Inhibition of Intrahepatic Gamma Interferon Production by Hepatitis C Virus Nonstructural Protein 5A in Transgenic Mice
Inhibition of Intrahepatic Gamma Interferon Production by Hepatitis C Virus Nonstructural Protein 5A in Transgenic Mice
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DOI：
10.1128/jvi.00751-09
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发表时间：
2009-09-01
影响因子：
5.4
通讯作者：
Ray, Ratna B.
中科院分区：
文献类型：
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作者：
Kanda, Tatsuo;Steele, Robert;Ray, Ratna B.
丙型肝炎病毒(HCV)利用抑制或逃避宿主免疫反应的策略来建立持续感染。我们先前已经证明，丙型肝炎病毒非结构蛋白5A(NS5A)可损害肿瘤坏死因子-α(TNF-α)介导的细胞凋亡。在这项研究中，我们研究了在转基因小鼠(NS5A-TG)肝脏中丙型肝炎病毒NS5A蛋白的免疫调节作用。将嗜肝腺病毒静脉注射到NS5A-TG小鼠和对照组小鼠体内，比较3周后病毒从肝脏的清除情况。采用实时荧光定量逆转录-聚合酶链式反应技术检测84个细胞因子相关基因、信号通路分子、转录因子和细胞表面分子的差异表达水平。NS5A-TG小鼠在感染后3周内未能清除肝脏中的腺病毒，而对照组小鼠在1~2周内清除了病毒。随后的研究发现，在NS5A-TG小鼠中，γ-干扰素(干扰素-γ)在mRNA和蛋白水平上都受到抑制，转录因子GATA-3和Tbx21的表达相反。然而，在NS5A-TG和对照组小鼠中，肿瘤坏死因子-α的mRNA和蛋白表达均升高。综上所述，我们的结果提示，丙型肝炎病毒NS5A通过抑制干扰素-γ的产生而发挥免疫调节剂的作用，并可能在慢性丙型肝炎病毒感染的建立中发挥重要作用。
Hepatitis C virus (HCV) utilizes strategies to suppress or evade the host immune response for establishment of persistent infection. We have shown previously that HCV nonstructural protein 5A (NS5A) impairs tumor necrosis factor alpha (TNF-alpha)-mediated apoptosis. In this study, we have examined the immunomodulatory role of HCV NS5A protein in transgenic mouse (NS5A-Tg) liver when mice were challenged with an unrelated hepatotropic adenovirus as a nonspecific stimulus. Hepatotropic adenovirus was introduced intravenously into NS5A-Tg mice and control mice, and virus clearance from liver was compared over a time course of 3 weeks. The differential mRNA expression levels of 84 cytokine-related genes, signal pathway molecules, transcription factors, and cell surface molecules were determined using real-time reverse transcription-PCR array. NS5A-Tg mice failed to clear adenovirus from liver up to 3 weeks postinfection while control mice cleared virus within 1 to 2 weeks. Subsequent study revealed that gamma interferon (IFN-gamma) expression is inhibited at both the mRNA and protein levels in NS5A-Tg mice, and an inverse expression of transcription factors Gata-3 and Tbx21 is observed. However, TNF-alpha mRNA and protein expression were elevated in both NS5A-Tg and control mice. Together, our results suggested that HCV NS5A acts as an immunomodulator by inhibiting IFN-gamma production and may play an important role toward establishment of chronic HCV infection.