EGFR activation suppresses respiratory virus-induced IRF1-dependent CXCL10 production.
Airway epithelial cells are the primary cell type involved in respiratory viral infection. Upon infection, airway epithelium plays a critical role in host defense against viral infection by contributing to innate and adaptive immune responses. Influenza A virus, rhinovirus, and respiratory syncytial virus (RSV) represent a broad range of human viral pathogens that cause viral pneumonia and induce exacerbations of asthma and chronic obstructive pulmonary disease. These respiratory viruses induce airway epithelial production of IL-8, which involves epidermal growth factor receptor (EGFR) activation. EGFR activation involves an integrated signaling pathway that includes NADPH oxidase activation of metalloproteinase, and EGFR proligand release that activates EGFR. Because respiratory viruses have been shown to activate EGFR via this signaling pathway in airway epithelium, we investigated the effect of virus-induced EGFR activation on airway epithelial antiviral responses. CXCL10, a chemokine produced by airway epithelial cells in response to respiratory viral infection, contributes to the recruitment of lymphocytes to target and kill virus-infected cells. While respiratory viruses activate EGFR, the interaction between CXCL10 and EGFR signaling pathways is unclear, and the potential for EGFR signaling to suppress CXCL10 has not been explored. Here, we report that respiratory virus-induced EGFR activation suppresses CXCL10 production. We found that influenza virus-, rhinovirus-, and RSV-induced EGFR activation suppressed IFN regulatory factor (IRF) 1-dependent CXCL10 production. In addition, inhibition of EGFR during viral infection augmented IRF1 and CXCL10. These findings describe a novel mechanism that viruses use to suppress endogenous antiviral defenses, and provide potential targets for future therapies.
Department of Medicine, Yale University, New Haven, Connecticut;
April
A
Kalinowski
Department of Medicine and Cardiovascular Research Institute, University of California, San Francisco, California;
Iris
I
Ueki
Department of Microbiology and Immunology, and Cancer Research Institute, University of California, San Francisco, California; and.
Gundula
G
Min-Oo
University of California, Irvine, California.
Eric
E
Ballon-Landa
Department of Medicine, Yale University, New Haven, Connecticut;
David
D
Knoff
Department of Medicine, Yale University, New Haven, Connecticut;
Benjamin
B
Galen
Department of Microbiology and Immunology, and Cancer Research Institute, University of California, San Francisco, California; and.
Lewis L
LL
Lanier
Department of Medicine and Cardiovascular Research Institute, University of California, San Francisco, California;
Jay A
JA
Nadel
Department of Medicine, Yale University, New Haven, Connecticut; jon.koff@yale.edu.
Jonathan L
JL
Koff
D001980:Bronchi / Q000166:cytology; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D054357:Chemokine CXCL10 / Q000096:biosynthesis*; D004847:Epithelial Cells / Q000378:metabolism*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D000077156:Gefitinib; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype; D050856:Interferon Regulatory Factor-1 / Q000502:physiology*; D016209:Interleukin-8 / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000502:physiology; D011799:Quinazolines / Q000494:pharmacology; D012136:Respiratory Syncytial Viruses; D012229:Rhinovirus; D015398:Signal Transduction; D014777:Virus Diseases / Q000503:physiopathology*
C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D016209:Interleukin-8; D011799:Quinazolines; D066246:ErbB Receptors; D000077156:Gefitinib
CXCL10; epidermal growth factor receptor; innate immunity; interferon regulatory factor 1