Novel Aspects of Hepatic Innate and Adaptive Immunity to HCV Infection

肝脏对 HCV 感染的先天性和适应性免疫的新特点

基本信息

项目摘要

Approximately 200 million throughout the world have chronic hepatitis C viral (HCV) infection. HCV is leading cause of liver cancer and indication for liver transplantation. Enhanced understanding of HCV-host interactions and the mechanisms that regulate immunity within the liver is required to combat this virus and to develop improved therapies. Our laboratory has focused on understanding the role of innate immune cells such as dendritic and natural killer cells, as well as adaptive immunity mediated by CD4+ and CD8+ T cells. Recently our laboratory has become interested in liver sinusoidal endothelial cells (LSECs) which are highly frequent in the liver. Although LSEC-mediated suppression is critical for control of inflammation, it likely compromises protective immunity against HCV infection. Surprisingly little is known about LSECs in HCV infection. We will use a combination of human derived specimens, including LSECs, hepatocytes, and T cells, as well as pharmacologic and silencing strategies in multi-cellular models. In this new application, we will determine the differential effects of HCV sensing by human liver sinusoidal endothelial cells (LSECs) on antiviral IFN signaling. We hypothesize that HCV employs multiple strategies to target LSECs, including direct infection, pinocytosis, or binding of HCV-specific proteins such as core. The uptake of apoptotic HCV-infected hepatocytes or enhancement of an inflammatory state that may regulate the expression of viral or trafficking receptors may ultimately play either protective or adverse roles in HCV dissemination within the liver. In addition, we will characterize the mechanisms that enhance or antagonize LSEC-derived factors' ability to inhibit viral replication in primary and immortalized hepatocytes, the autocrine effects of Type I and III IFNs, and the transcriptional elements that regulate IL-28B (IFN- 3) induction within LSECs. Understanding the multiple ways in which HCV interacts with LSECs to modulate the production of antiviral cytokines such as IFNs, the specific intracellular signaling pathways involved, as well as effects within the hepatic sinusoidal microenvironment will ultimately provide novel mechanistic insights and potential therapeutic targets for this common infection. We will also define the specific processes whereby HCV- experienced LSECs induce a regulatory CD4+ T cell phenotype and impair function of CTLs, identifying mechanisms to reverse this suppression in order to enhance anti-viral immunity. To date, we have found that LSECs upregulate Galectin-9 and reactive oxygen species with HCV core protein. Completion of the aims outlined in this application would ultimately provide a vertical step in the field by linking innate LSEC function to control of adaptive immunity.
全世界约有2亿人患有慢性丙型肝炎病毒(HCV)感染。hcv是 肝癌的主要原因和肝移植的指征。增强对HCV宿主的了解 需要肝脏内的相互作用和调节免疫力的机制来对抗这种病毒并 开发更好的治疗方法。我们的实验室致力于了解先天免疫细胞的作用 如树突细胞和自然杀伤细胞,以及由CD4+和CD8 + T细胞介导的适应性免疫。 最近,我们的实验室对肝窦内皮细胞(LSEC)产生了兴趣, 常见于肝脏。虽然LSEC介导的抑制对于控制炎症至关重要,但它可能 损害了对HCV感染的保护性免疫。令人惊讶的是,对HCV中的LSEC知之甚少 感染我们将使用人源性标本的组合,包括LSEC、肝细胞和T细胞, 以及多细胞模型中的药理学和沉默策略。 在这个新的应用中,我们将确定人类肝脏正弦信号对HCV传感的差异效应。 内皮细胞(LSEC)对抗病毒IFN信号传导的影响。我们假设HCV采用多种策略, 靶向LSEC,包括直接感染、胞饮作用或HCV特异性蛋白质如核心的结合。的 HCV感染的肝细胞凋亡的吸收或可能调节细胞凋亡的炎症状态的增强 病毒或运输受体的表达可能最终在HCV中发挥保护或不利作用, 在肝脏内扩散。此外,我们将描述增强或拮抗 LSEC衍生因子抑制原代和永生化肝细胞中病毒复制的能力, I型和III型IFN的作用,以及调节IL-28 B(IFN-3)诱导的转录元件, LSEC了解HCV与LSECs相互作用以调节 抗病毒细胞因子如IFN,所涉及的特异性细胞内信号传导途径,以及 肝窦微环境将最终提供新的机制见解和潜力, 这种常见感染的治疗目标。我们还将定义HCV的具体过程- 经验丰富的LSEC诱导调节性CD4 + T细胞表型并损害CTL的功能, 逆转这种抑制的机制,以增强抗病毒免疫。迄今为止,我们发现, LSECs上调Galectin-9和活性氧与HCV核心蛋白。完成目标 本申请中概述的方法最终将通过将先天LSEC功能 来控制适应性免疫

