title: Respiratory syncytial virus can infect basal cells and alter human airway epithelial differentiation.
abstract: Respiratory syncytial virus (RSV) is a major cause of morbidity and mortality worldwide, causing severe respiratory illness in infants and immune compromised patients. The ciliated cells of the human airway epithelium have been considered to be the exclusive target of RSV, although recent data have suggested that basal cells, the progenitors for the conducting airway epithelium, may also become infected in vivo. Using either mechanical or chemical injury models, we have demonstrated a robust RSV infection of p63+ basal cells in air-liquid interface (ALI) cultures of human bronchial epithelial cells. In addition, proliferating basal cells in 2D culture were also susceptible to RSV infection. We therefore tested the hypothesis that RSV infection of this progenitor cell would influence the differentiation status of the airway epithelium. RSV infection of basal cells on the day of seeding (MOI≤0.0001), resulted in the formation of an epithelium that showed a profound loss of ciliated cells and gain of secretory cells as assessed by acetylated α-tubulin and MUC5AC/MUC5B immunostaining, respectively. The mechanism driving the switch in epithelial phenotype is in part driven by the induced type I and type III interferon response that we demonstrate is triggered early following RSV infection. Neutralization of this response attenuates the RSV-induced loss of ciliated cells. Together, these data show that through infection of proliferating airway basal cells, RSV has the potential to influence the cellular composition of the airway epithelium. The resulting phenotype might be expected to contribute towards both the severity of acute infection, as well as to the longer-term consequences of viral exacerbations in patients with pre-existing respiratory diseases.
authors.affiliation: Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, United States of America.
authors.forename: B David
authors.initials: BD
authors.lastname: Persson
authors.affiliation: Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, United States of America.
authors.forename: Aron B
authors.initials: AB
authors.lastname: Jaffe
authors.affiliation: Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Rachel
authors.initials: R
authors.lastname: Fearns
authors.affiliation: Respiratory Disease Area, Novartis Institutes for BioMedical Research, Horsham, United Kingdom.
authors.forename: Henry
authors.initials: H
authors.lastname: Danahay
mesh_terms: D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology* / Q000821:virology; D006801:Humans; D007370:Interferon Type I / Q000276:immunology; D007372:Interferons; D007378:Interleukins / Q000276:immunology; D055271:Mucin 5AC / Q000378:metabolism; D055257:Mucin-5B / Q000378:metabolism; D020545:Respiratory Mucosa / Q000166:cytology / Q000821:virology*; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology* / Q000473:pathology* / Q000821:virology; D012136:Respiratory Syncytial Viruses / Q000276:immunology / Q000472:pathogenicity; D013234:Stem Cells / Q000821:virology; D014404:Tubulin / Q000378:metabolism; D000095022:Interferon Lambda
chemical_list: D007370:Interferon Type I; D007372:Interferons; D007378:Interleukins; D055271:Mucin 5AC; D055257:Mucin-5B; D014404:Tubulin; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C524678:MUC5AC protein, human; C524578:MUC5B protein, human