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Impact of virus infection on the host proteome

Final Report Summary - IVIP (Impact of virus infection on the host proteome)

Stand-alone description of the project and its outcomes:
Virus infection induces a plethora of responses in the host proteome. We conducted unbiased proteome-wide studies to obtain a systematic view of these changes. We used a wide array of diverse viruses in order to identify both common and virus-specific effects. The analysis highlighted critical proteins that are altered on protein expression level, change their interaction profiles, are targeted by viral proteins or change their phosphorylation status. The unconventional approaches employed brought to light yet another additional set of key factors. For instance, the investigation of protein turn-over and stability rates by pulse-SILAC approaches allowed identifying otherwise elusive cellular factors whose net abundance in a cell remains the same, thereby escaping to more traditional techniques. Loss-of-function studies highlighted some of these proteins as either important regulators of the innate immune response or as directly involved in antiviral innate immunity.
A more specific example relates to the influence of Zika virus (ZIKV) as a highly important emerging pathogen. We discovered a number of critical host factors that are targeted by ZIKV proteins, change their phosphorylation status or abundance upon ZIKV infection, or are specifically modulated by ZIKV in the context of neuronal differentiation. Thus our analysis provided critical insights into Zika-virus induced neuropathology, identified a subset of novel cellular proteins as highly promising targets for therapeutic interventions and delivered the most extensive database of ZIKV-related proteomic changes to the scientific community.
Assessing the data generated, we could identify a novel cell-death pathway triggered by intracellular reactive oxygen species (ROS). This pathway, now termed “oxeiptosis”, is particularly active during virus infections and mediates execution of a non-inflammatory, apoptosis-like cell death program. Murine loss-of-function studies demonstrated exacerbated lungs inflammation after ozone exposure and a more severe pathological outcome of Influenza A virus infections. Oxeiptosis activity in many diverse cell types and disease-associated SNPs suggest that it may also be affected in transformed cancer tissue.