Periodic Reporting for period 2 - E-T1IFNs (Elaboration of the type I interferonopathies) Reporting period: 2020-05-01 to 2021-10-31 Summary of the context and overall objectives of the project Type I interferons represent both key molecules in anti-viral defence and mediators of inflammatory disease, so that the induction, transmission and resolution of the interferon response are tightly regulated - balancing protection against infection versus the risk of immunopathology. Monogenic type I interferonopathies (T1IFNs), and related ‘complex’ phenotypes such as systemic lupus erythematosus and dermatomyositis, represent examples of a disturbance of the homeostatic control of this system, where a constitutive upregulation of type I interferon activity is considered directly relevant to pathology. Set against the absence of a routine assay in clinical medicine for the detection of upregulated type I interferon, the current application addresses major questions in the developing T1IFN field. Analogous to other screening strategies (e.g. using mouse ENU mutagenesis or yeast gene deletion series), we have established a pipeline for the systematic identification of human mutant states predisposing to upregulated type I interferon signalling. Such an approach will allow for the comprehensive definition of important themes in interferon biology, informing our understanding of anti-viral signalling and self-non-self discrimination. Furthermore, these studies will have direct translational benefit - since the identification of a phenotype as a T1IFN implies the possibility of therapy to reduce type I interferon levels and / or block interferon signalling. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far The current project began in November 2018. Since that time, we have been involved in establishing the systems necessary to drive the ET1IFNs project forward. We are currently engaged in some exciting work relating to several aspects of type I interferon biology:1. The definition of genotypes predisposing to type I interferon dysregulation due to a disturbance of chromatin/histone stoichiometry. 2. Interrogation of the role of the ER-Golgi axis in the regulation of type I interferon signalling.3. Exploration of mitochondria as a source of immunogenic nucleic acid. Papers relating to all three of these aspects have been published / are under review. Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) I believe that we are working on highly novel aspects of the control of type I interferon signalling, that we have discovered as a result of the use of our unique pipeline - involving the systematic assessment of interferon signalling in patients, followed by next generation sequencing, aimed at identifying novel type I interferonopathies and related proteins not necessarily recognised to play a role in nucleic acid sensing/interferon signalling. In particular, our most recent results shed light on emerging themes around chromatin biology, the ER-Golgi axis and mitochondria. In spite of the SARS-CoV-2 pandemic, I consider that we have made excellent progress during the first 30 months of my ERC advanced Fellowship, and I am hopeful that we can take our work forward to define further exciting new knowledge relating to the role of type I interferon signalling in human health and disease.