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).
1. Andersen LL, Mørk N, Reinert LS, Kofod-Olsen E, Narita R, Jørgensen SE, Skipper KA, Höning K, Gad HH, Østergaard L, Ørntoft TF, Hornung V, Paludan SR, Mikkelsen JG, Fujita T, Christiansen M, Hartmann R, Mogensen TH. (2015). Functional IRF3 deficiency in a patient with herpes simplex encephalitis. Journal of Experimental Medicine (IF: 17.58).
2. Ogunjimi B, Zhang SY, Sørensen K, et al…… Mogensen TH (2017). Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections. Journal of Clinical Investigation (IF: 19.46).
3. Lafaille FG, Harschnitz O, Lee YS…..Mogensen TH…..Casanova J-L, and Zhang S-Y. (2019). Human SNORA31 variations impair cortical neuron-intrinsic immunity to HSV-1 and underlie herpes simplex encephalitis. Nature Medicine (IF: 87.241).
4. Paludan SR, Pradeu T, Masters S, Mogensen TH (2020). Constitutive immune mechanisms: mediators of host defence and immune regulation. Nature Reviews Immunology. doi: 10.1038/s41577-020-0391-5. Online ahead of print. (IF: 108.6).
5. Zhang Q, Jing H, Bastard P….Mogensen TH….Cobat A, Casanova JL, and Su H. (2020). Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science (IF: 63.714) (Selected as a Top 10 scientific discovery of the year in 2020 by Nature. Joint with ref 6).
6. Bastard P, Rosen L, Zhang Q….Mogensen TH……Abel L, Su H and Casanova JL (2020). Autoantibodies against type I IFNs in patients with life-threatening COVID-19. Science (IF: 69.5) (Selected as a Top 10 scientific discovery of the year in 2020 by Nature. Joint with ref 5).
7. Olagnier D, Farahani E, Herengt A, Thyrsted J, Cadanet J, Hait AS…….Alcami A, Mogensen TH, Paludan SR, and Holm CK (2020). SARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate. Nature Communications (IF: 17.69).
8. Hait AS, Sancho-Chimizu V, Skipper KA, Olagnier DCP, Brandt CT, Helleberg M, Larsen SM, Bodda C, Moldovan LI, Christiansen M, Krisensen LS, Brinck-Andersen NS, Thomsen M, Olesen R, Jørgensen SE, Mikkelsen JG, Paludan SR, Mogensen TH (2020). Defects in LC3B2 and ATG4A underlie HSV2 meningitis and reveal a critical role for autophagy in antiviral defense in humans. Science Immunology (IF: 30.63).
9. Duncan CJA, Skouboe MK, Howarth S, Hollensen AK, Chen R, Børresen ML …… Hambleton S, and Mogensen TH (2022). Life-threatening viral disease in a novel form of autosomal recessive IFNAR2 deficiency in the Arctic. Journal of Experimental Medicine (IF: 17.58).
10. Mogensen TH, Skouboe MK, Mølle I (2022). Successful use of interferon alfa-2a for chronic parvovirus B19 infection. The Lancet Infectious Diseases (IF: 71.421).