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; Priestnall, S L; Hartmann, R; Wack, A

Abstract

Interferons (IFNs) are central to antiviral immunity. Viral recognition elicits IFN production, which in turn triggers the transcription of IFN-stimulated genes (ISGs), which engage in various antiviral functions. Type I IFNs (IFN-α and IFN-β) are widely expressed and can result in immunopathology during viral infections. By contrast, type III IFN (IFN-λ) responses are primarily restricted to mucosal surfaces and are thought to confer antiviral protection without driving damaging proinflammatory responses. Accordingly, IFN-λ has been proposed as a therapeutic in coronavirus disease 2019 (COVID-19) and other such viral respiratory diseases (see the Perspective by Grajales-Reyes and Colonna). Broggi et al. report that COVID-19 patient morbidity correlates with the high expression of type I and III IFNs in the lung. Furthermore, IFN-λ secreted by dendritic cells in the lungs of mice exposed to synthetic viral RNA causes damage to the lung epithelium, which increases susceptibility to lethal bacterial superinfections. Similarly, using a mouse model of influenza infection, Major et al. found that IFN signaling (especially IFN-λ) hampers lung repair by inducing p53 and inhibiting epithelial proliferation and differentiation. Complicating this picture, Hadjadj et al. observed that peripheral blood immune cells from severe and critical COVID-19 patients have diminished type I IFN and enhanced proinflammatory interleukin-6– and tumor necrosis factor-α–fueled responses. This suggests that in contrast to local production, systemic production of IFNs may be beneficial. The results of this trio of studies suggest that the location, timing, and duration of IFN exposure are critical parameters underlying the success or failure of therapeutics for viral respiratory infections.

Citation

Major, J., Crotta, S., Llorian, M., McCabe, T. M., Gad, H. H., Priestnall, S. L., Hartmann, R., & Wack, A. (2020). Type I and III interferons disrupt lung epithelial repair during recovery from viral infection. Science, 369(6504), 712-717. https://doi.org/10.1126/science.abc2061

• Journal Article Type: Article
• Acceptance Date: Jun 8, 2020
• Publication Date: Aug 7, 2020
• Deposit Date: Sep 8, 2020
• Publicly Available Date: Sep 8, 2020
• Journal: Science
• Print ISSN: 0036-8075
• Electronic ISSN: 1095-9203
• Publisher: American Association for the Advancement of Science
• Peer Reviewed: Peer Reviewed
• Volume: 369
• Issue: 6504
• Pages: 712-717
• DOI: https://doi.org/10.1126/science.abc2061
• Public URL: https://rvc-repository.worktribe.com/output/1376323
• Publisher URL: https://doi.org/10.1126/science.abc2061