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

Advanced age is the most important risk factor for severe or even lethal COVID-19, but a thorough understanding of the underlying differences in infection-induced inflammation and cellular pathogenesis is missing. In samples from SARS-CoV-2 infected patients aged 1 to 84 years, we observed a continuous rewiring of type I interferon signaling and signal transducer and activator of transcription (STAT) usage across monocytes, CD4+ T cells and B cells during aging. In vitro investigations using cells from controls confirmed this as a general age-induced phenomenon. Conversion in interferon signaling from STAT1 to STAT3 was associated with increased inflammatory profiles, cytokine release and delayed contraction of infection-induced CD4+ T cells. A shift from solely interferon-responsive germinal center B (GCB) cells towards CD69high GCB and atypical B cells was linked to formation of IgA in children vs complement fixing IgG in adults. Our data provide molecular explanations for inflammation-prone responses to infections during aging.