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SUMOFLU Report Summary

Project ID: 335809
Funded under: FP7-IDEAS-ERC
Country: Switzerland

Mid-Term Report Summary - SUMOFLU (Interplay between influenza viruses and host SUMO pathways)

Influenza viruses cause a significant seasonal disease burden and continually threaten to initiate human pandemics. Antivirals are available for treatment of influenza, however drug-resistant viruses often emerge. Thus, there is urgent need to develop new antivirals with lower chances of selecting resistance. As viruses rely extensively on cellular functions, one way to minimise resistance is to target new antivirals against host factors. This concept requires a fundamental understanding of the molecular mechanisms underpinning the interplay between influenza viruses and their hosts.

This project focuses on the role that a host post-translational modification pathway, called SUMOylation, plays during influenza virus replication. Dynamic SUMOylation underpins the control of almost all functions in the cell nucleus. Thus, extensive SUMO ‘re-wiring’ can be driven by both the infected host-cell nucleus as a defence response, and by the invading virus as a means to propagate efficiently. By uncovering the principles underlying cell signalling pathways that are switched ‘on’ or ‘off’ by SUMOylation during influenza virus infection, we seek to provide new insights into the cell biology of these important pathogens.

The specific aim of this project is to establish functional and mechanistic links between specific SUMO modifications, the host enzymes that cause them, and their biological impact on the influenza virus replication cycle. To date, we have found that influenza virus infection causes a dramatic increase in SUMO conjugation to host-cell proteins. This induction of SUMOylation is triggered by RNA viruses that replicate in the nucleus (such as influenza A and B viruses), but not by cytoplasmic-replicating RNA viruses. We could also reveal that changes in SUMO distribution occur largely in response to activity of the viral RNA synthesis machinery, allowing us to speculate that virus RNA replication in the nucleus is a signal triggering a previously uncharacterised host-cell stress response.

To further understand this potential new stress response, we established technologies to identify SUMOylated host proteins. We identified 63 host proteins whose SUMOylation status was robustly increased during influenza virus infection, and many of these had not been implicated in influenza virus biology previously. Follow-up work revealed that several of these SUMO targets act to either promote or restrict virus replication, and mechanistic studies provided valuable new insights into how specific SUMO modifications could regulate virus replication and host antiviral responses.

Overall, our ongoing analyses of SUMO post-translational modifications are establishing new frameworks for understanding the way in which the host-cell nucleus is ‘re-wired’ during influenza virus infection. A long-term goal is to investigate the link between these newly identified cellular signalling pathways and influenza disease outcome, as well as to exploit this knowledge for the development of novel therapeutics.

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