Viral manipulation of DBC1: a novel strategy to promote cell survival and suppress inflammation

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Human and animal cells have very sophisticated networks to communicate and respond to stress. Infection by a virus is a stress that can lead to the death of the cell. Accordingly cells respond vigorously to viral infection with the aim of blocking viral multiplication and alerting the body's immune system to the ongoing infection. Only viruses that have the capacity to avoid this hostile cell response survive. How viruses achieve this is not always clear. However, if and when one of these viral strategies is discovered, an opportunity for the development of antiviral interventions emerges. This project concerns the discovery of one of those strategies employed by a group of viruses named poxviruses, a member of which was responsible for the devastating disease smallpox. The smallpox virus killed more people in recorded history than all other infectious diseases combined, but fortunately was eradicated thanks to a worldwide vaccination campaign that used vaccinia virus (VACV), another member of the poxvirus family. VACV is currently being studied as a vaccine against another smallpox-like disease known as monkeypox as well as other several important human and animal diseases such as tuberculosis, AIDS, or rabies. This project will study how poxviruses manipulate the activity of a cellular protein termed DBC1. DBC1 belongs to one of those communication networks that cells use to respond to external stress. Its main role is to block the action of another protein known as SIRT1. Both DBC1 and SIRT1 were only discovered ~10 years ago, so our understanding of how they work is still in its infancy. However, it is now clear that both DBC1 and SIRT1 are very important in the process of ageing and in age-related diseases such as cancer and chronic inflammation. This project demonstrates that poxviruses specifically bind and relocalise DBC1, the negative regulator of SIRT1, in a part of the cell where SIRT1 is not normally present. This suggests that poxviruses break the DBC1-SIRT1 connection and benefit from this in a number of ways that are not fully understood yet. This project will therefore determine 1) how poxviruses sequester DBC1 away from SIRT1, 2) what advantage this has for the virus, and 3) what consequences this viral action has in disease and vaccination. To address how, detailed molecular biology and protein localisation studies will be developed. To address why, we will conduct a series of functional tests in cells previously modified to lack DBC1, SIRT1 or both genes. The response of these cells to infection will be studied and compared to that of normal cells. The conclusions from these studies will establish for the first time the role of the DBC1-SIRT1 axis during infection with viruses, and will provide valuable information not only for emerging poxviruses such as the monkeypox virus, but perhaps also for other viruses with similar biology such the African Swine Fever virus - an emerging, economically important pig pathogen that might also sequester DBC1.Finally, given the importance of VACV as a vaccine, the project will study the impact of the DBC1-SIRT1 axis in vaccination using viruses modified in the laboratory to relocate DBC1 or not. The response to vaccination is known to be complex and to change with age. If the modified virus that does not break the DBC1-SIRT1 connection triggers a better immune response, this modification can be introduced into VACV-based vaccines that are currently being developed. Therefore this project has the potential to impact on the design of vaccines and to improve our understanding of ageing and its biology.