Exploring interferon-mediated lung inflammation through the study of monogenic diseases – LUNG-In

As emphasised by the SARS-CoV-2 pandemic, understanding the pathogenesis of inflammatory lung disease is of high relevance to human health, with persistent pulmonary inflammation leading to fibrosis and end-stage respiratory failure. The potential of type I interferon (IFN) to mediate lung inflammation has been recently highlighted. However, the precise mechanism remains unknown. I propose to study the type I interferonopathies (TI1s), a group of inborn errors of immunity with chronically enhanced type I IFN signalling, to explore how IFN-mediated lung inflammation is precisely triggered and induces fibrosis. In particular, I have acquired an internationally-recognised expertise in the life-threatening pulmonary disease observed in two TI1s.
Employing state-of-the-art technologies (including single-cell transcriptomics and induced pluripotent stem cells, iPSCs) on never assessed rare human samples, I will unravel the cellular and molecular pathogenesis of IFN-mediated lung inflammation in the context of monogenic disease and provide an integrated disease model to study pathogenic pathways. I will then validate novel therapeutic targets in in vitro and murine models. Finally, I propose to identify novel human mutant genotypes predisposing to upregulated IFN signalling and lung inflammation, using an established clinical-experimental medicine pipeline informed by our results.
My knowledge of in vitro systems and IFN biology, combined with unprecedented access to patient material/clinical data, and already established expert collaborations, places me in a unique position to develop this exciting new area of translational clinical medicine. Importantly, my proposal will not only improve the diagnosis and management of rare monogenic disorders, it will also have relevance to the pathology of more common diseases associated with lung inflammation-induced fibrosis, including systemic lupus erythematosus, dermatomyositis, idiopathic pulmonary fibrosis and viral infection.