Manganese Homeostasis in Group A Streptococcus Is Critical for Resistance to Oxidative Stress and Virulence

ABSTRACT Streptococcus pyogenes (group A Streptococcus [GAS]) is an obligate human pathogen responsible for a spectrum of human disease states. Metallobiology of human pathogens is revealing the fundamental role of metals in both nutritional immunity leading to pathogen starvation and metal poisonin...

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Autores principales:	Andrew G. Turner, Cheryl-lynn Y. Ong, Christine M. Gillen, Mark R. Davies, Nicholas P. West, Alastair G. McEwan, Mark J. Walker
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2015
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/c94bf085fa44439ea2d69609cf53a656
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spelling	oai:doaj.org-article:c94bf085fa44439ea2d69609cf53a6562021-11-15T15:41:33ZManganese Homeostasis in Group A Streptococcus Is Critical for Resistance to Oxidative Stress and Virulence10.1128/mBio.00278-152150-7511https://doaj.org/article/c94bf085fa44439ea2d69609cf53a6562015-05-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00278-15https://doaj.org/toc/2150-7511ABSTRACT Streptococcus pyogenes (group A Streptococcus [GAS]) is an obligate human pathogen responsible for a spectrum of human disease states. Metallobiology of human pathogens is revealing the fundamental role of metals in both nutritional immunity leading to pathogen starvation and metal poisoning of pathogens by innate immune cells. Spy0980 (MntE) is a paralog of the GAS zinc efflux pump CzcD. Through use of an isogenic mntE deletion mutant in the GAS serotype M1T1 strain 5448, we have elucidated that MntE is a manganese-specific efflux pump required for GAS virulence. The 5448ΔmntE mutant had significantly lower survival following infection of human neutrophils than did the 5448 wild type and the complemented mutant (5448ΔmntE::mntE). Manganese homeostasis may provide protection against oxidative stress, explaining the observed ex vivo reduction in virulence. In the presence of manganese and hydrogen peroxide, 5448ΔmntE mutant exhibits significantly lower survival than wild-type 5448 and the complemented mutant. We hypothesize that MntE, by maintaining homeostatic control of cytoplasmic manganese, ensures that the peroxide response repressor PerR is optimally poised to respond to hydrogen peroxide stress. Creation of a 5448ΔmntE-ΔperR double mutant rescued the oxidative stress resistance of the double mutant to wild-type levels in the presence of manganese and hydrogen peroxide. This work elucidates the mechanism for manganese toxicity within GAS and the crucial role of manganese homeostasis in maintaining GAS virulence. IMPORTANCE Manganese is traditionally viewed as a beneficial metal ion to bacteria, and it is also established that most bacteria can tolerate high concentrations of this transition metal. In this work, we show that in group A Streptococcus, mutation of the mntE locus, which encodes a transport protein of the cation diffusion facilitator (CDF) family, results in accumulation of manganese and sensitivity to this transition metal ion. The toxicity of manganese is indirect and is the result of a failure of the PerR regulator to respond to oxidative stress in the presence of high intracellular manganese concentrations. These results highlight the importance of MntE in manganese homeostasis and maintenance of an optimal manganese/iron ratio in GAS and the impact of manganese on resistance to oxidative stress and virulence.Andrew G. TurnerCheryl-lynn Y. OngChristine M. GillenMark R. DaviesNicholas P. WestAlastair G. McEwanMark J. WalkerAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 6, Iss 2 (2015)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Andrew G. Turner Cheryl-lynn Y. Ong Christine M. Gillen Mark R. Davies Nicholas P. West Alastair G. McEwan Mark J. Walker Manganese Homeostasis in Group A Streptococcus Is Critical for Resistance to Oxidative Stress and Virulence
description	ABSTRACT Streptococcus pyogenes (group A Streptococcus [GAS]) is an obligate human pathogen responsible for a spectrum of human disease states. Metallobiology of human pathogens is revealing the fundamental role of metals in both nutritional immunity leading to pathogen starvation and metal poisoning of pathogens by innate immune cells. Spy0980 (MntE) is a paralog of the GAS zinc efflux pump CzcD. Through use of an isogenic mntE deletion mutant in the GAS serotype M1T1 strain 5448, we have elucidated that MntE is a manganese-specific efflux pump required for GAS virulence. The 5448ΔmntE mutant had significantly lower survival following infection of human neutrophils than did the 5448 wild type and the complemented mutant (5448ΔmntE::mntE). Manganese homeostasis may provide protection against oxidative stress, explaining the observed ex vivo reduction in virulence. In the presence of manganese and hydrogen peroxide, 5448ΔmntE mutant exhibits significantly lower survival than wild-type 5448 and the complemented mutant. We hypothesize that MntE, by maintaining homeostatic control of cytoplasmic manganese, ensures that the peroxide response repressor PerR is optimally poised to respond to hydrogen peroxide stress. Creation of a 5448ΔmntE-ΔperR double mutant rescued the oxidative stress resistance of the double mutant to wild-type levels in the presence of manganese and hydrogen peroxide. This work elucidates the mechanism for manganese toxicity within GAS and the crucial role of manganese homeostasis in maintaining GAS virulence. IMPORTANCE Manganese is traditionally viewed as a beneficial metal ion to bacteria, and it is also established that most bacteria can tolerate high concentrations of this transition metal. In this work, we show that in group A Streptococcus, mutation of the mntE locus, which encodes a transport protein of the cation diffusion facilitator (CDF) family, results in accumulation of manganese and sensitivity to this transition metal ion. The toxicity of manganese is indirect and is the result of a failure of the PerR regulator to respond to oxidative stress in the presence of high intracellular manganese concentrations. These results highlight the importance of MntE in manganese homeostasis and maintenance of an optimal manganese/iron ratio in GAS and the impact of manganese on resistance to oxidative stress and virulence.
format	article
author	Andrew G. Turner Cheryl-lynn Y. Ong Christine M. Gillen Mark R. Davies Nicholas P. West Alastair G. McEwan Mark J. Walker
author_facet	Andrew G. Turner Cheryl-lynn Y. Ong Christine M. Gillen Mark R. Davies Nicholas P. West Alastair G. McEwan Mark J. Walker
author_sort	Andrew G. Turner
title	Manganese Homeostasis in Group A Streptococcus Is Critical for Resistance to Oxidative Stress and Virulence
title_short	Manganese Homeostasis in Group A Streptococcus Is Critical for Resistance to Oxidative Stress and Virulence
title_full	Manganese Homeostasis in Group A Streptococcus Is Critical for Resistance to Oxidative Stress and Virulence
title_fullStr	Manganese Homeostasis in Group A Streptococcus Is Critical for Resistance to Oxidative Stress and Virulence
title_full_unstemmed	Manganese Homeostasis in Group A Streptococcus Is Critical for Resistance to Oxidative Stress and Virulence
title_sort	manganese homeostasis in group a streptococcus is critical for resistance to oxidative stress and virulence
publisher	American Society for Microbiology
publishDate	2015
url	https://doaj.org/article/c94bf085fa44439ea2d69609cf53a656
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Manganese Homeostasis in Group A Streptococcus Is Critical for Resistance to Oxidative Stress and Virulence

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