P06

Overview:

We have previously shown that the acid sphingomyelinase/ceramide system is an important mediator of bacterial infections. Recently, we showed that acid sphingomyelinase and ceramide mediate the disruption of tight junctions of endothelial cells in vitro and in vivo upon infection with Staphylococcus aureus (S. aureus). We further demonstrated that the acid sphingomyelinase/ceramide system is necessary for the development of lung edema during S. aureus sepsis and that genetic deficiency or pharmacological inhibition of acid sphingomyelinase protects mice from S. aureus-induced lung edema, disruption of endothelial tight junction proteins, and recruitment of neutrophils into the lung. Most importantly, acid sphingomyelinase deficiency also prevents the lethal effects of systemic infection with S. aureus. Using a panel of S. aureus mutants and recombinant or purified toxins, we will define the bacterial toxins that activate the acid sphingomyelinase/ceramide system in endothelial cells and thereby induce lung edema; characterize the molecular mechanisms by which these toxins stimulate acid sphingomyelinase and trigger the release of ceramide; and define the cellular targets that disrupt endothelial tight junctions upon S. aureus-mediated activation of the acid sphingomyelinase/ceramide system in vitro and in vivo.

Publications:

1.) Peng H, Li C, Kadow S, Henry BD, Steinmann J, Becker KA, Riehle A, Beckmann N, Wilker B, Li PL, Pritts T, Edwards MJ, Zhang Y, Gulbins E, Grassmé H. (2015) Acid sphingomyelinase inhibition protects mice from lung edema and lethal Staphylococcus aureus sepsis. J. Mol. Med. (Berl) 93:675-689.

2.) Grosz M, Kolter J, Paprotka K, Winkler AC, Schäfer D, Chatterjee SS, Geiger T, Wolz C, Ohlsen K, Otto M, Rudel T, Sinha B, Fraunholz M. (2014) Cytoplasmic replication of Staphylococcus aureus upon phagosomal escape triggered by phenol-soluble modulin α. Cell Microbiol 16:451-465.

3.) Das S, Lindemann C, Young BC, Muller J, Österreich B, Nicola Ternette N, Winkler AC, Paprotka K, Reinhardt R, Förstner KU, Allen E, Flaxman A, Yamaguchi Y, Rollier CS, Van Diemen P, Blättner S, Remmele CW, Selle M, Dittrich M, Müller T, Vogel J, Ohlsen K, Crook D, Massey R, Wilson DJ, Rudel T, Wyllie DH, Fraunholz MJ. Naturally occurring mutations in a Staphylococcus aureus virulence regulator attenuate cytotoxicity but permit bacteremia and abscess formation. PNAS 2016, in press.

4.) Henry BD*, Neill DR*, Becker KA*, Gore S, Bricio-Moreno L, Ziobro R, Edwards MJ, Mühlemann K, Steinmann J, Kleuser B, Japtok L, Luginbühl M, Wolfmeier, Scherag A, Gulbins E*, Kadioglu A*, Draeger A*, Babiychuk EB*. 82015) Engineered liposomes sequester bacterial endotoxins and protect from severe invasive infections in mice. Nat Biotechnol 2015;33:81-88. *Shared first authorship and senior authorship.