A Superoxide Dismutase Capable of Functioning with Iron or Manganese Promotes the Resistance of Staphylococcus aureus to Calprotectin and Nutritional Immunity

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.

Role of Calprotectin in Withholding Zinc and Copper from Candida albicans

“…As previously mentioned, a major adaptation to low Cu in C. albicans involves Cu sparing whereby the major cuproprotein Sod1 is downregulated (7,9). CP can induce Mnsparing responses in Staphylococcus aureus (50,51), and we tested whether the same is true for Cu sparing in C. albicans. In cells grown in the presence of CP, we observed an ϳ7-fold reduction in SOD1 mRNA and a 15-fold increase in SOD3 (encoding the non-Cu alternative to Sod1) (Fig.…”

Chemical Warfare at the Microorganismal Level: A Closer Look at the Superoxide Dismutase Enzymes of Pathogens

“…However, mis-incorporation of the wrong metal (ie., Fe in the active site of SodA or vice versa) usually results in an inactive enzyme due to differences in redox tuning 33–34 . Nevertheless, there exists a subset of bacterial Mn/Fe-dependent SOD enzymes that are capable of maintaining SOD activity with either metal, so called cambialistic SODs 38, 40, 107 . Cambialistic SODs have been shown to be important for the virulence of some pathogenic bacteria 38 .…”

“…During host invasion, S. aureus is subjected to severe Mn limitation caused by the host’s metal-binding protein calprotectin 108 . Although Mn-SodA is vulnerable to Mn deprivation, S. aureus maintains intracellular SOD activity through SodM, a cambialistic SOD that switches to utilizing Fe as its cofactor under Mn-limiting conditions 38 . Another example includes the secreted Mn-SodA of M. tuberculosis that appears to maintain activity with Fe as its cofactor and is thus also classified as cambialistic 73 .…”

Targeting fundamental pathways to disrupt Staphylococcus aureus survival: clinical implications of recent discoveries

“…The manganese transporter MntABC is necessary for bacterial growth and resistance to oxidative stress, in part due to the critical role of manganese as a cofactor for superoxide dismutases A and M (SodA, SodM), with SodM being unique to S. aureus (17). Diminished manganese uptake renders MntABC mutants highly sensitive to killing by human neutrophils (18) and growth deficient (19).…”

“…(B) Numerous critical steps have been identified for the acquisition of host metals by S. aureus. The MntABC transporter delivers manganese, which, among other roles, is a required cofactor for superoxide dismutase (17)(18)(19)(20). α-Hemolysin-mediated (Hla-mediated) RBC lysis liberates host heme, resulting in a bacterial iron source via the Isd system (10-13).…”