title: Systematic Analysis of Cell-Type Differences in the Epithelial Secretome Reveals Insights into the Pathogenesis of Respiratory Syncytial Virus-Induced Lower Respiratory Tract Infections.
abstract: Lower respiratory tract infections from respiratory syncytial virus (RSV) are due, in part, to secreted signals from lower airway cells that modify the immune response and trigger airway remodeling. To understand this process, we applied an unbiased quantitative proteomics analysis of the RSV-induced epithelial secretory response in cells representative of the trachea versus small airway bronchiolar cells. A workflow was established using telomerase-immortalized human epithelial cells that revealed highly reproducible cell type-specific differences in secreted proteins and nanoparticles (exosomes). Approximately one third of secretome proteins are exosomal; the remainder are from lysosomal and vacuolar compartments. We applied this workflow to three independently derived primary human cultures from trachea versus bronchioles. A total of 577 differentially expressed proteins from control supernatants and 966 differentially expressed proteins from RSV-infected cell supernatants were identified at a 1% false discovery rate. Fifteen proteins unique to RSV-infected primary human cultures from trachea were regulated by epithelial-specific ets homologous factor. A total of 106 proteins unique to RSV-infected human small airway epithelial cells was regulated by the transcription factor NF-κB. In this latter group, we validated the differential expression of CCL20/macrophage-inducible protein 3α, thymic stromal lymphopoietin, and CCL3-like 1 because of their roles in Th2 polarization. CCL20/macrophage-inducible protein 3α was the most active mucin-inducing factor in the RSV-infected human small airway epithelial cell secretome and was differentially expressed in smaller airways in a mouse model of RSV infection. These studies provide insights into the complexity of innate responses and regional differences in the epithelial secretome participating in RSV lower respiratory tract infection-induced airway remodeling.
authors.affiliation: Institute for Translational Sciences, University of Texas Medical Branch, Galveston, TX 77555.|Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555.|Sealy Center for Molecular Medicine, University of Texas Medical Branch, Galveston, TX 77555; and.
authors.forename: Yingxin
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Institute for Translational Sciences, University of Texas Medical Branch, Galveston, TX 77555.|Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Jamaluddin
authors.affiliation: Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555.
authors.forename: Yueqing
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555.
authors.forename: Hong
authors.identifier: 0000-0003-0678-2616
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of Pediatrics, University of Texas Medical Branch, Galveston, TX 77555.
authors.forename: Teodora
authors.initials: T
authors.lastname: Ivanciuc
authors.affiliation: Institute for Translational Sciences, University of Texas Medical Branch, Galveston, TX 77555.|Sealy Center for Molecular Medicine, University of Texas Medical Branch, Galveston, TX 77555; and.|Department of Pediatrics, University of Texas Medical Branch, Galveston, TX 77555.
authors.forename: Roberto P
authors.initials: RP
authors.lastname: Garofalo
authors.affiliation: Institute for Translational Sciences, University of Texas Medical Branch, Galveston, TX 77555; arbrasie@utmb.edu.|Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555.|Sealy Center for Molecular Medicine, University of Texas Medical Branch, Galveston, TX 77555; and.
authors.forename: Allan R
authors.identifier: 0000-0002-5012-4090
authors.initials: AR
authors.lastname: Brasier
mesh_terms: D056151:Airway Remodeling / Q000276:immunology*; D055745:Bronchioles / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D040901:Proteomics / Q000379:methods*; D020545:Respiratory Mucosa / Q000276:immunology / Q000378:metabolism; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology* / Q000378:metabolism; D018113:Respiratory Syncytial Virus, Human / Q000276:immunology; D012141:Respiratory Tract Infections / Q000276:immunology* / Q000378:metabolism; D014132:Trachea / Q000276:immunology / Q000378:metabolism