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To evaluate the role of nasal viruses and bacteria in driving these responses, we performed cytokine profiling and comprehensive, symptom-agnostic testing for respiratory viruses and bacterial pathobionts in nasopharyngeal samples from children tested for SARS-CoV-2 in 2021\u201322 (n = 467). Respiratory viruses and\/or pathobionts were highly prevalent (82% of symptomatic and 30% asymptomatic children; 90 and 49% for children &amp;lt;5 years). Virus detection and load correlated with the nasal interferon response biomarker CXCL10, and the previously reported discrepancy between SARS-CoV-2 viral load and nasal interferon response was explained by viral coinfections. Bacterial pathobionts correlated with a distinct proinflammatory response with elevated IL-1\u03b2 and TNF but not CXCL10. Furthermore, paired samples from healthy 1-year-olds collected 1\u20132 wk apart revealed frequent respiratory virus acquisition or clearance, with mucosal immunophenotype changing in parallel. These findings reveal that frequent, dynamic host\u2013pathogen interactions drive nasal innate immune activation in children.<\/jats:p>","DOI":"10.1084\/jem.20230911","type":"journal-article","created":{"date-parts":[[2024,6,13]],"date-time":"2024-06-13T02:20:58Z","timestamp":1718245258000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":20,"title":["High burden of viruses and bacterial pathobionts drives heightened nasal innate immunity in children"],"prefix":"10.1084","volume":"221","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1607-1335","authenticated-orcid":true,"given":"Timothy A.","family":"Watkins","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03pnmqc26","id-type":"ROR","asserted-by":"publisher"}],"name":"Yale School of Medicine 1 Department of Laboratory Medicine, , New Haven, CT, USA"},{"id":[{"id":"https:\/\/ror.org\/03pnmqc26","id-type":"ROR","asserted-by":"publisher"}],"name":"Yale 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