{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T15:19:52Z","timestamp":1783091992242,"version":"3.54.6"},"reference-count":150,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T00:00:00Z","timestamp":1783036800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The concurrent circulation of influenza A virus (IAV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has unveiled complex host\u2013pathogen interactions governed by temporal dynamics of innate immune activation. This narrative review synthesizes evidence from human air\u2013liquid interface (ALI) epithelial models, animal studies (hamster, ferret), clinical cohorts, and randomized controlled trials (2015\u20132026) to delineate the molecular mechanisms underlying viral interference between these two major respiratory pathogens. Prior IAV infection induces a robust type I\/III interferon (IFN) response and broad interferon-stimulated gene (ISG) upregulation that restricts subsequent SARS-CoV-2 replication within a critical 24\u201372 h temporal window. Conversely, SARS-CoV-2 employs a multi-layered immune evasion strategy that blunts IFN induction, providing minimal heterologous protection. Simultaneous co-infection tends to exacerbate disease severity. Host genetic determinants, including OAS1 and TLR7 variants, modulate interference capacity. Therapeutically, early pegylated IFN-\u03bb shows clinical benefit, while experimental evidence from in vitro and animal models suggests oseltamivir may paradoxically reduce IAV-induced interference. These findings underscore the need for multi-pathogen diagnostics, temporally informed clinical decision-making, and IFN-based therapeutic strategies during co-circulation periods.<\/jats:p>","DOI":"10.3390\/ijms27135994","type":"journal-article","created":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T14:33:06Z","timestamp":1783089186000},"page":"5994","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Temporal Dynamics of Innate Immune Activation and Viral Interference During Sequential Co-Infection with Influenza A Virus and SARS-CoV-2: Molecular Mechanisms, Clinical Evidence, and Therapeutic Implications"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1907-3632","authenticated-orcid":false,"given":"Jaime","family":"Angamarca-Iguago","sequence":"first","affiliation":[{"name":"Facultad de Ciencias de la Salud y Bienestar Humano, Universidad Tecnol\u00f3gica Indoam\u00e9rica, Ambato 180150, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5223-3370","authenticated-orcid":false,"given":"Juan Marcos","family":"Parise-Vasco","sequence":"additional","affiliation":[{"name":"Facultad de Ciencias de la Salud y Bienestar Humano, Universidad Tecnol\u00f3gica Indoam\u00e9rica, Ambato 180150, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-4234-5524","authenticated-orcid":false,"given":"Claudia","family":"Reytor-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Facultad de Ciencias de la Salud y Bienestar Humano, Universidad Tecnol\u00f3gica Indoam\u00e9rica, Ambato 180150, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaen","family":"Cagua-Ordo\u00f1ez","sequence":"additional","affiliation":[{"name":"Facultad de Ciencias de la Salud y Bienestar Humano, Universidad Tecnol\u00f3gica Indoam\u00e9rica, Ambato 180150, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3641-1501","authenticated-orcid":false,"given":"Daniel","family":"Simancas-Racines","sequence":"additional","affiliation":[{"name":"Facultad de Ciencias de la Salud y Bienestar Humano, Universidad Tecnol\u00f3gica Indoam\u00e9rica, Ambato 180150, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1038\/s41579-020-00468-6","article-title":"Coronavirus Biology and Replication: Implications for SARS-CoV-2","volume":"19","author":"Kratzel","year":"2021","journal-title":"Nat. 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