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Elaboration of the type I interferonopathies

Periodic Reporting for period 1 - E-T1IFNs (Elaboration of the type I interferonopathies)

Reporting period: 2018-11-01 to 2020-04-30

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.
The current project began in November 2018. Since that time I have been involved in establishing my group (having moved to Edinburgh from Paris in March 2018), and setting up the systems necessary to drive the ET1IFNs project forward. We are currently engaged in some exciting work relating to several aspects:

1. The definition of three genotypes predisposing to type I interferon dysregulation due to a disturbance of chromatin biology.

2. Interrogation of the role of the ER-Golgi axis in the regulation of type I interferon signalling.

3. Definition of the molecular and phenotypic landscape related to mutations in IFIH1.

Papers relating to all three of these aspects have been submitted for review, or will be submitted in the next few months.
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 IFN signalling in patients, followed by next generation sequencing, aimed at identifying novel T1Is and related proteins not necessarily recognised to play a role in nucleic acid sensing/IFN signalling. In particular, these touch on emerging themes around chromatin biology and the ER-Golgi axis. We have made excellent progress in this regard and I am hopeful that this work will result in high impact publications in the next 12 -18 months.