Journal
CELL HOST & MICROBE
Volume 21, Issue 6, Pages 707-+Publisher
CELL PRESS
DOI: 10.1016/j.chom.2017.05.001
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Funding
- DFG [GU 335/35-1, GRK 2098]
- NIH [2 R01 HL075 316-09]
- MRC Clinician Scientist Fellowship [MR/M008797/1]
- Medical Research Council [MR/M008797/1, G0800419] Funding Source: researchfish
- MRC [MR/M008797/1, G0800419] Funding Source: UKRI
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Chronic 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 beta 1-integrins accumulate on the luminal membrane of upper-airway epithelial cells from mice and humans with CF. beta 1-integrin accumulation is due to increased ceramide and the formation of ceramide platforms that trap beta 1-integrins on the luminal pole of bronchial epithelial cells. beta 1-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 beta 1-integrin internalization via anti-beta 1-integrin antibodies or the RGD peptide ligand-or by genetic or pharmacological correction of ceramide levels-normalizes beta 1-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.
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