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

项目摘要/摘要： 与研究宿主防御转录图谱相关的一个挥之不去的难题是，特定的细胞如何 “记住”他们是否应该积极转录特定的基因，这将促进他们的 参与炎症反应。我们的实验室正在研究新的表观遗传学变化， 通过组蛋白的翻译后修饰，作为调节细胞表达谱的机制 在炎症反应过程中派生的介质。我们已经解决了导致 流感引起的免疫病理学，使用正常和感染的人类细胞系统和 传染性流感的实验模型。后一种模型将被用来指导我们的人类细胞 系统。我们提供的数据表明，流感所建立的细胞因子环境诱导了 特定的表观遗传机制，控制宿主防御介体的表达。我们确认了 干扰素β以自分泌/旁分泌的方式导致SetDB2的表达，这是一种表观遗传学- 基于赖氨酸甲基转移酶，负责设置抑制组蛋白标记，导致宿主 抗菌防御基因沉默。虽然这一系列事件很可能对主要的 流感感染，意想不到的结果是针对细菌感染的防御系统受损。 这一情景可能提供了继发性细菌性肺炎与最初的 流感感染。我们的数据显示，在人类和老鼠的流感模型中，这种表观遗传学是相同的 可以确定途径我们假设在原发性流感肺炎的演变过程中 建立以高水平干扰素-B为特征的细胞因子环境来控制原发病毒 然而，这个过程涉及一种基于表观遗传的机制，它抑制M-Φ亲- 炎症反应，使宿主容易受到继发性细菌感染。这 假说将通过以下具体目标进行研究：确定(S) 流感诱导的干扰素-B/STAT1途径导致染色质修饰赖氨酸的表达 人类原代细胞中的甲基转移酶SETDB2.研究一种新的机制，通过该机制SETDB2. 通过与特定的转录因子结合，引导到靶基因上的启动子位置，从而产生染色质 精确启动子位置的修饰。评价SetDB2基因表达对M-Φ的抑制作用 在初级流感感染期间的活动，这会降低吞噬功能和T细胞功能，并 机械性地促进宿主对继发性细菌感染的易感性。 。

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. .