Innate Immunity and Herpes Simplex Infection

先天免疫和单纯疱疹感染

• 批准号: 7695247
• 负责人: Robert William Finberg
• 金额: $ 185.64万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-14 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7695247
• 关键词: Innate; Immunity; Herpes; Simplex; Infection

DESCRIPTION (provided by applicant): The discovery of the Toll-Like Receptor Proteins (TLRs) and their importance in the regulation of host response to infection has led to a series of investigations related to the role of host proteins and cytokines in microbial pathogenesis. Recent work has demonstrated that not only do these TLRs function as cell surface receptors for foreign antigens, but also that TLRs (especially TLR 3, 7, 8 and 9) are endosomally localized and they recognize infectious agents (particularly viruses and viral nucleic acids). In addition to the TLRs, the production of type 1 interferons (IFNs) has been shown to be regulated by cytoplasmic RNA helicase proteins, like RIG-I and Mda-5, and by inflammosame proteins like NLRP-3 (or NALP-3, Cryopyrin) which are related to the NOD family of proteins. Several Interferon Regulatory Factors (IRFs), which control the production of type I IFNs, have been implicated downstream of these different viral sensing pathways. The overall hypothesis of the Project is that pattern recognition proteins respond to particular viral antigens and that those responses are regulated by other viral proteins and it is the effect of the host cytokines induced as a result of this interaction that determines the pathogenic potential of a virus. Project 1 (Kurt-Jones) will define the role of TLRs in HSV induced inflammatory responses and viral pathogenesis and how IRF-1 signaling regulates these responses. Project 2 (Fitzgerald) will define the role of IL-I, NLRP-3, and TLR-independent DNA sensors in the virus-induced production of inflammatory cytokines and type I interferons, and the control of anti-viral immunity. Project 3 (Knipe) will define how certain viral proteins regulate TLR signaling and TLR adapters (and other pattern recognition proteins) and affect the secretion of interferon and cytokines. Project 4 (Finberg) will examine how recently defined polymorphisms in TLRs and other host genes important in innate immunity, affect reactivation of HSV. All Projects involve the use of common reagents and the definition of new paradigms related to recognition and response of the host to HSV. PROJECT 1: TLRs and IRF1 in the Innate Immune Responses to HSV-1 (Kurt-Jones, E) PROJECT 1 DESCRIPTION (provided by applicant): The innate immune response is the first line of defense against viral pathogens. In the absence of an antiviral innate response, viral replication is uncontrolled and lethal disseminated infection can occur. Pattern recognition receptors (PRRs) are critically involved in the development of innate anti-viral immunity. Innate immune activation by viruses may occur via cell surface, intracellular and/or cytosolic pattern recognition receptors. These receptors may sense different viral components and may activate unique downstream pathways to generate anti-viral immunity. We hypothesize that PRR interaction with herpes viruses activates IRF1-dependent downstream pathways in innate immune cells that are critically involved in the control of the inflammatory response to HSV infection. In this project, we will; 1. Define the role of TLRs in HSV innate immune responses 2. Define the mechanism of IRF1 regulation of innate immunity and protection from lethal HSV encephalitis 3. Define the role of HSV in TLR signaling and IRF1 activation of pro- and anti-inflammatory anti-viral pathways. We will define the PRRs, particularly TLRs that sense HSV infection and trigger innate immune responses. We will define the mechanism of IRF1 regulated HSV responses by defining the receptors and mediators upstream of IRF1 activation as well as the target genes and factors downstream of IRF1 in HSV infection. These studies are complemented by studies of Dr. Fitzgerald (Project 2) examining a unique intracellular virus sensing pathway that is also dependent on IRF1. We will utilize pathway specific reagents generated by Dr. Fitzgerald as well as viruses and viral mutants generated by Dr. Knipe (Project 3) to define the mechanisms of PRR-virus interactions leading to IRF1 activation. The role of PRR pathways in HSV immunity will be extended to human patients by studies conducted by Dr. Finberg (Project 4). These studies will further the overall goals of the Program Project by defining the cells, receptors and viral components that are critically involved in the initiation of viral immunity and protection of the host from lethal encephalitis.

