title: Streptococcus pneumoniae triggers progression of pulmonary fibrosis through pneumolysin.
abstract: BACKGROUND
  Respiratory tract infections are common in patients suffering from pulmonary fibrosis. The interplay between bacterial infection and fibrosis is characterised poorly.
  
  
  OBJECTIVE
  To assess the effect of Gram-positive bacterial infection on fibrosis exacerbation in mice.
  
  
  METHODS
  Fibrosis progression in response to Streptococcus pneumoniae was examined in two different mouse models of pulmonary fibrosis.
  
  
  RESULTS
  We demonstrate that wild-type mice exposed to adenoviral vector delivery of active transforming growth factor-β1 (TGFß1) or diphteria toxin (DT) treatment of transgenic mice expressing the DT receptor (DTR) under control of the surfactant protein C (SPC) promoter (SPC-DTR) to induce pulmonary fibrosis developed progressive fibrosis following infection with Spn, without exhibiting impaired lung protective immunity against Spn. Antibiotic treatment abolished infection-induced fibrosis progression. The cytotoxin pneumolysin (Ply) of Spn caused this phenomenon in a TLR4-independent manner, as Spn lacking Ply (SpnΔply) failed to trigger progressive fibrogenesis, whereas purified recombinant Ply did. Progressive fibrogenesis was also observed in AdTGFβ1-exposed Ply-challenged TLR4 KO mice. Increased apoptotic cell death of alveolar epithelial cells along with an attenuated intrapulmonary release of antifibrogenic prostaglandin E2 was found to underlie progressive fibrogenesis in Ply-challenged AdTGFβ1-exposed mice. Importantly, vaccination of mice with the non-cytotoxic Ply derivative B (PdB) substantially attenuated Ply-induced progression of lung fibrosis in AdTGFβ1-exposed mice.
  
  
  CONCLUSIONS
  Our data unravel a novel mechanism by which infection with Spn through Ply release induces progression of established lung fibrosis, which can be attenuated by protein-based vaccination of mice.
authors.affiliation: Department of Experimental Pneumology, Hannover Medical School, Hannover, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Knippenberg
authors.affiliation: Department of Experimental Pneumology, Hannover Medical School, Hannover, Germany.
authors.forename: Bianca
authors.initials: B
authors.lastname: Ueberberg
authors.affiliation: Department of Experimental Pneumology, Hannover Medical School, Hannover, Germany.
authors.forename: Regina
authors.initials: R
authors.lastname: Maus
authors.affiliation: Department of Experimental Pneumology, Hannover Medical School, Hannover, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Bohling
authors.affiliation: Department of Experimental Pneumology, Hannover Medical School, Hannover, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Ding
authors.affiliation: Department of Experimental Pneumology, Hannover Medical School, Hannover, Germany.
authors.forename: Meritxell
authors.initials: M
authors.lastname: Tort Tarres
authors.affiliation: Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany.
authors.forename: Heinz-Gerd
authors.initials: HG
authors.lastname: Hoymann
authors.affiliation: Institute of Pathology, Hannover Medical School, Hannover, Germany.
authors.forename: Danny
authors.initials: D
authors.lastname: Jonigk
authors.affiliation: Institute of Pathology, Hannover Medical School, Hannover, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Izykowski
authors.affiliation: Research Centre for Infectious Diseases, School of Molecular and Biomedical Science, University of Adelaide, Adelaide, Australia.
authors.forename: James C
authors.initials: JC
authors.lastname: Paton
authors.affiliation: Research Centre for Infectious Diseases, School of Molecular and Biomedical Science, University of Adelaide, Adelaide, Australia.
authors.forename: Abiodun D
authors.initials: AD
authors.lastname: Ogunniyi
authors.affiliation: Center for Sepsis Control and Care, University Hospital Jena, Friedrich Schiller University, Jena, Germany.
authors.forename: Sandro
authors.initials: S
authors.lastname: Lindig
authors.affiliation: Center for Sepsis Control and Care, University Hospital Jena, Friedrich Schiller University, Jena, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Bauer
authors.affiliation: Clinic for Pneumology, Hannover Medical School, Hannover, Germany German Centre for Lung Research, partner site BREATH and UGMLC.
authors.forename: Tobias
authors.initials: T
authors.lastname: Welte
authors.affiliation: German Centre for Lung Research, partner site BREATH and UGMLC Faculty of Medicine, Department of Internal Medicine, Universities of Giessen and Marburg Lung Center, Giessen, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.affiliation: German Centre for Lung Research, partner site BREATH and UGMLC Faculty of Medicine, Department of Internal Medicine, Universities of Giessen and Marburg Lung Center, Giessen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Guenther
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Hospital, Michigan, USA.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Sisson
authors.affiliation: Department of Medicine, Pathology, and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Jack
authors.initials: J
authors.lastname: Gauldie
authors.affiliation: Department of Medicine, Pathology, and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Kolb
authors.affiliation: Department of Experimental Pneumology, Hannover Medical School, Hannover, Germany German Centre for Lung Research, partner site BREATH and UGMLC.
authors.forename: Ulrich A
authors.initials: UA
authors.lastname: Maus
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001426:Bacterial Proteins / Q000494:pharmacology / Q000502:physiology; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D004167:Diphtheria Toxin; D004195:Disease Models, Animal; D018450:Disease Progression; D004847:Epithelial Cells / Q000187:drug effects; D005260:Female; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D022242:Pneumococcal Vaccines; D011018:Pneumonia, Pneumococcal / Q000150:complications* / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000276:immunology / Q000378:metabolism / Q000382:microbiology* / Q000517:prevention & control; D013301:Streptolysins / Q000172:deficiency / Q000494:pharmacology / Q000502:physiology*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004167:Diphtheria Toxin; D022242:Pneumococcal Vaccines; D013301:Streptolysins; D053773:Transforming Growth Factor beta1; C032290:plY protein, Streptococcus pneumoniae
keywords: Bacterial Infection; Idiopathic pulmonary fibrosis; Respiratory Infection