Sphingoid long chain bases prevent lung infection by <i>Pseudomonas aeruginosa</i>

Pewzner-Jung, Yael; Tabazavareh, Shaghayegh Tavakoli; Grassmé, Heike; Becker, Katrin Anne; Japtok, Lukasz; Steinmann, Jörg; Joseph, Tammar; Lang, Stephan; Tuemmler, B.; Schuchman, Edward H.; Lentsch, Alex B.; Kleuser, Burkhard; Edwards, Michael J.; Futerman, Anthony H.; Gulbins, Erich

doi:10.15252/emmm.201404075

Cited by 111 publications

(224 citation statements)

References 25 publications

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“…Cystic fibrosis mice are also protected from P. aeruginosa infection by inhaling sphingosine analogs such as FTY 720. These results have also been demonstrated in ceramide synthase 2 (CerS2)-deficient mice, which also lack sphingosine in their epithelial cells and that are highly susceptible to pulmonary bacterial infection (Pewzner-Jung et al, 2014).…”

Section: Sphingosine In Cystic Fibrosis and Pulmonary Infectionsmentioning

confidence: 76%

“…Cystic fibrosis epithelial cells, conversely, lack sphingosine, and enhanced ceramide concentrations promote lung infection by inducing chronic inflammation, reducing mucociliary clearance, and inducing the death of epithelial cells. These findings also suggest that acid ceramidase, sphingosine, or sphingosine analogs may be novel treatment options for patients susceptible to bacterial pneumonia (Pewzner-Jung et al, 2014). Healthy airways contain low concentrations of ceramide and high levels of sphingosine, whereas the concentrations of the two lipids are just the opposite in cystic fibrosis cells.…”

Section: Sphingosine In Cystic Fibrosis and Pulmonary Infectionsmentioning

confidence: 89%

“…In cystic fibrosis lungs, the concentrations of both sphingosine and ceramide are altered, and these alterations result in high susceptibility to infection. Although sphingosine and ceramide are certainly not the only molecules controlling infection, their normalization is sufficient to prevent infection in cystic fibrosis mice, even if other defense mechanisms are still impaired (Pewzner-Jung et al, 2014). Our current hypothesis is that sphingosine kills invading bacteria in healthy epithelial cells.…”

Section: Sphingosine In Cystic Fibrosis and Pulmonary Infectionsmentioning

confidence: 90%

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Ceramide and sphingosine in pulmonary infections

Seitz

Grassmé

Edwards

et al. 2015

Biological Chemistry

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Acid sphingomyelinase and ceramide have previously been shown to play a central role in infections with Neisseria gonorrhoeae, Staphylococcus aureus, Listeria monocytogenes, Pseudomonas aeruginosa, Salmonella typhimurium, Escherichia coli, and Mycobacterium avium. Recent studies have extended the role of sphingolipids in bacterial infections and have demonstrated that ceramide and sphingosine are central to the defense of lungs against bacterial pathogens. Ceramide accumulates in the airway epithelium of cystic fibrosis and ceramide synthase 2 (CerS2)-deficient mice, which respond to the lack of very long chain (C22-C24-) ceramides with a profound compensatory increase of long chain (mainly C16-) ceramides. In contrast, sphingosine is present in healthy airways and is almost completely absent from diseased or deficient epithelial cells. Both sphingolipids are crucially involved in the high susceptibility to infection of cystic fibrosis and CerS2-deficient mice, as indicated by findings showing that the normalization of ceramide and sphingosine levels rescue these mice from acute infection with P. aeruginosa.

