Project description:In many pathogens, quorum-sensing systems regulate virulence. Quorum-sensing is therefore often proposed as a target for antivirulence drug development. Coagulase-negative staphylococci are leading causes of nosocomial blood infections and of mortality due to sepsis as the most extreme consequence of such infections. However, there is a severe lack of understanding how virulence and especially quorum-sensing affects coagulase-negative staphylococcal sepsis. Using a mouse systemic infection model, we here show that the staphylococcal Agr quorum-sensing system has a strong impact on mortality from sepsis caused by the exemplary coagulase-negative staphylococcal species Staphylococcus haemolyticus. To that end, we analyzed the mechanism and regulon of S. haemolyticus Agr, which revealed a strong focus of quorum-sensing regulation of phenol-soluble modulin toxins. Our results further indicate that PSMs are the virtually exclusive mediators of the Agr effect on S. haemolyticus sepsis and suggest that the predominant underlying mechanism is cytolytic capacity of PSMs. These findings imply that Agr and PSMs represent promising targets for antivirulence drug development targeting sepsis caused by coagulase-negative staphylococci. This contrasts quorum-sensing targeted efforts to control S. aureus blood infections, for which such approaches are considered less promising - a difference our results suggest is due to the much more focused role of Agr control in coagulase-negative staphylococci, where among toxins, Agr exclusively and exceptionally tightly controls PSMs.
