Streptococcus pneumoniae triggers progression of pulmonary fibrosis through pneumolysin.
Thorax
; 70(7): 636-46, 2015 Jul.
Article
em En
| MEDLINE
| ID: mdl-25964315
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 MAINRESULTS:
We demonstrate that wild-type mice exposed to adenoviral vector delivery of active transforming growth factor-ß1 (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 AdTGFß1-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 AdTGFß1-exposed mice. Importantly, vaccination of mice with the non-cytotoxic Ply derivative B (PdB) substantially attenuated Ply-induced progression of lung fibrosis in AdTGFß1-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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pneumonia Pneumocócica
/
Fibrose Pulmonar
/
Estreptolisinas
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Thorax
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
Alemanha