to support HCV entry. High concentrations of HCV particles could stimulate macrophages to express TNF-α, providing a direct mechanism for the virus to promote infection. Conclusion: This study shows a new role for TNF-α to increase virus entry and highlights the potential for HCV to exploit existing innate immune responses in the liver to promote de novo infection events. (Hepatology 2014;59:1320-1330)
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