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

Jack Major,Teresa M Mccabe,Andreas Wack,Hans Henrik Gad,Simon L Priestnall,Stefania Crotta,Rune Hartmann,Miriam Llorian

doi:10.1126/science.abc2061

Abstract

Excessive cytokine signaling frequently exacerbates lung tissue damage during respiratory viral infection. Type I (IFN-α and IFN-β) and III (IFN-λ) interferons are host-produced antiviral cytokines. Prolonged IFN-α and IFN-β responses can lead to harmful proinflammatory effects, whereas IFN-λ mainly signals in epithelia, thereby inducing localized antiviral immunity. In this work, we show that IFN signaling interferes with lung repair during influenza recovery in mice, with IFN-λ driving these effects most potently. IFN-induced protein p53 directly reduces epithelial proliferation and differentiation, which increases disease severity and susceptibility to bacterial superinfections. Thus, excessive or prolonged IFN production aggravates viral infection by impairing lung epithelial regeneration. Timing and duration are therefore critical parameters of endogenous IFN action and should be considered carefully for IFN therapeutic strategies against viral infections such as influenza and coronavirus disease 2019 (COVID-19).

Highlights

During infection with respiratory viruses, disease severity is linked to lung epithelial destruction, owing to both cytopathic viral effects and immune-mediated damage
Because of widespread expression of the type I IFN receptor (IFNAR) in immune cells, IFN-a/b responses can result in immunopathology during viral infections, including influenza virus and severe acute respiratory syndrome–coronavirus 1 (SARS-CoV-1) [1,2,3,4]
The IFN-l receptor (IFNLR) is mainly expressed at epithelial barriers, and IFN-l responses are often characterized by their ability to confer localized antiviral protection at the site of infection without driving damaging proinflammatory responses like those associated with IFN-a/b

Summary

Introduction

During infection with respiratory viruses, disease severity is linked to lung epithelial destruction, owing to both cytopathic viral effects and immune-mediated damage. To further investigate the dynamics of lung repair after influenza virus infection, epithelial cell proliferation was analyzed by flow cytometry using the proliferation marker Ki67 To compare the effects of equipotent amounts of IFN-a, IFN-b, and IFN-l on lung repair, mice were treated during recovery from influenza virus infection Both IFN-a and IFN-b treatments significantly reduced the proliferation of AT2 cells on day 11 after influenza virus infection (Fig. 1C).

Results

Conclusion