Staphylococcus aureus is both a commensal of humans and a highly dangerous bacterial pathogen. S. aureus pathogenesis is mediated by a large repertoire of secreted and cell wall-associated virulence factors. To mount successful infections the bacteria must regulate expression of the genes encoding these virulence factors in a temporal and spatial manner. Two component signal transduction systems (TCS) are one type of regulatory circuit that bacterial cells use to sense their environment and modify gene expression accordingly. The Sae TCS is a global regulator of secreted protein production in S. aureus and a variety of well-studied virulence factors are known to be directly controlled by the Sae system. Activity of the Sae system is dependent on the balance between the kinase and phosphatase activities of the sensor protein SaeS. Human neutrophil peptide 1 (HNP-1) is known to activate SaeS kinase activity, while the Sae auxiliary proteins SaePQ induce phosphatase activity. Recent work in our laboratory has identified a potent, novel activator of the Sae system. Overexpression of the tsr37 gene in S. aureus results in a dramatic increase in Sae activity and upregulation of Sae target genes. In this proposal we will investigate the nature of the tsr37 gene product, investigate how tsr37 activates the Sae system, and determine the contribution of tsr37 to virulence. In addition, we will study the in vivo expression profile of tsr37 to determine when and where it is expressed during systemic infection. We anticipate that the results from this study will demonstrate that a short protein, Tsr37, acts as a potent activator of the Sae TCS. Understanding how a small peptide interacts with, and activates, the Sae system could inform future studies to design Sae inhibitors which could be used as a novel therapeutic to treat S. aureus infection.
The Sae regulatory system controls expression of a large number of virulence genes in Staphylococcus aureus. We have identified a novel protein, Tsr37, that is a potent activator of the Sae system. In this proposal we will further characterize Tsr37, investigate how it activates the Sae system, and determine its role during infection.