Tim-3-mediated IL-12 dysregulation in antiviral responses to HCV infection

Tim-3 介导的 HCV 感染抗病毒反应中 IL-12 失调

• 批准号: 8456093
• 负责人: Zhi Q. Yao
• 金额: $ 30.64万
• 依托单位: EAST TENNESSEE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-10 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8456093
• 关键词: Affect; Anabolism; Antiviral Agents; Antiviral Response; Antiviral Therapy; Apoptosis; Biological Models; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Differentiation process; Cells; Cessation of life; Chronic; Chronic Hepatitis C; Clinical; Coculture Techniques; Cytokine Inducible SH2-Containing Protein; Data; Dendritic Cells; Epidemic; Functional disorder; Genetic Transcription; Genotype; Goals; Hepatitis C; Hepatitis C virus; Hepatocyte; Human; Immune; Immune response; Immunity; Immunoglobulins; Immunomodulators; Immunotherapy; Impairment; Individual; Infection; Inflammatory; Interferons; Interleukin-12; Lead; Link; Liver; Mediating; MicroRNAs; Modeling; Mucins; Natural Immunity; Outcome; Patients; Play; Production; Regulation; Role; Signal Pathway; Signal Transduction; System; T cell response; T-Lymphocyte; Tertiary Protein Structure; Testing; Th1 Cells; Th2 Cells; Toll-like receptors; Translations; Up-Regulation; Vaccines; Viral; Viral Antigens; Virus; Virus Diseases; Virus Replication; adaptive immunity; base; cohort; combat; cytokine; exhaustion; global health; improved; macrophage; monocyte; novel; novel strategies; programs; receptor; response; tool; translational approach; treatment response; virus core; virus host interaction

DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) is remarkable at disrupting human immunity to establish chronic infection; it is a global health problem with limited treatment options and no available vaccine. The mechanisms by which the virus persists in the majority of infected liver by overcoming the host innate to adaptive immunity is currently unclear, partly due to our incomplete understanding of HCV-host interactions that lead to this immune disruption. We have previously demonstrated that chronic HCV infection leads to immunodysregulation mediated through up- regulation of negative immunomodulators, including programmed death-1 (PD-1), suppressor of cytokine signaling-1 (SOCS-1), and most recently, T cell immunoglobulin and mucin domain protein-3 (Tim-3). While Tim-3 has been shown to play a critical role in T cell exhaustion during chronic viral infections, its expression and function on innate immune cells in HCV persistence and antiviral responses remain unknown. We have recently discovered that Tim-3 plays a pivotal role in negative regulation of Toll-like receptor (TLR)-mediated innate immune responses, being up-regulated on monocytes/macrophages (M/M?) isolated from chronically HCV-infected individuals and healthy M/M??co-cultured with HCV-expressing hepatocytes. Importantly, blocking Tim-3 signaling restores the expression of IL-12, a key pro-inflammatory cytokine linking innate to adaptive immune responses. This novel observation suggests that the inability to clear virus in chronically HCV-infected hosts may be a function of a Tim-3-mediated impairment of innate immunity, with subsequent dysfunction of adaptive immune responses. We thus hypothesize that HCV-mediated Tim-3 up-regulation on M/M??plays a central role in innate immune and IL-12 dysregulation, such that blockade of Tim-3 signaling in M/M??may rescue impaired antiviral immune responses. To test this hypothesis, we will carry out the following specific aims: 1) Define the role of Tim-3 up-regulation on M/M? from HCV-infected patients following antiviral therapy with defined outcomes, comparing with those naturally resolved HCV infection or healthy subjects, by examining both Tim-3 expression and M/M??functions, and in particular, IL-12 production. 2) Determine the mechanisms by which Tim-3 is up-regulated on M/M??using an HCV-expressing hepatocyte model system, focusing on specific HCV antigen-mediated regulation of Tim-3 transcription, translation, biosynthesis and degradation. 3) Determine the effects of Tim-3 signaling in M/M??on host antiviral responses, including dendritic cell (DC) IL-12 expression, virus-specific CD4+ and CD8+ T lymphocyte responses, hepatocyte interferon (IFN) signaling and HCV replication. The overall goal of this proposal is to employ a translational approach to obtain a unified overview of how HCV-mediated Tim-3 up-regulation on M/M? alters IL-12 expression and host innate to adaptive immune responses to HCV infection, so as to develop effective strategies to combat this common viral disease.

描述（由申请人提供）：丙型肝炎病毒（HCV）在破坏人类免疫力以建立慢性感染方面非常明显。这是一个全球健康问题，治疗方案有限，没有可用的疫苗。目前尚不清楚，通过克服宿主先天到适应性免疫而在大多数感染肝脏中持续存在的机制尚不清楚 部分原因是我们对导致这种免疫破坏的HCV-host相互作用的不完全理解。我们先前已经证明，慢性HCV感染会导致通过上调节阴性免疫调节剂（包括程序性死亡-1（PD-1）（PD-1），细胞因子信号1（SOCS-1）的抑制器）和T细胞免疫球蛋白的抑制器，导致免疫调节介导的免疫调节。和粘蛋白结构域蛋白3（TIM-3）。尽管已显示TIM-3在慢性病毒感染期间在T细胞衰竭中起关键作用，但其在HCV持久性中对先天免疫细胞的表达和功能仍然未知。我们最近发现，TIM-3在收费受体（TLR）介导的先天免疫反应的负调控中起关键作用，在从长期HCV感染的个体中分离出的单核细胞/巨噬细胞（M/M？）上上调和健康的M/M？与表达HCV的肝细胞共同培养。重要的是，阻止TIM-3信号传导恢复了IL-12的表达，IL-12的表达是一种关键的促炎细胞因子，将先天性与自适应免疫反应联系起来。这一新颖的观察结果表明，无法清除慢性HCV感染宿主中的病毒可能是TIM-3介导的先天免疫损害的函数，随后适应性免疫反应功能障碍。因此，我们假设HCV介导的M/M上的TIM-3上调在先天免疫和IL-12失调中起着核心作用，从而使M/M中的TIM-3信号阻断tim-3信号的阻塞可能会营救受损的抗病毒。免疫反应。为了检验这一假设，我们将执行以下具体目的：1）定义TIM-3上调对M/M的作用？通过检查TIM-3表达和M/M ??功能，尤其是IL-12的产生，与抗病毒治疗后的HCV感染患者相比，与自然解决的HCV感染或健康受试者进行了比较。 2）确定使用表达HCV的肝细胞模型系统在M/m上上调TIM-3的机制，重点是特定的HCV抗原介导的TIM-3转录，翻译，生物合成和降解的调节。 3）确定TIM-3信号在m/m ??中的影响对宿主抗病毒反应，包括树突状细胞（DC）IL-12表达，病毒特异性CD4+和CD8+ T淋巴细胞反应，肝细胞Interferon（IFN）信号和HCV复制。该提案的总体目标是采用翻译方法来获得统一的概述，概述了HCV介导的TIM-3上调如何在m/m上进行中调？改变IL-12的表达并寄主先天以适应对HCV感染的免疫反应，以制定有效的策略来打击这种常见的病毒疾病。