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）：发现类似受体样受体蛋白（TLR）及其在调节宿主对感染反应的重要性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理中的作用相关的研究。最近的工作表明，这些TLR不仅充当外国抗原的细胞表面受体，而且TLR（尤其是TLR 3、7、8和9）也是内体局部定位的，它们识别感染剂（尤其是病毒和病毒核酸）。除TLR之外，还显示出1型干扰素（IFN）的产生受到胞质RNA解旋酶蛋白的调节，例如RIG-I和MDA-5，以及与NLRP-3（或NALP-3，CRYOPYRIN）（或NALP-3，CRYOPYRIN）这样的炎性蛋白（如NLRP-3），这些蛋白质与NOD蛋白质家族有关。控制I型IFN的生产的几个干扰素调节因子（IRF）已与这些不同病毒感应途径的下游有关。该项目的总体假设是，模式识别蛋白对特定的病毒抗原有反应，并且这些反应受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病毒潜力。项目1（Kurt-Jones）将定义TLR在HSV诱导的炎症反应和病毒发病机理以及IRF-1信号传导如何调节这些反应中的作用。项目2（Fitzgerald）将定义IL-I，NLRP-3和TLR独立的DNA传感器在病毒诱导的炎症细胞因子和I型干扰素的产生中的作用，以及对抗病毒免疫的控制。项目3（knipe）将定义某些病毒蛋白如何调节TLR信号传导和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）将研究最近在TLR和其他对先天免疫力重要的宿主基因中定义的多态性，影响HSV的重新激活。所有项目都涉及使用常见试剂以及与宿主对HSV的识别和响应有关的新范式的定义。 项目1：对HSV-1的先天免疫反应中的TLR和IRF1（Kurt-Jones，E） 项目1描述（由申请人提供）：先天免疫反应是针对病毒病原体的第一道防线。在没有抗病毒先天反应的情况下，病毒复制是不受控制的，可能会发生致命的传播感染。模式识别受体（PRR）与先天抗病毒免疫的发展至关重要。病毒的先天免疫激活可能通过细胞表面，细胞内和/或胞质模式识别受体发生。这些受体可能会感觉到不同的病毒成分，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免疫细胞中的IRF1依赖性下游途径，这些途径与炎症反应对HSV感染的控制非常重要。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先天免疫和保护免受致命性HSV脑炎的调节的机制3.定义HSV在TLR信号传导和IRF1激活中的作用和抗激活的抗炎和抗炎性抗炎病毒。我们将定义PRR，尤其是感知HSV感染并引发先天免疫反应的TLR。我们将通过定义IRF1激活上游的受体和介体以及HSV感染中IRF1下游的靶基因和因子来定义IRF1调节HSV反应的机制。这些研究得到了Fitzgerald博士（项目2）研究的研究，该研究研究了一种独特的细胞内病毒感应途径，该途径也取决于IRF1。我们将利用Fitzgerald博士产生的途径特定的试剂以及Knipe博士（项目3）生成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（项目4）进行的研究将PRR途径在HSV免疫中的作用扩展到人类患者。这些研究将通过定义与宿主对宿主免受致命性脑炎的启动和保护有关的细胞，受体和病毒成分来进一步的总体目标。