The Immune Response to Pathogens is Controlled by the Cytokine-Induced Epigenetics Signature

对病原体的免疫反应由细胞因子诱导的表观遗传学特征控制

• 批准号: 9526608
• 负责人: Steven Lynn Kunkel
• 金额: $ 62.23万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9526608
• 关键词: Address; Admission activity; Anti-Bacterial Agents; Bacteria; Bacterial Infections; Bacterial Pneumonia; Binding; Cell physiology; Cells; Cessation of life; Chromatin; Communicable Diseases; Data; Environment; Epigenetic Process; Event; Evolution; Experimental Models; Gene Expression Regulation; Gene Silencing; Gene Targeting; Genes; Genetic Transcription; Histones; Host Defense; Human; Immune; Immune response; Immunity; Impairment; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Influenza; Influenza A Virus, H1N1 Subtype; Intensive Care; Interferon-beta; Laboratories; Location; Lung; Lysine; Mediator of activation protein; Methyltransferase; Modeling; Molecular; Molecular Profiling; Morbidity - disease rate; Mus; Pathway interactions; Patient Care; Phagocytosis; Play; Pneumonia; Post-Translational Protein Processing; Predisposition; Process; Publications; Relaxation; Reproducibility; Role; STAT1 gene; Scientist; Seasons; Secondary to; Site; System; T-Lymphocyte; Time; Tissues; Transferase; Viral Genes; Virus Diseases; autocrine; base; chromatin modification; cost; cytokine; histone modification; immunopathology; influenzavirus; macrophage; mortality; mouse model; novel; pandemic disease; paracrine; pathogen; programs; promoter; receptor; response; statistics; transcription factor

Project Summary/Abstract: A lingering conundrum associated with studying host defense transcription profiles is how do specific cells “remember” whether or not they should be actively transcribing specific genes, which would facilitate their participation in an inflammatory response. Our laboratory is investigating novel epigenetic changes, induced via post-translational modifications of histones, as mechanisms to regulate the expression profiles of cell derived mediators during an inflammatory response. We have addressed epigenetic mechanisms that result in the immunopathology caused by influenza, using both normal and infected human cell-based systems and an experimental model of infectious influenza. The latter model will be used to guide our human cell based system. We present data that the cytokine environment established by influenza induces the expression of specific epigenetic machinery that controls the expression of host defense mediators. We identified that interferon beta serves in an autocrine/paracrine manner to cause the expression of Setdb2, an epigenetic- based lysine methyl transferase that is responsible for setting a suppressive histone mark, resulting in host anti-bacterial defense gene silencing. While this sequence of events is likely beneficial against the primary influenza infection, the unintended result is that the defense system that target bacterial infections is impaired. This scenario may provide the mechanism whereby secondary bacterial pneumonia is associated with initial influenza infections. Our data reveals that in both human and mouse models of influenza this same epigenetic pathway can be identified We hypothesize that during the evolution of primary influenza pneumonia a cytokine environment characterized by high levels of IFN-B is established to control the primary viral infection; however, this process engages an epigenetic-based mechanism, which suppresses MΦ pro- inflammatory responses, rendering the host susceptible to secondary bacterial infection. This hypothesis will be investigated via the following specific aims: To determine the mechanism(s) whereby the influenza-induced IFN-B/STAT1 pathway results in the expression of a chromatin modifying lysine methyltransferase, SETDB2, in primary human cells. To investigate a novel mechanism whereby SETDB2 is guided to promoter sites on targeted genes via binding to specific transcription factors, resulting in chromatin modifications at precise promoter locations. To assess the suppressive role of Setdb2 expression on MΦ activity during a primary influenza infection, which decreases both phagocytosis and T cell function and mechanistically contributes to the host susceptibility to secondary bacterial infection. .

项目概要/摘要： 与研究宿主防御转录谱相关的一个挥之不去的难题是， “记住”他们是否应该积极地转录特定的基因，这将有助于他们的 参与炎症反应。我们的实验室正在研究新的表观遗传变化，诱导 通过组蛋白的翻译后修饰，作为调节细胞表达谱的机制， 在炎症反应期间衍生的介质。我们已经解决了表观遗传机制， 流感引起的免疫病理学，使用正常和感染的人类细胞为基础的系统和 传染性流感的实验模型。后一种模型将用于指导我们的基于人类细胞的 系统我们目前的数据表明，流感病毒建立的细胞因子环境诱导了 控制宿主防御介质表达的特定表观遗传机制。我们发现 干扰素β以自分泌/旁分泌的方式引起Setdb 2的表达，Setdb 2是一种表观遗传的- 基于赖氨酸甲基转移酶，负责设置抑制性组蛋白标记，导致宿主 抗细菌防御基因沉默。虽然这一系列事件可能对主要的 流感病毒感染后，意想不到的结果是针对细菌感染的防御系统受损。 这种情况可能提供了继发性细菌性肺炎与初始肺炎相关的机制。 流感感染。我们的数据显示，在人类和小鼠流感模型中， 我们假设在原发性流感肺炎的演变过程中， 建立了以高水平IFN-B为特征的细胞因子环境，以控制原发性病毒感染， 感染;然而，这一过程涉及一种基于表观遗传的机制，其抑制MΦ pro- 炎症反应，使宿主易受继发性细菌感染。这 假设将通过以下具体目标进行研究：确定 流感诱导的IFN-B/STAT 1途径导致染色质修饰赖氨酸的表达 原代人类细胞中的甲基转移酶（SETDB 2）。为了研究SETDB 2被激活的新机制， 通过与特异性转录因子结合，引导至靶基因的启动子位点， 在精确的启动子位置进行修饰。探讨Setdb 2对MΦ的抑制作用 在原发性流感感染期间的活性，其降低吞噬作用和T细胞功能， 机械地有助于宿主对继发性细菌感染的易感性。 .