Manganese Detoxification by MntE Is Critical for Resistance to Oxidative Stress and Virulence of <italic toggle="yes">Staphylococcus aureus</italic>

ABSTRACT Manganese (Mn) is an essential micronutrient critical for the pathogenesis of Staphylococcus aureus, a significant cause of human morbidity and mortality. Paradoxically, excess Mn is toxic; therefore, maintenance of intracellular Mn homeostasis is required for survival. Here we describe a M...

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Autores principales:	Caroline M. Grunenwald, Jacob E. Choby, Lillian J. Juttukonda, William N. Beavers, Andy Weiss, Victor J. Torres, Eric P. Skaar
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	Staphylococcus aureus iron metabolism manganese metal resistance oxidative stress Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/60f1432fa64645f791d315ca384e153c
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spelling	oai:doaj.org-article:60f1432fa64645f791d315ca384e153c2021-11-15T15:55:14ZManganese Detoxification by MntE Is Critical for Resistance to Oxidative Stress and Virulence of <italic toggle="yes">Staphylococcus aureus</italic>10.1128/mBio.02915-182150-7511https://doaj.org/article/60f1432fa64645f791d315ca384e153c2019-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02915-18https://doaj.org/toc/2150-7511ABSTRACT Manganese (Mn) is an essential micronutrient critical for the pathogenesis of Staphylococcus aureus, a significant cause of human morbidity and mortality. Paradoxically, excess Mn is toxic; therefore, maintenance of intracellular Mn homeostasis is required for survival. Here we describe a Mn exporter in S. aureus, MntE, which is a member of the cation diffusion facilitator (CDF) protein family and conserved among Gram-positive pathogens. Upregulation of mntE transcription in response to excess Mn is dependent on the presence of MntR, a transcriptional repressor of the mntABC Mn uptake system. Inactivation of mntE or mntR leads to reduced growth in media supplemented with Mn, demonstrating MntE is required for detoxification of excess Mn. Inactivation of mntE results in elevated levels of intracellular Mn, but reduced intracellular iron (Fe) levels, supporting the hypothesis that MntE functions as a Mn efflux pump and Mn efflux influences Fe homeostasis. Strains inactivated for mntE are more sensitive to the oxidants NaOCl and paraquat, indicating Mn homeostasis is critical for resisting oxidative stress. Furthermore, mntE and mntR are required for full virulence of S. aureus during infection, suggesting S. aureus experiences Mn toxicity in vivo. Combined, these data support a model in which MntR controls Mn homeostasis by balancing transcriptional repression of mntABC and induction of mntE, both of which are critical for S. aureus pathogenesis. Thus, Mn efflux contributes to bacterial survival and virulence during infection, establishing MntE as a potential antimicrobial target and expanding our understanding of Mn homeostasis. IMPORTANCE Manganese (Mn) is generally viewed as a critical nutrient that is beneficial to pathogenic bacteria due to its function as an enzymatic cofactor and its capability of acting as an antioxidant; yet paradoxically, high concentrations of this transition metal can be toxic. In this work, we demonstrate Staphylococcus aureus utilizes the cation diffusion facilitator (CDF) family protein MntE to alleviate Mn toxicity through efflux of excess Mn. Inactivation of mntE leads to a significant reduction in S. aureus resistance to oxidative stress and S. aureus-mediated mortality within a mouse model of systemic infection. These results highlight the importance of MntE-mediated Mn detoxification in intracellular Mn homeostasis, resistance to oxidative stress, and S. aureus virulence. Therefore, this establishes MntE as a potential target for development of anti-S. aureus therapeutics.Caroline M. GrunenwaldJacob E. ChobyLillian J. JuttukondaWilliam N. BeaversAndy WeissVictor J. TorresEric P. SkaarAmerican Society for MicrobiologyarticleStaphylococcus aureusiron metabolismmanganesemetal resistanceoxidative stressMicrobiologyQR1-502ENmBio, Vol 10, Iss 1 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Staphylococcus aureus iron metabolism manganese metal resistance oxidative stress Microbiology QR1-502
