THE IMPACT OF IRF-3-DEPENDENT MECHANISMS ON THE REPLICATION AND VIRULENCE OF HSV

IRF-3 依赖性机制对 HSV 复制和毒力的影响

• 批准号: 8168325
• 负责人: David A Leib
• 金额: $ 19.99万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8168325
• 关键词: Agreement; Cells; Computer Retrieval of Information on Scientific Projects Database; Data; Dendritic Cells; Funding; Genes; Goals; Grant; Growth; Herpesvirus 1; Immune system; In Vitro; Institution; Interferons; Measures; Mus; Pathogenesis; Pathway interactions; Phase; Predisposition; Research; Research Personnel; Resources; Role; Simplexvirus; Source; Specificity; Testing; Tissues; United States National Institutes of Health; Virulence; Virus; human IRF3 protein; in vivo; interferon regulatory factor-3; mouse model; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Interferon regulatory factor 3 (IRF3) is critical in the induction phase of the IFN response. Its role, however, in the control of replication of certain viruses, including HSV-1, is enigmatic. A number of HSV genes interfere with the localization and function of IRF-3 in vitro, suggesting that IRF-3 is critical for controlling HSV replication. The deficiency ofIRF-3 would therefore be predicted to preclude the function of early recognition pathways and thereby impact HSV-1 replication. Paradoxically,IRF-3 deficient mice (IRF3-/-) show no increased susceptibility to HSV-1,and no changes in HSV replication in primary IRF-3-/- MEFs have been observed. In agreement with this, we have shown that primary MEFs do not exert such control. Other recent preliminary data, however, showed significantly increased growth of HSV in IRF3-/- dendritic cells, suggesting that cells derived from the immune system exert IRF-3 dependent control over HSV replication. We reasoned that there were two possible hypotheses to explain these observations. First, that HSV controls IRF-3 activity so completely that, in certain cells, IRF-3 is rendered redundant. Second, that there is a tissue-specificity to the control of HSV replication in vitro and in vivo, and virulence in vivo by IRF-3- dependent mechanisms. The over-arching goal of this proposal is therefore, to test these hypotheses and distinguish between them. Specific aim 1: To measure and assess the impact of IRF-3- dependent mechanisms upon the replication of HSV in primary cells derived from the immune system in vitro. Specific aim 2: To measure and assess the impact of IRF-3- dependent mechanisms upon the replication and virulence of HSV in mouse models of HSV pathogenesis and latency in vivo.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 干扰素调节因子3（IRF3）在IFN响应的诱导阶段至关重要。然而，它在控制某些病毒（包括HSV-1）复制中的作用是神秘的。 许多HSV基因在体外干扰IRF-3的定位和功能，这表明IRF-3对于控制HSV复制至关重要。 因此，IRF-3的缺陷将被预测排除早期识别途径的功能，从而影响HSV-1复制。矛盾的是，IRF-3缺陷小鼠（IRF3 - / - ）对HSV-1的敏感性没有增加，并且未观察到原代IRF-3 - / - MEF中HSV复制的变化。同意这一点，我们已经表明，主要MEF不会施加这种控制。然而，其他最近的初步数据显示，IRF3 - / - 树突状细胞中HSV的生长显着增加，这表明源自免疫系统的细胞对IRF-3的控制依赖于HSV复制。 我们认为有两个可能的假设可以解释这些观察结果。 首先，HSV完全控制IRF-3活性，以至于在某些单元中，IRF-3被冗余。其次，在体外和体内控制HSV复制的组织特异性以及通过IRF-3依赖性机制在体内毒力。 因此，该提案的总体目标是检验这些假设并区分它们。 具体目的1：测量和评估IRF-3依赖机制对体外免疫系统中原代细胞中HSV复制的影响。具体目的2：测量和评估IRF-3依赖机制对HSV发病机理和体内潜伏期小鼠模型中HSV复制和毒力的影响。