Dysplastic alveolar remodeling is characterized by the ectopic expansion of KRT5⁺ cells in the lung alveoli, forming a scar-like structure that persists in the injured alveoli and impedes normal alveolar epithelium regeneration. This remodeling response has been observed in patients following severe influenza or COVID-19 infection, as well as in experimental mouse models of respiratory viral infection. 

Interestingly, in other non-viral infection-induced lung injury settings, this dysplastic remodeling response is either weakly induced or not induced at all. The molecular mechanisms by which viral infection activates the formation of these cells, and how dysplastic cells maintain their cell fate in the lung alveoli, remain unclear.

In a study published in the Journal of Clinical Investigation, researchers from the Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology of the Chinese Academy of Sciences (CAS), and the Shanghai Institute of Immunity and Infection of CAS, found that virus infection-induced immune factor IFN-γ regulates the expansion of dysplastic KRT5⁺ cells through the Yes-associated protein 1 (YAP) axis.

By comparing the immune response between influenza A virus (IAV)- and bleomycin-injured lung tissues, researchers found that virus infection-induced IFN-γ plays a role in regulating dysplastic alveolar remodeling. Using Ifngr1 conditional Knockout and Yap conditional knockout mice, they confirmed that IFN-γ-Yap signaling is required for the expansion of dysplastic KRT5⁺ cells, and that disrupting IFN-γ-Yap signaling ameliorates lung fibrosis, reduces aberrant tuft cell and goblet cell formation, and improves lung recovery.

The long persistence of dysplastic cells in the alveoli hinders lung recovery and lays the groundwork for chronic diseases. Researchers successfully converted dysplastic KRT5⁺ cells into distal club cells, which can function as distal airway progenitor cells to repair injured lung alveoli by generating new alveolar type 2 cells (AT2s) through the inhibition of YAP in persistent dysplastic cells.

By analyzing single-cell RNA-seq data, human 3D organoid cultures, and immunofluorescence staining of lung tissues from COVID-19 patients, researchers found that dysplastic alveolar remodeling might also be regulated through IFN-γ-YAP signaling following SARS-CoV-2 infection.

This study reveals the role of immune-epithelial interactions in regulating dysplastic alveolar remodeling, and the underlying mechanism of "long COVID-19," suggesting a potential therapeutic target for controlling viral pneumonia-induced dysplastic alveolar remodeling in human lungs.