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CMV如何诱导和规避宿主免疫对于抗击CMV疾病至关重要。近年来，人们发现CMV病毒粒子能刺激或抑制大量的细胞基因。最值得注意的是，干扰素刺激基因(ISG)家族中的细胞基因被强有力地诱导。我们的实验室确定了导致这种细胞反应的病毒成分是糖蛋白B(GB)。Gb诱导的ISGs与获得抗病毒状态相关。这些观察结果表明，gB是CMV的一个组成部分，具有激活宿主对感染的先天免疫反应的能力。这项研究的长期目标是了解CMV激活并最终抑制先天免疫反应的机制。这一建议的中心假设是巨细胞病毒糖蛋白(S)以类似于细菌和真菌病原体的方式受到先天感知的影响。Toll样受体(TLRs)是一种古老的固有宿主防御系统的组成部分，在识别病原体的不适当模式后触发细胞反应。我们将直接检验这一假设，即GB启动信号反应的机制是激活Toll样受体。这一假说得到了初步数据的支持，这些数据清楚地表明TLR通路中存在中央信号机制。第二个研究领域涉及对导致干扰素反应的信号转导途径的定义。我们发现干扰素反应是由细胞外病毒信号启动的，这一发现揭示了病毒诱导固有反应的新途径。其他努力的重点是鉴定CMV基因产物，这些基因产物在病毒复制过程中抑制宿主反应。这一提议的最终特定目的将检验GB激活的信号转导事件是CMV致病的标志这一假设。将在CMV病理学中的关键细胞类型：内皮细胞和单核/巨噬细胞中确定GB反应信号转导机制的转录图谱和特征。鉴于宿主先天免疫反应在控制病毒感染和促进适应性宿主反应方面的重要作用，这项工作可能会对设计改进的CMV疗法产生影响。

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 and circumvents host immunity is of critical importance in efforts to combat CMV disease. In recent years, it was discovered that CMV virions stimulate, or repress, a large number of cellular genes. Most notably, cellular genes in the interferon stimulated gene (ISG) family were robustly induced. Our laboratory identified the viral component responsible for initiation of this cellular response as glycoprotein B (gB). Induction of ISGs by gB correlates with acquisition of an antiviral state. These observations point to gB as a CMV component with the capacity to activate the host innate immune response to infection. The long-term qoal of this research is to develop an understandinq of the mechanism by which CMV activates, and ultimately represses, innate immune responses. The central hypothesis of this proposal is that CMV glycoprotein(s) are subject to innate sensing in a manner similar to bacterial and fungal pathogens. Toll-like receptors (TLRs) are components of an ancient innate host defense that trigger cellular responses after recognition of inappropriate patterns on pathogens. We will directly test the hypothesis that the mechanism of initiation of the signaling response by gB is activation of a Toll-like receptor. This hypothesis is supported by preliminary data clearly implicating central signaling machinery in TLR pathways. A second area of investigation involves definition of the signal transduction pathway that leads to interferon responses. Our discovery that interferon responses are initiated from an extracellular viral signal reveals novel pathways for virus induction of innate responses. Other efforts are focused on the identification of CMV gene products involved in dampening the host response during virus replication. The final specific aim of this proposal will test the hypothesis that gB activated signal transduction events are a hallmark of CMV pathogenesis. Transcriptional profiling and characterization of gB-responsive signal transduction machinery will be determined in critical cell types in CMV pathology; endothelial cells and monocyte/macrophages. Given the significant role of host innate immune response in controlling viral infections and facilitating an adaptive host response, this work will potentially have impact in efforts to design improved CMV therapeutics.