title: Respiratory Syncytial Virus Infection Triggers Epithelial HMGB1 Release as a Damage-Associated Molecular Pattern Promoting a Monocytic Inflammatory Response.
abstract: Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in infant and elderly populations worldwide. Currently, there is no efficacious vaccine or therapy available for RSV infection. The molecular mechanisms underlying RSV-induced acute airway disease and associated long-term consequences remain largely unknown; however, experimental evidence suggests that the lung inflammatory response plays a fundamental role in the outcome of RSV infection. High-mobility group box 1 (HMGB1) is a nuclear protein that triggers inflammation when released from activated immune or necrotic cells and drives the pathogenesis of various infectious agents. Although HMGB1 has been implicated in many inflammatory diseases, its role in RSV-induced airway inflammation has not been investigated. This study investigates the molecular mechanism of action of extracellularly released HMGB1 in airway epithelial cells (A549 and small airway epithelial cells) to establish its role in RSV infection. Immunofluorescence microscopy and Western blotting results showed that RSV infection of human airway epithelial cells induced a significant release of HMGB1 as a result of translocation of HMGB1 from the cell nuclei to the cytoplasm and subsequent release into the extracellular space. Treating RSV-infected A549 cells with antioxidants significantly inhibited RSV-induced HMGB1 extracellular release. Studies using recombinant HMGB1 triggered immune responses by activating primary human monocytes. Finally, HMGB1 released by airway epithelial cells due to RSV infection appears to function as a paracrine factor priming epithelial cells and monocytes to inflammatory stimuli in the airways.
  
  
  OBJECTIVE
  RSV is a major cause of serious lower respiratory tract infections in young children and causes severe respiratory morbidity and mortality in the elderly. In addition, to date there is no effective treatment or vaccine available for RSV infection. The mechanisms responsible for RSV-induced acute airway disease and associated long-term consequences remain largely unknown. The oxidative stress response in the airways plays a major role in the pathogenesis of RSV. HMGB1 is a ubiquitous redox-sensitive multifunctional protein that serves as both a DNA regulatory protein and an extracellular cytokine signaling molecule that promotes airway inflammation as a damage-associated molecular pattern. This study investigated the mechanism of action of HMGB1 in RSV infection with the aim of identifying new inflammatory pathways at the molecular level that may be amenable to therapeutic interventions.
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, Texas, USA Institute for Translational Sciences, The University of Texas Medical Branch, Galveston, Texas, USA yahosako@utmb.edu.
authors.forename: Yashoda M
authors.initials: YM
authors.lastname: Hosakote
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, The University of Texas Medical Branch, Galveston, Texas, USA Sealy Center for Molecular Medicine, The University of Texas Medical Branch, Galveston, Texas, USA Institute for Translational Sciences, The University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Allan R
authors.initials: AR
authors.lastname: Brasier
authors.affiliation: Sealy Center for Molecular Medicine, The University of Texas Medical Branch, Galveston, Texas, USA Department of Pediatrics, The University of Texas Medical Branch, Galveston, Texas, USA Sealy Center for Vaccine Development, The University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Antonella
authors.initials: A
authors.lastname: Casola
authors.affiliation: Sealy Center for Molecular Medicine, The University of Texas Medical Branch, Galveston, Texas, USA Department of Pediatrics, The University of Texas Medical Branch, Galveston, Texas, USA Sealy Center for Vaccine Development, The University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Roberto P
authors.initials: RP
authors.lastname: Garofalo
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, Texas, USA Sealy Center for Molecular Medicine, The University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kurosky
mesh_terms: D000072283:A549 Cells; D000293:Adolescent; D000328:Adult; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000378:metabolism / Q000821:virology; D024243:HMGB1 Protein / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000821:virology; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism* / Q000821:virology; D011014:Pneumonia / Q000378:metabolism* / Q000821:virology*; D018357:Respiratory Syncytial Virus Infections / Q000378:metabolism* / Q000821:virology; D018113:Respiratory Syncytial Virus, Human / Q000378:metabolism*; D055815:Young Adult
chemical_list: D024243:HMGB1 Protein; C585491:HMGB1 protein, human