Streptococcus pneumoniae triggers progression of pulmonary fibrosis through pneumolysin.

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-?1 (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 (Spn?ply) failed to trigger progressive fibrogenesis, whereas purified recombinant Ply did. Progressive fibrogenesis was also observed in AdTGF?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?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?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.

SUBMITTER: Knippenberg S 

PROVIDER: S-EPMC6729139 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature