Innate Immunity and Herpes Simplex Infection

先天免疫和单纯疱疹感染

基本信息

批准号：
7914345
负责人：
Robert William Finberg
金额：
$ 182.82万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-14 至 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7914345
关键词：
Innate Immunity Herpes Simplex Infection

项目摘要

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.

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。