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. Blood was collected from children and adults acutely infected with COVID-19 as well as age- and sex-matched uninfected donors. PBMCs were isolated and a part of the PBMCs from each donor was enriched for B cells. Total PBMCs and enriched B cells were subjected to 5' GEX scRNAseq and 5' VDJ library preparation. Samples were pooled with Antibody-based Hashtags and demultiplexed based on both Hashtags and SNPs. Sample groups included are : uninfected children (median age = 7), uninfected adults (median age = 66), infected children (median age = 9; asymptomatic n = 5, symptomatic n = 8) and infected adults (median age = 67; mild n = 5, severe n = 7, severe with IFN autoantibodies n = 7). *************************************************************** Submitter states that missing raw files are due to patient privacy concerns. ***************************************************************