Cargando…
Zinc-dependent substrate-level phosphorylation powers Salmonella growth under nitrosative stress of the innate host response
The metabolic processes that enable the replication of intracellular Salmonella under nitrosative stress conditions engendered in the innate response of macrophages are poorly understood. A screen of Salmonella transposon mutants identified the ABC-type high-affinity zinc uptake system ZnuABC as a c...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6221366/ https://www.ncbi.nlm.nih.gov/pubmed/30365536 http://dx.doi.org/10.1371/journal.ppat.1007388 |
_version_ | 1783369007165865984 |
---|---|
author | Fitzsimmons, Liam Liu, Lin Porwollik, Steffen Chakraborty, Sangeeta Desai, Prerak Tapscott, Timothy Henard, Calvin McClelland, Michael Vazquez-Torres, Andres |
author_facet | Fitzsimmons, Liam Liu, Lin Porwollik, Steffen Chakraborty, Sangeeta Desai, Prerak Tapscott, Timothy Henard, Calvin McClelland, Michael Vazquez-Torres, Andres |
author_sort | Fitzsimmons, Liam |
collection | PubMed |
description | The metabolic processes that enable the replication of intracellular Salmonella under nitrosative stress conditions engendered in the innate response of macrophages are poorly understood. A screen of Salmonella transposon mutants identified the ABC-type high-affinity zinc uptake system ZnuABC as a critical determinant of the adaptation of Salmonella to the nitrosative stress generated by the enzymatic activity of inducible nitric oxide (NO) synthase of mononuclear phagocytic cells. NO limits the virulence of a znuB mutant in an acute murine model of salmonellosis. The ZnuABC transporter is crucial for the glycolytic function of fructose bisphosphate aldolase, thereby fueling growth of Salmonella during nitrosative stress produced in the innate response of macrophages. Our investigations demonstrate that glycolysis mediates resistance of Salmonella to the antimicrobial activity of NO produced in an acute model of infection. The ATP synthesized by substrate-level phosphorylation at the payoff phase of glycolysis and acetate fermentation powers the replication of Salmonella experiencing high levels of nitrosative stress. In contrast, despite its high potential for ATP synthesis, oxidative phosphorylation is a major target of inhibition by NO and contributes little to the antinitrosative defenses of intracellular Salmonella. Our investigations have uncovered a previously unsuspected conjunction between zinc homeostasis, glucose metabolism and cellular energetics in the adaptation of intracellular Salmonella to the reactive nitrogen species synthesized in the innate host response. |
format | Online Article Text |
id | pubmed-6221366 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-62213662018-11-19 Zinc-dependent substrate-level phosphorylation powers Salmonella growth under nitrosative stress of the innate host response Fitzsimmons, Liam Liu, Lin Porwollik, Steffen Chakraborty, Sangeeta Desai, Prerak Tapscott, Timothy Henard, Calvin McClelland, Michael Vazquez-Torres, Andres PLoS Pathog Research Article The metabolic processes that enable the replication of intracellular Salmonella under nitrosative stress conditions engendered in the innate response of macrophages are poorly understood. A screen of Salmonella transposon mutants identified the ABC-type high-affinity zinc uptake system ZnuABC as a critical determinant of the adaptation of Salmonella to the nitrosative stress generated by the enzymatic activity of inducible nitric oxide (NO) synthase of mononuclear phagocytic cells. NO limits the virulence of a znuB mutant in an acute murine model of salmonellosis. The ZnuABC transporter is crucial for the glycolytic function of fructose bisphosphate aldolase, thereby fueling growth of Salmonella during nitrosative stress produced in the innate response of macrophages. Our investigations demonstrate that glycolysis mediates resistance of Salmonella to the antimicrobial activity of NO produced in an acute model of infection. The ATP synthesized by substrate-level phosphorylation at the payoff phase of glycolysis and acetate fermentation powers the replication of Salmonella experiencing high levels of nitrosative stress. In contrast, despite its high potential for ATP synthesis, oxidative phosphorylation is a major target of inhibition by NO and contributes little to the antinitrosative defenses of intracellular Salmonella. Our investigations have uncovered a previously unsuspected conjunction between zinc homeostasis, glucose metabolism and cellular energetics in the adaptation of intracellular Salmonella to the reactive nitrogen species synthesized in the innate host response. Public Library of Science 2018-10-26 /pmc/articles/PMC6221366/ /pubmed/30365536 http://dx.doi.org/10.1371/journal.ppat.1007388 Text en https://creativecommons.org/publicdomain/zero/1.0/ This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 (https://creativecommons.org/publicdomain/zero/1.0/) public domain dedication. |
spellingShingle | Research Article Fitzsimmons, Liam Liu, Lin Porwollik, Steffen Chakraborty, Sangeeta Desai, Prerak Tapscott, Timothy Henard, Calvin McClelland, Michael Vazquez-Torres, Andres Zinc-dependent substrate-level phosphorylation powers Salmonella growth under nitrosative stress of the innate host response |
title | Zinc-dependent substrate-level phosphorylation powers Salmonella growth under nitrosative stress of the innate host response |
title_full | Zinc-dependent substrate-level phosphorylation powers Salmonella growth under nitrosative stress of the innate host response |
title_fullStr | Zinc-dependent substrate-level phosphorylation powers Salmonella growth under nitrosative stress of the innate host response |
title_full_unstemmed | Zinc-dependent substrate-level phosphorylation powers Salmonella growth under nitrosative stress of the innate host response |
title_short | Zinc-dependent substrate-level phosphorylation powers Salmonella growth under nitrosative stress of the innate host response |
title_sort | zinc-dependent substrate-level phosphorylation powers salmonella growth under nitrosative stress of the innate host response |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6221366/ https://www.ncbi.nlm.nih.gov/pubmed/30365536 http://dx.doi.org/10.1371/journal.ppat.1007388 |
work_keys_str_mv | AT fitzsimmonsliam zincdependentsubstratelevelphosphorylationpowerssalmonellagrowthundernitrosativestressoftheinnatehostresponse AT liulin zincdependentsubstratelevelphosphorylationpowerssalmonellagrowthundernitrosativestressoftheinnatehostresponse AT porwolliksteffen zincdependentsubstratelevelphosphorylationpowerssalmonellagrowthundernitrosativestressoftheinnatehostresponse AT chakrabortysangeeta zincdependentsubstratelevelphosphorylationpowerssalmonellagrowthundernitrosativestressoftheinnatehostresponse AT desaiprerak zincdependentsubstratelevelphosphorylationpowerssalmonellagrowthundernitrosativestressoftheinnatehostresponse AT tapscotttimothy zincdependentsubstratelevelphosphorylationpowerssalmonellagrowthundernitrosativestressoftheinnatehostresponse AT henardcalvin zincdependentsubstratelevelphosphorylationpowerssalmonellagrowthundernitrosativestressoftheinnatehostresponse AT mcclellandmichael zincdependentsubstratelevelphosphorylationpowerssalmonellagrowthundernitrosativestressoftheinnatehostresponse AT vazqueztorresandres zincdependentsubstratelevelphosphorylationpowerssalmonellagrowthundernitrosativestressoftheinnatehostresponse |