Host defense against Pseudomonas aeruginosa requires ceramide-rich membrane rafts

Grassmé, Heike; Jendrossek, Verena; Riehle, Andrea; Kürthy, Gabriele von; Berger, Jürgen; Schwarz, Heinz; Weller, Michael; Kolesnick, Richard; Gulbins, Erich

doi:10.1038/nm823

Cited by 511 publications

(577 citation statements)

References 37 publications

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“…These enzymes catalyze the breakdown of sphingomyelin to ceramide and phosphocholine (Goni & Alonso, 2002). Interestingly, neutral sphingomyelinase (NSM) and ASM are activated in response to various stress stimuli, including hydrogen peroxide, hypoxia, TNF‐α, and infection (Hannun & Luberto, 2000; Grassme et al , 2003; Marchesini & Hannun, 2004). …”

Section: Resultsmentioning

confidence: 99%

Stress‐induced host membrane remodeling protects from infection by non‐motile bacterial pathogens

et al. 2018

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While mucosal inflammation is a major source of stress during enteropathogen infection, it remains to be fully elucidated how the host benefits from this environment to clear the pathogen. Here, we show that host stress induced by different stimuli mimicking inflammatory conditions strongly reduces the binding of Shigella flexneri to epithelial cells. Mechanistically, stress activates acid sphingomyelinase leading to host membrane remodeling. Consequently, knockdown or pharmacological inhibition of the acid sphingomyelinase blunts the stress‐dependent inhibition of Shigella binding to host cells. Interestingly, stress caused by intracellular Shigella replication also results in remodeling of the host cell membrane, in vitro and in vivo, which precludes re‐infection by this and other non‐motile pathogens. In contrast, Salmonella Typhimurium overcomes the shortage of permissive entry sites by gathering effectively at the remaining platforms through its flagellar motility. Overall, our findings reveal host membrane remodeling as a novel stress‐responsive cell‐autonomous defense mechanism that protects epithelial cells from infection by non‐motile bacterial pathogens.

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Section: Resultsmentioning

confidence: 99%

Stress‐induced host membrane remodeling protects from infection by non‐motile bacterial pathogens

et al. 2018

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“…Previous studies published by our group indicate that P. aeruginosa infection of epithelial cells and macrophages activates the acid sphingomyelinase and triggers a translocation of the enzyme onto the extracellular leaflet of the cell membrane [19, 20]. The activity of the acid sphingomyelinase triggers the formation of ceramide-enriched membrane platforms in the outer leaflet.…”

Section: P Aeruginosa Infections and Ceramidementioning

confidence: 97%

“…In vivo studies indicate that stimulation of CD95 and, thus, presumably induction of apoptosis in epithelial cells is central for a coordinated defense against pulmonary P. aeruginosa infections. It might be possible that the induction of apoptosis in epithelial cells modulates the local immune response to the pathogen and prevents an over-exaggerated release of cytokines [19, 20]. Studies from Kumar et al .…”

Section: Inflammation In Cystic Fibrosismentioning

confidence: 99%

“…Ceramide molecules self-associate to small ceramide-enriched membrane microdomains, which have the tendency to spontaneously fuse to large ceramide-enriched membrane domains [36-38]. The formation of ceramide-enriched membrane domains was shown to occur in cells after stimulation via a variety of stimuli including CD95 [39-41], CD40 [42], DR5 [43], FcγRII [44], the PAF-receptor [45], but also after infection with P. aeruginosa [19], Neisseriae gonorrhoeae [46] , Rhinovirus [47], application of stress stimuli such as UV-light [48], cisplatin [49] or Cu 2+ -treatment [50]. The great variety of stimuli that trigger the formation of ceramide-enriched membrane platforms suggests that these membrane domains facilitate signal transduction, but are very likely not part of the specific signal transduction pathway elicited by the these stimuli.…”

Section: Ceramidementioning

confidence: 99%

“…This defect might be caused by the altered pH in intracellular vesicles in Cftr -deficient cells, although the cause for the failure of P. aeruginosa to trigger acid sphingomyelinase and ceramide in Cftr -deficient cells remains to be determined. Ceramide-enriched membrane domains might serve the clustering of receptors, for instance CD95 and Cftr [19]. Genetic deficiency of the acid sphingomyelinase or disruption of rafts by interference with cellular cholesterol prevents formation of ceramide-enriched membrane platforms, internalisation of the bacteria and induction of apoptosis in epithelial cells upon infection with P. aeruginosa , but results in an uncontrolled cytokine release [19].…”

Section: P Aeruginosa Infections and Ceramidementioning

confidence: 99%

See 2 more Smart Citations

The Role of Sphingolipids and Ceramide in Pulmonary Inflammation in Cystic Fibrosis

Becker

Riethmüller²,

Zhang³

et al. 2010

TORMJ

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Sphingolipids and in particular ceramide have been shown to be critically involved in the response to many receptor-mediated, but also receptor-independent, mainly stress stimuli. Recent studies demonstrate that ceramide plays an important role in the pathogenesis of cystic fibrosis, a hereditary metabolic disorder caused by mutations of the Cystic Fibrosis Transmembrane Conductance Regulator. Patients with cystic fibrosis suffer from chronic pulmonary inflammation and microbial lung infections, in particular with Pseudomonas aeruginosa. Chronic pulmonary inflammation in these patients seems to be the initial pathophysiological event. Inflammation may finally result in the high infection susceptibility of these patients, fibrosis and loss of lung function. Recent studies demonstrated that ceramide accumulates in lungs of cystic fibrosis mice and causes age-dependent pulmonary inflammation as indicated by accumulation of neutrophils and macrophages in the lung and increased pulmonary concentrations of Interleukins 1 and 8, death of bronchial epithelial cells, deposition of DNA in bronchi and high susceptibility to Pseudomonas aeruginosa infections. Genetic or pharmacological inhibition of the acid sphingomyelinase blocks excessive ceramide production in lungs of cystic fibrosis mice and corrects pathological lung findings. First clinical studies confirm that inhibition of the acid sphingomyelinase with small molecules might be a novel strategy to treat patients with cystic fibrosis.

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The role of brain innate immune response in lysosomal storage disorders: fundamental process or evolutionary side effect?

Vitner

2020

FEBS Letters

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Sphingolipidoses are diseases caused by mutations in genes responsible for sphingolipid degradation and thereby lead to sphingolipid accumulation. Most sphingolipidoses have a neurodegenerative manifestation characterized by innate immune activation in the brain. However, the role of the immune response in disease progression is ill-understood. In contrast to infectious diseases, immune activation is unable to eliminate the offending agent in sphingolipidoses resulting in ineffective, chronic inflammation. This paradox begs two fundamental questions: Why has this immune response evolved in sphingolipidoses? What role does it play in disease progression? Here, starting from the observation that sphingolipids (SLs) are elevated also in infectious diseases, I discuss the possibility that the activation of the brain immune response by SLs has evolved as a part of the immune response against pathogens and plays no major role in sphingolipidoses.

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Host defense against Pseudomonas aeruginosa requires ceramide-rich membrane rafts

Cited by 511 publications

References 37 publications

Stress‐induced host membrane remodeling protects from infection by non‐motile bacterial pathogens

Stress‐induced host membrane remodeling protects from infection by non‐motile bacterial pathogens

The Role of Sphingolipids and Ceramide in Pulmonary Inflammation in Cystic Fibrosis

The role of brain innate immune response in lysosomal storage disorders: fundamental process or evolutionary side effect?

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