Dissecting type I interferon signaling in life-threatening viral infections: Genetics and mechanisms

The COVID-19 pandemic has ravaged the world, with high fatality rates among elderly and immunocompromised individuals. Fatalities and severe morbidity has also been registered in a large number of young, previously healthy adults.

Immunological and host genetic analyses have revealed that the type I interferon (IFN) system is critical for protection from severe COVID-19, uncovering genetic determinants but also highlighting shortcomings in genetic understanding and diagnostic tools.

Based on promising preliminary data, we seek support to combine genome analyses with functional assessments of the type I IFN system in young Swedish adults severely affected by COVID-19 to identify rare, endemic variants associated with impaired anti-viral responses.

Moreover, we aim to develop improved functional assays for clinical diagnostic evaluation of the type I interferon system in patients.

Finally, we outline efforts to dissect how specific IFN-stimulated genes (ISG), associated with impaired innate immunity to viruses, restrict viral replication and integrate in cellular responses.

Our efforts promise to systematically determine the degree to which impairments in the IFN pathway render individuals susceptible to severe COVID-19, potentially uncovering new genes and regulatory elements, and provide diagnostic tools for rapid identification of patients that could benefit from IFN-targeted therapies.

We will also provide novel mechanistic insights to how ISGs can restrict viral infection.