Chemokines and Acute Hepatitis C

丙型肝炎的组织学特征是免疫细胞强烈渗透到肝脏。这个项目 试图了解丙型肝炎病毒感染肝细胞是如何导致诱导趋化因子导致免疫的 细胞回到肝脏的家。当肝细胞受到感染时，至少有两个模式识别受体 (PRR)、TLRs和RIG-I，检测到丙型肝炎病毒RNA病原体相关的非分子模式(PAMP)，导致 激活先天的抗病毒和炎症反应。我们的团队是第一个在试管中证明 在体内，丙型肝炎病毒感染与CXCL8的诱导有关，CXCL8是一种高度炎症的趋化因子。我们有 自从发现RIG-I感应丙型肝炎病毒感染导致CXCL8通过h/vo诱导以来，主要机制如下： 转录激活和mRNA稳定。丙型肝炎病毒感染PRR检测的趋同性 炎性趋化因子的诱导将是拟议研究的重点。其他组织的研究表明 由于发现了诸如CXCL9(由干扰素伽马诱导的单核细胞因子；Mig)等趋化因子的关联， CXCL-10(干扰素-γ诱导蛋白-10；IP-10)和CXCL11(干扰素-诱导T细胞α 化学诱导剂；L-他克)与慢性丙型肝炎。此外，CXCL9-11通过CXCR3和这 已知趋化因子受体在T细胞、树突状细胞和NKT等免疫细胞的迁移中是不可或缺的 细胞进入肝脏。因此，丙型肝炎病毒感染肝细胞后趋化因子的诱导是免疫的中心。 细胞转运到肝脏并诱导炎症反应，从而导致肝脏损害，以及 正如我们已经证明的，干扰素治疗的有效性降低。然而，关于如何做到这一点的信息很少。 导致免疫细胞回到肝脏的趋化因子是在丙型肝炎病毒感染期间诱导的。中环 该项目的假设是，在肝细胞中检测到丙型肝炎病毒感染的PRR导致趋化因子 CXCR3+免疫细胞向肝脏募集。为了解决这一假设，我们提出了三个具体目标 这将决定TLR-3和RIG-I在趋化因子诱导中的相对贡献，决定如何 丙型肝炎病毒感染的细胞感应导致趋化因子mRNAs的稳定，并将趋化因子评估为 免疫细胞趋化性和获得性免疫反应之间的联系 肝细胞：丙型肝炎病毒感染过程中的免疫细胞相互作用。拟议的研究将提供基本的见解 在PRR诱导的炎症反应中，趋化因子在肝脏炎症和 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.