Periodic Reporting for period 4 - E-T1IFNs (Elaboration of the type I interferonopathies)
Reporting period: 2023-05-01 to 2024-10-31
As brutally demonstrated by the SARS-CoV-2 pandemic, the ability to mount an interferon-mediated anti-viral response is essential to human health. Developed over evolutionary time, viral nucleic acid detection, and the subsequent induction of a type I interferon response, represents a central pillar in the armamentarium employed to combat foreign viral invasion. Given that our own cells are replete with self-DNA and RNA, the adoption of such a strategy necessitates the efficient differentiation of pathogen- from host-derived nucleic acid in order to maintain cellular homeostasis. The importance then of the type I interferonopathies (T1IFNs) as a pathogenic grouping lies in both the highlighting of the toxic potential of type I interferons, and the demonstration that essential anti-viral systems, sensing either viral DNA or RNA, can also be triggered by host-derived nucleic acid.
Set against the absence of a routine assay in clinical medicine for the detection of upregulated type I interferon in patients, the E-T1IFNs project was designed to further develop the type I interferonopathy concept first proposed in 2011. In doing so, the project has contributed important novel insights into type I interferon biology only available through studies in man, and informed changes in clinical practice with major benefit to human health.
Set against the absence of a routine assay in clinical medicine for the detection of upregulated type I interferon in patients, the E-T1IFNs project was designed to further develop the type I interferonopathy concept first proposed in 2011. In doing so, the project has contributed important novel insights into type I interferon biology only available through studies in man, and informed changes in clinical practice with major benefit to human health.
T1IFNs are Mendelian genetic diseases associated with chronically enhanced type I interferon signalling, proposed to be directly relevant to pathogenicity. Through the use of a pipeline for the systematic identification of human mutant genetic states predisposing to upregulated type I interferon signalling, this ERC Advanced Fellowship (running from 11/2018 to 10/2024) has defined multiple new T1IFNs, and further characterised a number of previously described T1IFNs. Notable outputs of the project have included the identification of novel disease-associated Mendelian genotypes due to mutations in the mitochondrial protein ATAD3A, the small GTPase ARF1, the protein tyrosine phosphatase PTP1B, and in components of the replication-dependent histone pre-mRNA processing complex. In this way, the project has highlighted the importance of mitochondrial nucleic acid, intracellular trafficking of the adaptor protein STING, and chromatin modification of genomic DNA in the maintenance of cellular immunological homeostasis. Further, the project has made step-change contributions to the development of rational therapeutic approaches to the treatment of the T1IFNs, most particularly through studies on the JAK1/2 inhibitors ruxolitinib and baricitinib, and the use of reverse transcriptase inhibitors.
The E-T1IFN project has leveraged the power of Mendelian disease to deconvolute complex biology in the human context, with the overarching goals being to inform fundamental principles of cellular homeostasis relevant to human health, and ensure translational impact through diagnostics, therapeutics and public engagement. The specific focus of the Fellowship has related to the definition of cellular contexts in which self-derived nucleic acid ligands are generated and sensed, and translational efforts to limit the generation of such putative nucleic acid ligands, or block signalling downstream of an interferon stimulus. Toward these aims, the E-T1IFNs project has helped to define multiple cell-intrinsic molecular programs, dysfunction of which can lead to a failure of self/non-self discrimination and the induction of inappropriate anti-viral signalling. Importantly, this work has had immediate translational impact in terms of both diagnostic molecular genetic provision, and the trialling of novel ‘anti-interferon’ therapies which are now being used in patients worldwide. Notably, such therapeutic approaches are potentially also relevant to a larger group of non-Mendelian autoinflammatory diseases such as systemic lupus erythematosus.