Abstract
Responding to stress is critical to the survival of life, especially for microbes that have a limited ability to manipulate their environment. During infection, Staphylococcus aureus and other invaders must overcome both the host-imposed absence of manganese and the oxidative burst of immune cells, which increases the need for this essential metal. The current investigations revealed that a small RNA, RsaC, integrates the staphylococcal responses to manganese starvation and oxidative stress. Upon manganese limitation, RsaC activates a manganese-sparing response, which decreases the cellular demand for manganese, enabling growth in manganese-restricted environments. However, the benefit of this response is environment-dependent as RsaC suppresses the expression of the manganese-dependent superoxide dismutase SodA, sensitizing S. aureus to oxidative stress. Despite this suppression, RsaC is necessary for S. aureus to cause infection, with its importance dependent on the efficacy of the host's manganese withholding response. These results reveal a previously unappreciated manganese-sparing response that is important for bacterial virulence, and the imperative role of sRNAs in balancing bacterial adaptation to stressors that place conflicting demands on cellular physiology. IMPORTANCE: During infection, pathogens must utilize processes that impose conflicting cellular demands. This conflict is exemplified by the need of Staphylococcus aureus to preserve essential processes and survive the oxidative burst of immune cells, both of which require manganese despite experiencing host-imposed manganese starvation. The current investigations revealed that S. aureus activates a manganese-sparing response controlled by the regulatory RNA, RsaC, in response to host-imposed manganese starvation. This small RNA sacrifices the expression of a manganese-dependent superoxide dismutase to preserve the activity of essential manganese-dependent processes. Despite this, RsaC is necessary for infection, revealing the important role of this manganese-sparing response to pathogenesis and that invaders must actively compromise ideal stress responses to cause disease.