Convergent hub pathways targeted by IAV, SARS-CoV-2, and RSV in type II alveolar epithelial cells: molecular mechanisms and therapeutic implications

DOI record: { "DOI": "10.3389/fimmu.2026.1781447", "ISSN": [ "1664-3224" ], "URL": "http://dx.doi.org/10.3389/fimmu.2026.1781447", "abstract": "<jats:p>Type II alveolar epithelial cells (AEC2s) maintain surfactant homeostasis, support distal-lung repair, and contribute to antiviral innate defense. Influenza A virus (IAV), SARS-CoV-2, and respiratory syncytial virus (RSV) use distinct entry receptors, yet severe disease is repeatedly marked by AEC2 dysfunction, alveolar barrier failure, and dysregulated inflammation. We synthesize cross-virus evidence for convergence on a small set of host hubs: innate sensing and interferon signaling, mitochondria-centered immunometabolism and oxidative stress, post-translational signaling modules, barrier and surfactant programs, and regulated cell-death checkpoints. We summarize structural and post-translational mechanisms by which viral proteins disrupt pattern recognition receptor (PRR)–mitochondrial antiviral signaling protein (MAVS) signaling, couple mitochondrial injury to weakened antiviral responses, and bias epithelial fate toward inflammatory lytic injury. Where AEC2-specific evidence is incomplete, especially for integrated PANoptosis-like programs, we label these elements as working models and highlight validation needs. We compare model systems used to study AEC2 infection, including ALI cultures, organoids, lung-on-chip platforms, and single-cell or network analyses. Finally, we discuss host-directed therapeutic opportunities along the cascade, separating near-term approaches from longer-term platform strategies such as targeted protein degradation and targeted nanodelivery, and noting constraints in distal-lung delivery, onset kinetics, and safety. This AEC2-centered convergence framework supports mechanism-driven interpretation of severe viral pneumonia and guides broader-spectrum intervention concepts.</jats:p>", "alternative-id": [ "10.3389/fimmu.2026.1781447" ], "article-number": "1781447", "author": [ { "affiliation": [ { "name": "Department of Clinical Laboratory, Wanbei Coal Electric Group General Hospital", "place": [ "Suzhou, China" ] } ], "family": "Zhang", "given": "Kaixuan", "sequence": "first" }, { "affiliation": [ { "name": "Department of Clinical Laboratory, Wanbei Coal Electric Group General Hospital", "place": [ "Suzhou, China" ] } ], "family": "Zhu", "given": "Sudi", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Clinical Laboratory, Wanbei Coal Electric Group General Hospital", "place": [ "Suzhou, China" ] } ], "family": "Zhang", "given": "Mengyu", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Clinical Laboratory, Wanbei Coal Electric Group General Hospital", "place": [ "Suzhou, China" ] } ], "family": "Hu", "given": "Henggui", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Clinical Laboratory, Wanbei Coal Electric Group General Hospital", "place": [ "Suzhou, China" ] } ], "family": "Qin", "given": "Shuguo", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Clinical Laboratory, Wanbei Coal Electric Group General Hospital", "place": [ "Suzhou, China" ] } ], "family": "Li", "given": "Huihui", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Clinical Laboratory, Wanbei Coal Electric Group General Hospital", "place": [ "Suzhou, China" ] } ], "family": "Zhao", "given": "Pingping", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Clinical Laboratory, Wanbei Coal Electric Group General Hospital", "place": [ "Suzhou, China" ] } ], "family": "Xu", "given": "Yuanyuan", "sequence": "additional" } ], "container-title": "Frontiers in Immunology", "container-title-short": "Front. Immunol.", "content-domain": { "crossmark-restriction": true, "domain": [ "frontiersin.org" ] }, "created": { "date-parts": [ [ 2026, 3, 11 ] ], "date-time": "2026-03-11T06:52:31Z", "timestamp": 1773211951000 }, "deposited": { "date-parts": [ [ 2026, 3, 11 ] ], "date-time": "2026-03-11T06:52:34Z", "timestamp": 1773211954000 }, "indexed": { "date-parts": [ [ 2026, 3, 11 ] ], "date-time": "2026-03-11T22:40:07Z", "timestamp": 1773268807219, "version": "3.50.1" }, "is-referenced-by-count": 0, "issued": { "date-parts": [ [ 2026, 3, 11 ] ] }, "license": [ { "URL": "https://creativecommons.org/licenses/by/4.0/", "content-version": "vor", "delay-in-days": 0, "start": { "date-parts": [ [ 2026, 3, 11 ] ], "date-time": "2026-03-11T00:00:00Z", "timestamp": 1773187200000 } } ], "link": [ { "URL": "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1781447/full", "content-type": "unspecified", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "1965", 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