title: 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.
authors.affiliation: Department of Microbiology, University of Illinois Urbana-Champaign, Urbana, IL, United States of America.
authors.forename: Yuritzi M
authors.identifier: 0000-0002-3858-4684
authors.initials: YM
authors.lastname: Garcia
authors.affiliation: Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Anna
authors.identifier: 0000-0002-9342-2805
authors.initials: A
authors.lastname: Barwinska-Sendra
authors.affiliation: Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Emma
authors.initials: E
authors.lastname: Tarrant
authors.affiliation: Department of Pathology Microbiology and Immunology, Vanderbilt University Medical Center Nashville TN, United States of America.
authors.forename: Eric P
authors.initials: EP
authors.lastname: Skaar
authors.affiliation: Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Kevin J
authors.identifier: 0000-0002-5577-7357
authors.initials: KJ
authors.lastname: Waldron
authors.affiliation: Department of Microbiology, University of Illinois Urbana-Champaign, Urbana, IL, United States of America.
authors.forename: Thomas E
authors.identifier: 0000-0001-8234-1113
authors.initials: TE
authors.lastname: Kehl-Fie
mesh_terms: D000818:Animals; D002852:Chromatography, Ion Exchange; D004195:Disease Models, Animal; D007501:Iron / Q000378:metabolism*; D039841:Leukocyte L1 Antigen Complex / Q000276:immunology; D008345:Manganese / Q000378:metabolism*; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D013203:Staphylococcal Infections / Q000276:immunology / Q000378:metabolism*; D013211:Staphylococcus aureus / Q000276:immunology / Q000378:metabolism / Q000472:pathogenicity*; D013482:Superoxide Dismutase / Q000378:metabolism*
chemical_list: D039841:Leukocyte L1 Antigen Complex; D008345:Manganese; D007501:Iron; D013482:Superoxide Dismutase