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Summary of our research findings

Studying patients with rare mutations causing extreme clinical phenotypes to infections provides a unique platform to uncover fundamental insight into the immune system. My group was the first in Denmark to take this scientific approach and first identified a novel primary immunodeficiency (PID) caused by a mutation in the transcription factor IRF3 associated with herpes encephalitis (J Exp Med, 2015) and defects in IRF3 and IRF7 in patients with severe influenza (Eur J Immunol, 2019; MMI, 2019). We also discovered a novel mechanism underlying ectodermal dysplasia with immunodeficiency (EDA-ID) through an intronic branch-point mutation in the NEMO gene involved in NF-κB activation (J Allergy Clin Immunol, 2016). Next, we identified a novel PID involving deficiency in the cytosolic viral nucleic acid sensor POLR3, in children with severe VZV infection in the CNS or lungs (J Clin Invest, 2017). Further studies from our group demonstrated a role of POLR3 in immunity to VZV CNS infection in adults (Neurology, 2018; Trends Mol Med, 2018).

Recently, we have proposed a role for constitutive and non-receptor-mediated immune mechanisms in antiviral defense (Nature Rev Immunol, 2020), and have described PIDs associated with variations in the nucleolar protein SNORA31 and autophagy genes underlying herpes encephalitis and meningitis, respectively (Nature Med, 2019; Science Immunol, 2020).

A novel research focus is on the genetic and immunological basis of severe COVID-19 within a global consortium covidhge (covidhge.com) (Cell, 2020). This has so far resulted in two publications describing rare genetic variants in interferon (IFN) pathway genes (Zhang et al Science, 2020) and autoantibodies to type I IFN in severely ill COVID-19 patients (Bastard et al Science, 2020), together establishing an important role of IFN in antiviral immunity to SARS-CoV2 and linking functionally defective IFNs to development of severe disease. These articles were selected as Top 10 scientific discoveries in 2020 by Nature. Finally, I am collaborator on a study describing a new antiviral compound against SARS-CoV2 (Nature Comm 2020).

10 most important publications