CMV Activation of Innate Immunity

描述（由申请人提供）：人巨细胞病毒（CMV）与其人类宿主关系密切，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对抗巨细胞病毒疾病至关重要。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性的激活是先天免疫的标志，并且在促进适应性应答和暂时减缓病原体中起关键作用。一些证据已经提高了人们的认识，即CMV在感染的最早阶段，在进入过程中激活先天免疫反应。我们最近发现Toll样受体（TLR）家族的成员（TLR 2）检测CMV。CMV的TLR 2传感导致NF-κ B依赖性信号转导途径的激活和炎性细胞因子的合成。TLR是古老的、进化上保守的模式识别受体，其检测广泛的微生物病原体。这一令人兴奋的新知识提供了一个重要的机会，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。我们建议的第一个目的是进一步表征TLR 2在炎症的CMV激活中的作用。此外，我们将确定TLR 2相关的合作伙伴（TLR 1或TLR 6），以及主要的细胞质信号转导衔接蛋白的途径。目的2将检查TLR 2和干扰素途径的诱导之间的机制联系。一个新发现的细胞质适配器，TICAM已被证明与TLR 2相互作用，并激活干扰素调节因子3（IRF-3）的作用，将被测试参与CMV途径。目标3将建立在令人兴奋的新的初步数据上，这些数据表明CMV包膜糖蛋白B（g B）可以与TLR 2物理结合。此外，我们表明，gB具有内在的能力，激活细胞因子诱导TLR 2依赖的方式。将进行详细的结构/功能分析，以了解gB显示的分子模式。最后，我们将把工作转向以发病机制为导向的研究。先天性免疫应答的特征在于对CMV发病机制至关重要的细胞类型，例如内皮细胞和单核细胞/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.