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(申请人提供)：Toll样受体蛋白(TLRs)的发现及其在调节宿主对感染的反应中的重要性导致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TLRs不仅作为外来抗原的细胞表面受体发挥作用，而且TLR3、7、8和9(特别是TLR3、7、8和9)是内分泌的，它们识别感染性病原体(特别是病毒和病毒核酸)。除了TLR外，1型干扰素(IFN)的产生还受到细胞质RNA解旋酶蛋白(如RIG-I和Mda-5)以及与NOD蛋白家族相关的炎症蛋白(如NLRP-3(或NALP-3，Cryopyrin))的调节。在这些不同的病毒感应通路下游，有几个控制I型干扰素产生的干扰素调节因子(IRFs)参与其中。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，这些反应受到其他病毒蛋白的调节，正是这种相互作用诱导的宿主细胞因子的影响决定了病毒的致病潜力。项目1(Kurt-Jones)将定义TLRs在HSV诱导的炎症反应和病毒致病机制中的作用，以及IRF-1信号如何调节这些反应。项目2(Fitzgerald)将确定IL-I、NLRP-3和TLR非依赖的DNA传感器在病毒诱导的炎性细胞因子和I型干扰素的产生以及抗病毒免疫控制中的作用。项目3(Knipe)将定义某些病毒蛋白如何调节TLR信号和TLR适配器(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TLRs和其他在先天性免疫中重要的宿主基因的多态如何影响HSV的重新激活。所有项目都涉及使用通用试剂和确定与宿主对单纯疱疹病毒的识别和反应有关的新范例。 项目1：HSV-1先天免疫反应中的TLRs和IRF1(Kurt-Jones，E) 项目1说明(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，可能发生致命的传播性感染。模式识别受体(PRRs)在先天抗病毒免疫的形成中起着至关重要的作用。病毒的先天免疫激活可以通过细胞表面、细胞内和/或细胞内的模式识别受体来实现。这些受体可能感知不同的病毒成分，并可能激活独特的下游途径，以产生抗病毒免疫。我们假设PRR与疱疹病毒的相互作用激活了先天性免疫细胞中依赖IRF1的下游通路，这些通路在控制HSV感染的炎症反应中起着关键作用。在本项目中，我们将：1.明确TLRs在HSV天然免疫反应中的作用2.明确IRF1调节天然免疫和保护致死性HSV脑炎的机制3.明确HSV在TLR信号转导和IRF1激活促炎症和抗炎抗病毒途径中的作用。我们将定义PRRs，特别是感知HSV感染并触发先天性免疫反应的TLRs。我们将通过定义IRF1激活的上游受体和介体，以及在HSV感染中IRF1下游的靶基因和因子来确定IRF1调节HSV应答的机制。这些研究与Fitzgerald博士(项目2)的研究相辅相成，研究了一种也依赖于IRF1的独特的细胞内病毒感知途径。我们将利用Fitzgerald博士产生的途径特异性试剂以及Knipe博士产生的病毒和病毒突变(项目3)来确定PRR-病毒相互作用导致IRF1激活的机制。通过芬伯格博士进行的研究(项目4)，PRR途径在HSV免疫中的作用将扩展到人类患者。这些研究将通过确定在启动病毒免疫和保护宿主免受致死性脑炎的保护中至关重要的细胞、受体和病毒成分，来推动该计划项目的总体目标。