Date of Degree
PhD (Doctor of Philosophy)
Alexander R. Horswill
First Committee Member
Linda L McCarter
Second Committee Member
John R Kirby
Third Committee Member
Craig D Ellermeier
Fourth Committee Member
W. Scott Moye-Rowley
Two-component systems (TCSs) are highly conserved across bacteria and are used to rapidly sense and respond to changing environmental conditions. The human pathogen Staphylococcus aureus uses the S. aureus exoprotein expression (sae) TCS to sense host signals and activate transcription of virulence factors essential to pathogenesis. Despite its importance, the mechanism by which the sae sensor kinase SaeS recognizes specific host stimuli is unknown. This thesis describes topology and mutagenesis studies of the sensing domain of SaeS, including basal expression and inducer-dependent phenotypes. Meanwhile, investigation of the sae auxiliary protein SaeP has identified a novel DNA binding function for this surface expressed lipoprotein that may be involved in fine-tuning the activity of the sae system. Overall, these structure-function studies provide insight into the sae signal transduction mechanism and raise some new questions regarding the role the sae system plays in the larger regulatory network S. aureus uses to control expression of its secreted virulence factors.
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.
sae, SaeP, SaeS, signal transduction, Staphylococcous aureus, two-component system
xviii, 217 pages
Includes bibliographical references (pages 207-217).
Copyright © 2014 Caralyn E. Flack
Flack, Caralyn E.. "Mutagenesis and structural analysis of the Staphylococcus Aureus Sae two-component system reveals the intricate nature of virulence regulation." PhD (Doctor of Philosophy) thesis, University of Iowa, 2014.