{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T19:53:55Z","timestamp":1792785235155,"version":"4.5.0"},"reference-count":40,"publisher":"National Academy of Sciences","issue":"39","license":[{"start":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T00:00:00Z","timestamp":1789948800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"MOST | National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["22222611"],"award-info":[{"award-number":["22222611"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Strategic Priority Research Program of the Chinese Academy of Science","award":["XDB0750300"],"award-info":[{"award-number":["XDB0750300"]}],"id":[{"id":"https:\/\/ror.org\/034t30j35","id-type":"ROR","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"MOST | National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["U24A20771"],"award-info":[{"award-number":["U24A20771"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,9,29]]},"abstract":"<jats:p>Perfluorooctane sulfonate (PFOS), a prominent per- and polyfluoroalkyl substance (PFAS), has raised significant public health concerns due to its widespread use, environmental persistence, and bioaccumulation potential. Both epidemiological and experimental studies demonstrate that PFOS exposure causes immunotoxicity and disrupts both innate and adaptive immunity. However, the specific effects of PFOS on innate antiviral immunity remain poorly understood. Here, by integrating multi-omics analysis with in vitro and in vivo studies, we establish that PFOS exposure at subtoxic doses compromises antiviral defense by suppressing type I interferon production, thereby enhancing the replication of a broad range of viruses. Mechanistically, PFOS interacts with IRF3 at Val319, Asp328, and Arg341, inducing conformational changes that disrupt the TBK1\u2013IRF3 interaction. This disruption inhibits subsequent IRF3 phosphorylation, dimerization, and nuclear translocation, which in turn suppresses type I interferon production and facilitates viral replication. Additionally, wild-type IRF3, but not a binding-deficient mutant, restores PFOS-mediated suppression of innate antiviral immunity in IRF3-deficient cells or knockout mice. Furthermore, association studies in patients with respiratory syncytial virus, influenza, or hepatitis B virus infection showed that elevated serum PFOS levels are correlated with increased viral loads, as indicated by lower Ct values or higher HBV DNA levels. Similarly, NHANES data link higher serum PFOS to lower vaccine antibody levels. Together, our results demonstrate that PFOS directly targets IRF3 to impair innate antiviral immunity, thereby enhancing host susceptibility to viral infection at environmental exposure levels.<\/jats:p>","DOI":"10.1073\/pnas.2536274123","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T19:12:05Z","timestamp":1790017925000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Perfluorooctane sulfonate directly interacts with IRF3 to attenuate antiviral innate immunity"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7220-0349","authenticated-orcid":false,"given":"Qiuju","family":"Liang","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/034t30j35","id-type":"ROR","asserted-by":"publisher"}],"name":"State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of 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S. E. P. Agency Maximum contaminant level goals for Perfluorooctanoic Acid (PFOA) and Perfluorooctane Sulfonic Acid (PFOS) in drinking water (EPA-815-R-24-010) (2024) [Accessed 24 April 2025]."},{"key":"e_1_3_4_22_2","article-title":"Risk to human health related to the presence of perfluorooctane sulfonic acid and perfluorooctanoic acid in food [J]","volume":"16","author":"EFSA Panel on Contaminants in the Food Chain (CONTAM)","year":"2018","unstructured":"EFSA Panel on Contaminants in the Food Chain (CONTAM), H. K. Knutsen , Risk to human health related to the presence of perfluorooctane sulfonic acid and perfluorooctanoic acid in food [J]. 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J. Liang Transcriptome analysis of mouse lungs following environmentally relevant low-dose PFOS exposure in mice. Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE312025. Deposited 1 December 2025."},{"key":"e_1_3_4_40_2","unstructured":"Q. J. Liang M. Gao Multi-omics analysis reveals PFOS-induced disruption of pulmonary immune homeostasis and antiviral defense networks. iProX. https:\/\/proteomecentral.proteomexchange.org\/cgi\/GetDataset?ID=PXD071691. Deposited 6 December 2025."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2536274123","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T19:12:55Z","timestamp":1790017975000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2536274123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,21]]},"references-count":40,"journal-issue":{"issue":"39","published-print":{"date-parts":[[2026,9,29]]}},"alternative-id":["10.1073\/pnas.2536274123"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2536274123","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,21]]},"assertion":[{"value":"2025-12-12","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-24","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-21","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2536274123"}}