Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Microbiology and Immunology

Supervisor

Heinrichs, David E.

Abstract

All microorganisms require transition metals for key metabolic processes, thus during infection microbial access to essential metals is tightly regulated by the host in a process termed nutritional immunity. Iron acquisition is critical to the pathogenesis of the formidable human pathogen, Staphylococcus aureus, which utilizes heme-uptake systems and two high-affinity iron-scavenging siderophores, staphyloferrin A (SA) and staphyloferrin B (SB) for iron acquisition. In this study, I identify sbnI as encoding a transcription factor required for expression of genes in the sbn operon, the biosynthetic operon for SB synthesis. I also show that SbnI is a novel hemoprotein, where binding to heme abrogates its ability to bind DNA. Thus this work proposes a novel mechanism in which S. aureus controls SB synthesis in response to heme. Although free iron is scarce in the host, copper at the host-pathogen interface is found in excess. Copper is highly reactive and in macrophages is imported into phagosomes where it exerts bactericidal effects. S. aureus flourishes within macrophages and therefore must resist copper-mediated killing. I demonstrate that the USA300 strain of Community-Associated MRSA relies on CopAZ and CopBL for copper detoxification; where CopA and newly identified CopB are copper-translocating efflux pumps, CopZ is a copper-binding chaperone, and CopL is a novel copper-responsive lipoprotein. Finally, CopAZ, in accord with CopBL, aid in S. aureus survival in murine macrophages. This study examines two important facets of nutritional immunity and the virulence factors used by S. aureus to overcome obstacles posed by the host in maintaining metal homeostasis.

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