title: EGFR Interacts with the Fusion Protein of Respiratory Syncytial Virus Strain 2-20 and Mediates Infection and Mucin Expression.
abstract: Respiratory syncytial virus (RSV) is the major cause of viral lower respiratory tract illness in children. In contrast to the RSV prototypic strain A2, clinical isolate RSV 2-20 induces airway mucin expression in mice, a clinically relevant phenotype dependent on the fusion (F) protein of the RSV strain. Epidermal growth factor receptor (EGFR) plays a role in airway mucin expression in other systems; therefore, we hypothesized that the RSV 2-20 F protein stimulates EGFR signaling. Infection of cells with chimeric strains RSV A2-2-20F and A2-2-20GF or over-expression of 2-20 F protein resulted in greater phosphorylation of EGFR than infection with RSV A2 or over-expression of A2 F, respectively. Chemical inhibition of EGFR signaling or knockdown of EGFR resulted in diminished infectivity of RSV A2-2-20F but not RSV A2. Over-expression of EGFR enhanced the fusion activity of 2-20 F protein in trans. EGFR co-immunoprecipitated most efficiently with RSV F proteins derived from "mucogenic" strains. RSV 2-20 F and EGFR co-localized in H292 cells, and A2-2-20GF-induced MUC5AC expression was ablated by EGFR inhibitors in these cells. Treatment of BALB/c mice with the EGFR inhibitor erlotinib significantly reduced the amount of RSV A2-2-20F-induced airway mucin expression. Our results demonstrate that RSV F interacts with EGFR in a strain-specific manner, EGFR is a co-factor for infection, and EGFR plays a role in RSV-induced mucin expression, suggesting EGFR is a potential target for RSV disease.
authors.affiliation: Department of Pediatrics, Emory University, Atlanta, Georgia, United States of America.|Children's Healthcare of Atlanta, Atlanta, Georgia, United States of America.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Currier
authors.affiliation: Department of Pediatrics, Emory University, Atlanta, Georgia, United States of America.|Children's Healthcare of Atlanta, Atlanta, Georgia, United States of America.
authors.forename: Sujin
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Pediatrics, Emory University, Atlanta, Georgia, United States of America.|Children's Healthcare of Atlanta, Atlanta, Georgia, United States of America.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Stobart
authors.affiliation: Department of Pediatrics, Emory University, Atlanta, Georgia, United States of America.|Children's Healthcare of Atlanta, Atlanta, Georgia, United States of America.
authors.forename: Anne L
authors.initials: AL
authors.lastname: Hotard
authors.affiliation: Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Science, Queens University Belfast, Belfast, Northern Ireland.
authors.forename: Remi
authors.initials: R
authors.lastname: Villenave
authors.affiliation: Department of Pediatrics, Emory University, Atlanta, Georgia, United States of America.|Children's Healthcare of Atlanta, Atlanta, Georgia, United States of America.
authors.forename: Jia
authors.initials: J
authors.lastname: Meng
authors.affiliation: Department of Pediatrics, Emory University, Atlanta, Georgia, United States of America.|Children's Healthcare of Atlanta, Atlanta, Georgia, United States of America.
authors.forename: Carla D
authors.initials: CD
authors.lastname: Pretto
authors.affiliation: Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Science, Queens University Belfast, Belfast, Northern Ireland.|The Royal Belfast Hospital for Sick Children, Belfast, Northern Ireland.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Shields
authors.affiliation: Department of Pediatrics, Emory University, Atlanta, Georgia, United States of America.|Children's Healthcare of Atlanta, Atlanta, Georgia, United States of America.
authors.forename: Minh Trang
authors.initials: MT
authors.lastname: Nguyen
authors.affiliation: Department of Pediatrics, Emory University, Atlanta, Georgia, United States of America.|Children's Healthcare of Atlanta, Atlanta, Georgia, United States of America.
authors.forename: Sean O
authors.initials: SO
authors.lastname: Todd
authors.affiliation: Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Chi
authors.affiliation: Department of Pediatrics, Emory University, Atlanta, Georgia, United States of America.|Children's Healthcare of Atlanta, Atlanta, Georgia, United States of America.
authors.forename: Jason
authors.initials: J
authors.lastname: Hammonds
authors.affiliation: Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia, United States of America.
authors.forename: Stefanie A
authors.initials: SA
authors.lastname: Krumm
authors.affiliation: Department of Pediatrics, Emory University, Atlanta, Georgia, United States of America.|Children's Healthcare of Atlanta, Atlanta, Georgia, United States of America.
authors.forename: Paul
authors.initials: P
authors.lastname: Spearman
authors.affiliation: Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia, United States of America.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Plemper
authors.affiliation: Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, Georgia, United States of America.
authors.forename: Kaori
authors.initials: K
authors.lastname: Sakamoto
authors.affiliation: Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: R Stokes
authors.initials: RS
authors.lastname: Peebles
authors.affiliation: Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Science, Queens University Belfast, Belfast, Northern Ireland.
authors.forename: Ultan F
authors.initials: UF
authors.lastname: Power
authors.affiliation: Department of Pediatrics, Emory University, Atlanta, Georgia, United States of America.|Children's Healthcare of Atlanta, Atlanta, Georgia, United States of America.
authors.forename: Martin L
authors.initials: ML
authors.lastname: Moore
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D055785:Gene Knockdown Techniques; D047468:Immunoprecipitation; D051379:Mice; D008807:Mice, Inbred BALB C; D009077:Mucins / Q000096:biosynthesis*; D060888:Real-Time Polymerase Chain Reaction; D018357:Respiratory Syncytial Virus Infections / Q000378:metabolism*; D018113:Respiratory Syncytial Virus, Human; D014760:Viral Fusion Proteins / Q000378:metabolism*
chemical_list: C526850:F protein, human respiratory syncytial virus; D009077:Mucins; D014760:Viral Fusion Proteins; C541485:EGFR protein, mouse; D066246:ErbB Receptors