Nature https://doi.org/10.1038/04345-x (2022)

One of the characteristic features of COVID-19 is the much milder disease course seen in children; however, the mechanisms that underlie this are incompletely understood. To address this question, Mayer and colleagues use multi-omics approaches to compare immune responses in matched samples from the respiratory tracts and blood of adults and children. Both children and adults show similar expression of SARS-CoV-2 entry receptors in the respiratory tract but the interferon (IFN) response signature is clearly distinct. In healthy children, the epithelium shows an increased IFN signature with poor induction during COVID-19. By contrast, adults have an initially weak IFN signature that is strongly induced in COVID-19. Systemically, children show a generally naive immune compartment during COVID-19 whereas adults show a strong cytotoxic and inflammatory signature. Collectively, this suggests that the higher steady-state expression of IFN in children restricts SARS-CoV-2 in the upper respiratory tract and prevents more severe systemic inflammation.