title: Epidermal growth factor receptor signaling impairs the antiviral activity of interferon-alpha.
abstract: Interferon-alpha (IFN-α) exhibits its antiviral activity through signal transducer and activator of transcription protein (STAT) signaling and the expression of IFN response genes (IRGs). Viral infection has been shown to result in activation of epidermal growth factor receptor (EGFR)-a host cell entry factor used by several viruses, including hepatitis C virus. However, the effect of EGFR activation for cellular antiviral responses is unknown. Here, we uncover cross-talk between EGFR and IFN-α signaling that has a therapeutic effect on IFN-α-based therapies and functional relevance for viral evasion and IFN resistance. We show that combining IFN-α with the EGFR inhibitor, erlotinib, potentiates the antiviral effect of each compound in a highly synergistic manner. The extent of the synergy correlated with reduced STAT3 phosphorylation in the presence of erlotinib, whereas STAT1 phosphorylation was not affected. Furthermore, reduced STAT3 phosphorylation correlated with enhanced expression of suppressors of cytokine signaling 3 (SOCS3) in the presence of erlotinib and enhanced expression of the IRGs, radical S-adenosyl methionine domain containing 2 and myxovirus resistance protein 1. Moreover, EGFR stimulation reduced STAT1 dimerization, but not phosphorylation, indicating that EGFR cross-talk with IFN signaling acts on the STATs at the level of binding DNA.
  
  
  CONCLUSIONS
  Our results support a model where inhibition of EGFR signaling impairs STAT3 phosphorylation, leading to enhanced IRG expression and antiviral activity. These data uncover a novel role of EGFR signaling in the antiviral activity of IFN-α and open new avenues of improving the efficacy of IFN-α-based antiviral therapies.
authors.affiliation: Inserm, U1110, Institut de Virologie, Strasbourg, France; Université de Strasbourg, Strasbourg, France.
authors.forename: Joachim
authors.initials: J
authors.lastname: Lupberger
authors.forename: François H T
authors.initials: FH
authors.lastname: Duong
authors.forename: Isabel
authors.initials: I
authors.lastname: Fofana
authors.forename: Laetitia
authors.initials: L
authors.lastname: Zona
authors.forename: Fei
authors.initials: F
authors.lastname: Xiao
authors.forename: Christine
authors.initials: C
authors.lastname: Thumann
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Durand
authors.forename: Patrick
authors.initials: P
authors.lastname: Pessaux
authors.forename: Mirjam B
authors.initials: MB
authors.lastname: Zeisel
authors.forename: Markus H
authors.initials: MH
authors.lastname: Heim
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Baumert
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000821:virology; D002460:Cell Line; D002478:Cells, Cultured; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology*; D000069347:Erlotinib Hydrochloride; D016174:Hepacivirus / Q000187:drug effects*; D006526:Hepatitis C / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D022781:Hepatocytes / Q000187:drug effects* / Q000473:pathology / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology* / Q000627:therapeutic use; D008113:Liver Neoplasms / Q000473:pathology / Q000821:virology; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D011799:Quinazolines; C106644:SOCS3 protein, human; D050796:STAT3 Transcription Factor; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases