EGFR interacts with the fusion protein of respiratory syncytial virus strain 2-20 and mediates infection and mucin expression.

Michael G. Currier, Sujin Lee, Christopher C. Stobart, Anne L. Hotard, Remi Villenave, Jia Meng, Carla Pretto, Michael D. Shields, Minh Trang Nguyen, Sean O. Todd, Michael H. Chi, Jason Hammonds, Stefanie A. Krumm, Paul Spearman, Richard K. Plemper, Kaori Sakamoto, R. Stokes Peebles, Ultan F. Power, Martin L. Moore

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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.
Original languageEnglish
JournalPLoS Pathogens
Volume12
Issue number5
DOIs
Publication statusPublished - 06 May 2016

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    Currier, M. G., Lee, S., Stobart, C. C., Hotard, A. L., Villenave, R., Meng, J., Pretto, C., Shields, M. D., Nguyen, M. T., Todd, S. O., Chi, M. H., Hammonds, J., Krumm, S. A., Spearman, P., Plemper, R. K., Sakamoto, K., Peebles, R. S., Power, U. F., & Moore, M. L. (2016). EGFR interacts with the fusion protein of respiratory syncytial virus strain 2-20 and mediates infection and mucin expression. PLoS Pathogens, 12(5). https://doi.org/10.1371/journal.ppat.1005622