Interferon Deficiencies and Viral Disease

We are interested to understand human genetic and non-genetic factors in the interferon (IFN) system that modulate susceptibility to viral infection and disease severity (reviewed in Stertz & Hale, Trends in Microbiology, 2021). In particular, a major focus in recent years has been the study of human autoantibodies (autoAbs) that bind to IFN cytokines themselves (Hale, European Journal of Immunology, 2023). We have confirmed reports that autoAbs neutralizing the function of IFNs are present in an unexpectedly high proportion (~10%) of patients critically-ill with COVID-19, and that these autoAbs appear to increase susceptibility to other viruses such as herpesviruses (Busnadiego et al., PLoS Biology, 2022). We have also undertaken in-depth longitudinal studies in large cohorts to understand the age-related development of IFN autoAbs in humans, revealing immunological factors associated with their appearance, their impacts on innate immune function, and their lifelong persistence with consequences for virus susceptibility decades later (Fernbach et al., Journal of Experimental Medicine, 2024; UZH News). Recently, we have dissected the molecular mechanisms by which pathogenic IFN autoAbs neutralize IFN function, and used the knowledge gained to design new inhibitory ‘decoy’ molecules that might be able to reverse autoAb-mediated virus susceptibility (Groen et al., Journal of Experimental Medicine, 2025; UZH News). We are actively interested in evaluating the prevalence and consequences of different IFN autoAbs in various human populations, and are keen to establish conceptual frameworks for new targeted diagnostics or therapies.

Figure legend: Loss of tolerance precedes triggering and lifelong persistence of pathogenic type I interferon autoantibodies (Fernbach et al., Journal of Experimental Medicine, 2024).