Local and systemic responses to SARS-CoV-2 infection in children and adults

Background: Children typically present with milder coronavirus disease 2019 (COVID-19) severity compared to adults. The molecular basis of the differences in COVID-19 progression between children and adults remains to be elucidated. Here we investigated the age-specific differences of airway mucosal immunology as well as systemic immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Methods: We analysed matched nasal, tracheal and blood samples from healthy and COVID-19 patients from infancy to adulthood (n=93) by means of single cell multi-omic profiling. Results: In healthy children, airway mucosal immunity is in a pre-activated interferon state which is further induced in response to SARS-CoV2 infection. This higher local innate immune response in children could restrict disease progression. We identified novel epithelial cell states that associate with COVID-19 and age. The systemic immune response in children was characterised by increases in naive lymphocytes and greater clonotype diversity, while in adults was dominated by cytotoxic populations. Integration of matched nasal and blood data showed that interferon response in the airways correlate with the induction of novel systemic interferon-stimulated subpopulations within multiple immune cells, which were greatly reduced in children. Conclusions: Our study demonstrates multiple age-specific differences in airway and systemic response to SARS-CoV-2, reflecting the changes of the immune landscape over development. These insights could contribute to pinpointing the triggers of severe disease in adults with a view towards risk stratification and therapeutic intervention.