All four genes are cotranscribed from a promoter that is strongly induced by active SaeR (Geiger et al., 1994). A second promoter drives the expression of saeRS alone and is modestly repressed by these regulatory gene products (Geiger et al., 1994). Activation of the Sae system seems to involve sensing changes in the overall integrity of

Proteasome activity the cell envelope and is highly stimulated by hydrogen peroxide and cationic peptides including α-defensins (Geiger et al., 1994; Novick & Jiang, 2003). Active SaeR promotes the induction of a number of virulence genes in S. aureus through binding of a consensus sequence found upstream of promoters for hla, sbi, efb, lukS-PVL, splA, and saeP (Nygaard et al., 2010). Additionally, expression of β-hemolysin, fibrinogen-binding proteins, lactose catabolizing enzymes, and the chromosomal arginine deiminase operon are all highly affected by Sae (Voyich et al., 2009). It has been shown that SaeRS expression is higher in USA300 than in USA400 clones (Geiger et al., 1994; Montgomery et al., 2008), which may be a result of overactive Agr system (see above) because RNAIII is known to positively regulate Sae expression (Novick Selleckchem BMN-673 & Jiang, 2003). Deletion of saeRS resulted in almost complete loss of Hla expression and a significant drop in PVL levels as well (Montgomery et al., 2010; Nygaard et al., 2010). Moreover, ∆sae USA300

was attenuated in murine sepsis, peritonitis, dermonecrosis, and pneumonia Tobramycin models (Voyich et al., 2009; Montgomery et al., 2010; Nygaard et al., 2010; Watkins et al., 2011). This was surprising given that in USA400, Sae was only essential for sepsis and peritonitis

and not for survival within skin abscesses (Voyich et al., 2009; Watkins et al., 2011). However, USA400 clones do not induce the same level of dermonecrosis and do not express high levels of Hla as in USA300 infections (Montgomery et al., 2008; Li et al., 2010). Thus, it appears as though some of the hypervirulence attributed to USA300 clones in skin/soft tissue infections is likely due to Sae-mediated Hla overproduction. However, HA-MRSA USA500 clones also exhibit severe dermonecrosis during skin infections and overproduce Hla and PSMs yet have not disseminated as widely as USA300. While it has not been directly tested, it is tempting to hypothesize that the overactive Agr system inherent to USA300 results in excessive PSMs and Sae expression, the latter of which leads to high Hla expression. However, the mechanism driving high Agr activity in USA300 is not defined. Agr activity can be modulated through the actions of a number of trans-acting regulators including SarA (Cheung & Projan, 1994), Stk1 (Tamber et al., 2010), MgrA (Ingavale et al., 2005), SigB (Lauderdale et al., 2009), CodY (Majerczyk et al., 2008), CcpA (Seidl et al., 2006), Sar-family proteins other than SarA (Schmidt et al., 2001; Manna & Cheung, 2003, 2006; Tamber & Cheung, 2009), ArlRS (Liang et al.