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.

Epidermal growth factor receptor inhibitors trigger a type I interferon response in human skin

“…Erlotinib impairs infection by all major hepatitis C virus genotypes and viral escape variants in cell cultures and in a human liver chimeric mouse model in vivo [64, 65]. Erlotinib also diminishes infectivity of specific strains of syncytial virus in respiratory epithelial cell cultures and in mouse models in vivo [66]. Analogously, gefitinib was shown to suppress influenza A virus and rhinovirus infection of bronchial epithelial cells and in mouse models [42].…”

Respiratory Syncytial Virus: Infection, Detection, and New Options for Prevention and Treatment

“…There have been many candidate cellular receptors described for RSV entry, including annexin II (70), CX3 chemokine receptor 1 (CX3CR1) (71,72), epidermal growth factor (EGF) receptor (73), calcium-dependent lectins (70), Toll-like receptor 4 (TLR4) (74,75), intercellular adhesion molecule 1 (ICAM-1) (76), nucleolin (77,78), and heparan sulfate proteoglycans (HSPGs) (79). Some receptors like EGF are purportedly used by only certain strains of RSV (73). It is also interesting that of these receptors, annexin II, HSPGs, and C-type lectins (including surfactant proteins A and D, which are soluble and bind to RSV prior to cellular attachment) have been implicated in binding the carbohydrate-rich regions of the RSV-F and -G proteins.…”

Respiratory syncytial virus entry and how to block it

“…Virions containing only F on the surface retain ~50% of their infectivity for cells treated with heparinase or deficient in GAG synthesis, suggesting that F also interacts with one or more non-GAG attachment factors. Several proteins have been proposed to interact with F and facilitate RSV entry, including intercellular adhesion molecule 1 (ICAM1) 103 , epidermal growth factor receptor (EGFR) 104 and nucleolin 105 . Of these, the data for nucleolin are the strongest, and nucleolin has been shown to interact with many other viruses, including parainfluenza type 3 (PIV-3) 106 , enterovirus 71 (reF.…”