The Increased Accumulation of Staphylococcus aureus Virulence Factors Is Maximized in a Mutant by the Increased Production of SarA and Decreased Production of Extracellular Proteases.

Mutation of was previously shown to enhance the virulence of in a murine sepsis model, and this cannot be fully explained by increased expression of genes within the purine biosynthesis pathway. Rather, the increased production of specific virulence factors, including alpha toxin and the fibronectin-binding proteins, was shown to play an important role. Mutation of was also shown previously to result in increased abundance of SarA. Here, we demonstrate by transposon sequencing that mutation of in the USA300 strain LAC increases fitness in a biofilm while mutation of has the opposite effect. Therefore, we assessed the impact of on reported -associated phenotypes by characterizing isogenic , , and mutants. The results confirmed that mutation of results in increased abundance of alpha toxin, protein A, the fibronectin-binding proteins, and SarA, decreased production of extracellular proteases, an increased capacity to form a biofilm, and increased virulence in an osteomyelitis model. Mutation of had the opposite effects on all of these phenotypes and, other than bacterial burdens in the bone, all of the phenotypes of / mutants were comparable to those of mutants. Limiting the production of extracellular proteases reversed all of the phenotypes of mutants and most of those of mutants. We conclude that a critical component defining the virulence of a mutant is the enhanced production of SarA, which limits protease production to an extent that promotes the accumulation of critical virulence factors.