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Periodic Report Summary 1 - IFNDNA (Innate immune recognition of intracellular DNA as 'stranger' and 'danger' signal)

Innate immune recognition of intracellular DNA as 'stranger' and 'danger' signal

Most cells in the body are able to sense the presence of foreign DNA, for instance when they have been infected with a DNA virus. One of the responses to 'foreign' DNA is the production of interferons, cytokines and chemokines, which then act to limit the infection and alert more specialised immune cells to the danger. This is part of the innate immune response, which occurs within the first minutes and hours of infection, and eliminates many infectious agents before they cause any harm to the host. In some circumstances the body's own DNA can also be recognised as a 'danger' signal, e.g. when the cell's own DNA has been damaged, or when DNA from dying cells is not cleared effectively. Recognition of DNA as 'danger' signal may be important for the response to vaccine adjuvants, and in the clearance of cancer cells by the immune system. However, if the response to the body's own DNA is not sufficiently regulated, it can lead to the development of autoimmune diseases such as lupus erythematosus.

Several receptors for intracellular DNA have been identified in recent years, but it is still unclear whether they perform redundant functions, act in a ligand- or cell type specific manner, or co-operate in one signalling pathway. The overall aim of this project is to investigate the molecular mechanisms involved in the recognition of intracellular DNA as 'stranger' and 'danger' signal. We study DNA sensing in human keratinocytes, as these cells at the surface of our skin are the first point of contact for many pathogens, and are exposed to physical and chemical damage, e.g. from UV light or environmental toxins.

The questions that this project will address are:
1.) Which of the proposed DNA receptors are required for the interferon response to DNA as 'stranger' and 'danger' signal?
2.) What is the relationship between the different DNA receptors: Do they compete, co-operate or adopt specific functions?
3.) How are the DNA-activated signalling pathways regulated?
4.) How does the cell distinguish between viral DNA and its own genome?

We have been able to answer some of these questions, and have made some important discoveries about DNA sensing in human cells. For instance, we found that two DNA sensors, cGAS and IFI16, need to co-operate to detect foreign DNA during viral infection. Both cGAS and IFI16 bind to DNA, but act independently to activate the adaptor protein STING at the endoplasmic reticulum. We find that STING can only be fully activated if both cGAS and IFI16 are present, suggesting that the two signals might provide a fail-safe switch to prevent the spurious activation of a potentially damaging innate immune response. The observation that there is co-operation rather than redundancy between different DNA sensors in human cells addresses a major point of contention in the field, and explains the seemingly contradictory data about the involvement of different DNA receptors/co-receptors in human cells. However, our findings also raise questions about the precise molecular mechanisms of synergy between the two different DNA receptors, and particularly the nature of STING activation by IFI16.

Our work on the co-operation between IFI16 and cGAS has recently been published: Almine et al. (2017). IFI16 and cGAS co-operate in the activation of STING during DNA sensing in human keratinocytes. Nature Communications 3: 14392.

We also investigated how our own DNA can be detected as "danger" signal, for instance when it has been damaged. We found sub-lethal DNA damage can elicit a cell-intrinsic innate immune response, which results in the secretion of interferons, cytokines and chemokines by the damaged cell. This response is particularly potent in keratinocytes, which may help them respond to frequent damage incurred by UV exposure. We found that the innate immune response to DNA damage shared features with the response to foreign DNA, but was due to DNA sensing in the nucleus, rather than the cytosol. We also found that well-known tumour suppressor proteins such as p53 and ATM were involved in the response, and played a role in activating the DNA sensing adaptor STING in response to DNA damage. One striking observation arising from this work was that STING can be activated in different ways, and, depending on the input, can co-ordinate different transcriptional responses.

Taken together, our work into the fundamental mechanisms of how cells sense infection and injury may have important implications for clinical applications, in the fields of vaccination, autoimmunity and cancer.

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Life Sciences
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