Role of the acid sphingomyelinase/ceramide system in lung edema induced by Staphylococcus aureus toxin
Final Report Abstract
The present proposal aimed to investigate whether (i) Staphylococcus α-toxin mediates its cellular effects via the acid sphingomyelinase, (ii) to define the molecular mechanisms how α-toxin regulates the acid sphingomyelinase and (iii) to characterize the cellular effects of an activation of the acid sphingomyelinase by α-toxin. In our studies we were able to demonstrate that S. aureus α-toxin activates the acid sphingomyelinase via a pathway that involves ADAM-10, CD44 and oxygen radicals. In vivo studies revelaed that activation of the acid sphingomyelinase results in massive alterations of tight junctions in a septic mouse model. In addition, activation of the acid sphingomyelinase by α-toxin induces stimulation of the Rho-GTPase and a translocation of ezrin, radixin und moesin to the cell membrane. Infection of cystic fibrosis mice with a the wildtype strain of S. aureus resulted in a pneumonia, while S. aureus mutants that lack expression of α-toxin were much less pathogenic. We were also able to show that treatment of macrophages with α-toxin triggers the formation of ceramide within lysosomes. Lysosomal ceramide mediates a release of cathepsin B into the cytoplasm that in turn activates the inflammasome and a release of IL-1β. Further, we investigated the effects of a panel of other toxins on the acid sphingomyelinase: The results showed a rather specific activation of the acid sphingomyelinase by α-toxin. Studies on the mechanisms of the interaction between α-toxin and the acid sphingomyelinase finally revealed that membrane integration of staphylococcal α-toxin results in a recruitment of peripheral lysosomes to the host cell surface and a release of the acid sphingomyelinase. These results indicate that staphylococcal α-toxin triggers a membrane repair mechanism, during which acid sphingomyelinase is recruited to the extracellular leaflet of the cell membrane or released into the extracellular space.
Publications
-
Staphylococcus aureus α-Toxin induces inflammatory cytokines via lysosomal acid sphingomyelinase and ceramides. Cell Physiol Biochem 2017;43:2170-2184
Ma, Jie; Gulbins, Erich; Edwards, Michael J.; Caldwell, Charles C.; Fraunholz, Martin & Becker, Katrin Anne
-
Staphylococcus survives in cystic fibrosis macrophages forming a reservoir for chronic pneumonia. Infect Immun 2017;85,pii: e00883-16
Li, Cao; Wu, Yuqing; Riehle, Andrea; Ma, Jie; Kamler, Markus; Gulbins, Erich & Grassmé, Heike
-
Pulmonary infection of cystic fibrosis mice with Staphylococcus aureus requires expression of α-toxin. Biol Chem 2018;399:1203-1213
Keitsch, Simone; Riethmüller, Joachim; Soddemann, Matthias; Sehl, Carolin; Wilker, Barbara; Edwards, Michael J.; Caldwell, Charles C.; Fraunholz, Martin; Gulbins, Erich & Becker, Katrin Anne
-
Regulation of Staphylococcus aureus infection of macrophages by CD44, reactive oxygen species and acid sphingomyelinase. Antioxid Redox Signal 2018;28:916-934
Li, Cao; Wu, Yuqing; Riehle, Andrea; Orian-Rousseau, Véronique; Zhang, Yang; Gulbins, Erich & Grassmé, Heike
-
Staphylococcus aureus alpha-toxin disrupts endothelial-cell tight junctions via acid sphingomyelinase and ceramide. Infect Immun 2017;86. pii: e00606-17
Becker, Katrin Anne; Fahsel, Björn; Kemper, Hannes; Mayeres, Joelina; Li, Cao; Wilker, Barbara; Keitsch, Simone; Soddemann, Matthias; Sehl, Carolin; Kohnen, Marcus; Edwards, Michael J.; Grassmé, Heike; Caldwell, Charles C.; Seitz, Aaron; Fraunholz, Martin & Gulbins, Erich
