Abstract
Staphylococcus aureus pathogenesis is significantly influenced by the iron status of the host. However, the regulatory impact of host iron sources on S. aureus gene expression remains unknown. In this study, we combine multivariable difference gel electrophoresis and mass spectrometry with multivariate statistical analyses to systematically cluster cellular protein response across distinct iron-exposure conditions. Quadruplicate samples were simultaneously analyzed for alterations in protein abundance and/or post-translational modification state in response to environmental (iron chelation, hemin treatment) or genetic (Δfur) alterations in bacterial iron exposure. We identified 120 proteins representing several coordinated biochemical pathways that are affected by changes in iron-exposure status. Highlighted in these experiments is the identification of the heme-regulated transport system (HrtAB), a novel transport system which plays a critical role in staphylococcal heme metabolism. Further, we show that regulated overproduction of acidic end-products brought on by iron starvation decreases local pH resulting in the release of iron from the host iron-sequestering protein transferrin. These findings reveal novel strategies used by S. aureus to acquire scarce nutrients in the hostile host environment and begin to define the iron and heme-dependent regulons of S. aureus.
Highlights
Staphylococcus aureus requires iron to successfully colonize the host [1]
To identify proteins that are affected by alterations in host iron sources, we performed differential expression analyses on S. aureus cultures grown under various conditions of iron exposure
Cytoplasmic proteins were prepared from wildtype and Dfur mutant cells grown under either iron-replete conditions, after iron starvation elucidated by treatment with 2,29-dipyridyl (DIP), or after exposure to hemin
Summary
Staphylococcus aureus requires iron to successfully colonize the host [1]. To ensure efficient uptake and metabolism of host iron sources, bacterial pathogens regulate a variety of genes in response to the levels of available iron. The canonical bacterial repressor responsible for this iron-dependent regulation is the ferric uptake regulator (Fur) [2]. S. aureus has a functional Fur which has been implicated in the iron-dependent repression of a subset of genes [3,4,5]. An S. aureus Dfur mutant has a significant defect in virulence in a mouse model of infection, underscoring the importance of iron metabolism to staphylococcal pathogenicity [6]. The demonstrated role for iron and Fur in staphylococcal pathogenesis emphasizes the importance of identifying the iron-dependent Fur regulon of S. aureus
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