Innate Defense Program against HCV

 描述（由申请人提供）：丙型肝炎病毒（HCV）有效地建立持续感染，目前全球有2亿人感染。在美国，慢性HCV感染导致15，000人死于终末期肝病，如肝癌和失代偿性肝硬化。此外，每年有近20，000人新感染HCV，从而对公共卫生构成持续威胁。因此，有效的预防策略对于减轻HCV的负担仍然至关重要。为了实现这一最终目标，进一步了解宿主对病毒感染的免疫力起着至关重要的作用。干扰素刺激基因（Interferon stimulated gene，ISG）是300多种先天免疫效应子的总称，它们共同作用限制病毒感染，是获得性免疫有效发挥的关键决定因素。ISG表达是动态的，通过干扰素（IFN）信号传导的不同强度和持续时间发生。然而，调节ISG表达以促进病毒限制的过程定义不清。寻找刺激ISG的新宿主因子 表达抑制HCV感染，我们进行了全面的全基因组cDNA筛选。这些研究确定了非受体酪氨酸激酶1（TNK1）作为增强ISG表达和限制HCV感染的关键信号分子。我们的研究表明，TNK1主持一个新的信号通路，赋予丝氨酸磷酸化的STAT1，导致诱导一组特定的ISG，具有强大的抗HCV活性。因此，拟议的研究旨在研究TNK1途径通过STAT1激活的独特过程诱导抗HCV效应子的假设。我们将进行以下目的：（目的1）确定TNK1的活化机制和表征其酶活性，（目的2）确定TNK1介导的STAT1丝氨酸磷酸化的信号级联，和（目的3）确定TNK1在肝脏抗病毒天然免疫中的体内作用。这项研究的结果将为对抗病毒感染的前线防御提供新的见解，并有助于对抗HCV感染和新出现的病毒性疾病的预防策略。

 DESCRIPTION (provided by applicant): Hepatitis C Virus (HCV) efficiently establishes persistent infection, with 200 million people currently infected worldwide. In the US, chronic HCV infection accounts for 15,000 deaths via end-stage liver diseases such as liver cancer and decompensated cirrhosis. In addition, nearly 20,000 individuals are newly infected with HCV annually, thereby posing a continuous threat to public health. Thus, an effective prevention strategy remains essential to mitigating the burden of HCV. Towards this ultimate goal, furthering our understanding of host immunity against viral infection plays a critical role. Interferon stimulated genes (ISG) constitute over 300 innate immune effectors which cooperatively restrict viral infection and are critical determinants for efficient mounting of adaptive immunity. ISG expression is dynamic, occurring through differential strength and duration of interferon (IFN) signaling. However, the processes that regulate ISG expression to facilitate viral restriction are poorly defined. In search of novel host factors that stimulate ISG expression for the suppression of HCV infection, we have conducted comprehensive genome-wide cDNA screening. These studies identified the non-receptor tyrosine kinase 1 (TNK1) as a signaling molecule pivotal for enhanced ISG expression and restriction of HCV infection. Our studies indicate that TNK1 presides over a novel signaling pathway that imparts serine phosphorylation of STAT1, resulting in induction of a specific group of ISG that have potent anti-HCV activity. Therefore the proposed studies aim to investigate the hypothesis that the TNK1 pathway induces anti-HCV effectors through a unique process of STAT1 activation. We will conduct the following aims: (Aim 1) Determine the mechanism of TNK1 activation and characterize its enzymatic activity, (Aim 2) Define the signaling cascade governed by TNK1 mediated serine phosphorylation of STAT1, and (Aim 3) Determine the in vivo role of TNK1 in hepatic antiviral innate immunity. The results from this study will provide novel insights into a front line defense against viral infection and contribute to a prevention strategy against HCV infection and emerging viral diseases.