Immune Regulation of Virus Clearance and Tissue Injury at Sites of Infection

病毒清除和感染部位组织损伤的免疫调节

• 批准号: 8096720
• 负责人: Thomas J Braciale
• 金额: $ 157.24万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-18 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8096720
• 关键词: Immune; Regulation; Virus; Clearance; Tissue

DESCRIPTION (provided by applicant): This U19 application for a Multi-Investigator Program to examine Immune Mechanisms of Virus Control focuses on the role of CD8 + effector T-cells in orchestrating clearance of virus and in the control of tissue inflammation and injury associated with the host response to virus infection. Four highly interactive and synergistic Projects and two supporting scientific cores comprise program. These projects are designed to explore the role of innate immune cells (notably natural killer (NK) cells and dendritic cell/macrophages) and their products in regulating the development of effector CD8 + T cells which can efficiently eliminates virus/virus infected cells and control excess and potentially injurious inflammation associated with T cell recognition of viruses at different sites of infection. The Specific Aims of the Program fulfill several of the stated Aims of the RFA including understanding and defining the role of innate immune cells in regulating adaptive responses at different sites of virus infection.' This Program also deals with a topic as important as effective virus clearance that is the control of tissue inflammation and injury and explores the contribution of intrinsic mechanisms of control of tissue inflammation and injury exhibited by effector CD8 + T cells (i.e. effector T cell derived I L-10 and inhibitory NK receptor expression by the effector T cells). The Program brings together project leaders with unique expertise and diverse and complementary skills in the areas of Viral Immunology, Mammalian Genetics, Virology and Clinical Medicine. The individual Project Leaders and Core Directors have both prior and ongoing collaborations. In this program we proposed to examine the following questions: How does I L-10 (interleukin-10) produced by antiviral CD8 + effector T-cells affect virus clearance and control lung inflammation in acute respiratory virus infection and what factors control the production of this regulatory cytokine by effector T-cells (Project 1)?; 2. What is the nature of the defect in the CD8 + T-cell effector response to hepatotropic virus infection and adaptive immune induction in the liver and how do liver NK cells (and liver dendritic cell-NK cell interactions) regulate the magnitude and the quality of the CD8 + T cell response (Project 2)7; 3. How does NK cell mediated control of early virus replication at the site of infection in a secondary lymphoid organ i.e. the spleen, and the activation state of the NK cells, affect virus elimination and the tempo and quality of the antiviral CD8 + T cell response (Project 3)?; 4. What are the factors that control the expression of an inhibitory NK-type receptor NKG2A on CD8 + effector T cells and how does that engagement of this inhibitory receptor control excess Inflammation and inhibit immune pathology in the virus infected lungs (Project 4)? PROJECT 1: lnterleukin-10 in acute respiratory virus infection (Braciale, T) PROJECT 1 DESCRIPTION (provided by applicant): Pulmonary inflammation and injury is a frequent (and, in some instances, lethal) outcome of virus infections of the respiratory tract. Respiratory virus infection triggers a coordinated response from the host innate and adaptive immune systems. The host response is essential for virus clearance and recovery, but is also a significant cause of pulmonary injury that can accompany virus elimination. Relevant recent examples of this are the immune-mediated lung inflammation/injury observed in human infections with the SARS coronavirus and the H5N1 avian influenza viruses. The long-term goal of Project 1 is to define and characterize the interactions between cells of the innate immune system i.e. dendritic cells, monocyte/ macrophage, NK cells and adaptive immune effector T lymphocytes (Te) in the process of virus clearance and in the control of inflammation/injury during experimental virus infection of the respiratory tract. The foundation for this application is our recent and unexpected findings in the murine model of type A influenza infection that anti-viral effector T-cells (both CD4 +Te and more prominently CD8 +Te) infiltrating the infected lungs produce high levels of the anti-inflammatory/regulatory cytokines IL-10 during the Te response to infection and virus elimination. Furthermore, we found that blocking the effect of Te-derived IL- 10 during infection results in increased pulmonary inflammation and lethal injury. Our evidence further suggests that this Te-derived IL-10 plays a central role in controlling the level of lung inflammation/injury produced by mononuclear cells infiltrating the infected lungs in response to virus infection and the proinflammatory mediators released by virus- immune (Te). We wish to analyze the expression and regulation of IL-10 and specifically Te-derived IL-10 in the infected lungs and the impact of this cytokine on the control of virus clearance and lung inflammation/injury. The aims of Project 1 are: 1. To evaluate the cellular sources and effects of IL-10 on influenza virus infection; 2. To analyze the regulation of IL-10 production by Te during influenza infection; 3. To determine the impact of viral infection on the production of Te-derived IL- 10. The proposed studies are designed to complement ongoing related studies in Projects 2, 3 and 4.