描述（由申请人提供）：Toll 样受体蛋白（TLR）的发现及其在调节宿主对感染的反应中的重要性引发了一系列与宿主蛋白和细胞因子在微生物发病机制中的作用相关的研究。最近的研究表明，这些 TLR 不仅充当外来抗原的细胞表面受体，而且 TLR（尤其是 TLR 3、7、8 和 9）位于内体中，并且识别感染因子（尤其是病毒和病毒核酸） 。除了 TLR 之外，1 型干扰素 (IFN) 的产生也被证明受到细胞质 RNA 解旋酶蛋白（如 RIG-I 和 Mda-5）以及炎性蛋白（如 NLRP-3（或 NALP-3， Cryopyrin），与 NOD 蛋白家族相关。控制 I 型干扰素产生的几种干扰素调节因子 (IRF) 与这些不同病毒传感途径的下游有关。该项目的总体假设是模式识别蛋白对特定的病毒抗原做出反应，并且这些反应受到其他病毒蛋白的调节，并且由于这种相互作用而诱导的宿主细胞因子的作用决定了病毒的致病潜力。项目 1 (Kurt-Jones) 将定义 TLR 在 HSV 诱导的炎症反应和病毒发病机制中的作用，以及 IRF-1 信号如何调节这些反应。项目 2（Fitzgerald）将定义 IL-1、NLRP-3 和 TLR 独立 DNA 传感器在病毒诱导的炎症细胞因子和 I 型干扰素的产生以及抗病毒免疫的控制中的作用。项目 3 (Knipe) 将定义某些病毒蛋白如何调节 TLR 信号传导和 TLR 接头（以及其他模式识别蛋白）并影响干扰素和细胞因子的分泌。项目 4 (Finberg) 将研究最近定义的 TLR 和其他在先天免疫中重要的宿主基因的多态性如何影响 HSV 的重新激活。所有项目都涉及通用试剂的使用以及与宿主对 HSV 的识别和反应相关的新范例的定义。 项目 1：HSV-1 先天免疫反应中的 TLR 和 IRF1 (Kurt-Jones, E) 项目 1 描述（由申请人提供）：先天免疫反应是抵御病毒病原体的第一道防线。在缺乏抗病毒先天反应的情况下，病毒复制不受控制，可能会发生致命的播散性感染。模式识别受体（PRR）在先天抗病毒免疫的发展中发挥着重要作用。病毒的先天免疫激活可以通过细胞表面、细胞内和/或胞质模式识别受体发生。这些受体可以感知不同的病毒成分，并可以激活独特的下游途径以产生抗病毒免疫力。我们假设 PRR 与疱疹病毒的相互作用会激活先天免疫细胞中 IRF1 依赖性下游通路，这些通路在控制 HSV 感染的炎症反应中发挥着重要作用。在这个项目中，我们将； 1. 定义 TLR 在 HSV 先天免疫反应中的作用 2. 定义 IRF1 调节先天免疫和预防致命性 HSV 脑炎的机制 3. 定义 HSV 在 TLR 信号传导和 IRF1 激活促炎和抗炎抗炎药物中的作用-病毒途径。我们将定义 PRR，特别是感知 HSV 感染并触发先天免疫反应的 TLR。我们将通过定义HSV感染中IRF1激活上游的受体和介质以及IRF1下游的靶基因和因子来定义IRF1调节HSV反应的机制。 Fitzgerald 博士（项目 2）的研究对这些研究进行了补充，该研究检查了也依赖于 IRF1 的独特细胞内病毒传感途径。我们将利用 Fitzgerald 博士产生的途径特异性试剂以及 Knipe 博士（项目 3）产生的病毒和病毒突变体来定义导致 IRF1 激活的 PRR-病毒相互作用的机制。 Finberg 博士进行的研究（项目 4）将把 PRR 通路在 HSV 免疫中的作用扩展到人类患者。这些研究将通过定义与启动病毒免疫和保护宿主免受致命性脑炎至关重要的细胞、受体和病毒成分来进一步实现该计划项目的总体目标。