MODULATION OF INNATE IMMUNE RESPONSES BY CYTOMEGALOVIRUS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 免疫系统最终无法从宿主中消除巨细胞病毒（CMV）可能是由于靶向宿主免疫系统许多方面的复杂病毒逃避机制。在这个项目中，我们将试图更好地了解CMV调节先天性免疫应答，特别是干扰素应答的分子机制。 具体目的1：确定HCMV激活IRF 3的机制 目前尚不清楚HCMV如何激活干扰素调节因子3（IRF 3）。我们将通过小干扰RNA（siRNA）系统性基因敲低来鉴定HCMV和dsDNA依赖性IRF 3激活所必需的宿主细胞蛋白。 具体目标2：确定Hpp 71、Rpp 71和Rpp 65 a如何干扰IRF 3依赖性ISG激活 表达Hpp 71或感染RhCMV的成纤维细胞对HCMV以及干扰素刺激性DNA的IRF 3激活完全无效。这种干扰的机制尚不清楚，将为此目的进行研究。 具体目的3：表征pp 65和pp 71在控制对HCMV和RhCMV的先天性免疫应答中的作用 我们假设Rpp 65 a和Rpp 71抑制了RhCMV感染细胞中先天免疫应答基因的诱导，Hpp 71限制了HCMV感染期间的诱导。我们将产生RhCMV突变体来测试这一假设。

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. The ultimate inability of the immune system to eliminate cytomegalovirus (CMV) from the host is likely due to sophisticated viral evasion mechanisms that target many aspects of the host immune system. In this project, we will try to gain a better understanding of the molecular mechanisms by which CMV modulates the induction of innate immune responses, particularly the interferon response. Specific Aim 1: To identify the mechanism of IRF3 activation by HCMV It is not known how HCMV activates interferon-regulatory factor 3 (IRF3). We will identify host cell proteins that are essential for HCMV and dsDNA-dependent IRF3 activation using systematic gene knockdown by small interfering RNA (siRNA). Specific Aim 2: To determine how Hpp71, Rpp71 and Rpp65a interfere with IRF3-dependent ISG activation Fibroblasts expressing Hpp71, or infected with RhCMV, are completely refractory to IRF3 activation by HCMV as well as interferon-stimulatory DNA. The mechanism of this interference is not known and will be studied in this aim. Specific Aim 3: To characterize the role of pp65 and pp71 in controlling the innate immune response to HCMV and RhCMV We hypothesize that Rpp65a and Rpp71 inhibit the induction of innate immune response genes in RhCMV-infected cells and that Hpp71 limits their induction during HCMV infection. We will generate RhCMV mutants to test this hypothesis.