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The goal of this study was to better understand the regulation of innate IFN\u2010lambda responses in vitro in primary human infant airway epithelial cells (AECs) and in vivo using nasal aspirates during viral respiratory infections.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>IFN\u2010lambda protein levels were quantified: (a) in human infant AECs exposed to (poly(I:C) dsRNA) under different experimental conditions (n\u00a0=\u00a08 donors); and (b) in nasal aspirates of young children (\u22643\u00a0years) hospitalized with viral respiratory infection (n\u00a0=\u00a0138) and in uninfected controls (n\u00a0=\u00a074). In vivo IFN\u2010lambda airway levels during viral infections were correlated with individual characteristics and respiratory disease parameters.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Our in vitro experiments showed that the poly(I:C)\u2010induced innate production of IFN lambda in human infant AECs is regulated by (a) p38\u2010MAPK\/NF\u2010kB dependent mechanism; and (b) exposure to pro\u2010inflammatory signals such as IL1\u03b2. Our in vivo studies demonstrated that (a) infants (&lt;18\u00a0months) had higher virus\u2010induced IFN\u2010lambda airway secretion; (b) subjects with RSV infection showed the highest IFN\u2010lambda airway levels; and (c) individuals with the highest virus\u2010induced IFN\u2010lambda levels (&gt;90th percentile) had higher viral loads and were more likely to have respiratory sick visits within 12\u00a0months of discharge (OR\u00a0=\u00a05.8).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>IFN\u2010lambda responses to dsRNA in the human infant airway epithelium are regulated by p38\u2010MAPK and NF\u2010kB signalling. High in vivo IFN\u2010lambda production is influenced by virus type and associated with recurrent respiratory sick visits in young children.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cea.13701","type":"journal-article","created":{"date-parts":[[2020,7,5]],"date-time":"2020-07-05T08:27:00Z","timestamp":1593937620000},"page":"1044-1054","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Innate IFN\u2010lambda responses to dsRNA in the human infant airway epithelium and clinical regulatory factors during viral respiratory infections in early life"],"prefix":"10.1111","volume":"50","author":[{"given":"Kyle","family":"Salka","sequence":"first","affiliation":[{"name":"Division of Pediatric Pulmonary and Sleep Medicine. Children\u2019s National Medical Center George Washington University Washington DC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Arroyo","sequence":"additional","affiliation":[{"name":"Division of Pediatric Pulmonary and Sleep Medicine. Children\u2019s National Medical Center George Washington University Washington DC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Chorvinsky","sequence":"additional","affiliation":[{"name":"Division of Pediatric Pulmonary and Sleep Medicine. Children\u2019s National Medical Center George Washington University Washington DC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karima","family":"Abutaleb","sequence":"additional","affiliation":[{"name":"Division of Pediatric Pulmonary and Sleep Medicine. 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Children\u2019s National Medical Center George Washington University Washington DC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jered","family":"Weinstock","sequence":"additional","affiliation":[{"name":"Division of Pediatric Pulmonary and Sleep Medicine. Children\u2019s National Medical Center George Washington University Washington DC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria J.","family":"Gutierrez","sequence":"additional","affiliation":[{"name":"Division of Pediatric Allergy and Immunology Johns Hopkins University Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcos","family":"P\u00e9rez\u2010Losada","sequence":"additional","affiliation":[{"name":"Computational Biology Institute Department of Biostatistics and Bioinformatics Milken Institute School of Public Health George Washington University Washington DC USA"},{"name":"CIBIO\u2010InBIO Centro de Investiga\u00e7\u00e3o em Biodiversidade e Recursos Gen\u00e9ticos Universidade do Porto Vair\u00e3o Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dinesh K.","family":"Pillai","sequence":"additional","affiliation":[{"name":"Division of Pediatric Pulmonary and Sleep Medicine. 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