Rewired type I IFN signaling is linked to age-dependent differences in COVID-19.
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 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.
| Authors: | Petrov L, Brumhard S, Wisniewski S, Georg P, Hillus D, Hiller A, Astaburuaga-García R, Blüthgen N, Wyler E, Vogt K, Dey HP, von Stillfried S, Iwert C, Bülow RD, Märkl B, Maas L, Langner C, Meyer T, Loske J, Eils R, Lehm |
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| Journal: | Cell Rep Med;2025Aug19; 6 (8) 102285. doi:10.1016/j.xcrm.2025.102285 |
| Year: | 2025 |
| PubMed: | PMID: 40834853 (Go to PubMed) |