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Streptococcus pneumoniae triggers progression of pulmonary fibrosis through pneumolysin
  1. Sarah Knippenberg1,
  2. Bianca Ueberberg1,
  3. Regina Maus1,
  4. Jennifer Bohling1,
  5. Nadine Ding1,
  6. Meritxell Tort Tarres1,
  7. Heinz-Gerd Hoymann2,
  8. Danny Jonigk3,
  9. Nicole Izykowski3,
  10. James C Paton4,
  11. Abiodun D Ogunniyi4,
  12. Sandro Lindig5,
  13. Michael Bauer5,
  14. Tobias Welte6,7,
  15. Werner Seeger7,8,
  16. Andreas Guenther7,8,
  17. Thomas H Sisson9,
  18. Jack Gauldie10,
  19. Martin Kolb10,
  20. Ulrich A Maus1,7
  1. 1Department of Experimental Pneumology, Hannover Medical School, Hannover, Germany
  2. 2Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany
  3. 3Institute of Pathology, Hannover Medical School, Hannover, Germany
  4. 4Research Centre for Infectious Diseases, School of Molecular and Biomedical Science, University of Adelaide, Adelaide, Australia
  5. 5Center for Sepsis Control and Care, University Hospital Jena, Friedrich Schiller University, Jena, Germany
  6. 6Clinic for Pneumology, Hannover Medical School, Hannover, Germany
  7. 7German Centre for Lung Research, partner site BREATH and UGMLC
  8. 8Faculty of Medicine, Department of Internal Medicine, Universities of Giessen and Marburg Lung Center, Giessen, Germany
  9. 9Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Hospital, Michigan, USA
  10. 10Department of Medicine, Pathology, and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
  1. Correspondence to Professor Ulrich A Maus, Department of Experimental Pneumology, Hannover Medical School, Feodor-Lynen-Strasse 21, Hannover 30625, Germany; Maus.Ulrich{at}mh-hannover.de

Abstract

Rationale Respiratory tract infections are common in patients suffering from pulmonary fibrosis. The interplay between bacterial infection and fibrosis is characterised poorly.

Objectives 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.

Measurements and main 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.

  • Idiopathic pulmonary fibrosis
  • Respiratory Infection
  • Bacterial Infection

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