Project Details
Projekt
Role of the acid sphingomyelinase/ceramide system in lung edema induced by Staphylococcus aureus toxin
Subject Area
Parasitology and Biology of Tropical Infectious Disease Pathogens
Term
from 2017 to 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 242127429
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.
DFG Programme
Research Units
Subproject of
FOR 2123:
Sphingolipid Dynamics in Infection Control
