YjbH contributes to <i>Staphylococcus aureus</i> skin pathology and immune response through Agr-mediated α-toxin regulation

<i>Staphylococcus aureus</i> is the most common cause of skin and soft tissue infections (SSTIs) with Methicillin-Resistant <i>S. aureus</i> (MRSA) strains being a major contributor in both community and hospital settings. <i>S. aureus</i> relies on metabolic diversity and a large repertoire of virulence factors to cause disease. This includes α-hemolysin (Hla), an integral player in tissue damage found in various models, including SSTIs. Previously, we identified a role for the Spx adapter protein, YjbH, in the regulation of several virulence factors and as an inhibitor of pathogenesis in a sepsis model. In this study, we found that YjbH is critical for tissue damage during SSTI, and its absence leads to decreased proinflammatory chemokines and cytokines in the skin. We identified no contribution of YjbI, encoded on the same transcript as YjbH. Using a combination of reporters and quantitative hemolysis assays, we demonstrated that YjbH impacts Hla expression and activity both <i>in vitro</i> and <i>in vivo</i>. Additionally, expression of Hla from a non-native promoter reversed the tissue damage phenotype of the Δ<i>yjbIH</i> mutant. Lastly, we identified reduced Agr activity as the likely cause for reduced Hla production in the Δ<i>yjbH</i> mutant. This work continues to define the importance of YjbH in the pathogenesis of <i>S. aureus</i> infection as well as identify a new pathway important for Hla production.