• Heike Grassmé, Brian Henry, Regan Ziobro, Katrin Anne Becker, Joachim Riethmüller, Aaron Gardner, Aaron P Seitz, Joerg Steinmann, Stephan Lang, Christopher Ward, Edward H Schuchman, Charles C Caldwell, Markus Kamler, Michael J Edwards, Malcolm Brodlie, and Erich Gulbins.
• Department of Molecular Biology, University of Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany.
• Cell Host Microbe. 2017 Jun 14; 21 (6): 707-718.e8.

AbstractChronic pulmonary colonization with bacterial pathogens, particularly Pseudomonas aeruginosa, is the primary cause of morbidity and mortality in patients with cystic fibrosis (CF). We observed that β1-integrins accumulate on the luminal membrane of upper-airway epithelial cells from mice and humans with CF. β1-integrin accumulation is due to increased ceramide and the formation of ceramide platforms that trap β1-integrins on the luminal pole of bronchial epithelial cells. β1-integrins downregulate acid ceramidase expression, resulting in further accumulation of ceramide and consequent reduction of surface sphingosine, a lipid that kills bacteria. Interrupting this vicious cycle by triggering surface β1-integrin internalization via anti-β1-integrin antibodies or the RGD peptide ligand-or by genetic or pharmacological correction of ceramide levels-normalizes β1-integrin distribution and sphingosine levels in CF epithelial cells and prevents P. aeruginosa infection in CF mice. These findings suggest a therapeutic avenue to ameliorate CF-associated bacterial infections.Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

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