Additionally, patients with autoantibodies against type I interferon exhibited the most severe immune dysregulation. This age-associated signaling shift was also replicated in COVID-19-infected hamsters, affirming its broader relevance to aging-related immune changes.

Our in vitro experiments revealed diminished responsiveness to type I interferons in cells from uninfected adults, reducing their capacity to suppress inflammatory cytokines like IFNg and IL-6. Elevated IL-1b levels in older individuals further exacerbated this inflammatory feedback loop.

Moreover, adult immune responses showed prolonged activity, evidenced by sustained activation of CD4+ T cells beyond two weeks post-infection, and heightened production of complement-activating antibodies.

Adults uniquely displayed extrafollicular B cell activation following infection, a phenomenon not detected in pediatric cases.

These signaling modifications correlated with inflammatory profiles in monocytes and T cells, aligning with our previous findings (Schulte-Schrepping et al. 2020 Cell, Georg et al. 2022 Cell). Notably, these inflammatory signatures were consistent even within individual family units.

Immune profiling showed distinct patterns: infection-associated clusters in pediatric patients had strong interferon-stimulated gene expression, whereas adult clusters lacked this, despite similar type I interferon concentrations. Instead, adult clusters prominently expressed S100A family genes.

We observed a notable shift in type I interferon signaling pathways, transitioning from a STAT1-dominant response to a STAT3-driven mechanism, potentially amplified by elevated IL-1b levels.

Employing multi-omics analyses on samples from 254 individuals aged between 1 and 86, we extensively characterized immune responses, identified key signaling mechanisms, and validated findings through targeted in vitro experiments.