Type I and III interferons disrupt lung epithelial repair during recovery from viral infection

Major, J.; Crotta, S.; Llorian, M.; McCabe, T. M.; Gad, H. H.; Hartmann, R.; Wack, A.

Excessive cytokine signalling frequently exacerbates lung tissue damage during respiratory viral infection. Type I and III interferons (IFN-α/β and IFN-λ) are host-produced antiviral cytokines and currently considered as COVID-19 therapy. Prolonged IFN-α/β responses can lead to harmful proinflammatory effects, whereas IFN-λ mainly signals in epithelia, inducing localised antiviral immunity. Here we show that IFN signalling interferes with lung repair during influenza recovery, with IFN-λ driving these effects most potently. IFN-induced p53 directly reduces epithelial proliferation and differentiation, increasing disease severity and susceptibility to bacterial superinfections. Hence, excessive or prolonged IFN-production aggravates viral infection by impairing lung epithelial regeneration. Therefore, timing and duration are critical parameters of endogenous IFN action, and should be considered carefully for IFN therapeutic strategies against viral infections like influenza and COVID-19. One Sentence Summary A novel IFN-mediated mechanism of immunopathology during respiratory virus infection by interference with lung tissue repair.