Mutagenesis and structural analysis of the Staphylococcus Aureus Sae two-component system reveals the intricate nature of virulence regulation

Staphylococcus aureus is a ubiquitous pathogen that can cause both acute and chronic diseases in a variety of human tissues. S. aureus’s ability to cause such a wide range of diseases is made possible by the large arsenal of toxins, exoenzymes and adhesins encoded in its genome. Activating a specific set of these virulence factors based on its surrounding environment allows S. aureus to evade and destroy host immune cells. This thesis provides insight into how S. aureus uses the SaeS sensor kinase from the sae two-component system to recognize specific pieces of the human immune system and induce a transcriptional response tailored for its environment. A mutation was identified that can prevent activation of the sae system and prevent the production of many of S. aureus’s major toxins including α-toxin, significantly reducing its virulence. This thesis also investigates the role of the sae auxiliary protein SaeP and provides evidence to suggest a novel DNA binding function that may be involved in fine-tuning the activity of the sae system. Overall, these studies provide insight into the sae signal transduction mechanism and illustrate the intricate nature of bacterial signaling and the complexity of host-pathogen interactions.