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(+) 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.

• Petrov, L.
• Brumhard, S.
• Wisniewski, S.
• Georg, P.
• Hillus, D.
• Hiller, A.
• Astaburuaga-García, R.
• Blüthgen, N.
• Wyler, E.
• Vogt, K.
• Dey, H. P.
• von Stillfried, S.
• Iwert, C.
• Bülow, R. D.
• Märkl, B.
• Maas, L.
• Langner, C.
• Meyer, T.
• Loske, J.
• Eils, R.
• Lehmann, I.
• Ondruschka, B.
• Ralser, M.
• Trimpert, J.
• Boor, P.
• Bedoui, S.
• Meisel, C.
• Mall, M. A.
• Corman, V. M.
• Sander, L. E.
• Röhmel, J.
• Sawitzki, B.