Innate Immunity and Herpes Simplex Infection

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。最近的工作已经证明，不仅这些TLR作为外源抗原的细胞表面受体起作用，而且TLR（特别是TLR 3、7、8和9）是内体定位的，并且它们识别感染因子（特别是病毒和病毒核酸）。除了TLR之外，1型干扰素（IFN）的产生已显示受细胞质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）调节，所述炎性蛋白与NOD蛋白家族相关。控制I型IFN产生的几种干扰素调节因子（IRF）已经涉及这些不同病毒传感途径的下游。该项目的总体假设是，模式识别蛋白对特定病毒抗原做出反应，并且这些反应受其他病毒蛋白的调节，并且正是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信号传导如何调节这些反应。项目2（Fitzgerald）将确定IL-1、NLRP-3和TLR非依赖性DNA传感器在病毒诱导的炎性细胞因子和I型干扰素产生中的作用，以及抗病毒免疫的控制。项目3（Alfreppe）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TLR和其他先天免疫重要宿主基因的多态性如何影响HSV的再激活。所有项目都涉及使用通用试剂和定义与宿主对HSV的识别和反应相关的新范例。

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.