Antiviral and Immunoregulatory Effects of Indoleamine-2,3-Dioxygenase in Hepatitis C Virus Infection.
Antiviral and Immunoregulatory Effects of Indoleamine-2,3-Dioxygenase in Hepatitis C Virus Infection.
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DOI：
10.1159/000375161
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发表时间：
2015
影响因子：
5.3
通讯作者：
Barth H
中科院分区：
文献类型：
--
作者：
Lepiller Q;Soulier E;Li Q;Lambotin M;Barths J;Fuchs D;Stoll-Keller F;Liang TJ;Barth H
在丙型肝炎病毒(HCV)感染患者中，吲哚乙胺-2，3-双加氧酶1(IDO)活性增强已有报道。IDO是一种色氨酸分解酶，被认为既是一种天然的防御机制，也是免疫反应的重要调节因子。在丙型肝炎病毒感染中诱导IDO的分子机制及其在抗病毒免疫反应中的作用尚不清楚。利用原代人肝细胞，我们发现丙型肝炎病毒感染刺激IDO的表达。在丙型肝炎病毒感染的肝细胞中，IDO基因的诱导是短暂的，并且与I型和III型干扰素(IFN)和干扰素刺激基因(ISGs)的表达一致。在丙型肝炎病毒感染之前，肝脏IDO的过表达显著损害了肝细胞中的丙型肝炎病毒复制，这表明IDO限制了丙型肝炎病毒在肝脏内的传播。SiRNA介导的IDO基因敲除揭示了IDO作为干扰素介导的抗丙型肝炎病毒效应器的功能。干扰素-γ最能诱导肝脏IDO的表达，持续的丙型肝炎病毒复制可以显著上调IDO的表达。IRF1和STAT1调节肝脏IDO的表达。肝脏IDO的表达对CD4+T细胞增殖也有明显的抑制作用。我们的数据表明，肝脏IDO通过抑制病毒复制和调节宿主免疫反应，在丙型肝炎病毒感染过程中发挥双重作用。
In patients with hepatitis C virus (HCV) infection, enhanced activity of indoleamine-2,3-dioxygenase 1 (IDO) has been reported. IDO - a tryptophan-catabolizing enzyme – has been considered as both an innate defence mechanism and an important regulator of the immune response. The molecular mechanism of IDO induction in HCV infection and its role in the antiviral immune response remain unknown. Using primary human hepatocytes, we show that HCV infection stimulates IDO expression. IDO gene induction was transient and coincided with the expression of type I and type III interferons (IFNs) and IFN-stimulated genes (ISGs) in HCV-infected hepatocytes. Overexpression of hepatic IDO prior to HCV infection markedly impaired HCV replication in hepatocytes, suggesting that IDO limits the spread of HCV within the liver. siRNA-mediated IDO knockdown revealed that IDO functions as an IFN-mediated anti-HCV effector. Hepatic IDO was most potently induced by IFN-γ and ongoing HCV replication could significantly upregulate IDO expression. IRF1 and STAT1 regulated hepatic IDO expression. Hepatic IDO expression also had a significant inhibitory effect on CD4+ T cell proliferation. Our data suggest that hepatic IDO plays a dual role during HCV infection by retarding viral replication and also regulating host immune responses.