S. aureus is a natural commensal of the human host and an opportunistic pathogen that causes a wide range of diseases. Biofilm formation is an important S. aureus virulence determinant. S. aureus colonisation of medical devices and host tissues as a biofilm can impede treatment as genetically and metabolically diverse cells in the different layers of the film can prevent the penetration or activity of the therapeutic agent used. Biofilm formation is a multi-factorial process which can be influenced by many environmental factors. A major environmental stress encountered by bacteria in vivo is severe iron-restriction. However, pathogenic bacteria can use low iron concentrations as a signal to up regulate factors responsible for virulence. This work demonstrates for the first time that S. aureus biofilm formation is iron regulated. It demonstrates that biofilms formed in low iron are dependant on the proteins Eap and Emp which are also iron regulated and are positively regulated by the ferric uptake regulator, Fur. This work has also identified that PNAG, which currently has a controversial role in biofilm formation, was capable of compensating for the loss of Eap and Emp in low iron when it was over expressed, but that wild type levels of PNAG appeared to have a limited role. Nevertheless, the ica operon responsible for the production of PNAG was essential for the expression of Eap and Emp. In addition, Sae, Fur, Agr, SarA and Hfq were shown to all have interlinking roles in the expression of these and other proteins associated with virulence and low iron biofilm formation. The identification of the importance of Eap and Emp in low iron biofilm formation and the regulatory network controlling their expression may have implications on the development of new therapeutic agents essential for the prevention and treatment of S. aureus infection
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