Respiratory syncytial virus activates epidermal growth factor receptor to suppress interferon regulatory factor 1-dependent interferon-lambda and antiviral defense in airway epithelium

• Published in: Mucosal immunology Vol. 11; no. 3; pp. 958 - 967
• Main Authors: Kalinowski, A, Galen, B T, Ueki, I F, Sun, Y, Mulenos, A, Osafo-Addo, A, Clark, B, Joerns, J, Liu, W, Nadel, J A, Dela Cruz, C S, Koff, J L
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.05.2018; Elsevier Limited
• Subjects: Allergology; Antibodies; Antigens, Viral - immunology; Biomedical and Life Sciences; Biomedicine; Cell Line; Cytokines - metabolism; Down-Regulation; Epidermal growth factor; Epidermal growth factor receptors; Epithelium; ErbB Receptors - genetics; ErbB Receptors - metabolism; F protein; Gastroenterology; Humans; Immune response; Immunity; Immunology; Infections; Interferon; Interferon regulatory factor; Interferon regulatory factor 1; Interferon Regulatory Factor-1 - metabolism; Lung diseases; Morbidity; Mucosal immunity; Protein-tyrosine kinase receptors; Respiratory Mucosa - pathology; Respiratory Mucosa - physiology; Respiratory Mucosa - virology; Respiratory syncytial virus; Respiratory Syncytial Virus Infections - immunology; Respiratory Syncytial Viruses - physiology; Respiratory tract diseases; Signal Transduction; Viral infections
• ISSN: 1933-0219; 1935-3456
• DOI: 10.1038/mi.2017.120

Respiratory syncytial virus (RSV) persists as a significant human pathogen that continues to contribute to morbidity and mortality. In children, RSV is the leading cause of lower respiratory tract infections, and in adults RSV causes pneumonia and contributes to exacerbations of chronic lung diseases. RSV induces airway epithelial inflammation by activation of the epidermal growth factor receptor (EGFR), a tyrosine kinase receptor. Recently, EGFR inhibition was shown to decrease RSV infection, but the mechanism(s) for this effect are not known. Interferon (IFN) signaling is critical for innate antiviral responses, and recent experiments have implicated IFN-λ (lambda), a type III IFN, as the most significant IFN for mucosal antiviral immune responses to RSV infection. However, a role for RSV-induced EGFR activation to suppress airway epithelial antiviral immunity has not been explored. Here, we show that RSV-induced EGFR activation suppresses IFN regulatory factor (IRF) 1-induced IFN-λ production and increased viral infection, and we implicate RSV F protein to mediate this effect. EGFR inhibition, during viral infection, augmented IRF1, IFN-λ, and decreased RSV titers. These results suggest a mechanism for EGFR inhibition to suppress RSV by activation of endogenous epithelial antiviral defenses, which may be a potential target for novel therapeutics.