The long reach of influenza and other respiratory viruses: from acute epithelial injury to post-viral lung disease

SUMMARY Respiratory viral infections cause extensive cell death in the lung epithelium, resulting from both direct viral action and exuberant immune responses. Recovery following viral infection requires rapid and coordinated repair programs, ensuring the replacement of the damaged tissue through proliferation, migration, and differentiation of respiratory epithelial progenitor cells. Viral infection and the resulting inflammatory milieu alter host gene expression. Notably, growing evidence indicates that these infections can induce long-term changes in epithelial progenitor cells, which persist even after the infection has resolved. These alterations may play a key role in the development of post-viral lung disease (PVLD). In this review, we discuss current knowledge regarding respiratory viral infections and how these may alter the gene expression and function of epithelial progeny cells arising from the surviving progenitors. We do so by exploring the influenza virus as an example and comparing it with what is known about other important respiratory viruses, such as respiratory syncytial virus (RSV), rhinovirus (HRV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV2). We highlight the impact of respiratory viral infection and ensuing inflammation on lung epithelial memory, considering the importance of viral strains, and discuss potential new therapeutic strategies that could maximize long-term lung health.