Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, Galveston, Texas 77555-1019, USA.
Gastroenterology. 2011 Aug;141(2):674-85, 685.e1-6. doi: 10.1053/j.gastro.2011.04.060. Epub 2011 May 6.
BACKGROUND & AIMS: The hepatitis C virus (HCV) serine protease NS3/4A can cleave mitochondria-associated antiviral signaling protein (MAVS) and block retinoic acid-inducible gene I-mediated interferon (IFN) responses. Although this mechanism is thought to have an important role in HCV-mediated innate immunosuppression, its significance in viral persistence is not clear.
We generated transgenic mice that express the HCV NS3/4A proteins specifically in the liver and challenged the animals with a recombinant vesicular stomatitis virus, a synthetic HCV genome, IFN alfa, or IFN beta. We evaluated the effects of HCV serine protease on the innate immune responses and their interactions.
Expression of HCV NS3/4A resulted in cleavage of intrahepatic MAVS; challenge of transgenic mice with vesicular stomatitis virus or a synthetic HCV genome induced strong, type I IFN-mediated responses that were not significantly lower than those of control mice. Different challenge agents induced production of different ratios of IFN alfa and beta, resulting in different autophagic responses and vesicular trafficking patterns of endoplasmic reticulum- and mitochondria-associated viral proteins. IFN beta promoted degradation of the viral proteins by the autolysosome. Variant isoforms of MAVS were associated with distinct, type I IFN-mediated autophagic responses; these responses have a role in trafficking of viral components to endosomal compartments that contain Toll-like receptor-3.
IFN beta mediates a distinct autophagic mechanism of antiviral host defense. MAVS has an important role in type I IFN-induced autophagic trafficking of viral proteins.
丙型肝炎病毒（HCV）丝氨酸蛋白酶 NS3/4A 可以切割线粒体抗病毒信号蛋白（MAVS）并阻断视黄酸诱导基因 I 介导的干扰素（IFN）反应。尽管这种机制被认为在 HCV 介导的先天免疫抑制中具有重要作用，但它在病毒持续存在中的意义尚不清楚。
我们生成了在肝脏中特异性表达 HCV NS3/4A 蛋白的转基因小鼠，并使用重组水疱性口炎病毒、合成 HCV 基因组、IFN alfa 或 IFN beta 对动物进行了挑战。我们评估了 HCV 丝氨酸蛋白酶对先天免疫反应的影响及其相互作用。
HCV NS3/4A 的表达导致肝内 MAVS 的切割；水疱性口炎病毒或合成 HCV 基因组的挑战引起了强烈的、I 型 IFN 介导的反应，与对照小鼠相比并没有明显降低。不同的挑战剂诱导产生不同比例的 IFN alfa 和 beta，导致内质网和线粒体相关病毒蛋白的自噬反应和囊泡运输模式不同。IFN beta 通过自噬溶酶体促进病毒蛋白的降解。MAVS 的变异同工型与不同的、I 型 IFN 介导的自噬反应相关；这些反应在将病毒成分运输到包含 Toll 样受体 3 的内体隔室中起作用。
IFN beta 介导了抗病毒宿主防御的一种独特的自噬机制。MAVS 在 I 型 IFN 诱导的病毒蛋白自噬运输中具有重要作用。
