Linking Virulence and Iron Limitation Response in <i>Staphylococcus aureus</i>: The sRNA IsrR Is Involved in SaeRS Activation

The Gram-positive opportunistic pathogen <i>Staphylococcus aureus</i> colonizes ∼30% of the human population but also causes various diseases. Precise regulation of genes involved in virulence and metabolic functions is required to adapt to changing host conditions, such as severe restriction of iron availability. In addition to the global regulator Fur (ferric uptake regulator), the iron limitation response of <i>S. aureus</i> is shaped by the recently identified sRNA IsrR (iron sparing response regulator). IsrR mediates an iron sparing response by inhibiting the synthesis of nonessential iron-containing proteins, which are in particular involved in the central metabolism. In addition, we demonstrate that <i>isrR</i> expression is positively associated with α-hemolysin levels and the hemolysis activity of <i>S. aureus</i> HG001. To investigate the influence of IsrR on virulence factor production, we performed a mass spectrometry-based secretome analysis of <i>isrR</i>-expressing and nonexpressing strains under iron-limited and iron-sufficient conditions. The SaeR regulon was positively influenced by the presence of IsrR, and IsrR is likely involved in the activation of the Sae system. Additionally, IsrR also positively affected the protein levels of the <i>isdABCDEFGH</i>-encoded heme uptake system (e.g., IsdB). Taken together, IsrR establishes a link between the iron limitation response and the virulence in <i>S. aureus</i>.