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

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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.