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. .

项目摘要/摘要： 与研究宿主防御转录曲线相关的挥之不去的难题是特定细胞如何 “记住”他们是否应该积极转录特定基因，这将有助于他们 参与炎症反应。我们的实验室正在研究新型的表观遗传变化，引起 通过组蛋白的翻译后修饰，作为调节细胞表达谱的机制 在炎症反应中衍生的介体。我们已经解决了导致的表观遗传机制 由影响力引起的免疫病理，使用正常和受感染的人类细胞系统以及 传染性影响力的实验模型。后来的模型将用于指导基于人类细胞 系统。我们提供的数据表明，细胞因子环境通过影响的表达 控制宿主防御介体的表达的特定表观遗传机制。我们确定了这一点 干扰素β以自分泌/旁分泌方式使用，引起setDB2的表达，一种表观遗传学 - 基于基于抑制性组蛋白标记的赖氨酸甲基转移，导致宿主 抗菌防御基因沉默。虽然这一系列事件可能对初级有益 流感感染，意想不到的结果是靶向细菌感染的防御系统受到损害。 这种情况可能提供了次要细菌肺炎与初始细菌肺炎相关的机制 影响力感染。我们的数据表明，在人类和小鼠的影响力模型中，这种表观遗传学 可以确定途径，我们假设在原发性影响力肺炎A的演变过程中 建立以高水平IFN-B为特征的细胞因子环境以控制主要病毒 感染;但是，此过程与基于表观遗传学的机制相关，从而抑制MφPro- 炎症反应，使宿主容易受到继发细菌感染的影响。这 假设将通过以下特定目的进行研究：确定机制 影响力诱导的IFN-B/STAT1途径导致染色质修饰歌词的表达 原代人细胞中的甲基转移酶SetDB2。研究一种新的机制，setDB2是 通过与特定转录因子结合到靶向基因上的启动子位点，导致染色质 在精确的启动子位置进行修改。评估setDB2表达在mφ上的抑制作用 主要影响期间的活动，从而降低了吞噬作用和T细胞功能，并且 机械上有助于宿主对继发细菌感染的敏感性。 。