Date Published: January 19, 2017
Publisher: Public Library of Science
Author(s): Yuritzi M. Garcia, Anna Barwinska-Sendra, Emma Tarrant, Eric P. Skaar, Kevin J. Waldron, Thomas E. Kehl-Fie, Andreas Peschel.
Staphylococcus aureus is a devastating mammalian pathogen for which the development of new therapeutic approaches is urgently needed due to the prevalence of antibiotic resistance. During infection pathogens must overcome the dual threats of host-imposed manganese starvation, termed nutritional immunity, and the oxidative burst of immune cells. These defenses function synergistically, as host-imposed manganese starvation reduces activity of the manganese-dependent enzyme superoxide dismutase (SOD). S. aureus expresses two SODs, denoted SodA and SodM. While all staphylococci possess SodA, SodM is unique to S. aureus, but the advantage that S. aureus gains by expressing two apparently manganese-dependent SODs is unknown. Surprisingly, loss of both SODs renders S. aureus more sensitive to host-imposed manganese starvation, suggesting a role for these proteins in overcoming nutritional immunity. In this study, we have elucidated the respective contributions of SodA and SodM to resisting oxidative stress and nutritional immunity. These analyses revealed that SodA is important for resisting oxidative stress and for disease development when manganese is abundant, while SodM is important under manganese-deplete conditions. In vitro analysis demonstrated that SodA is strictly manganese-dependent whereas SodM is in fact cambialistic, possessing equal enzymatic activity when loaded with manganese or iron. Cumulatively, these studies provide a mechanistic rationale for the acquisition of a second superoxide dismutase by S. aureus and demonstrate an important contribution of cambialistic SODs to bacterial pathogenesis. Furthermore, they also suggest a new mechanism for resisting manganese starvation, namely populating manganese-utilizing enzymes with iron.
The spread of antibiotic resistance amongst bacteria has led both the Centers for Disease Control and Prevention and the World Health Organization to state that infections represent a serious threat to human health [1, 2]. This threat is exemplified by Staphylococcus aureus, a Gram-positive bacterium that asymptomatically colonizes one third of the population and is a leading cause of antibiotic-resistant infections [3–5]. A promising area of investigation is elucidating how pathogens overcome host defenses such as the active withholding of essential nutrients and the oxidative burst of immune cells.
During infection the innate immune system combats invading microbes by restricting the availability of the essential nutrient Mn [9, 12, 14]. At the same time, S. aureus and other pathogens must also overcome other host defenses including the oxidative burst of immune cells . Accomplishing this latter task is made more challenging, as host-imposed Mn starvation inactivates bacterial Mn-dependent SODs . The current investigations revealed that the possession of a cambialistic SOD enables S. aureus to counter these dual host threats both in culture and during infection. This strategy represents an entirely new mechanism for resisting host-imposed Mn starvation and establishes that cambialistic SODs contribute to bacterial pathogenesis.