| dc.description.abstract | During infection, pathogens must sense and respond to their environment to survive. In this thesis, I explore the mechanisms by which the gram-positive pathogens Bacillus anthracis and Staphylococcus aureus sense and adapt to their environment to maintain homeostasis. Two-component systems (TCSs) are a conserved mechanism used by bacteria to sense and respond to environmental stimuli. HitRS and HssRS are two important TCSs used by B. anthracis to sense cell envelope damage and heme levels, respectively. Since the signals which activate HitRS and HssRS may damage the membrane-bound histidine kinases, it was previously unknown how B. anthracis maintains appropriate TCS signaling in the face of membrane damage. Here, we describe a mechanism by which components of the HitRS and HssRS TCSs are regulated by the proteostatic regulators DnaJ and ClpX in Bacillus anthracis. Future directions for investigating the mechanism of TCS regulation by DnaJ and ClpX and elucidating the host factors that activate HitRS are also discussed.
Heme is an important, yet toxic, molecule that serves as a redox-active cofactor in many organisms including the pathogen Staphylococcus aureus. Elevated heme levels are sensed by the HssRS TCS, which induces the expression of the HrtAB efflux pump. The synthesis of heme must also be tightly regulated to avoid heme toxicity. In the latter chapters of this thesis, I describe experiments investigating how heme status regulates the heme synthesis enzyme GtrR. Additionally, I identify Stk1 and Stp1, a conserved kinase and phosphatase pair, as potential regulators of heme synthesis. Future directions investigating the trafficking of heme and regulation of heme synthesis by Sk1 and Stp1 are also discussed. The results of the work described expand our understanding of how gram-positive pathogens maintain appropriate stress sensing and regulate the synthesis of heme to maintain homeostasis. | |
