Staphylococcus aureus (S. aureus ) is an extremely versatile bacterial pathogen that causes significant disease burden. Its effectiveness in causing disease is due in part to its ability to adapt to diverse host niches. S. aureus senses environmental changes and subsequently adjusts the production of virulence factors needed to initiate and sustain an infection, while combating host immune defenses. Despite the importance of environmental cues on S. aureus pathogenicity, only a limited number of these signals have been investigated in detail for their ability to modulate virulence. During this thesis work, we showed that the central metabolite pyruvate alters the overall metabolic flux of S. aureus, influencing pathways such as central metabolism and amino acid metabolism, and ultimately enhancing the pathogenicity of S. aureus. We demonstrated that pyruvate stimulates production of virulence factors such as the cytolytic leukocidins, and that this induction is responsible for the increased virulence we observe in USA300 LAC, a strain of community acquired methicillin resistant S. aureus (CA-MRSA). Specifically, we showed that an efficient “pyruvate response” requires the ArlRS two-component system, which modulates the Agr quorum sensing system to reduce the production of Rot, a key repressor of toxins. Altogether, these studies further establish a strong relationship between metabolism and virulence and, through activation of intricate but complex regulatory networks identifies pyruvate as an important regulatory signal for the coordination of S. aureus virulence.
|Advisor:||Torres, Victor J.|
|Commitee:||Borowiec, James, Boyd, Jeffrey, Darwin, Andrew, Shopsin, Bo|
|School:||New York University|
|Department:||Basic Medical Science|
|School Location:||United States -- New York|
|Source:||DAI-B 79/08(E), Dissertation Abstracts International|
|Subjects:||Molecular biology, Microbiology|
|Keywords:||ArlRS, Leukocidin, Pyruvate, Staphylococcus aureus, Two-component system, Virulence|
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