Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Microbiology and Immunology

Supervisor

Dr. David Heinrichs

Abstract

Staphylococcus aureus is a human pathogen capable of causing infections that range from mild skin and soft tissue infections to severe infections of the bone, muscle, heart, and lung. To survive and thrive in such diverse host environments, S. aureus must maintain sufficient levels of metabolites and cofactors to support virulence determinant production and replication. The branched-chain amino acids (BCAAs; Ile, Leu, Val) represent an important group of nutrients for S. aureus metabolism, as they are required for protein synthesis and synthesis of membrane branched-chain fatty acids (BCFAs), which are important for S. aureus environmental adaptation. Moreover, the BCAAs are co-repressors for the global transcriptional regulator CodY, which coordinates expression of nutrient scavenging and synthesis systems, as well as virulence genes, upon depletion of both BCAAs and GTP. The requirement of BCAAs for both S. aureus replication and niche adaptation necessitates that it either synthesize these nutrients or acquire them from the environment. Although S. aureus possesses the genes required for BCAA biosynthesis, it was previously reported as auxotrophic for Leu and Val. Further, BCAAs are presumed to be limited at host infection sites. In this study, we used a genetic approach to examine the mechanisms of BCAA acquisition in S. aureus and determine the conditions where BCAA synthesis is turned on. We found that S. aureus necessitates two BCAA transporters, BrnQ1 and BcaP, for growth and BCFA synthesis, with the requirement for BCAA transport in vivo depending on the infection site. We further determined that S. aureus does indeed engage in BCAA biosynthesis, but it represses synthesis in the presence of an exogenous BCAA source. This source preference is regulated by at least two mechanisms that sense exogenous levels of BCAAs, resolving the conundrum of why S. aureus appeared auxotrophic for Leu and Val. Altogether, this research defines the major pathways of BCAA acquisition in S. aureus and reveals the niche-specific requirement of nutrient acquisition pathways for S. aureus virulence, highlighting the impressive adaptability of S. aureus to nutrient deprivation and its sophistication at exploiting host nutrient sources.

Available for download on Sunday, September 01, 2019


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