Chemokines and Acute Hepatitis C

丙型肝炎的组织学特征是免疫细胞强烈浸润到肝脏中。这个项目 试图了解HCV感染肝细胞如何诱导趋化因子， 细胞回到肝脏。当肝细胞被感染时，至少有两种模式识别受体 (PRR)TLRS和RIG-I检测HCV RNA病原体相关的分子模式（PAMP）， 激活先天性抗病毒和炎症反应。我们的小组是第一个证明， 并且体内HCV感染与CXCL 8（一种高度炎性趋化因子）的诱导有关。我们有 自从发现RIG-I感应HCV感染引起CXCL 8通过h/vo诱导以来，主要机制是： 转录激活和mRNA稳定。HCV感染的PRR感应与 炎性趋化因子诱导将是所提出的研究的焦点。其他团体的研究表明， 自从发现趋化因子如CXCL 9（干扰素γ诱导的单核因子; Mig）， CXCL-10（干扰素-γ-诱导蛋白-10; IP-10）和CXCL 11（干扰素-诱导T细胞α 化学引诱物; l-TAC）与慢性丙型肝炎。此外，CXCL 9 -11通过CXCR 3发出信号， 已知趋化因子受体在包括T、树突和NKT的免疫细胞的迁移中是不可或缺的 细胞进入肝脏。因此，HCV感染肝细胞后的趋化因子诱导是免疫调节的核心。 细胞运输至肝脏并诱导炎症反应，这会导致肝损伤，以及 如我们所示，干扰素治疗的功效降低。然而，关于如何实现这一目标的信息很少。 在HCV感染期间，诱导趋化因子使免疫细胞归巢至肝脏。中央 该项目假设是肝细胞中HCV感染的PRR感应导致趋化因子 CXCR 3+免疫细胞向肝脏的募集。为了解决这一假设，我们提出了3个具体目标 这将确定TLR-3和RIG-I在趋化因子诱导中的相对贡献， HCV感染的细胞传感导致趋化因子mRNA的稳定，并评估趋化因子作为 先天性和适应性免疫反应在免疫细胞趋化性方面的联系， 肝细胞：HCV感染期间免疫细胞相互作用。拟议的研究将提供基本的见解 PRR诱导炎症反应，趋化因子在肝脏炎症中的作用， 疾病，以及先天免疫和适应性免疫之间的联系。

Hepatitis C is characterized histologically by an intense infiltration of immune cells into the liver. This project seeks to understand how HCV infection of hepatocytes leads to induction of chemokines that cause immune cells to home to the liver. When hepatocytes become infected, at least two pattern recognition receptors (PRR), TLRS and RIG-I, sense the HCV RNA pathogen associated nnolecular pattern (PAMP), resulting in activation of innate antiviral and inflammatory responses. Our group was the first to show that both in vitro and in vivo HCV infection is associated with induction of CXCL8, a highly inflammatory chemokine. We have since found that RIG-I sensing of HCV infection causes CXCL8 induction by h/vo major mechanisms: transcriptional activation and mRNA stabilization. The convergence of PRR sensing of HCV infection with inflammatory chemokine induction will be the focus of the proposed studies. Studies by other groups have since found associations of chemokines such as CXCL9 (monokine induced by interferon gamma; Mig), CXCL-10 (interferon-gamma-inducible protein-10; IP-10), and CXCL11 (interferon-Inducible T-cell alpha chemoattractant; l-TAC) with chronic hepatitis C. Moreover, CXCL9-11 signal through CXCR3 and this chemokine receptor is known to be integral in the migration of immune cells including T, dendritic, and NKT cells into the liver. Chemokine induction following HCV infection of a liver cell is therefore central to immune cell trafficking to the liver and induction of an inflammatory response, which contributes to liver damage, and as we have shown, reduced efficacy of interferon therapy. However, there is a paucity of information on how chemokines that cause immune cells to home to the liver are induced during HCV infection. The central hypothesis of this project is that PRR sensing of HCV infection in hepatocytes leads to chemokine recruitment of CXCR3+ immune cells to the liver. To address the hypothesis, we propose 3 Specific Aims that will determine the relative contribution of TLR-3 and RIG-I in chemokine induction, determine how cellular sensing of HCV infection results in stabilization of chemokine mRNAs, and evaluate chemokines as a link between innate and adaptive immune responses in terms of immune cell chemotaxis and hepatocyte:immune cell interactions during HCV infection. The proposed studies will provide basic insight into PRR induction of an inflammatory response, the roles of chemokines in hepatic inflammation and disease, and links between innate and adaptive immunity.