‘Multi-omics’ of the Interferon System

Interferons (IFNs) are key cytokines produced by infected cells that signal to neighboring tissues and induce an antiviral state to inhibit pathogen spread. As such, the IFN system constitutes a major innate immune barrier to zoonotic virus transmission and limits the severity of seasonal and pandemic disease. Furthermore, IFN-based therapies could be potent, host-directed, broad-spectrum measures for virus control and prevention in emergency situations (Busnadiego et al., mBio, 2020).

We are interested to understand more about the fundamental signaling mechanisms underlying regulation of the IFN system in humans during healthy and diseased conditions. This is essential to fully exploit the concept of using IFN-based therapies, and to suggest optimal targets for new intervention strategies. We are currently adopting a ‘multi-omics’ approach to learn more about the IFN signaling pathway and the cellular processes that occur during mounting of the host antiviral response. For example, we recently employed genome-scale CRISPR discovery approaches to identify BRD9 as a new, druggable component of IFN signaling that could also be a novel anti-inflammatory target (Börold et al., EMBO Reports, 2021). In addition, we have performed restriction factor screening assays to identify new human proteins that mediate the antiviral action of IFN (Fernbach et al., Cell Reports, 2022). We are currently complementing these studies with proteome-wide mass spectrometry for post-translational modifications, and state-of-the-art spatial and temporal protein interactome analyses. These efforts should illuminate the dynamic IFN-induced signaling landscape in human cells, and will help to understand the mechanisms by which specific factors impact host antiviral defenses.