Skip to main content

Interplay between influenza viruses and host SUMO pathways

Final 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 focused 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 sought to provide new insights into the cell biology of these important pathogens.

The specific aim of this project was 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. We found that influenza virus infection causes a dramatic change in SUMO conjugation to many host-cell proteins. To understand this response, we established technologies to identify these SUMOylated host proteins, and went on to reveal how several of these SUMO targets act to either promote or restrict virus replication. In particular, we provided insights into how species-specific variants of host ANP32A may function to promote influenza virus replication, and demonstrated the importance of such variants during virus adaptation to new hosts. We also uncovered a new regulated role for host TRIM28 in triggering immune defences against viruses by allowing the cell to produce ‘self’ immunostimulatory signals.

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