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

Petrov, L.; Brumhard, S.; Wisniewski, S.; Georg, P.; Hillus, D.; Hiller, A.; Astaburuaga-Garcia, R.; Bluethgen, N.; Wyler, E.; Vogt, K.; Dey, H.-P.; von Stillfried, S.; Iwert, C.; Buelow, R. D.; Maerkl, 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.; Roehmel, J.; Sawitzki, B.

doi:10.1101/2024.10.23.619479

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bioRxiv · 10.1101/2024.10.23.619479

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

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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 samples from SARS-CoV-2 infected persons aged 1 to 84 years, revealed 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 interferon IFN signaling was 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 towards CD69high GCB and atypical B cells corresponded to the formation of IgA in children while complement fixing IgG was dominant in adults. Our data provide a mechanistic basis for inflammation-prone responses to infections and associated pathology during aging. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=144 SRC="FIGDIR/small/619479v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@723896org.highwire.dtl.DTLVardef@e12b2aorg.highwire.dtl.DTLVardef@d8de22org.highwire.dtl.DTLVardef@1df96ec_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Petrov, L., Brumhard, S., Wisniewski, S., Georg, P., Hillus, D., Hiller, A., Astaburuaga-Garcia, R., Bluethgen, N., Wyler, E., Vogt, K., Dey, H.-P., von Stillfried, S., Iwert, C., Buelow, R. D., Maerkl, 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., Roehmel, J., Sawitzki, B.. 2024-10-23. Rewired type I IFN signaling is linked to age-dependent differences in COVID-19. https://doi.org/10.1101/2024.10.23.619479

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