Streptococcus pneumoniae triggers progression of pulmonary fibrosis through pneumolysin.

Thorax. 2015 May 11. pii: thoraxjnl-2014-206420. doi: 10.1136/thoraxjnl-2014-206420. [Epub ahead of print]

Streptococcus pneumoniae triggers progression of pulmonary fibrosis through pneumolysin.

Knippenberg S1, Ueberberg B1, Maus R1, Bohling J1, Ding N1, Tort Tarres M1, Hoymann HG2, Jonigk D3, Izykowski N3, Paton JC4, Ogunniyi AD4, Lindig S5, Bauer M5, Welte T6, Seeger W7, Guenther A7, Sisson TH8, Gauldie J9, Kolb M9, Maus UA10.

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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-β1 (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 AdTGFβ1-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 AdTGFβ1-exposed mice. Importantly, vaccination of mice with the non-cytotoxic Ply derivative B (PdB) substantially attenuated Ply-induced progression of lung fibrosis in AdTGFβ1-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.

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KEYWORDS:

Bacterial Infection; Idiopathic pulmonary fibrosis; Respiratory Infection

PMID: 25964315 [PubMed - as supplied by publisher]