Restoration of type I interferon expression by heme and related tetrapyrroles through inhibition of NS3/4A protease.
Restoration of type I interferon expression by heme and related tetrapyrroles through inhibition of NS3/4A protease.
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DOI：
10.1093/infdis/jit338
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发表时间：
2013-11
期刊：
影响因子：
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通讯作者：
Zhao-feng Zhu;M. Mathahs;W. Schmidt
中科院分区：
文献类型：
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作者：
Zhao-feng Zhu;M. Mathahs;W. Schmidt
背景技术四吡咯底物和血红素加氧酶产物是丙型肝炎病毒(HCV)复制的有效抑制剂。目前尚不清楚这是通过 I 型干扰素 (IFN) 的初级诱导、病毒 NS3/4A 蛋白酶的抑制还是这些机制的组合来发生的。我们研究了四吡咯的抗病毒作用及其对 I 型 IFN 诱导的潜在影响。方法 在用 NS3/4A 蛋白酶转染的 HCV 允许细胞、复制子或人胚肾 (HEK) 293 细胞中评估四吡咯对 NS3/4A 蛋白酶活性和 I 型 IFN 诱导的影响。在转染双链替代核酸抗原或用确定序列的 HCV 细胞培养物 (HCVcc) RNA 感染后，确定先天免疫信号的激活。结果 四吡咯在抑制 HCV 复制和 NS3/4A 蛋白酶活性的浓度下无法直接诱导 IFN 表达。然而，他们在用 NS3/4A 蛋白酶减弱后有效地恢复了 IFN 诱导，这一过程伴随着接头蛋白、线粒体抗病毒信号蛋白的保存、IFN 调节因子 3 的核定位以及 IFN 刺激的基因产物的增强。结论 四吡咯不直接诱导 IFN，但在 NS3/4A 蛋白酶减弱后可显着恢复 I 型 IFN 信号通路。它们具有免疫调节和抗蛋白酶活性，可用于治疗 HCV 感染。
BACKGROUND Tetrapyrrole substrates and products of heme oxygenase are potent inhibitors of hepatitis C virus (HCV) replication. It is not clear whether this occurs through primary induction of type I interferon (IFN), inhibition of viral NS3/4A protease, or a combination of these mechanisms. We studied the antiviral actions of tetrapyrroles and their potential influence on type I IFN induction. METHODS The effects of tetrapyrrole on NS3/4A protease activity and type I IFN induction were assessed in HCV-permissive cells, replicons, or human embryonic kidney (HEK) 293 cells transfected with NS3/4A protease. Activation of innate immune signaling was determined after transfection of double-strand surrogate nucleic acid antigens or infection with defined sequence HCV cell culture (HCVcc) RNA. RESULTS Tetrapyrroles failed to directly induce IFN expression at concentrations that inhibited HCV replication and NS3/4A protease activity. However, they potently restored IFN induction after attenuation with NS3/4A protease, a process accompanied by preservation of the adapter protein, mitochondrial antiviral signaling protein, nuclear localization of IFN regulatory factor 3, and augmentation of IFN-stimulated gene products. CONCLUSIONS Tetrapyrroles do not directly induce IFN, but they dramatically restore type I IFN signaling pathway after attenuation with NS3/4A protease. They show immunomodulatory as well as antiprotease activity and may be useful for treatment of HCV infection.