Immune Mechanisms of HCV Persistence and Pathogenesis

HCV 持续存在和发病机制的免疫机制

基本信息

批准号：
8212128
负责人：
JIAREN SUN
金额：
$ 32.67万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-02-01 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8212128
关键词：
Address Adenoviruses Adopted American Animal Model Animals Antigen Presentation Antiviral Agents Antiviral Response Area Biochemical Biological Assay Blood Circulation Bone Marrow Breeding CD40 Antigens Cell physiology Cessation of life Chimeric Proteins Chronic Complement Complex Disease Disease Progression Enzymes Epitopes Estrogen Receptors Fatty Liver Fluorescence Resonance Energy Transfer Future Gene Expression Genes HCV Animal Models HLA-A2.1 Hepatic Hepatitis C Hepatitis C Therapeutics Hepatitis C virus Host Defense Human Human papillomavirus 16 E1 protein Immune Immune response Immune system Immunologics Immunosuppression Infection Inflammation Injury Interferon-alpha Interferons LacZ Genes Liver Measures Mediating Molecular Mus Mutate Myelogenous Natural Killer Cells Nonstructural Protein Outcome Pathogenesis Patients Persons Phase Process Production Prophylactic treatment Reporter Research Research Personnel Role Severity of illness Signaling Molecule Structural Protein System T cell response T-Lymphocyte TNFRSF5 gene Tamoxifen Technology Testing The Sun Time Transgenes Transgenic Mice Transgenic Organisms United States Vaccines Viral Viral Antigens Viral Pathogenesis Viral Proteins Virus Western Blotting Work base defense response design enzyme linked immunospot assay flexibility gene induction hepatitis C virus nucleocapsid protein immune function in vivo insight intrahepatic liver transplantation mouse model new therapeutic target novel protein expression protein function research study response virus pathogenesis

项目摘要

Nearly 4 million Americans are currently infected with hepatitis C virus (HCV). HCV infection is responsible for approximately 8,000-10,000 deaths annually and is the leading reason for liver transplantation in the United States. There is no vaccine for the control of hepatitis C. A small number of people infected with.HCV overcome the virus during the initial infection and clear it from the bloodstream. The remaining 75%-85% develop a chronic infection. The severity of the disease varies greatly from person to person. The molecular basis for viral persistence, disease progression and potential virus/host targets for novel therapeutics is not well understood. We hypothesize that parenchymal HCV antigen presentation leading to inappropriate T cell function contributes to immune-mediated liver inflammation and that direct immunosuppression by viral proteins is a component of an integrated strategy of HCV survival. Three complementary approaches will be used to test these hypotheses: 1) To test the function of immune costimulatory molecules (e.g. CD40) in HCV-related liver injuries, we will establish a lineage of mice that conditionally express HCV structural proteins and CD40 molecules in the liver. Pathological changes in the liver, hepatic T cell priming and effector functions in these mice will be measured by FACS, ELISPOT and immunohistological analyses. 2) To examine whether HCV nonstructural (NS) proteins, especially NS3, interfere with the host antiviral responses leading to viral persistence, we will generate mice conditionally expressing HCV-NS genes, which are controlled by a novel tamoxifen-inducible system. We will examine these animals' interferon (IFN)-alpha/beta and adaptive immune responses in response to a viral challenge in the liver. Hepatic injury and viral persistence in these animals will be determined by biochemical, histopathological and immunochemical, and real-time PCR analyses. 3) Finally, we will examine the synergistic effects of HCV-S and-NS genes on disease pathogenesis and viral persistence in animals conditionally expressing the entire HCV genes in the liver. The immunosuppressive effect of the total complement HCV proteins will be tested following a viral challenge. These studies would provide important information concerning molecular mechanisms responsible for viral persistence and disease progression in vivo, and may aid in devising future strategies targeted at blocking specific candidates.

目前有近 400 万美国人感染丙型肝炎病毒 (HCV)。 HCV感染是罪魁祸首每年约有 8,000-10,000 人死亡，是肝移植的主要原因美国。没有疫苗可以控制丙型肝炎。少数人感染.HCV 在最初感染期间克服病毒并将其从血液中清除。剩余75%-85% 发展为慢性感染。疾病的严重程度因人而异。分子病毒持久性、疾病进展和新疗法的潜在病毒/宿主靶标的基础尚不明确很好理解。我们假设实质 HCV 抗原呈递导致不适当的 T 细胞功能有助于免疫介导的肝脏炎症，并通过病毒直接进行免疫抑制蛋白质是 HCV 生存综合策略的组成部分。三种互补的方法将用于检验这些假设：1）检验免疫共刺激分子（例如CD40）在 HCV相关的肝损伤，我们将建立条件表达HCV结构的小鼠谱系肝脏中的蛋白质和 CD40 分子。肝脏的病理变化、肝 T 细胞启动和这些小鼠的效应功能将通过 FACS、ELISPOT 和免疫组织学分析进行测量。 2）检查 HCV 非结构 (NS) 蛋白，尤其是 NS3 是否干扰宿主抗病毒药物导致病毒持续存在的反应，我们将产生条件表达 HCV-NS 基因的小鼠，这是由一种新型他莫昔芬诱导系统控制的。我们将检查这些动物的干扰素 (IFN)-α/β 和适应性免疫反应响应肝脏中的病毒挑战。肝损伤这些动物中的病毒持久性将通过生化、组织病理学和免疫化学和实时 PCR 分析。 3）最后，我们将检查HCV-S的协同效应和-NS基因对条件表达整个动物的疾病发病机制和病毒持久性的影响肝脏中的 HCV 基因。将测试总补体HCV蛋白的免疫抑制作用在病毒式挑战之后。这些研究将提供有关分子的重要信息负责体内病毒持续存在和疾病进展的机制，并可能有助于设计未来的策略旨在阻止特定候选人。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Aberrant transcription and post-transcriptional processing of hepatitis C virus non-structural genes in transgenic mice.

转基因小鼠丙型肝炎病毒非结构基因的异常转录和转录后加工。

DOI：
10.1007/s11248-011-9494-x
发表时间：
2011
期刊：
Transgenic research
影响因子：
3
作者：
Desai,MayuraM;Tumurbataar,Batbayar;Zhang,Yueqing;Chan,Lee-NienLillian;Sun,Jiaren;Chan,Teh-Sheng
通讯作者：
Chan,Teh-Sheng

Intrahepatic innate lymphoid cells secrete IL-17A and IL-17F that are crucial for T cell priming in viral infection.

DOI：
10.4049/jimmunol.1303281
发表时间：
2014-04-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
Jie Z;Liang Y;Hou L;Dong C;Iwakura Y;Soong L;Cong Y;Sun J
通讯作者：
Sun J

Early IL-17 production by intrahepatic T cells is important for adaptive immune responses in viral hepatitis.

DOI：
10.4049/jimmunol.1201970
发表时间：
2013-01-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
Hou L;Jie Z;Desai M;Liang Y;Soong L;Wang T;Sun J
通讯作者：
Sun J

Parenchymal expression of CD40 exacerbates adenovirus-induced hepatitis in mice.

DOI：
10.1002/hep.24270
发表时间：
2011-05
期刊：
HEPATOLOGY
影响因子：
13.5
作者：
Yan, Jiabin;Jie, Zuliang;Hou, Lifei;Wanderley, Joao L.;Soong, Lynn;Gupta, Shalini;Qiu, Suimin;Chan, Tehsheng;Sun, Jiaren
通讯作者：
Sun, Jiaren