Rewired type I IFN signaling is linked to age-dependent differences in COVID-19
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<sup>+</sup> 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<sup>+</sup> T cells. A shift from IFN-responsive germinal center B (GCB) cells toward CD69<sup>high</sup> 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.
Authors
- Jakob Trimpert (ORCID: https://orcid.org/0000-0003-1616-0810)
- Anna Hiller (ORCID: https://orcid.org/0000-0002-5252-0986)
- Rosario Astaburuaga-García (ORCID: https://orcid.org/0000-0003-1179-4080)
- Bruno Märkl (ORCID: https://orcid.org/0000-0002-7704-850X)
- Birgit Sawitzki (ORCID: https://orcid.org/0000-0001-8166-8579)
- Christina Iwert (ORCID: https://orcid.org/0000-0003-4414-0462)
- Sophia Brumhard (ORCID: https://orcid.org/0000-0002-1202-6684)
- Leif Erik Sander (ORCID: https://orcid.org/0000-0002-0476-9947)
- Saskia von Stillfried (ORCID: https://orcid.org/0000-0002-5260-8494)
- Roland Eils (ORCID: https://orcid.org/0000-0002-0034-4036)
- Benjamin Ondruschka (ORCID: https://orcid.org/0000-0002-8277-6616)
- Marcus Alexander Mall (ORCID: https://orcid.org/0000-0002-4057-2199)
- Peter Boor (ORCID: https://orcid.org/0000-0001-9921-4284)
- David Hillus (ORCID: https://orcid.org/0000-0002-3138-9050)
- Tim Meyer (ORCID: https://orcid.org/0000-0003-0782-8647)
- Sammy Bedoui (ORCID: https://orcid.org/0000-0002-7443-0543)
- Christine Langner (ORCID: https://orcid.org/0000-0001-7311-3477)
- Irina Lehmann (ORCID: https://orcid.org/0000-0001-8875-5587)
- Christian Meisel
- Markus Ralser (ORCID: https://orcid.org/0000-0001-9535-7413)
- Victor M. Corman (ORCID: https://orcid.org/0000-0002-3605-0136)
- Emanuel Wyler (ORCID: https://orcid.org/0000-0002-9884-1806)
- Hannah-Philine Dey
- Jennifer Loske (ORCID: https://orcid.org/0000-0003-3222-9777)
- Nils Blüthgen (ORCID: https://orcid.org/0000-0002-0171-7447)
- L. A. Petrov (ORCID: https://orcid.org/0000-0002-1884-0900)
- Philipp Georg (ORCID: https://orcid.org/0000-0001-9934-7415)
- Roman David Bülow (ORCID: https://orcid.org/0000-0002-8527-7353)
- Lukas Maas (ORCID: https://orcid.org/0000-0002-5830-6710)
- Katrin Vogt
- Sebastian Wisniewski (ORCID: https://orcid.org/0000-0001-9129-8997)
- Jobst Röhmel
Institutions
- Centre for Human Genetics (GB)
- Universität Hamburg (DE)
- University of Augsburg (DE)
- Max Delbrück Center (DE)
- Humboldt-Universität zu Berlin (DE)
- Peter Doherty Institute (AU)
- University Medical Center Hamburg-Eppendorf (DE)
- Vivantes Klinikum (DE)
- Universitätsklinikum Aachen (DE)
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
- Freie Universität Berlin (DE)
- Charité - Universitätsmedizin Berlin (DE)
- RWTH Aachen University (DE)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2025-08-01
- DOI
- https://doi.org/10.1016/j.xcrm.2025.102285
- Citations
- 1
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 0.80