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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.

American Journal of Respiratory and Critical Care Medicine 191 (2015), Art. A3920
ISSN: 1073-449X
ISSN: 0003-0805
ISSN: 1535-4970
American Thoracic Society (ATS International Conference) <2015, Denver/Colo.>
English
Abstract
Fraunhofer ITEM ()

Abstract
Rationale: Respiratory tract infections are common in patients suffering from pulmonary fibrosis. The interplay between bacterial infection and fibrosis is poorly characterized. It is still unclear whether bacterial infections in IPF are merely a secondary complication in a high-risk patient group, or if they can also worsen the underlying fibrosis. Therefore, we here analyzed the effect of Gram-positive bacterial infection on fibrosis exacerbation in mice. Methods: Fibrosis progression in response to S. pneumoniae was examined in two different mouse models of pulmonary fibrosis. The first model consists of adenoviral vector delivery of active transforming growth factor- 1 (TGF1) gene into the lungs of mice to induce pulmonary fibrosis. The other mouse model consists of diphtheria toxin (DT) administration to transgenic SPC-DTR mice to cause repetitive alveolar type II epithelial cell injury and subsequent pulmonary fibrosis. As a second hit, mice with established lung fibrosis underwent pulmonary infection with the prototypic community-acquired lung pathogen Streptococcus pneumoniae (Spn). Results: We demonstrate that wild-type (WT) mice exposed to adenoviral vector delivery of active transforming growth factor-1 (TGF1) or transgenic SPC-DTR mice exposed to diphtheria toxin 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 (Spnply) failed to trigger progressive fibrogenesis, whereas purified recombinant Ply did. Progressive fibrogenesis was also observed in AdTGF1-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 AdTGF1exposed mice. Importantly, vaccination of mice with the non-cytotoxic Ply derivative PdB substantially attenuated Ply-induced progression of lung fibrosis in AdTGF1 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.

: http://publica.fraunhofer.de/documents/N-382941.html