项目成果

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HUGO Ramon ROSEN其他文献

HUGO Ramon ROSEN的其他文献

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{{ truncateString('HUGO Ramon ROSEN', 18)}}的其他基金

Mechanisms of Advanced NAFLD Disparities in Hispanics: A Multi-level Analysis
西班牙裔晚期 NAFLD 差异的机制:多层次分析
  • 批准号:
    10155155
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
Innate Immunity, Cholesterol, and NASH Pathogenesis
先天免疫、胆固醇和 NASH 发病机制
  • 批准号:
    9886092
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
Innate and Adaptive Immunity to HCV in Human Pregnancy
人类妊娠期对 HCV 的先天性和适应性免疫
  • 批准号:
    9696625
  • 财政年份:
    2018
  • 资助金额:
    --
  • 项目类别:
RESUBMISSION -R01 AI120622 –Restoration of Immunity and Function with DAA Treatment in HCV infection
重新提交 -R01 AI120622 — 使用 DAA 治疗 HCV 感染恢复免疫和功能
  • 批准号:
    9246766
  • 财政年份:
    2017
  • 资助金额:
    --
  • 项目类别:
Hepatitis C viral sensing by non-parenchymal liver cells (NPC)
非实质肝细胞 (NPC) 感知丙型肝炎病毒
  • 批准号:
    8583255
  • 财政年份:
    2013
  • 资助金额:
    --
  • 项目类别:
Hepatitis C viral sensing by non-parenchymal liver cells (NPC)
非实质肝细胞 (NPC) 感知丙型肝炎病毒
  • 批准号:
    8662190
  • 财政年份:
    2013
  • 资助金额:
    --
  • 项目类别:
HEPATITIS C VIRAL INFECTION IN HUMAN PREGNANCY
人类妊娠期丙型肝炎病毒感染
  • 批准号:
    8535990
  • 财政年份:
    2012
  • 资助金额:
    --
  • 项目类别:
Midcareer Investigator Award in Patient-Oriented Research (K24)
以患者为导向的研究中的职业中期研究者奖 (K24)
  • 批准号:
    8497578
  • 财政年份:
    2009
  • 资助金额:
    --
  • 项目类别:
Midcareer Investigator Award in Patient-Oriented Research (K24)
以患者为导向的研究中的职业生涯中期研究者奖 (K24)
  • 批准号:
    8305732
  • 财政年份:
    2009
  • 资助金额:
    --
  • 项目类别:
Functional attributes of CD8+ T cells in recovery of hepatitis C virus infection
CD8 T 细胞在丙型肝炎病毒感染恢复中的功能特性
  • 批准号:
    7782728
  • 财政年份:
    2009
  • 资助金额:
    --
  • 项目类别:

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用于儿童抗病毒治疗的剂量灵活组合 3D 打印输送系统
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用于抗病毒治疗的布尼亚病毒核酸内切酶抑制剂的发现
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Discovery of Bunyaviral Endonuclease Inhibitors for Antiviral Therapy
用于抗病毒治疗的布尼亚病毒核酸内切酶抑制剂的发现
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抗病毒疗法发现的跨学科方法
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