Rewired type I IFN signaling is linked to age-dependent differences in COVID-19

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

Rewired type I IFN signaling is linked to age-dependent differences in COVID-19

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Item Type:	Article
Title:	Rewired type I IFN signaling is linked to age-dependent differences in COVID-19
Creators:	Petrov, Lev, Brumhard, Sophia, Wisniewski, Sebastian, Georg, Philipp, Hillus, David, Hiller, Anna, Astaburuaga-García, Rosario, Blüthgen, Nils, Wyler, Emanuel ORCID: https://orcid.org/0000-0002-9884-1806, 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 and Sawitzki, Birgit
Abstract:	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 CD69(high) 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.
Keywords:	Type I IFN, Signaling, Age, Children, COVID-19, SARS-CoV-2, STAT1, STAT3, Monocytes, T Cells, B Cells, Antibodies, Immune Response
Source:	Cell Reports Medicine
ISSN:	2666-3791
Publisher:	Elsevier / Cell Press
Volume:	6
Number:	8
Page Range:	102285
Date:	19 August 2025
Official Publication:	https://doi.org/10.1016/j.xcrm.2025.102285
PubMed:	View item in PubMed
Related to:	URL URL Type https://doi.org/10.6084/m9.figshare.26131711.v1 Dataset https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE271284 Dataset https://doi.org/10.17632/kz7cpw3bnt.1 Software

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