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

• Published in: Science (American Association for the Advancement of Science) Vol. 369; no. 6504; pp. 712 - 717
• Main Authors: Major, Jack, Crotta, Stefania, Llorian, Miriam, McCabe, Teresa M, Gad, Hans Henrik, Priestnall, Simon L, Hartmann, Rune, Wack, Andreas
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 07-08-2020; American Association for the Advancement of Science
• Subjects: Alveolar Epithelial Cells - immunology; Alveolar Epithelial Cells - pathology; Animals; Apoptosis; Bronchoalveolar Lavage Fluid - immunology; Cell Differentiation; Cell Proliferation; Cells, Cultured; Coronaviridae; Coronaviruses; COVID-19; Cytokines; Cytokines - administration & dosage; Cytokines - immunology; Cytokines - metabolism; Damage; Differentiation; Epithelium; Failure; Female; Immune system; Immunity; Immunology; Individualized Instruction; Infections; Influenza; Influenza A Virus, H3N2 Subtype; Interferon; Interferon Type I - administration & dosage; Interferon Type I - metabolism; Interferon Type I - pharmacology; Interferon-alpha - administration & dosage; Interferon-alpha - metabolism; Interferon-alpha - pharmacology; Interferon-beta - administration & dosage; Interferon-beta - metabolism; Interferon-beta - pharmacology; Interferons - administration & dosage; Interferons - metabolism; Interferons - pharmacology; Interleukins; Lung - pathology; Lungs; Male; Mice; Microbio; Orthomyxoviridae Infections - immunology; Orthomyxoviridae Infections - metabolism; Orthomyxoviridae Infections - pathology; Parameters; Receptor, Interferon alpha-beta - genetics; Receptor, Interferon alpha-beta - metabolism; Receptors, Interferon - genetics; Receptors, Interferon - metabolism; Recovery; Regeneration; Repair; Respiratory diseases; Signal Transduction; Signaling; Tumor Suppressor Protein p53 - metabolism; Viral diseases; Viral infections
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.abc2061

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).