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Streptococcus pneumoniae triggers progression of pulmonary fibrosis through pneumolysin

: Knippenberg, Sarah; Ueberberg, Bianca; Maus, Regina; Bohling, Jennifer; Ding, Nadine; Tort Tarres, Meritxell; Hoymann, Heinz-G.; Jonigk, Danny; Izykowski, Nicole; Paton, James C.; Ogunniyi, Abiodun D.; Lindig, Sandro; Bauer, Michael; Welte, Tobias; Seeger, Werner; Guenther, Andreas; Sisson, H. Thomas; Gauldie, Jack; Kolb, Martin; Maus, Ulrich A.


Thorax 70 (2015), No.7, pp.636-646
ISSN: 0040-6376
ISSN: 1468-3296
Journal Article
Fraunhofer ITEM ()
respiratory infection; bacterial infection; idiopathic pulmonary fibrosis

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.