IFN-γ is a pleiotropic cytokine made by many cells, including T lymphocytes. IFN-γ is best known for its ability to stimulate phagocyte killing of intracellular microbes. In addition, IFN-γ instructs cells to take on stable new phenotypes. For example, during acute respiratory infection, IFN-γ signaling to alveolar macrophages induces a new trained immunity state that persists indefinitely and improves lung immune defense against diverse microbes (14). Lin et al. (10) show that, after IAV infection, IFN-γ signaling to lung epithelium leads to a dysfunctional phenotype (dysplastic distal Krt5+ epithelial cells) as well as histopathological, biochemical, and physiological signs of lung fibrosis (10). Therefore, IFN-γ signaling to lung epithelial cells is highly pathogenic in this setting. Other recent reports identify prolonged IFN-γ release (15) and elevated IFN-γ signaling in the lung (16) as hallmarks of patients with long COVID. Blocking IFN-γ diminishes chronic inflammation and fibrosis in mice struggling to recover from SARS-CoV-2 infection (16). Altogether, converging lines of evidence suggest that IFN-γ seems to mediate at least some postacute sequelae of pneumonia. IFN-γ induction occurs during a wide variety of lung infections, most of which do not reliably cause postacute sequelae. It will be important for future studies to identify the factors that determine whether IFN-γ signaling to lung epithelial cells is detrimental or not. The amount and/or duration of IFN-γ may be key. In addition, IFN-γ signaling pathways may interact with other signaling pathways induced by infections to yield pathologic outcomes. Other signals involved in IAV-induced parenchymal Krt5+ cells include hypoxia-inducible factor 1α (HIF-1α) and Notch (17).

YAP and TAZ are important modulators of lung epithelial biology. Aberrant epithelial cells in fibrotic lungs are characterized by high levels of YAP/TAZ signaling (18, 19). Increasing YAP/TAZ activity, by deleting Hippo kinases in alveolar type 2 (AT2) cells (20) or by overexpressing a constitutively active form of YAP in AT2 cells (21), is sufficient to form aberrant epithelial cells in the mouse lung. Therefore, excessive YAP/TAZ in alveolar epithelial cells is harmful. However, after injury (from pneumococcal infection, bacterial lipopolysaccharide, or bleomycin), the combined absence of YAP and TAZ in AT2 cells consistently exaggerates inflammation and slows repair, worsening pathophysiology (22–24). Thus, YAP and/or TAZ in AT2 cells facilitates healthy responses to injury. In the bleomycin injury model, AT2 cell deletion of TAZ phenocopies the deletion of YAP and TAZ together; however, AT2 cell deletion of YAP has the opposite effect, diminishing inflammation and fibrosis (24). Considering that interruption of epithelial YAP while TAZ is maintained diminishes pulmonary pathophysiology after bleomycin injury (24) and curbs Krt5+ epithelial cells after IAV infection (10), it seems that YAP in lung epithelial cells has roles distinct from TAZ that are pathogenic in settings of injury. Future studies should determine the mechanisms by which epithelial YAP drives unhealthy outcomes including the emergence of distal Krt5+ cells.

The study by Lin et al. (10) provides insights into the development of aberrant epithelial cells that associate with and may contribute to lung disease, particularly postacute fibrotic sequelae of pneumonia. These findings suggest that disrupting signaling by IFN-γ, YAP, or the kinases connecting the IFN-γ receptor to YAP could potentially prove beneficial for some subsets of patients with or at risk of postacute sequelae of pneumonia. However, IFN-γ and YAP have important roles in immune defense and epithelial biology, and more precise understanding of which individuals have excessive or inappropriate IFN-γ or YAP signaling would be needed before such experimental approaches can be rationally considered.