Airway Epithelial SARS-CoV-2 Infectious and Repair Responses: Relationships to Age, Sex, and Post-COVID Pulmonary Syndromes

Dang, H.; Edwards, C. E.; Kato, T.; Reidel, B.; Meganck, R. M.; Esther, C. R.; Ehre, C.; Fulcher, M. L.; Bailey, A. B.; Cooley, M. R.; Mikami, Y.; Asakura, T.; Hawkins, P. E.; Saito, M.; Meyers, J. L.; Konopka, K.; Gerayeli, F. V.; Park, H. Y.; Sin, D. D.; Livraghi-Butrico, A.; Okuda, K.; Pickles, R. J.; Klein, S. L.; Randell, S. H.; O'Neal, W. K.; Baric, R. S.; Boucher, R. C.

doi:10.1101/2025.07.17.663733

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bioRxiv · 10.1101/2025.07.17.663733

Airway Epithelial SARS-CoV-2 Infectious and Repair Responses: Relationships to Age, Sex, and Post-COVID Pulmonary Syndromes

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Abstract

The long-term pulmonary sequelae of SARS-CoV-2 respiratory infections reflect infection severity, innate and adaptive immunity, and respiratory epithelial repair. This study investigated the acute and reparative responses as a function of age and sex in primary human bronchial epithelial (HBE) cultures utilizing a 14-day SARS-CoV-2 infection protocol. SARS-CoV-2 infection peaked at 3 days post-infection (dpi) with an [~] 2 log titer suppression at 14 dpi. SARS-CoV-2 infection induced interferon, interferon-induced gene, and cell damage responses. No age- or sex-dependent effects on SARS-CoV-2 infection were detected. Airway epithelia repaired to an abnormal mucus metaplastic/inflammatory state that reflected potentially beneficial and adverse consequences at 14 dpi. Repair processes were infection severity-dependent, not sex-dependent, and were more robust in young donor cultures. Analyses of long-COVID subjects with persistent pulmonary fibrosis or persistent bronchitic airway diseases exhibited expression of HBE 14 dpi failed repair gene signatures, including ISG gene signatures. Human airway epithelial repair post-SARS-CoV-2 is prolonged and incomplete in vitro over 14 days, and persistently abnormal repair may contribute to phenotypes of people with long-COVID pulmonary syndrome.

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Dang, H., Edwards, C. E., Kato, T., Reidel, B., Meganck, R. M., Esther, C. R., Ehre, C., Fulcher, M. L., Bailey, A. B., Cooley, M. R., Mikami, Y., Asakura, T., Hawkins, P. E., Saito, M., Meyers, J. L., Konopka, K., Gerayeli, F. V., Park, H. Y., Sin, D. D., Livraghi-Butrico, A., Okuda, K., Pickles, R. J., Klein, S. L., Randell, S. H., O'Neal, W. K., Baric, R. S., Boucher, R. C.. 2025-07-17. Airway Epithelial SARS-CoV-2 Infectious and Repair Responses: Relationships to Age, Sex, and Post-COVID Pulmonary Syndromes. https://doi.org/10.1101/2025.07.17.663733

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