Identification and characterization of interferon γ-stimulated effector proteins and interferon γ-repressed dependency factors limiting cytomegalovirus replication

• Applicants: Professor Dr. Albert Sickmann; Professor Dr. Mirko Trilling
• Subject Area: Virology
• Term: since 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 426496866

Interferon (IFN) secretion is among the first innate immune responses elicited upon infection. Numerous studies show that loss-of-function mutations affecting central components of IFN production or signaling pathways are incompatible with host survival after different virus infections. Type I IFNs and type III IFNs induce well-known effector proteins with direct antiviral activity, whereas type II IFN (IFNγ) is often thought to act predominantly by fostering adaptive immune responses by enhancing antigen presentation. In contrast to this simple dichotomy, we found that some viruses such as cytomegaloviruses (CMV) are more susceptible to IFNγ than to IFNα (see e.g., 1-4). The pronounced antiviral activity of IFNγ raises the question regarding the proteome alterations and the effector proteins that mediate the antiviral activity against CMV. To answer this question, we analyzed IFN-induced changes in murine and human fibroblasts by transcriptomics and proteomics 5,6. We observed a subset of IFN-stimulated genes (ISGs) that responds more vigorously to IFNγ than to IFNα2. We refer to such preferentially IFNγ-stimulated genes as ISGγ. Furthermore, we identified a set of IFNγ-repressed genes (IRepGs). IRepGs comprise regulators of translation, fatty acid metabolism, and the extracellular matrix, which are known to represent relevant battlegrounds between host and pathogens, suggesting a functional relevance of gene repression for antiviral activity. We hypothesize that so far uncharacterized ISGs and IRepGs contribute to the antiviral activity of IFNγ against viruses such as human cytomegalovirus (HCMV). We will address the following research questions: (I) How does IFNγ alter cellular and viral proteomes? (II) Which signaling events mediate gene repression by IFNγ? (III) Which ISGγ induction and IRepG repression events contribute to the antiviral activity against cytomegaloviruses? PIs AS and MT will combine their complementary expertise in protein analytics and virology, respectively, to understand how IFNγ limits CMV replication.

• DFG Programme: Research Grants