MntC-Dependent Manganese Transport Is Essential for <italic toggle="yes">Staphylococcus aureus</italic> Oxidative Stress Resistance and Virulence

ABSTRACT Staphylococcus aureus is a human pathogen that has developed several approaches to evade the immune system, including a strategy to resist oxidative killing by phagocytes. This resistance is mediated by production of superoxide dismutase (SOD) enzymes which use manganese as a cofactor. S. a...

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Autores principales:	Luke D. Handke, Alexey V. Gribenko, Yekaterina Timofeyeva, Ingrid L. Scully, Annaliesa S. Anderson
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	MntC Staphylococcus aureus manganese manganese transport virulence factors Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/5ee61b5aa68147609aa90d7776231e30
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spelling	oai:doaj.org-article:5ee61b5aa68147609aa90d7776231e302021-11-15T15:25:50ZMntC-Dependent Manganese Transport Is Essential for <italic toggle="yes">Staphylococcus aureus</italic> Oxidative Stress Resistance and Virulence10.1128/mSphere.00336-182379-5042https://doaj.org/article/5ee61b5aa68147609aa90d7776231e302018-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00336-18https://doaj.org/toc/2379-5042ABSTRACT Staphylococcus aureus is a human pathogen that has developed several approaches to evade the immune system, including a strategy to resist oxidative killing by phagocytes. This resistance is mediated by production of superoxide dismutase (SOD) enzymes which use manganese as a cofactor. S. aureus encodes two manganese ion transporters, MntABC and MntH, and a possible Nramp family manganese transporter, exemplified by S. aureus N315 SA1432. Their relative contributions to manganese transport have not been well defined in clinically relevant isolates. For this purpose, insertional inactivation mutations were introduced into mntC, mntH, and SA1432 individually and in combination. mntC was necessary for full resistance to methyl viologen, a compound that generates intracellular free radicals. In contrast, strains with an intact mntH gene had a minimal increase in resistance that was revealed only in mntC strains, and no change was observed upon mutation of SA1432 in strains lacking both mntC and mntH. Similarly, MntC alone was required for high cellular SOD activity. In addition, mntC strains were attenuated in a murine sepsis model. To further link these observations to manganese transport, an S. aureus MntC protein lacking manganese binding activity was designed, expressed, and purified. While circular dichroism experiments demonstrated that the secondary and tertiary structures of this protein were unaltered, a defect in manganese binding was confirmed by isothermal titration calorimetry. Unlike complementation with wild-type mntC, introduction of the manganese-binding defective allele into the chromosome of an mntC strain did not restore resistance to oxidative stress or virulence. Collectively, these results underscore the importance of MntC-dependent manganese transport in S. aureus oxidative stress resistance and virulence. IMPORTANCE Work outlined in this report demonstrated that MntC-dependent manganese transport is required for S. aureus virulence. These study results support the model that MntC-specific antibodies elicited by a vaccine have the potential to disrupt S. aureus manganese transport and thus abrogate to its virulence.Luke D. HandkeAlexey V. GribenkoYekaterina TimofeyevaIngrid L. ScullyAnnaliesa S. AndersonAmerican Society for MicrobiologyarticleMntCStaphylococcus aureusmanganesemanganese transportvirulence factorsMicrobiologyQR1-502ENmSphere, Vol 3, Iss 4 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	MntC Staphylococcus aureus manganese manganese transport virulence factors Microbiology QR1-502
spellingShingle	MntC Staphylococcus aureus manganese manganese transport virulence factors Microbiology QR1-502 Luke D. Handke Alexey V. Gribenko Yekaterina Timofeyeva Ingrid L. Scully Annaliesa S. Anderson MntC-Dependent Manganese Transport Is Essential for <italic toggle="yes">Staphylococcus aureus</italic> Oxidative Stress Resistance and Virulence
description	ABSTRACT Staphylococcus aureus is a human pathogen that has developed several approaches to evade the immune system, including a strategy to resist oxidative killing by phagocytes. This resistance is mediated by production of superoxide dismutase (SOD) enzymes which use manganese as a cofactor. S. aureus encodes two manganese ion transporters, MntABC and MntH, and a possible Nramp family manganese transporter, exemplified by S. aureus N315 SA1432. Their relative contributions to manganese transport have not been well defined in clinically relevant isolates. For this purpose, insertional inactivation mutations were introduced into mntC, mntH, and SA1432 individually and in combination. mntC was necessary for full resistance to methyl viologen, a compound that generates intracellular free radicals. In contrast, strains with an intact mntH gene had a minimal increase in resistance that was revealed only in mntC strains, and no change was observed upon mutation of SA1432 in strains lacking both mntC and mntH. Similarly, MntC alone was required for high cellular SOD activity. In addition, mntC strains were attenuated in a murine sepsis model. To further link these observations to manganese transport, an S. aureus MntC protein lacking manganese binding activity was designed, expressed, and purified. While circular dichroism experiments demonstrated that the secondary and tertiary structures of this protein were unaltered, a defect in manganese binding was confirmed by isothermal titration calorimetry. Unlike complementation with wild-type mntC, introduction of the manganese-binding defective allele into the chromosome of an mntC strain did not restore resistance to oxidative stress or virulence. Collectively, these results underscore the importance of MntC-dependent manganese transport in S. aureus oxidative stress resistance and virulence. IMPORTANCE Work outlined in this report demonstrated that MntC-dependent manganese transport is required for S. aureus virulence. These study results support the model that MntC-specific antibodies elicited by a vaccine have the potential to disrupt S. aureus manganese transport and thus abrogate to its virulence.
format	article
author	Luke D. Handke Alexey V. Gribenko Yekaterina Timofeyeva Ingrid L. Scully Annaliesa S. Anderson
author_facet	Luke D. Handke Alexey V. Gribenko Yekaterina Timofeyeva Ingrid L. Scully Annaliesa S. Anderson
author_sort	Luke D. Handke
title	MntC-Dependent Manganese Transport Is Essential for <italic toggle="yes">Staphylococcus aureus</italic> Oxidative Stress Resistance and Virulence
title_short	MntC-Dependent Manganese Transport Is Essential for <italic toggle="yes">Staphylococcus aureus</italic> Oxidative Stress Resistance and Virulence
title_full	MntC-Dependent Manganese Transport Is Essential for <italic toggle="yes">Staphylococcus aureus</italic> Oxidative Stress Resistance and Virulence
title_fullStr	MntC-Dependent Manganese Transport Is Essential for <italic toggle="yes">Staphylococcus aureus</italic> Oxidative Stress Resistance and Virulence
title_full_unstemmed	MntC-Dependent Manganese Transport Is Essential for <italic toggle="yes">Staphylococcus aureus</italic> Oxidative Stress Resistance and Virulence
title_sort	mntc-dependent manganese transport is essential for <italic toggle="yes">staphylococcus aureus</italic> oxidative stress resistance and virulence
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/5ee61b5aa68147609aa90d7776231e30
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MntC-Dependent Manganese Transport Is Essential for <italic toggle="yes">Staphylococcus aureus</italic> Oxidative Stress Resistance and Virulence

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