Perfluorooctane sulfonate directly interacts with IRF3 to attenuate antiviral innate immunity.

Authors

Qiuju Liang, Yun Li, Zeqing Sun, Longge Wang, Changying Li, Peiyu Fang, Qi Zhang, Juan Li, Xiaoyi Sun, Changguo Chen, Chu Wang, Guijie Guo, Ming Gao, Sijin Liu

Published in

Proceedings of the National Academy of Sciences of the United States of America. Volume 123. Issue 39. Pages e2536274123. Sep 29, 2026. Epub Sep 21, 2026.

Abstract

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-IRF3 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.

PMID:
42766748
Bibliographic data and abstract were imported from PubMed on 22 Sep 2026.

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