描述（由申请人提供）：本U19申请的多研究者项目旨在检查病毒控制的免疫机制，重点关注CD 8+效应T细胞在协调病毒清除和控制与宿主对病毒感染反应相关的组织炎症和损伤中的作用。四个高度互动和协同的项目和两个支持科学核心组成计划。这些项目旨在探索先天免疫细胞（特别是自然杀伤（NK）细胞和树突状细胞/巨噬细胞）及其产物在调节效应CD 8 + T细胞发育中的作用，该效应CD 8 + T细胞可以有效地消除病毒/病毒感染细胞，并控制与T细胞识别不同感染部位的病毒相关的过量和潜在有害炎症。该计划的具体目标实现了RFA的几个既定目标，包括理解和定义先天免疫细胞在调节病毒感染不同部位的适应性反应中的作用。该计划还涉及与有效的病毒清除同样重要的主题，其是组织炎症和损伤的控制，并探索了由效应CD 8 + T细胞（即效应T细胞衍生的IL-10和效应T细胞的抑制性NK受体表达）表现出的组织炎症和损伤控制的内在机制的贡献。该计划汇集了在病毒免疫学，哺乳动物遗传学，病毒学和临床医学领域具有独特专业知识和多样互补技能的项目领导人。个别项目负责人和核心主任既有以前的合作，也有正在进行的合作。在本项目中，我们提出了以下问题：在急性呼吸道病毒感染中，抗病毒CD 8+效应T细胞产生的IL-10（白细胞介素-10）如何影响病毒清除和控制肺部炎症，以及哪些因素控制效应T细胞产生这种调节性细胞因子（项目1）？2. CD 8 + T细胞效应子对嗜肝病毒感染的应答和肝脏中的适应性免疫诱导的缺陷的性质是什么，以及肝脏NK细胞（和肝脏树突状细胞-NK细胞相互作用）如何调节CD 8 + T细胞应答的幅度和质量（项目2）7; 3. NK细胞介导的对次级淋巴器官（即脾脏）感染部位早期病毒复制的控制以及NK细胞的活化状态如何影响病毒清除以及抗病毒CD 8 + T细胞应答的克里思和质量（项目3）？4.控制抑制性NK型受体NKG 2A在CD 8+效应T细胞上表达的因素是什么？这种抑制性受体的参与如何控制病毒感染肺部的过度炎症并抑制免疫病理学（项目4）？ 项目1：急性呼吸道病毒感染中的白细胞介素-10（Braciale，T） 项目1描述（由申请人提供）：肺部炎症和损伤是呼吸道病毒感染的常见（在某些情况下是致命的）结局。呼吸道病毒感染引发宿主先天性和适应性免疫系统的协调反应。宿主反应对于病毒清除和恢复至关重要，但也是可能伴随病毒清除的肺损伤的重要原因。最近的相关例子是在人类感染SARS冠状病毒和H5 N1禽流感病毒时观察到的免疫介导的肺部炎症/损伤。项目1的长期目标是定义和表征先天免疫系统细胞（即树突状细胞、单核细胞/巨噬细胞、NK细胞和适应性免疫效应T淋巴细胞（Te））在病毒清除过程中以及在呼吸道实验性病毒感染期间控制炎症/损伤中的相互作用。 本申请的基础是我们最近在A型流感感染的鼠模型中的意外发现，即浸润感染肺的抗病毒效应T细胞（CD 4 +Te和更显著的CD 8 +Te）在Te对感染和病毒消除的应答期间产生高水平的抗炎/调节细胞因子IL-10。此外，我们发现在感染期间阻断Te衍生的IL- 10的作用导致肺部炎症和致命性损伤增加。我们的证据进一步表明，这种Te衍生的IL-10在控制由响应于病毒感染和由病毒免疫（Te）释放的促炎介质而浸润受感染肺的单核细胞产生的肺炎症/损伤水平中起着核心作用。我们希望分析IL-10，特别是Te衍生的IL-10在感染的肺中的表达和调节，以及这种细胞因子对控制病毒清除和肺部炎症/损伤的影响。项目1的目标是：1。目的：1.探讨IL-10的细胞来源及其在流感病毒感染中的作用。分析Te对流感病毒感染过程中IL-10产生的调节作用。确定病毒感染对Te衍生的IL- 10产生的影响。拟议的研究旨在补充项目2、3和4中正在进行的相关研究。