Exploring the intersection of metal homeostasis and oxidative stress response gene regulation in Staphylococcus aureus

All forms of life require metals such as manganese, zinc, and iron to survive. In the context of infection, the human immune system takes advantage of this requirement by starving invading microbes of essential metals, thereby impeding their growth. Simultaneously, the host floods bacterial cells with toxic oxidants, including superoxide. To detoxify this harmful molecule, bacteria produce superoxide dismutases. However, these enzymes require metals to be active, and therefore metal limitation is a threat to their activity. Accordingly, microbes must meticulously manage the utilization of a limited pool of metals. However, it is unclear how bacteria coordinate a balanced response to both metal limitation and oxidative stress. This work reveals one way that the important human pathogen, Staphylococcus aureus, maintains the activity of crucial metal-dependent processes in the face of the combined stressors of metal limitation and oxidative stress. The bacterium produces a small regulatory RNA, RsaC, that suppresses the expression of a manganese-dependent superoxide dismutase when the cell is manganese starved. This process spares manganese for more essential enzymes, but does so by sacrificing a defense against oxidative stress. Despite this, loss of the regulatory RNA decreases S. aureus virulence. This indicates that RsaC successfully fine-tunes gene expression so that both essential manganese-requiring enzymes and adequate superoxide defense are maintained. Overall, this work reveals a previously unknown strategy used by S. aureus to balance conflicting pressures of the host immune system.