Sphingoid long chain bases prevent lung infection by Pseudomonas aeruginosa

EMBO Molecular Medicine

Yael Pewzner-Jung⁷  Shaghayegh Tavakoli Tabazavareh⁴  Heike Grassmé⁴  Katrin Anne Becker⁴  Lukasz Japtok⁵  Jörg Steinmann⁸  Tammar Joseph⁷  Stephan Lang²  Burkhard Tuemmler¹  Edward H Schuchman³  Alex B Lentsch⁶  Burkhard Kleuser⁵  Michael J Edwards⁶  Anthony H Futerman⁷ 

[1] Klinische Forschergruppe, OE 6710, Medizinische Hochschule Hannover, Hannover, Germany;Department of Otorhinolaryngology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany;Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA;Department of Molecular Biology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany;Department of Nutritional Science, University of Potsdam, Potsdam, Germany;Department of Surgery, University of Cincinnati, Cincinnati, OH, USA;Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel;Department of Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

关键词: cystic fibrosis;    long chain base;    lung infection;    Pseudomonas aeruginosa;    sphingosine;   

DOI  :  10.15252/emmm.201404075

来源: Wiley

【 摘 要 】

Abstract

Cystic fibrosis patients and patients with chronic obstructive pulmonary disease, trauma, burn wound, or patients requiring ventilation are susceptible to severe pulmonary infection by Pseudomonas aeruginosa. Physiological innate defense mechanisms against this pathogen, and their alterations in lung diseases, are for the most part unknown. We now demonstrate a role for the sphingoid long chain base, sphingosine, in determining susceptibility to lung infection by P. aeruginosa. Tracheal and bronchial sphingosine levels were significantly reduced in tissues from cystic fibrosis patients and from cystic fibrosis mouse models due to reduced activity of acid ceramidase, which generates sphingosine from ceramide. Inhalation of mice with sphingosine, with a sphingosine analog, FTY720, or with acid ceramidase rescued susceptible mice from infection. Our data suggest that luminal sphingosine in tracheal and bronchial epithelial cells prevents pulmonary P. aeruginosa infection in normal individuals, paving the way for novel therapeutic paradigms based on inhalation of acid ceramidase or of sphingoid long chain bases in lung infection.

Synopsis

Sphingosine functions as an important anti-bacterial agent in healthy airways but this defence mechanism is lost in cystic fibrosis. The sensitivity of cystic fibrosis mice to infection can be corrected by inhalation of sphingosine or acid ceramidase.

• Sphingosine is present on the luminal side of trachea and bronchi epithelia in healthy individuals.
• Sphingosine level is reduced on trachea and bronchi epithelia in diseases such as cystic fibrosis or in mice lacking ceramide synthase 2.
• Acid ceramidase or sphingosine inhalation corrects sphingosine levels in cystic fibrosis and ceramide synthase 2-deficient mice, prevents their infection with Pseudomonas aeruginosa and cures an existing Pseudomonas aeruginosa infection.
• Sphingosine kills a broad spectrum of pathogens at nanomolar to low micromolar concentrations including Pseudomomas aeruginosa, Acinetobacter baumannii, Haemophilus influenzae, Moraxella catarrhalis and Burkholderia cepacia.

【 授权许可】

CC BY   
© 2014 The Authors. Published under the terms of the CC BY 4.0 license

Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.