spellingShingle	Staphylococcus aureus iron metabolism manganese metal resistance oxidative stress Microbiology QR1-502 Caroline M. Grunenwald Jacob E. Choby Lillian J. Juttukonda William N. Beavers Andy Weiss Victor J. Torres Eric P. Skaar Manganese Detoxification by MntE Is Critical for Resistance to Oxidative Stress and Virulence of <italic toggle="yes">Staphylococcus aureus</italic>
description	ABSTRACT Manganese (Mn) is an essential micronutrient critical for the pathogenesis of Staphylococcus aureus, a significant cause of human morbidity and mortality. Paradoxically, excess Mn is toxic; therefore, maintenance of intracellular Mn homeostasis is required for survival. Here we describe a Mn exporter in S. aureus, MntE, which is a member of the cation diffusion facilitator (CDF) protein family and conserved among Gram-positive pathogens. Upregulation of mntE transcription in response to excess Mn is dependent on the presence of MntR, a transcriptional repressor of the mntABC Mn uptake system. Inactivation of mntE or mntR leads to reduced growth in media supplemented with Mn, demonstrating MntE is required for detoxification of excess Mn. Inactivation of mntE results in elevated levels of intracellular Mn, but reduced intracellular iron (Fe) levels, supporting the hypothesis that MntE functions as a Mn efflux pump and Mn efflux influences Fe homeostasis. Strains inactivated for mntE are more sensitive to the oxidants NaOCl and paraquat, indicating Mn homeostasis is critical for resisting oxidative stress. Furthermore, mntE and mntR are required for full virulence of S. aureus during infection, suggesting S. aureus experiences Mn toxicity in vivo. Combined, these data support a model in which MntR controls Mn homeostasis by balancing transcriptional repression of mntABC and induction of mntE, both of which are critical for S. aureus pathogenesis. Thus, Mn efflux contributes to bacterial survival and virulence during infection, establishing MntE as a potential antimicrobial target and expanding our understanding of Mn homeostasis. IMPORTANCE Manganese (Mn) is generally viewed as a critical nutrient that is beneficial to pathogenic bacteria due to its function as an enzymatic cofactor and its capability of acting as an antioxidant; yet paradoxically, high concentrations of this transition metal can be toxic. In this work, we demonstrate Staphylococcus aureus utilizes the cation diffusion facilitator (CDF) family protein MntE to alleviate Mn toxicity through efflux of excess Mn. Inactivation of mntE leads to a significant reduction in S. aureus resistance to oxidative stress and S. aureus-mediated mortality within a mouse model of systemic infection. These results highlight the importance of MntE-mediated Mn detoxification in intracellular Mn homeostasis, resistance to oxidative stress, and S. aureus virulence. Therefore, this establishes MntE as a potential target for development of anti-S. aureus therapeutics.
format	article
author	Caroline M. Grunenwald Jacob E. Choby Lillian J. Juttukonda William N. Beavers Andy Weiss Victor J. Torres Eric P. Skaar
author_facet	Caroline M. Grunenwald Jacob E. Choby Lillian J. Juttukonda William N. Beavers Andy Weiss Victor J. Torres Eric P. Skaar
author_sort	Caroline M. Grunenwald
title	Manganese Detoxification by MntE Is Critical for Resistance to Oxidative Stress and Virulence of <italic toggle="yes">Staphylococcus aureus</italic>
title_short	Manganese Detoxification by MntE Is Critical for Resistance to Oxidative Stress and Virulence of <italic toggle="yes">Staphylococcus aureus</italic>
title_full	Manganese Detoxification by MntE Is Critical for Resistance to Oxidative Stress and Virulence of <italic toggle="yes">Staphylococcus aureus</italic>
title_fullStr	Manganese Detoxification by MntE Is Critical for Resistance to Oxidative Stress and Virulence of <italic toggle="yes">Staphylococcus aureus</italic>
title_full_unstemmed	Manganese Detoxification by MntE Is Critical for Resistance to Oxidative Stress and Virulence of <italic toggle="yes">Staphylococcus aureus</italic>
title_sort	manganese detoxification by mnte is critical for resistance to oxidative stress and virulence of <italic toggle="yes">staphylococcus aureus</italic>
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/60f1432fa64645f791d315ca384e153c
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Manganese Detoxification by MntE Is Critical for Resistance to Oxidative Stress and Virulence of <italic toggle="yes">Staphylococcus aureus</italic>

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