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Despite similar viral load and infectivity rates between children and adults, children rarely develop severe illness. Differences in the host response to the virus at the primary infection site are among the mechanisms proposed to account for this disparity. Our objective was to investigate the host response to SARS-CoV-2 in the nasal mucosa in children and adults and compare it with the host response to respiratory syncytial virus (RSV) and influenza virus. We analyzed clinical outcomes and gene expression in the nasal mucosa of 36 children with SARS-CoV-2, 24 children with RSV, 9 children with influenza virus, 16 adults with SARS-CoV-2, and 7 healthy pediatric and 13 healthy adult controls. In both children and adults, infection with SARS-CoV-2 led to an IFN response in the nasal mucosa. The magnitude of the IFN response correlated with the abundance of viral reads, not the severity of illness, and was comparable between children and adults infected with SARS-CoV-2 and children with severe RSV infection. Expression of ACE2 and TMPRSS2 did not correlate with age or presence of viral infection. SARS-CoV-2\u2013infected adults had increased expression of genes involved in neutrophil activation and T-cell receptor signaling pathways compared with SARS-CoV-2\u2013infected children, despite similar severity of illness and viral reads. Age-related differences in the immune response to SARS-CoV-2 may place adults at increased risk of developing severe illness.<\/jats:p>","DOI":"10.1165\/rcmb.2021-0292oc","type":"journal-article","created":{"date-parts":[[2021,11,3]],"date-time":"2021-11-03T18:46:42Z","timestamp":1635965202000},"page":"206-222","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":47,"title":["Age-related Differences in the Nasal Mucosal Immune Response to SARS-CoV-2"],"prefix":"10.1093","volume":"66","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7424-6009","authenticated-orcid":false,"given":"Clarissa M.","family":"Koch","sequence":"first","affiliation":[{"name":"Department of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4454-5152","authenticated-orcid":false,"given":"Andrew D.","family":"Prigge","sequence":"additional","affiliation":[{"name":"Department of Pediatrics"},{"name":"Ann & Robert H. 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