Hall, Jeffrey W.2014-04-152014-04-152014-03https://hdl.handle.net/11299/162973University of Minnesota Ph.D. dissertation. March 2014. Major: Microbiology, Immunology and Cancer Biology. Advisor: Yinduo Ji, Ph.D. 1 computer file (PDF); xviii, 208 pages, appendix p. 208.<italic>Staphylococcus aureus<italic> is a major opportunistic pathogen and a common cause of hospital- and community-acquired infections. Furthermore, infections of livestock animals by <italic>S. aureus<italic> results in billion dollar losses to agriculture producers annually. Over the last five decades antibiotic resistance has dramatically increased in <italic>S. aureus<italic> and highly pathogenic strains have emerged that threaten human and animal health. Characterization of highly pathogenic strains and novel transcriptional mechanisms and pathways is of utmost importance as it will provide a critical evolutionary understanding of the transcriptional changes that led to the emergence of successfully infectious <italic>S. aureus<italic> strains and may identify novel targets for antibacterial development. The overarching goal of research described in this thesis was to characterize and understand how novel <italic>cis<italic>- and <italic>trans<italic>-acting factors affect gene expression in <italic>S. aureus<italic>. To that end, the work and data presented investigate the effect of promoter based single nucleotide polymorphisms (SNPs) of the <italic>hla<italic> gene, encoding &#945;-toxin, on gene transcription and gene product expression. The <italic>cis<italic>-acting SNPs increased the binding affinity of the promoter to the trans-acting transcription factor SarZ. Furthermore, the <italic>S. aureus<italic> RF122 strain had increased transcriptional expression of several positive regulators and decreased transcription of negative regulators of <italic>hla<italic>, which resulted in a dramatic increase in &#945;-toxin expression and likely contributes to the increased mastitis pathogenesis of RF122. Additionally, the essentiality of the <italic>yhcSR<italic> two-component system was confirmed in the hospital-acquired methicillin resistant <italic>S. aureus<italic> WCUH29 strain. The YhcSR TCS was identified to transcriptionally activate the <italic>lacABCDE<italic> and <italic>opuCABC<italic> operons involved in cellular metabolism and osmoregulatory mechanisms, respectively. In an effort determine if a relationship existed between YhcSR and pathogenesis, studies revealed that the YhcSR TCS transcriptionally regulated, in a positive manner, the <italic>sspABC<italic> and <italic>crtOPQMN<italic> operons, encoding exported proteases and staphyloxanthin biosynthesis, which contribute to the survival of <italic>S. aureus<italic> in human blood. The data indicate that the YhcSR TCS system is an essential <italic>trans<italic>-acting global regulator in <italic>S. aureus<italic>.en-USessentialSNPsStaphylococcusTranscriptionTwo-component systemThesis or Dissertation