title: Respiratory syncytial virus infection enhances Pseudomonas aeruginosa biofilm growth through dysregulation of nutritional immunity.
abstract: Clinical observations link respiratory virus infection and Pseudomonas aeruginosa colonization in chronic lung disease, including cystic fibrosis (CF) and chronic obstructive pulmonary disease. The development of P. aeruginosa into highly antibiotic-resistant biofilm communities promotes airway colonization and accounts for disease progression in patients. Although clinical studies show a strong correlation between CF patients' acquisition of chronic P. aeruginosa infections and respiratory virus infection, little is known about the mechanism by which chronic P. aeruginosa infections are initiated in the host. Using a coculture model to study the formation of bacterial biofilm formation associated with the airway epithelium, we show that respiratory viral infections and the induction of antiviral interferons promote robust secondary P. aeruginosa biofilm formation. We report that the induction of antiviral IFN signaling in response to respiratory syncytial virus (RSV) infection induces bacterial biofilm formation through a mechanism of dysregulated iron homeostasis of the airway epithelium. Moreover, increased apical release of the host iron-binding protein transferrin during RSV infection promotes P. aeruginosa biofilm development in vitro and in vivo. Thus, nutritional immunity pathways that are disrupted during respiratory viral infection create an environment that favors secondary bacterial infection and may provide previously unidentified targets to combat bacterial biofilm formation.
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219;
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Hendricks
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219;
authors.forename: Lauren P
authors.initials: LP
authors.lastname: Lashua
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219;
authors.forename: Douglas K
authors.initials: DK
authors.lastname: Fischer
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219;
authors.forename: Becca A
authors.initials: BA
authors.lastname: Flitter
authors.affiliation: Department of Pharmacy and Therapeutics, University of Pittsburgh School of Pharmacy, Pittsburgh, PA 15261;
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Eichinger
authors.affiliation: Department of Pathology and Laboratory Medicine, Rutgers-New Jersey Medical School, Newark, NJ 07101;
authors.forename: Joan E
authors.initials: JE
authors.lastname: Durbin
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219; Cancer Virology Program, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213.
authors.forename: Saumendra N
authors.initials: SN
authors.lastname: Sarkar
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219;
authors.forename: Carolyn B
authors.initials: CB
authors.lastname: Coyne
authors.affiliation: Department of Pharmacy and Therapeutics, University of Pittsburgh School of Pharmacy, Pittsburgh, PA 15261;
authors.forename: Kerry M
authors.initials: KM
authors.lastname: Empey
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219; jbomb@pitt.edu.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Bomberger
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D018441:Biofilms / Q000254:growth & development*; D001980:Bronchi / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid; D003550:Cystic Fibrosis / Q000382:microbiology / Q000473:pathology; D004847:Epithelial Cells / Q000187:drug effects / Q000382:microbiology / Q000821:virology; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D007109:Immunity; D016899:Interferon-beta / Q000494:pharmacology; D007501:Iron / Q000494:pharmacology; D051379:Mice; D056265:Microbial Interactions / Q000187:drug effects; D008954:Models, Biological; D009747:Nutritional Physiological Phenomena; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000502:physiology*; D018357:Respiratory Syncytial Virus Infections / Q000473:pathology*; D012136:Respiratory Syncytial Viruses / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D014168:Transferrin / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D014168:Transferrin; D016899:Interferon-beta; D007501:Iron
keywords: Pseudomonas aeruginosa; biofilm; cystic fibrosis; nutritional immunity; respiratory syncytial virus