Defining and exploiting the role of PML protein in innate immune responses to pathogens

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Just as we swap our lightweight summer clothes for winter ones when it gets cold, so our cells need to make different proteins to meet changing circumstances, such as when they are invaded by a virus. This project is about understanding how our cells change in response to virus infection, in particular, how they make what is termed an innate immune response. This response involves the cell making new proteins that act to limit the growth and spread of the virus. Proteins are produced from instructions carried in RNA molecules. These in turn are made by copying the information held in the cell's genes, a process known as transcription. So, when a cell is stressed by a virus infection, it responds by changes in its pattern of gene transcription. We have discovered that a protein known as PML-II behaves like a master regulator of genes whose transcription is turned on rapidly after a virus infection. A major aim of this project is to find out just how broad is the set of genes that responds to the presence of this protein and, most importantly, what distinguishes these genes from those that are independent of it. We plan to use the most modern techniques to examine events across all the 20,000 or more genes in the human genome when an innate immune response is launched. In this way, we will get a system-wide view of the effects of the PML-II protein that is not limited by any preconceptions.Going on from this, we intend to find out how differences in PML-II between individuals may influence how they respond to virus infection, since we know that there are major differences in the outcome of apparently similar infections between one person and another. We will be testing two types of difference in PML-II: first, differences at the gene level, as a result of the different genes we inherit; and second, differences that arise in cells as a result of the environment they experience. Here we will be looking particularly at heat stress - the kind of effect that can arise naturally when someone experiences a fever - and asking whether changes in PML that result from such stress are the basis for differences in innate responses and susceptibility to virus infection that we have already seen.It is really important to unravel the ways in which innate immune responses are generated in the body. Cells being unable to respond sufficiently could mean that an infection spreads further and faster than it would have done - making you more sick. Alternatively, an innate response that becomes overly prolonged can lead to chronic inflammation, a condition which is associated with significant human diseases such as rheumatoid arthritis. Building on the work we will do to understand the involvement of PML-II in innate responses, this project will also evaluate a new strategy aimed at controlling these responses.