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Recent work indicates that heightened nasal innate immunity in children may impact SARS-CoV-2 pathogenesis. Here, we identified drivers of nasal innate immune activation in children using cytokine profiling and multiplex pathogen detection in 291 pediatric nasopharyngeal samples from the 2022 Omicron surge. Nasal viruses and bacterial pathobionts were highly prevalent, especially in younger children (81% of symptomatic and 37% asymptomatic children overall; 91% and 62% in subjects <5 yrs). For SARS-CoV-2, viral load was highest in young children, and viral load in single infections or combined viral loads in coinfections best predicted nasal CXCL10, a biomarker of the mucosal interferon response. Bacterial pathobionts correlated with high nasal IL-1 beta and TNF, but not CXCL10, and viral-bacterial coinfections showed a combined immunophenotype. These findings reveal virus and bacteria as drivers of heightened nasal innate immunity in children and suggest that frequent host-pathogen interactions shape responses to respiratory viruses in this age group

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