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bioRxiv · 10.1101/2024.05.13.593878

Persistent lung inflammation and alveolar-bronchiolization due to Notch signaling dysregulation in SARS-CoV-2 infected hamster

Li, C.·Xiao, N.·Song, W.·Lam, A. H.-C.·Liu, F.·Cui, X.·Ye, Z.·Chen, Y.·Ren, P.·Cai, J.·Lee, A. C.-Y.·Chen, H.·Ou, Z.·Chan, J. F.-W.·Yuen, K.-Y.·Chu, H.·Zhang, A. J.-X.
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Abstract

Long COVID or Post-acute sequalae of COVID-19 (PASC) defines the persistent signs, symptoms, and conditions long after initial SARS-CoV-2 infection which affecting over 10% of COVID-19 patients, with 40% of them affecting respiratory system. The lung histopathological changes and underlying mechanism remain elusive. Here we systemically investigate histopathological and transcriptional changes at 7, 14, 42, 84 and 120 days-post-SARS-CoV-2-infection (dpi) in hamster. We demonstrate persistent viral residues, chronic inflammatory and fibrotic changes from 42dpi to 120dpi. The most prominent lung histopathological lesion is multifocal alveolar-bronchiolization observed in every animal from 14dpi until 120dpi. However, none of the above are observed in hamsters recovered from influenza A infection. We show airway progenitor CK14+ basal cells actively proliferate, differentiate into SCGB1A+ club cell or Tubulin+ ciliated cells, leading to alveolar-bronchiolization. Most importantly, Notch pathway is persistently upregulated. Intensive Notch3 and Hes1 protein expression are detected in alveolar-bronchiolization foci, suggesting the association of sustained Notch signaling with dysregulated lung regeneration. Lung spatial transcriptomics show upregulation of genes positively regulating Notch signaling is spatially overlapping with alveolar-bronchiolization region. To be noted, significant upregulation of tumor-related genes was detected in abnormal bronchiolization region by spatial transcriptomics analysis, indicating possible risk of lung carcinoma. Collectively, our data suggests SARS-CoV-2 infection caused chronic inflammatory and fibrotic tissue damages in hamster lung, sustained upregulation of Notch pathway signaling contributed to the dysregulated lung regeneration and CK14+ basal cells-driven alveolar-bronchiolization. The study provides important information for potential therapeutic approaches and probable long-term surveillance of malignancy in PASC management.

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Li, C., Xiao, N., Song, W., Lam, A. H.-C., Liu, F., Cui, X., Ye, Z., Chen, Y., Ren, P., Cai, J., Lee, A. C.-Y., Chen, H., Ou, Z., Chan, J. F.-W., Yuen, K.-Y., Chu, H., Zhang, A. J.-X.. 2024-05-13. Persistent lung inflammation and alveolar-bronchiolization due to Notch signaling dysregulation in SARS-CoV-2 infected hamster. https://doi.org/10.1101/2024.05.13.593878

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