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
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Staphylococcus aureus alpha-toxin disrupts endothelial-cell tight junctions via acid sphingomyelinase and ceramide. Infect Immun 2017;86. pii: e00606-17
Becker KA, Fahsel B, Kemper H, Mayeres J, Li C, Wilker B, Keitsch S, Soddemann M, Sehl C, Kohnen M, Edwards MJ, Grassmé H, Caldwell CC, Seitz A, Fraunholz M, Gulbins E
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Staphylococcus aureus α-Toxin induces inflammatory cytokines via lysosomal acid sphingomyelinase and ceramides. Cell Physiol Biochem 2017;43:2170-2184
Ma J, Gulbins E, Edwards MJ, Caldwell CC, Fraunholz M, Becker KA
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Staphylococcus survives in cystic fibrosis macrophages forming a reservoir for chronic pneumonia. Infect Immun 2017;85,pii: e00883-16
Li C, Wu Y, Riehle A, Ma J, Kamler M, Gulbins E, Grassmé H
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Pulmonary infection of cystic fibrosis mice with Staphylococcus aureus requires expression of α-toxin. Biol Chem 2018;399:1203-1213
Keitsch S, Riethmüller J, Soddemann M, Sehl C, Wilker B, Edwards MJ, Caldwell CC, Fraunholz M, Gulbins E, Becker KA
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Regulation of Staphylococcus aureus infection of macrophages by CD44, reactive oxygen species and acid sphingomyelinase. Antioxid Redox Signal 2018;28:916-934
Li C, Wu Y, Orian-Rousseau V, Zhang Y, Gulbins E, Grassmé H
