Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/92656
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Type: Journal article
Title: Streptococcus pneumoniae triggers progression of pulmonary fibrosis through pneumolysin
Author: Knippenberg, S.
Ueberberg, B.
Maus, R.
Bohling, J.
Ding, N.
Tort Tarres, M.
Hoymann, H.
Jonigk, D.
Izykowski, N.
Paton, J.
Ogunniyi, A.
Lindig, S.
Bauer, M.
Welte, T.
Seeger, W.
Guenther, A.
Sisson, T.
Gauldie, J.
Kolb, M.
Maus, U.
Citation: Thorax, 2015; 70(7):636-646
Publisher: BMJ
Issue Date: 2015
ISSN: 0040-6376
1468-3296
Statement of
Responsibility: 
Sarah Knippenberg, Bianca Ueberberg, Regina Maus, Jennifer Bohling, Nadine Ding, Meritxell Tort Tarres, Heinz-Gerd Hoymann, Danny Jonigk, Nicole Izykowski, James C Paton, Abiodun D Ogunniyi, Sandro Lindig, Michael Bauer, Tobias Welte, Werner Seeger, Andreas Guenther, Thomas H Sisson, Jack Gauldie, Martin Kolb, Ulrich A Maus
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.
Keywords: Pulmonary Alveoli
Epithelial Cells
Bronchoalveolar Lavage Fluid
Animals
Mice, Inbred C57BL
Mice, Transgenic
Mice, Knockout
Pneumonia, Pneumococcal
Pulmonary Fibrosis
Disease Models, Animal
Disease Progression
Diphtheria Toxin
Bacterial Proteins
Streptolysins
Pneumococcal Vaccines
Anti-Bacterial Agents
Apoptosis
Female
Transforming Growth Factor beta1
Description: Published online: 11 May 2015
Rights: Copyright © 2015 BMJ Publishing Group Ltd & British Thoracic Society. All rights reserved.
DOI: 10.1136/thoraxjnl-2014-206420
Appears in Collections:Aurora harvest 7
Molecular and Biomedical Science publications

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