AI Article Synopsis
- Post-acute sequelae of COVID-19 (PASC) refers to a range of ongoing respiratory symptoms and conditions that persist long after the initial SARS-CoV-2 infection, with the underlying lung changes still not fully understood.
- The study investigated lung changes in SARS-CoV-2 infected hamsters, comparing them with H1N1 infections, and found significant lung damage including inflammation, fibrosis, and persistent alveolar-bronchiolization linked to the activation of specific cell pathways.
- Findings suggest that sustained Notch signaling and the abnormal growth of certain lung cells during tissue healing may lead to ongoing respiratory issues, emphasizing the importance of monitoring and managing these conditions in individuals recovering from COVID-19.
Article Abstract
Background: Post-acute sequalae of COVID-19 defines a wide range of ongoing symptoms and conditions long after SARS-CoV-2 infection including respiratory diseases. The histopathological changes in the lung and underlying mechanism remain elusive.
Methods: We investigated lung histopathological and transcriptional changes in SARS-CoV-2-infected male hamsters at 7, 14, 42, 84 and 120dpi, and compared with A (H1N1)pdm09 infection.
Findings: We demonstrated viral residue, inflammatory and fibrotic changes in lung after SARS-CoV-2 but not H1N1 infection. The most prominent histopathological lesion was multifocal alveolar-bronchiolization observed in every SARS-CoV-2 infected hamster (31/31), from 42dpi to 120dpi. Proliferating (Ki67+) CK14+ basal cells accumulated in alveoli adjacent to bronchioles at 7dpi, where they proliferated and differentiated into SCGB1A+ club cell or Tubulin+ ciliated cells forming alveolar-bronchiolization foci. Molecularly, Notch pathway significantly upregulated with intensive Notch3 and Hes1 protein expression in alveolar-bronchiolization foci at 42 and 120dpi, suggesting Notch signaling involving the persistence of alveolar-bronchiolization. This is further demonstrated by spatial transcriptomic analysis. Intriguingly, significant upregulation of some cell-growth promoting pathways and genes such as Tubb4b, Stxbp4, Grb14 and Mlf1 were spatially overlapping with bronchiolization lesion.
Interpretation: Incomplete resolution of SARS-CoV-2 infection in lung with viral residue, chronic inflammatory and fibrotic damage and alveolar-bronchiolization impaired respiratory function. Aberrant activation of CK14+ basal cells during tissue regeneration led to persistent alveolar-bronchiolization due to sustained Notch signaling. This study advances our understanding of respiratory PASC, sheds light on disease management and highlights the necessity for monitoring disease progression in people with respiratory PASC.
Funding: Funding is listed in the Acknowledgements section.
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Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11470415 | PMC |
| http://dx.doi.org/10.1016/j.ebiom.2024.105363 | DOI Listing |
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