Journal article

Publication year: 2015

Pages: 636-646

Journal: Thorax

Volume number: 70

Issue number: 7

ISSN: 0040-6376

eISSN: 1468-3296

Open access status: Green

DOI Link: https://doi.org/10.1136/thoraxjnl-2014-206420

Publisher: BMJ Publishing Group

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-beta 1 (TGF beta 1) 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 (Spn Delta ply) failed to trigger progressive fibrogenesis, whereas purified recombinant Ply did. Progressive fibrogenesis was also observed in AdTGF beta 1-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 AdTGF beta 1-exposed mice. Importantly, vaccination of mice with the non-cytotoxic Ply derivative B (PdB) substantially attenuated Ply-induced progression of lung fibrosis in AdTGF beta 1-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.

Harvard Citation style: Knippenberg, S., Ueberberg, B., Maus, R., Bohling, J., Ding, N., Tarres, M., et al. (2015) Streptococcus pneumoniae triggers progression of pulmonary fibrosis through pneumolysin, Thorax, 70(7), pp. 636-646. https://doi.org/10.1136/thoraxjnl-2014-206420

APA Citation style: Knippenberg, S., Ueberberg, B., Maus, R., Bohling, J., Ding, N., 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. (2015). Streptococcus pneumoniae triggers progression of pulmonary fibrosis through pneumolysin. Thorax. 70(7), 636-646. https://doi.org/10.1136/thoraxjnl-2014-206420