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Here we describe upper respiratory tract (URT) and peripheral blood transcriptomes of 202 participants (age range of 1 week to 83 years), including 137 non-hospitalized individuals with mild SARS-CoV-2 infection and 65 healthy individuals. Among healthy children and adolescents, younger age is associated with higher URT expression of innate and adaptive immune pathways. SARS-CoV-2 infection induces broad upregulation of URT innate and adaptive immune responses among children and adolescents. Peripheral blood responses among SARS-CoV-2-infected children and adolescents are dominated by interferon pathways, while upregulation of myeloid activation, inflammatory, and coagulation pathways is observed only in adults. Among SARS-CoV-2-infected individuals, fever is associated with blunted URT immune responses and more pronounced systemic immune activation. These findings demonstrate that immune responses to SARS-CoV-2 differ across the lifespan, from distinct signatures in childhood and adolescence to age-associated alterations in adults.<\/jats:p>","DOI":"10.1038\/s41467-025-57655-3","type":"journal-article","created":{"date-parts":[[2025,3,10]],"date-time":"2025-03-10T14:47:52Z","timestamp":1741618072000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Age-associated differences in mucosal and systemic host responses to SARS-CoV-2 infection"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5079-9920","authenticated-orcid":false,"given":"Jillian H.","family":"Hurst","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aditya A.","family":"Mohan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6319-5253","authenticated-orcid":false,"given":"Trisha","family":"Dalapati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian A.","family":"George","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jhoanna N.","family":"Aquino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debra J.","family":"Lugo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trevor S.","family":"Pfeiffer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"Rodriguez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4406-2276","authenticated-orcid":false,"given":"Alexandre T.","family":"Rotta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0650-4894","authenticated-orcid":false,"given":"Nicholas A.","family":"Turner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0592-5822","authenticated-orcid":false,"given":"Thomas W.","family":"Burke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8034-1136","authenticated-orcid":false,"given":"Micah T.","family":"McClain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4980-845X","authenticated-orcid":false,"given":"Ricardo","family":"Henao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. 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K.M.W. held a sponsored research project from Moderna Therapeutics, Inc. on immune correlates of congenital CMV infection. C.W.W. is a consultant for and owns equity in Biomeme, Inc. M.S.K. is a consultant for Merck & Co, Inc. and Invivyd. N.A.T. has received research contracts with PDI, Purio, and Basilea as well as consulting for Techspert. A.M. is a consultant for Merck, Pfizer, Moderna, Astra-Zeneca, Enanta, and Sanofi-Pasteur. O.R. has received research grants from the Bill & Melinda Gates Foundation, Merck, and Janssen; fees for participation in advisory boards from Merck, Sanofi-Pasteur, Pfizer, and Moderna; and fees for lectures from Pfizer, AstraZeneca, Merck, and Sanofi-Pasteur. All other authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"2383"}}