Age- and Virus-Specific Signatures ofIn VitroReconstituted Human Airway Epithelia in the Presence and Absence of Respiratory Viral Infections

While Influenza Virus and Respiratory Syncytial Virus (RSV) are considered as a significant health burden in children, Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) causes milder diseases in this age group compared to adults. To investigate the involvement of the upper respiratory tract human airway epithelium (HAE) in this pattern, we established an in-house model of reconstituted HAE cultured in air-liquid interface from nasal swabs of children and adults and characterised it before and afterex vivorespiratory viral infections using focused and unbiased approaches. Fully differentiated paediatric HAE exhibited an increasing induction level of genes related to mucociliary clearance, while higher expression of innate immune pathways was found in the ones from adults. While similar viral replication kinetics in both age groups were shown for SARS-CoV-2, Influenza A Virus (IAV), RSV and Rhinovirus (RV) infection, transcriptomic analysis showed stronger and earlier induction of IFN-related pathways in SARS-CoV-2-infected HAE from children compared to IAV, RSV and RV. IAV and RSV had the weakest innate immune response increase in HAE from children versus adults. RV infection showed an intermediate pattern, resembling SARS-CoV-2 more than RSV or IAV. Our work demonstrates a distinct sensing of SARS-CoV-2 compared to other respiratory virusesex vivo, which may contribute to the milder course of disease in SARS-CoV-2 infected children and argues for a role of early virus-HAE interaction in shaping viral pathogenesis. Furthermore, we show that innate immune responses towards respiratory viruses are virus-specific and differ between age groups. Hence, findings on SARS-CoV-2 cannot be extrapolated to other respiratory viruses.