Multi-omic Signatures of Baseline Immunity Shape Antiviral Responses in Adults and Infants 2327944

Abstract Introduction Infants and young children are vulnerable to influenza and exhibit prolonged viral shedding, but their “baseline” immune state that influences their first infection response is poorly understood. Although often seen as immature, infant immunity quickly changes after birth. We investigated how early-life baseline immune architecture relates to systemic and mucosal antiviral responses. Methods We utilized a systems immunology approach, analyzing 929 samples from a longitudinal cohort of young children with natural infections (IMPRINT) and adults from a controlled infection (CHIM). We integrated proteomics, scRNA-seq and scATAC-seq to map immune states across pre-infection, acute, and convalescent stages. Results Multi-omic analysis revealed that healthy young children possess a “pre-activated” baseline state. Proteomics showed significantly elevated plasma interferons and pro-inflammatory cytokines in children compared to adults, which correlated with a blunted systemic response to influenza infection . Through scRNA-seq, we identified five distinct CD14+ monocyte subclusters. In adults, a higher baseline abundance of interferon-stimulated (ISG+) monocytes predicted better viral control; conversely, in children, a higher baseline abundance of inflammatory monocytes predicted poorer viral control. scATAC-seq supported this divergence, showing that opposing IRF and AP-1 chromatin accessibility programs are associated with these monocyte states. Finally, we identified a systemic—mucosal dichotomy: while children exhibited blunted blood responses, their nasal compartment was hyper-responsive, characterized by strong interferon/cytokine induction and epithelial—myeloid activation. Conclusion Our findings demonstrate that infant immunity is not merely underdeveloped but is a uniquely pre-activated and modularly organized system. By linking baseline epigenetic and transcriptional signatures to mucosal viral burden, this study identifies specific immune architectures that drive influenza susceptibility Funding Source n/a Topic Categories Computational and Systems Immunology (COMP)