Rewired type I IFN signaling is linked to age-dependent differences in COVID-19
Authors:
- Petrov, Lev
- Brumhard, Sophia
- Wisniewski, Sebastian
- Georg, Philipp
- Hillus, David
- Hiller, Anna
- Astaburuaga-García, Rosario
- Blüthgen, Nils
- Wyler, Emanuel
- Vogt, Katrin
- Dey, Hannah-Philine
- von Stillfried, Saskia
- Iwert, Christina
- Bülow, Roman D.
- Märkl, Bruno
- Maas, Lukas
- Langner, Christine
- Meyer, Tim
- Loske, Jennifer
- Eils, Roland
- Lehmann, Irina
- Ondruschka, Benjamin
- Ralser, Markus
- Trimpert, Jakob
- Boor, Peter
- Bedoui, Sammy
- Meisel, Christian
- Mall, Marcus A.
- Corman, Victor M.
- Sander, Leif Erik
- Röhmel, Jobst
- Sawitzki, Birgit
Details:
Cell Reports Medicine, Volume 6, Issue 8, 2025-08-19
Article Link: Click here
Advanced age is the most important risk factor for severe disease or death from COVID-19, but a thorough mechanistic understanding of the molecular and cellular underpinnings is lacking. Multi-omics analysis of 164 samples from SARS-CoV-2-infected persons aged 1 to 84 years reveals a rewiring of type I interferon (IFN) signaling with a gradual shift from signal transducer and activator of transcription 1 (STAT1) to STAT3 activation in monocytes, CD4+ T cells, and B cells with increasing age. Diversion of IFN signaling is associated with increased expression of inflammatory markers, enhanced release of inflammatory cytokines, and delayed contraction of infection-induced CD4+ T cells. A shift from IFN-responsive germinal center B (GCB) cells toward CD69high GCB and atypical B cells during aging correlates with immunoglobulin (Ig)A production in children, whereas complement-fixing IgG predominates in adults. Our data provide a mechanistic basis for inflammation-prone responses to infections and associated pathology during aging.