Abstract
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.
Highlights
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]
Pathogens must overcome the restriction of essential nutrients such as manganese by the host, while simultaneously coping with other host defenses such as the oxidative burst
Using the host protein that limits manganese availability during infection and mice lacking this effector, we determined that acquisition of a second superoxide dismutase that is capable of using either manganese or iron enhances the ability of Staphylococcus aureus to cause infection
Summary
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]. Pathogens must obtain all of their nutrients from the host, including the essential metal ions that are needed for the approximately one-third of all bacterial proteins that require a metal cofactor [6,7,8]. This requirement is exploited by the host, which restricts the availability of these essential nutrients, a defense termed nutritional immunity [9,10,11,12,13]. The second site or ‘Zn site’ is comprised of three histidines and an aspartic acid and binds Zn with picomolar or sub-picomolar affinity [14, 20, 22]
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