atients with COVID-19 exhibit a broad spectrum of disease progression, with 81% showing mild, moderate or no symptoms; 14% showing severe symptoms; and 5% experiencing critical disease with high mortality risk 1 . The risk of developing severe or critical disease has been associated with advanced age 1,2 , comorbidities 1,2 , hyperactivation of the immune system 3,4 , sex 1,2 and other factors. However, an understanding of these risk factors at the molecular and cellular levels is in its infancy.In this study, we investigated the immune response in patients with COVID-19 by single-cell RNA sequencing (scRNA-seq) of nasopharyngeal and bronchial samples to identify molecular correlates of disease severity. Two recent studies applied scRNA-seq to bronchioalveolar lavage fluid samples from patients with COVID-19 and provide an extensive characterization of the inflammatory immune phenotype in the lower respiratory tract 5,6 . However, SARS-CoV-2 and other coronaviruses infect and replicate in both COVID-19 severity correlates with airway epithelium-immune cell interactions identified by single-cell analysis

Children have reduced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection rates and a substantially lower risk for developing severe coronavirus disease 2019 compared with adults. However, the molecular mechanisms underlying protection in younger age groups remain unknown. Here we characterize the single-cell transcriptional landscape in the upper airways of SARS-CoV-2-negative (n = 18) and age-matched SARS-CoV-2-positive (n = 24) children and corresponding samples from adults (n = 44), covering an age range of 4 weeks to 77 years. Children displayed higher basal expression of relevant pattern recognition receptors such as MDA5 (IFIH1) and RIG-I (DDX58) in upper airway epithelial cells, macrophages and dendritic cells, resulting in stronger innate antiviral responses upon SARS-CoV-2 infection than in adults. We further detected distinct immune cell subpopulations including KLRC1 (NKG2A) + cytotoxic T cells and a CD8 + T cell population with a memory phenotype occurring predominantly in children. Our study provides evidence that the airway immune cells of children are primed for virus sensing, resulting in a stronger early innate antiviral response to SARS-CoV-2 infection than in adults.

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