HCV, Alcohol and Host Defense

HCV、酒精和宿主防御

基本信息

批准号：
8734297
负责人：
Gyongyi Szabo
金额：
$ 35.61万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-15 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8734297
关键词：
Alcohol consumption Alcohols Antigen Presentation Antiviral Agents Blood Circulation CD81 gene Cell Communication Cell physiology Cells Chronic Chronic Hepatitis C Defect Dendritic Cells Dinoprostone Double-Stranded RNA Frequencies Future Goals HCV Liver Disease Hepatitis C Hepatitis C virus Hepatocyte Host Defense Human IL2RA gene Immune Immune system Immunity In Vitro Individual Inflammation Inflammatory Instruction Interferon-alpha Interferons Interleukin-10 Interleukin-12 Kupffer Cells Liver Liver diseases Measures Mediating Methods MicroRNAs Molecular Myelogenous Natural Immunity Outcome Pathway interactions Patients Phenotype Play Population Production Proteins RNA RNA Viruses Regulation Regulatory T-Lymphocyte Role Signal Transduction Small Interfering RNA Specimen T cell response T-Cell Activation T-Lymphocyte TLR2 gene TLR3 gene Testing Therapeutic Intervention Transforming Growth Factor beta Viral Viral Proteins Virion Virus Activation adaptive immunity alcohol abuse therapy alcohol effect alcohol exposure base chronic liver disease desensitization gene induction hepatoma cell human TLR7 protein innate immune function interleukin-23 liver biopsy liver inflammation macrophage monocyte novel overexpression receptor research study response virus core

Alcohol consumption Alcohols Antigen Presentation Antiviral Agents Blood Circulation CD81 gene Cell Communication Cell physiology Cells Chronic Chronic Hepatitis C Defect Dendritic Cells Dinoprostone Double-Stranded RNA Frequencies Future Goals HCV Liver Disease Hepatitis C Hepatitis C virus Hepatocyte Host Defense Human IL2RA gene Immune Immune system Immunity In Vitro Individual Inflammation Inflammatory Instruction Interferon-alpha Interferons Interleukin-10 Interleukin-12 Kupffer Cells Liver Liver diseases Measures Mediating Methods MicroRNAs Molecular Myelogenous Natural Immunity Outcome Pathway interactions Patients Phenotype Play Population Production Proteins RNA RNA Viruses Regulation Regulatory T-Lymphocyte Role Signal Transduction Small Interfering RNA Specimen T cell response T-Cell Activation T-Lymphocyte TLR2 gene TLR3 gene Testing Therapeutic Intervention Transforming Growth Factor beta Viral Viral Proteins Virion Virus Activation adaptive immunity alcohol abuse therapy alcohol effect alcohol exposure base chronic liver disease desensitization gene induction hepatoma cell human TLR7 protein innate immune function interleukin-23 liver biopsy liver inflammation macrophage monocyte novel overexpression receptor research study response virus core

展开

项目摘要

Innate immune recognition of the single stranded RNA (ssRNA) virus and induction of a strong antiviral immunity play a critical role in the outcome of hepatitis C virus (HCV) infection. Alcohol consumption contributes to inflammation, innate immune defects, and HCV-induced progression of liver disease. HCV interacts with immune cells in the liver through interactions between HCV-infected hepatocytes or in the circulation in the form of infectious virus particle or its abundantly produced viral proteins. HCV represents danger signals for the host through Toll like receptor 7 and 8 that recognize ssRNA, TLR3 that senses dsRNA or TLR2 that is activated by HCV core and NSS proteins. These TLRs are expressed in immune cells and in hepatocytes but little is known about the role of interactions between HCV infected hepatocytes and innate immune cells such as monocytes and dendritic cells (DC) in the pathomechanism of HCV infection. Our studies demonstrated that chronic HCV infection as well as alcohol treatment results in increased monocyte pro-inflammatory activation but impaired IFN production by plasmacytoid dendritic cells. Therefore, we hypothesize that HCV and alcohol, individually and together, interfere with antiviral host defense at the level of viral recognition receptors and by subverting pivotal functions of monocytes and dendritic cells. We propose that interaction of innate immune cells (monocytes, macrophages, dendritic cells) with HCV-infected hepatocytes modulates their function and/or phenotype to result in impaired innate and adaptive immunity. We hypothesize that HCV-mediated signals play a role in HCV-induced alterations in dendritic cells (mDCI, mDC2, pDC) and contribute to the reduced T cell responses in HCV infection by induction of CD4+CD25+ regulatory T cells. The Specific Aims of this proposal are: 1. To determine the effect of alcohol exposure and HCV on the function and phenotype of monocytes and macrophages, 2. To investigate mechanisms by which alcohol modulates myeloid Type I dendritic cell-mediated defects of T cell activation in chronic HCV infection, 3. To evaluate the effects of alcohol on IFN-lambda in HCV infection, 4. To assess the effect of TLR-mediated/HCV-induced signals in altering dendritic cell functions.

对单链RNA（SSRNA）病毒的先天免疫识别和强抗病毒的诱导免疫力在丙型肝炎病毒（HCV）感染的结果中起关键作用。饮酒有助于炎症，先天免疫缺陷和HCV诱导的肝病进展。 HCV 通过HCV感染的肝细胞或中的相互作用与肝脏中的免疫细胞相互作用以传染病颗粒或其大量产生的病毒蛋白的形式循环。 HCV代表通过收费（如受体7和8）识别ssRNA，TLR3的危险信号由HCV核心和NSS蛋白激活的DSRNA或TLR2。这些TLR在免疫细胞中表达在肝细胞中，关于HCV感染的肝细胞与 HCV感染的病理机理中的固有免疫细胞，例如单核细胞和树突状细胞（DC）。我们的研究表明，慢性HCV感染以及酒精治疗导致增加单核细胞促炎性激活，但受质细胞类树突状细胞产生的IFN损害。因此，我们假设HCV和酒精单独和一起干扰抗病毒宿主在病毒识别受体水平上的防御和通过颠覆单核细胞的关键功能和树突状细胞。我们提出了先天免疫细胞（单核细胞，巨噬细胞，树突状细胞）的相互作用使用HCV感染的肝细胞调节其功能和/或表型，从而导致先天性受损自适应免疫。我们假设HCV介导的信号在HCV诱导的改变中起作用树突状细胞（MDCI，MDC2，PDC），并通过降低HCV感染的T细胞反应。诱导CD4+ CD25+调节T细胞。该提案的具体目的是：1。确定酒精暴露和HCV对单核细胞和巨噬细胞功能和表型的影响，2。研究酒精调节髓样型I型树突状细胞介导的T细胞的缺陷的机制慢性HCV感染中的激活，3。评估酒精对HCV感染中IFN-LAMBDA的影响，4。评估TLR介导的/HCV诱导的信号在改变树突状细胞功能中的影响。