Nitric Oxide Disrupts Zinc Homeostasis in <named-content content-type="genus-species">Salmonella enterica</named-content> Serovar Typhimurium

ABSTRACT Nitric oxide (NO·) produced by mammalian cells exerts antimicrobial actions that result primarily from the modification of protein thiols (S-nitrosylation) and metal centers. A comprehensive approach was used to identify novel targets of NO· in Salmonella enterica serovar Typhimurium (S. Ty...

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Autores principales:	Elaine R. Frawley, Joyce E. Karlinsey, Anshika Singhal, Stephen J. Libby, Paschalis-Thomas Doulias, Harry Ischiropoulos, Ferric C. Fang
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	Salmonella nitric oxide pathogenesis transporters zinc homeostasis Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/b1bf6fe5b949495ebbac88ff104fbf35
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spelling	oai:doaj.org-article:b1bf6fe5b949495ebbac88ff104fbf352021-11-15T16:00:15ZNitric Oxide Disrupts Zinc Homeostasis in <named-content content-type="genus-species">Salmonella enterica</named-content> Serovar Typhimurium10.1128/mBio.01040-182150-7511https://doaj.org/article/b1bf6fe5b949495ebbac88ff104fbf352018-09-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01040-18https://doaj.org/toc/2150-7511ABSTRACT Nitric oxide (NO·) produced by mammalian cells exerts antimicrobial actions that result primarily from the modification of protein thiols (S-nitrosylation) and metal centers. A comprehensive approach was used to identify novel targets of NO· in Salmonella enterica serovar Typhimurium (S. Typhimurium). Newly identified targets include zinc metalloproteins required for DNA replication and repair (DnaG, PriA, and TopA), protein synthesis (AlaS and RpmE), and various metabolic activities (ClpX, GloB, MetE, PepA, and QueC). The cytotoxic actions of free zinc are mitigated by the ZntA and ZitB zinc efflux transporters, which are required for S. Typhimurium resistance to zinc overload and nitrosative stress in vitro. Zinc efflux also ameliorates NO·-dependent zinc mobilization following internalization by activated macrophages and is required for virulence in NO·-producing mice, demonstrating that host-derived NO· causes zinc stress in intracellular bacteria. IMPORTANCE Nitric oxide (NO·) is produced by macrophages in response to inflammatory stimuli and restricts the growth of intracellular bacteria. Mechanisms of NO·-dependent antimicrobial actions are incompletely understood. Here, we show that zinc metalloproteins are important targets of NO· in Salmonella, including the DNA replication proteins DnaG and PriA, which were hypothesized to be NO· targets in earlier studies. Like iron, zinc is a cofactor for several essential proteins but is toxic at elevated concentrations. This study demonstrates that NO· mobilizes free zinc in Salmonella and that specific efflux transporters ameliorate the cytotoxic effects of free zinc during infection.Elaine R. FrawleyJoyce E. KarlinseyAnshika SinghalStephen J. LibbyPaschalis-Thomas DouliasHarry IschiropoulosFerric C. FangAmerican Society for MicrobiologyarticleSalmonellanitric oxidepathogenesistransporterszinc homeostasisMicrobiologyQR1-502ENmBio, Vol 9, Iss 4 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Salmonella nitric oxide pathogenesis transporters zinc homeostasis Microbiology QR1-502
spellingShingle	Salmonella nitric oxide pathogenesis transporters zinc homeostasis Microbiology QR1-502 Elaine R. Frawley Joyce E. Karlinsey Anshika Singhal Stephen J. Libby Paschalis-Thomas Doulias Harry Ischiropoulos Ferric C. Fang Nitric Oxide Disrupts Zinc Homeostasis in <named-content content-type="genus-species">Salmonella enterica</named-content> Serovar Typhimurium
description	ABSTRACT Nitric oxide (NO·) produced by mammalian cells exerts antimicrobial actions that result primarily from the modification of protein thiols (S-nitrosylation) and metal centers. A comprehensive approach was used to identify novel targets of NO· in Salmonella enterica serovar Typhimurium (S. Typhimurium). Newly identified targets include zinc metalloproteins required for DNA replication and repair (DnaG, PriA, and TopA), protein synthesis (AlaS and RpmE), and various metabolic activities (ClpX, GloB, MetE, PepA, and QueC). The cytotoxic actions of free zinc are mitigated by the ZntA and ZitB zinc efflux transporters, which are required for S. Typhimurium resistance to zinc overload and nitrosative stress in vitro. Zinc efflux also ameliorates NO·-dependent zinc mobilization following internalization by activated macrophages and is required for virulence in NO·-producing mice, demonstrating that host-derived NO· causes zinc stress in intracellular bacteria. IMPORTANCE Nitric oxide (NO·) is produced by macrophages in response to inflammatory stimuli and restricts the growth of intracellular bacteria. Mechanisms of NO·-dependent antimicrobial actions are incompletely understood. Here, we show that zinc metalloproteins are important targets of NO· in Salmonella, including the DNA replication proteins DnaG and PriA, which were hypothesized to be NO· targets in earlier studies. Like iron, zinc is a cofactor for several essential proteins but is toxic at elevated concentrations. This study demonstrates that NO· mobilizes free zinc in Salmonella and that specific efflux transporters ameliorate the cytotoxic effects of free zinc during infection.
format	article
author	Elaine R. Frawley Joyce E. Karlinsey Anshika Singhal Stephen J. Libby Paschalis-Thomas Doulias Harry Ischiropoulos Ferric C. Fang
author_facet	Elaine R. Frawley Joyce E. Karlinsey Anshika Singhal Stephen J. Libby Paschalis-Thomas Doulias Harry Ischiropoulos Ferric C. Fang
author_sort	Elaine R. Frawley
title	Nitric Oxide Disrupts Zinc Homeostasis in <named-content content-type="genus-species">Salmonella enterica</named-content> Serovar Typhimurium
title_short	Nitric Oxide Disrupts Zinc Homeostasis in <named-content content-type="genus-species">Salmonella enterica</named-content> Serovar Typhimurium
title_full	Nitric Oxide Disrupts Zinc Homeostasis in <named-content content-type="genus-species">Salmonella enterica</named-content> Serovar Typhimurium
title_fullStr	Nitric Oxide Disrupts Zinc Homeostasis in <named-content content-type="genus-species">Salmonella enterica</named-content> Serovar Typhimurium
title_full_unstemmed	Nitric Oxide Disrupts Zinc Homeostasis in <named-content content-type="genus-species">Salmonella enterica</named-content> Serovar Typhimurium
title_sort	nitric oxide disrupts zinc homeostasis in <named-content content-type="genus-species">salmonella enterica</named-content> serovar typhimurium
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/b1bf6fe5b949495ebbac88ff104fbf35
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Nitric Oxide Disrupts Zinc Homeostasis in <named-content content-type="genus-species">Salmonella enterica</named-content> Serovar Typhimurium

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