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

A. Kalinowski, B. T. Galen, I. F. Ueki, Y. Sun, A. Mulenos, A. Osafo-Addo, B. Clark, J. Joerns, W. Liu, J. A. Nadel, C. S. Dela Cruz, J. L. Koff

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

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-α (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-α production and increased viral infection, and we implicate RSV F protein to mediate this effect. EGFR inhibition, during viral infection, augmented IRF1, IFN-α, 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.

Original languageEnglish (US)
Pages (from-to)958-967
Number of pages10
JournalMucosal Immunology
Volume11
Issue number3
DOIs
StatePublished - May 1 2018
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    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. (2018). Respiratory syncytial virus activates epidermal growth factor receptor to suppress interferon regulatory factor 1-dependent interferon-lambda and antiviral defense in airway epithelium. Mucosal Immunology, 11(3), 958-967. https://doi.org/10.1038/mi.2017.120