Identification and characterization of interferon-gamma-stimulated effector proteins and interferon-gamma-repressed dependency factors effecting cytomegalovirus replication

病毒是专性细胞内病原体，可引起多种疾病。存活大多数病毒感染所必需的一种即时免疫反应是干扰素（ifn）的诱导。ifn是一种细胞因子，通过改变靶细胞的转录程序而赋予强大的抗病毒活性。基于它们的分子同源性、受体使用和转录因子激活谱，IFN被细分为I型IFN（例如IFN α / β）、II型IFN （IFN γ）和III型IFN （IFNλ）。根据一个过于简化的模型，I型和III型IFN直接引发细胞内在的抗病毒活性，而IFN γ主要通过增强适应性免疫反应起作用。对比这种二分法，我们和其他人观察到IFNγ对几种DNA病毒具有明显的直接抗病毒活性。这就提出了IFN γ调控的宿主蛋白质组变化执行抗病毒活性的问题。利用转录组学和蛋白质组学，我们确定了IFN γ特异性变化。除了表征IFN γ优先诱导的基因外，我们还鉴定了一类新的IFN抑制基因（IRepGs）。在拟议的项目中，我们旨在鉴定和表征IFN γ刺激基因（ISG γ）以及IFN γ依赖基因抑制事件，这些事件赋予了对巨细胞病毒的抗病毒活性。

Viruses are obligate intracellular pathogens, which cause various diseases. One immediate immune response necessary to survive most viral infections is the induction of interferons (IFNs). IFNs are cytokines, which confer strong antiviral activity by changing the transcriptional program of target cells. Based on their molecular homology, receptor usage, and transcription factor activation profile, IFNs are subdivided into type I IFNs (e.g. IFN alpha/beta), type II IFN (IFN gamma) and type III IFNs (IFNλ). According to an oversimplified model, type I and III IFNs elicit direct cell-intrinsic antiviral activity, whereas IFN gamma mainly acts by enhancing adaptive immune responses. Contrasting this dichotomy, we and others observed pronounced direct antiviral activity of IFNγ against several DNA viruses. This raises the question which IFN gamma-regulated changes of the host proteome execute the antiviral activity. Using transcriptomics and proteomics, we have determined IFN gamma-specific changes. In addition to the characterization of genes preferentially induced by IFN gamma, we identified a novel class of IFN-repressed genes (IRepGs). In the proposed project, we aim to identify and characterize the IFN gamma-stimulated genes (ISG gamma) as well as the IFN gamma-dependent gene repression events, which confer the antiviral activity against cytomegaloviruses.