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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 中心，不一定是研究者的机构。 干扰素调节因子 3 (IRF3) 在 IFN 反应的诱导阶段至关重要。然而，它在控制某些病毒（包括 HSV-1）复制方面的作用却很神秘。 许多 HSV 基因在体外干扰 IRF-3 的定位和功能，表明 IRF-3 对于控制 HSV 复制至关重要。 因此，IRF-3 的缺陷预计会妨碍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的易感性并未增加，并且在原代IRF-3-/- MEF中未观察到HSV复制的变化。与此一致的是，我们已经证明初级 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 HSV 复制发挥 IRF-3 依赖性控制。 我们推断有两种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，以至于在某些细胞中，IRF-3 变得多余。其次，HSV 体外和体内复制的控制以及体内毒力通过 IRF-3 依赖性机制具有组织特异性。 因此，该提案的首要目标是测试这些假设并区分它们。 具体目标 1：测量和评估 IRF-3 依赖性机制对体外免疫系统原代细胞中 HSV 复制的影响。具体目标 2：在 HSV 发病机制和体内潜伏期小鼠模型中测量和评估 IRF-3 依赖性机制对 HSV 复制和毒力的影响。