Innate Immunity and Hepatitis C Virus Infection

先天免疫和丙型肝炎病毒感染

• 批准号: 8101849
• 负责人: Ratna B. Ray
• 金额: $ 31.44万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8101849
• 关键词: Acute; Affect; Animal Model; Antiviral Agents; Attenuated; Autophagocytosis; Autophagosome; Cell Culture Techniques; Cells; Chronic; Chronic Hepatitis C; Cirrhosis; Cytokine Gene; Development; Disease Progression; Fibrosis; Future; Genes; Genotype; Goals; Growth; Hepatitis C; Hepatitis C Antiviral; Hepatitis C virus; Hepatocyte; Human; Immune response; Immune system; Infection; Interferon-beta; Interferons; Knowledge; Lead; Link; Liver; Modality; Molecular; National Institute of Diabetes and Digestive and Kidney Diseases; Natural Immunity; Pathway interactions; Patients; Primary carcinoma of the liver cells; Process; Proteins; Ribavirin; Signal Pathway; Specimen; Testing; Therapeutic; Treatment Failure; Treatment outcome; Vesicle; Viral; Viral Proteins; Virus; Virus Diseases; Virus Replication; base; immunoregulation; intrahepatic; microorganism; novel therapeutics; public health relevance; treatment strategy

DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) often causes chronic infection that affects over 200 million people worldwide. Chronic HCV infection is associated with fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The approved therapy for HCV infection is pegylated interferon-1 (IFN- 1) in combination with ribavirin that offers limited benefit depending on the genotype of the infecting virus. However, the molecular mechanisms underlying treatment failure remain unknown. Our long-term goal is to understand how HCV causes persistent infection at the molecular level, which will help in developing effective therapeutic modalities. Studies on HCV is challenging because of its limited growth in cell culture, and lack of a convenient animal model for virus infection and disease progression. We have recently shown that HCV infection in cell culture activates interferon beta (IFN-2) expression and induces autophagy. However, we do not fully understand how HCV blunts innate immune response and establishes chronic infection. We hypothesize that HCV interacts with cellular proteins and perturb their functions for establishment of persistent infection. Three complementary approaches will be used to test our hypothesis: Aim 1 will determine molecular processes by which HCV modulates intracellular IFN signaling pathway. Aim 2 will determine whether HCV impairs innate immunity by induction of autophagy. Finally, Aim 3 will examine intrahepatic innate immune response in HCV infected patients to correlate with treatment outcome. The results from our proposed studies will provide molecular mechanisms for viral persistence, and will aid in devising future therapeutic strategies for treatment of chronic HCV infection. PUBLIC HEALTH RELEVANCE: HCV infection affects over 200 million people worldwide. Our study will reveal the molecular mechanisms of viral persistence, which may lead to new therapeutic strategies for treatment of chronic HCV infection.

描述（由申请人提供）：丙型肝炎病毒 (HCV) 经常引起慢性感染，影响全球超过 2 亿人。慢性HCV感染与纤维化、肝硬化和肝细胞癌(HCC)有关。已批准的 HCV 感染治疗方法是聚乙二醇化干扰素 1 (IFN-1) 与利巴韦林联合治疗，但根据感染病毒的基因型，其疗效有限。然而，治疗失败的分子机制仍然未知。我们的长期目标是了解丙型肝炎病毒如何在分子水平上引起持续感染，这将有助于开发有效的治疗方式。 HCV 的研究具有挑战性，因为其在细胞培养中的生长有限，并且缺乏用于病毒感染和疾病进展的方便的动物模型。我们最近发现，细胞培养物中的 HCV 感染会激活干扰素 β (IFN-2) 表达并诱导自噬。然而，我们并不完全了解丙型肝炎病毒如何削弱先天免疫反应并形成慢性感染。我们假设 HCV 与细胞蛋白相互作用并扰乱其功能以建立持续感染。将使用三种互补的方法来检验我们的假设：目标 1 将确定 HCV 调节细胞内 IFN 信号通路的分子过程。目标 2 将确定 HCV 是否通过诱导自噬损害先天免疫。最后，目标 3 将检查 HCV 感染患者的肝内先天免疫反应，以与治疗结果相关联。我们提出的研究结果将提供病毒持久性的分子机制，并将有助于制定治疗慢性丙型肝炎病毒感染的未来治疗策略。公共卫生相关性：HCV 感染影响着全球 2 亿多人。我们的研究将揭示病毒持续存在的分子机制，这可能会带来治疗慢性丙型肝炎病毒感染的新治疗策略。