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Section: Sphingosine In Cystic Fibrosis and Pulmonary Infectionsmentioning

confidence: 76%

Section: Sphingosine In Cystic Fibrosis and Pulmonary Infectionsmentioning

confidence: 89%

Section: Sphingosine In Cystic Fibrosis and Pulmonary Infectionsmentioning

confidence: 90%

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Ceramide and sphingosine in pulmonary infections

Seitz

Grassmé

Edwards

et al. 2015

Biological Chemistry

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“…We have previously shown that ceramide accumulates in Cftr-deficient airway epithelial cells and macrophages, while sphingosine expression decreases in the epithelial cells of the upper respiratory tract of CF mice (40). The subcellular distribution of ceramide and sphingosine in Cftr-deficient macrophages cells was not investigated in these studies, and it is unknown whether the change in these two lipids in Cftr-deficient cells has an impact on vesicular trafficking and fusion.…”

Section: Discussionmentioning

confidence: 99%

Staphylococcus aureus Survives in Cystic Fibrosis Macrophages, Forming a Reservoir for Chronic Pneumonia

Cao

Riehle

et al. 2017

Infect Immun

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Staphylococcus aureus plays an important role in sepsis, pneumonia, wound infections, and cystic fibrosis (CF), which is caused by mutations of the cystic fibrosis transmembrane conductance regulator (Cftr). Pulmonary S. aureus infections in CF often occur very early and prior to colonization with other pathogens, in particular Pseudomonas aeruginosa. Here, we demonstrate that CF mice are highly susceptible to pulmonary infections with S. aureus and fail to clear the pathogen during infection. S. aureus is internalized by Cftr-deficient macrophages in the lung, but these macrophages are unable to kill intracellular bacteria. This failure might be caused by a defect in the fusion of phagosomes with lysosomes, while this process occurs rapidly in wild-type macrophages and serves to kill intracellular pathogens. Transplantation of infected Cftr-deficient alveolar macrophages into the lungs of noninfected CF mice is sufficient to induce pneumonia. This suggests that intracellular survival of S. aureus in macrophages may allow the pathogen to chronically infect CF lungs.

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“…Numerous studies have shown that expression of ceramide and sphingosine is altered in the respiratory tract of cystic fibrosis patients and mice and that both sphingolipids have an important role in P. aeruginosa infections [8,14,17,37]. Based on these findings, we aimed to determine if there is a difference in expression of the glycosphingolipids glucosylceramide (GlcCer) and lactosylceramide (LacCer) in the respiratory tract between wild type (WT) and CF mice.…”

Section: Glycosylsphingolipids In the Respiratory Tractmentioning

confidence: 99%

Glucosylceramide Critically Contributes to the Host Defense of Cystic Fibrosis Lungs

Kovacic

Sehl

Wilker

et al. 2017

Cell Physiol Biochem

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Background: Cystic fibrosis (CF) is the most common autosomal-recessive disorder in western countries. Previous studies have demonstrated an important role of sphingolipids in the pathophysiology of cystic fibrosis. It has been shown that ceramide has a central role in various pulmonary infections, including those with Pseudomonas aeruginosa (P. aeruginosa). Ceramide is accumulated in the airways of CF mice and patients. However, little is known about a potential role of glucosylceramide in cystic fibrosis. Methods: We investigated the expression of glucosylceramide and lactosylceramide in the respiratory tract of murine and human CF samples by immunohistochemistry and analyzed effects of glucosylceramide on P. aeruginosa in vitro. We performed pulmonary infections with P. aeruginosa and tested inhalation with glucosylceramide. Results: We demonstrate that glucosylceramide is down-regulated on the apical surface of bronchial and tracheal epithelial cells in cystic fibrosis mice. Although glucosylceramide did not have a direct bactericidal effect on Pseudomonas aeruginosa in vitro, inhalation of CF mice with glucosylceramide protected these mice from infection with P. aeruginosa, while non-inhaled CF mice developed severe pneumonia. Conclusion: Our data suggest that glucosylceramide acts in vivo in concert with ceramide and sphingosine to determine the pulmonary defense against P. aeruginosa.

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Sphingoid long chain bases prevent lung infection by Pseudomonas aeruginosa

Cited by 111 publications

References 25 publications

Ceramide and sphingosine in pulmonary infections

Ceramide and sphingosine in pulmonary infections

Staphylococcus aureus Survives in Cystic Fibrosis Macrophages, Forming a Reservoir for Chronic Pneumonia

Glucosylceramide Critically Contributes to the Host Defense of Cystic Fibrosis Lungs

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