Hepatitis C virus infection sensitizes human hepatocytes to TRAIL-induced apoptosis in a caspase 9-dependent manner
Hepatitis C virus infection sensitizes human hepatocytes to TRAIL-induced apoptosis in a caspase 9-dependent manner
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DOI：
10.4049/jimmunol.181.7.4926
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发表时间：
2008-10-01
影响因子：
4.4
通讯作者：
Baumert, Thomas F.
中科院分区：
文献类型：
--
作者：
Lan, Lin;Gorke, Sebastian;Baumert, Thomas F.
感染细胞的凋亡是抵抗病毒感染的一种关键的宿主防御机制。细胞凋亡对清除丙型肝炎病毒感染细胞的影响还知之甚少。TRAIL与肝炎感染患者的肝细胞死亡有关，但与正常肝细胞的死亡无关。为了确定TRAIL对病毒感染宿主细胞凋亡的影响，我们在一个丙型肝炎病毒感染的组织培养模型系统中研究了TRAIL诱导的细胞凋亡。我们发现，丙型肝炎病毒感染使原代人肝细胞变得敏感；Huh7.5肝癌细胞对TRAIL诱导的凋亡具有剂量和时间依赖关系。图谱研究发现，丙型肝炎病毒非结构蛋白是TRAIL致敏的关键介质。使用一组针对不同凋亡途径的抑制剂，我们证明了TRAIL的增敏依赖于caspase-9，并部分通过线粒体途径介导。肝细胞对TRAIL诱导的丙型肝炎病毒感染诱导的细胞凋亡的敏感性是一种新的抗病毒宿主防御机制，可能在丙型肝炎病毒感染的发病机制中具有重要意义，并可能有助于消除病毒感染的肝细胞。
Apoptosis of infected cells represents a key host defense mechanism against viral infections. The impact of apoptosis on the elimination of hepatitis C virus (HCV)-infected cells is poorly understood. The TRAIL has been implicated in the death of liver cells in hepatitis-infected but not in normal liver cells. To determine the impact of TRAIL on apoptosis of virus-infected host cells, we studied TRAIL-induced apoptosis in a tissue culture model system for HCV infection. We demonstrated that HCV infection sensitizes primary human hepatocytes; and Huh7.5 hepatoma cells to TRAIL induced apoptosis in a dose- and time-dependent manner. Mapping studies identified the HCV nonstructural proteins as key mediators of sensitization to TRAIL. Using a panel of inhibitors targeting different apoptosis pathways, we demonstrate that sensitization to TRAIL is caspase-9 dependent and mediated in part via the mitochondrial pathway. Sensitization of hepatocytes to TRAIL-induced apoptosis by HCV infection represents a novel antiviral host defense mechanism that may have important implications for the pathogenesis of HCV infection and may contribute to the elimination of virus-infected hepatocytes.