CMV Activation of Innate Immunity

描述(申请人提供)：人巨细胞病毒(CMV)与其宿主关系密切，疾病与感染者的免疫状态密切相关。了解巨细胞病毒如何诱导宿主免疫对于抗击巨细胞病毒病至关重要。这项研究的长期目标是了解CMV激活先天免疫反应的机制。炎性细胞因子和由I型干扰素驱动的抗病毒活动的激活是先天免疫的标志，在促进适应性反应和暂时减缓病原体的速度方面发挥关键作用。一些证据提高了人们的意识，即CMV在感染的最早阶段，即进入过程中，会激活先天免疫反应。我们最近发现，Toll样受体(TLR)家族的一个成员可以检测到CMV。巨噬细胞病毒TLR2的感应导致依赖于核因子-kappaB的信号转导通路的激活和炎性细胞因子的合成。TLRs是一种古老的、进化上保守的模式识别受体，可以检测到广泛的微生物病原体。这一令人兴奋的新知识为了解这些原始免疫传感器检测病毒病原体的分子基础以及阐明参与下游转录诱导的细胞机制提供了一个重要的机会。我们建议的第一个目标将进一步表征TLR2在巨细胞病毒激活炎症中的作用。此外，我们还将确定TLR2相关伙伴(TLR1或TLR6)以及该途径中主要的细胞质信号适配器蛋白。目标2将研究TLR2和干扰素途径诱导之间的机制联系。一种新发现的细胞质适配器TICAM已被证明与TLR2相互作用并激活干扰素调节因子3(IRF-3)，其作用将被测试是否参与CMV途径。AIM 3将建立在令人兴奋的新的初步数据基础上，这些数据表明CMV包膜糖蛋白B(GB)在物理上可以与TLR2相关联。此外，我们还证明了Gb具有以TLR2依赖的方式激活细胞因子诱导的内在能力。将进行详细的结构/功能分析，以努力了解GB所显示的分子模式。最后，我们将把工作转移到以发病机制为导向的研究。先天性免疫反应将以对CMV致病至关重要的细胞类型为特征，如内皮细胞和单核/巨噬细胞。

DESCRIPTION (provided by applicant): Human cytomegalovirus (CMV) has an intimate relationship with its human host and disease is tightly linked to the immune status of infected persons. An understanding of how CMV induces host immunity is of critical importance in efforts to combat CMV disease. The long-term goal of this research is to develop an understanding of the mechanism by which CMV activates innate immune responses. Inflammatory cytokines and activation of the antiviral activities driven by type I interferon are hallmarks of innate immunity and serve critical roles in promoting an adaptive response and in temporarily slowing the pathogen. Several lines of evidence have raised awareness that CMV activates innate immune responses at the earliest stage of infection, during the entry process. We recently discovered that a member of the Toll like receptor (TLR) family (TLR2) detects CMV. TLR2 sensing of CMV leads to activation of a NF-kappaB dependent signal transduction pathway and to synthesis of inflammatory cytokines. TLRs are ancient, evolutionarily conserved pattern recognition receptors that detect a wide range of microbial pathogens. This exciting new knowledge provides a significant opportunity to learn about the molecular basis by which these primordial immune sensors detect viral pathogens as well as elucidate the cellular machinery involved in the downstream transcription induction. The first aim of our proposal will further characterize the role of TLR2 in CMV activation of inflammation. In addition, we will identify the TLR2 associating partner (TLR1 or TLR6) as well as the primary cytoplasmic signaling adaptor proteins in the pathway. Aim 2 will examine a mechanistic link between TLR2 and the induction of the interferon pathway. The role of a newly discovered cytoplasmic adaptor, TICAM which has been shown to interact with TLR2 and to activate interferon regulatory factor 3 (IRF-3), will be tested for involvement in the CMV pathway. Aim 3 will build on exciting new preliminary data that show the CMV envelope glycoprotein B (gB) can physically associate with TLR2. In addition, we show that gB has the intrinsic ability to activate cytokine induction in a TLR2 dependent manner. Detailed structure/ function analysis will be conducted in efforts to understand the molecular pattern displayed by gB. Lastly we will move the work into pathogenesis-oriented research. Innate immune responses will be characterized in cell types critical to CMV pathogenesis, such as endothelial cells and monocyte/macrophages.