title: Overactive Epidermal Growth Factor Receptor Signaling Leads to Increased Fibrosis after Severe Acute Respiratory Syndrome Coronavirus Infection.
abstract: Severe acute respiratory syndrome coronavirus (SARS-CoV) is a highly pathogenic respiratory virus that causes morbidity and mortality in humans. After infection with SARS-CoV, the acute lung injury caused by the virus must be repaired to regain lung function. A dysregulation in this wound healing process leads to fibrosis. Many survivors of SARS-CoV infection develop pulmonary fibrosis (PF), with higher prevalence in older patients. Using mouse models of SARS-CoV pathogenesis, we have identified that the wound repair pathway, controlled by the epidermal growth factor receptor (EGFR), is critical to recovery from SARS-CoV-induced tissue damage. In mice with constitutively active EGFR [EGFR(DSK5) mice], we find that SARS-CoV infection causes enhanced lung disease. Importantly, we show that during infection, the EGFR ligands amphiregulin and heparin-binding EGF-like growth factor (HB-EGF) are upregulated, and exogenous addition of these ligands during infection leads to enhanced lung disease and altered wound healing dynamics. Our data demonstrate a key role of EGFR in the host response to SARS-CoV and how it may be implicated in lung disease induced by other highly pathogenic respiratory viruses.IMPORTANCEPF has many causative triggers, including severe respiratory viruses such as SARS-CoV. Currently there are no treatments to prevent the onset or limit the progression of PF, and the molecular pathways underlying the development of PF are not well understood. In this study, we identified a role for the balanced control of EGFR signaling as a key factor in progression to PF. These data demonstrate that therapeutic treatment modulating EGFR activation could protect against PF development caused by severe respiratory virus infection.
authors.affiliation: Department of Microbiology and Immunology, The University of Maryland at Baltimore, Baltimore, Maryland, USA.
authors.forename: Thiagarajan
authors.initials: T
authors.lastname: Venkataraman
authors.affiliation: Department of Microbiology and Immunology, The University of Maryland at Baltimore, Baltimore, Maryland, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Coleman
authors.affiliation: Department of Microbiology and Immunology, The University of Maryland at Baltimore, Baltimore, Maryland, USA mfrieman@som.umaryland.edu.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Frieman
mesh_terms: D066258:Amphiregulin / Q000008:administration & dosage / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000473:pathology* / Q000821:virology; D051379:Mice; D011658:Pulmonary Fibrosis / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D045473:Severe acute respiratory syndrome-related coronavirus / Q000472:pathogenicity* / Q000502:physiology; D045169:Severe Acute Respiratory Syndrome / Q000378:metabolism* / Q000473:pathology* / Q000821:virology; D015398:Signal Transduction; D014945:Wound Healing / Q000187:drug effects
chemical_list: D066258:Amphiregulin; C541485:EGFR protein, mouse; D066246:ErbB Receptors
keywords: Coronavirus; EGFR; SARS-CoV; fibrosis; viral pathogenesis