Blocks in Tricarboxylic Acid Cycle of <named-content content-type="genus-species">Salmonella enterica</named-content> Cause Global Perturbation of Carbon Storage, Motility, and Host-Pathogen Interaction

ABSTRACT The tricarboxylic acid (TCA) cycle is a central metabolic hub in most cells. Virulence functions of bacterial pathogens such as facultative intracellular Salmonella enterica serovar Typhimurium (S. Typhimurium) are closely connected to cellular metabolism. During systematic analyses of muta...

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Autores principales:	Janina Noster, Nicole Hansmeier, Marcus Persicke, Tzu-Chiao Chao, Rainer Kurre, Jasmin Popp, Viktoria Liss, Tatjana Reuter, Michael Hensel
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	TCA cycle glycogen metabolism chemotaxis phagocytosis Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/d1b75ac4f2264b5facceadbf5eefda27
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spelling	oai:doaj.org-article:d1b75ac4f2264b5facceadbf5eefda272021-11-15T15:22:24ZBlocks in Tricarboxylic Acid Cycle of <named-content content-type="genus-species">Salmonella enterica</named-content> Cause Global Perturbation of Carbon Storage, Motility, and Host-Pathogen Interaction10.1128/mSphere.00796-192379-5042https://doaj.org/article/d1b75ac4f2264b5facceadbf5eefda272019-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00796-19https://doaj.org/toc/2379-5042ABSTRACT The tricarboxylic acid (TCA) cycle is a central metabolic hub in most cells. Virulence functions of bacterial pathogens such as facultative intracellular Salmonella enterica serovar Typhimurium (S. Typhimurium) are closely connected to cellular metabolism. During systematic analyses of mutant strains with defects in the TCA cycle, a strain deficient in all fumarase isoforms (ΔfumABC) elicited a unique metabolic profile. Alongside fumarate, S. Typhimurium ΔfumABC accumulates intermediates of the glycolysis and pentose phosphate pathway. Analyses by metabolomics and proteomics revealed that fumarate accumulation redirects carbon fluxes toward glycogen synthesis due to high (p)ppGpp levels. In addition, we observed reduced abundance of CheY, leading to altered motility and increased phagocytosis of S. Typhimurium by macrophages. Deletion of glycogen synthase restored normal carbon fluxes and phagocytosis and partially restored levels of CheY. We propose that utilization of accumulated fumarate as carbon source induces a status similar to exponential- to stationary-growth-phase transition by switching from preferred carbon sources to fumarate, which increases (p)ppGpp levels and thereby glycogen synthesis. Thus, we observed a new form of interplay between metabolism of S. Typhimurium and cellular functions and virulence. IMPORTANCE We performed perturbation analyses of the tricarboxylic acid cycle of the gastrointestinal pathogen Salmonella enterica serovar Typhimurium. The defect of fumarase activity led to accumulation of fumarate but also resulted in a global alteration of carbon fluxes, leading to increased storage of glycogen. Gross alterations were observed in proteome and metabolome compositions of fumarase-deficient Salmonella. In turn, these changes were linked to aberrant motility patterns of the mutant strain and resulted in highly increased phagocytic uptake by macrophages. Our findings indicate that basic cellular functions and specific virulence functions in Salmonella critically depend on the proper function of the primary metabolism.Janina NosterNicole HansmeierMarcus PersickeTzu-Chiao ChaoRainer KurreJasmin PoppViktoria LissTatjana ReuterMichael HenselAmerican Society for MicrobiologyarticleTCA cycleglycogen metabolismchemotaxisphagocytosisMicrobiologyQR1-502ENmSphere, Vol 4, Iss 6 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	TCA cycle glycogen metabolism chemotaxis phagocytosis Microbiology QR1-502
spellingShingle	TCA cycle glycogen metabolism chemotaxis phagocytosis Microbiology QR1-502 Janina Noster Nicole Hansmeier Marcus Persicke Tzu-Chiao Chao Rainer Kurre Jasmin Popp Viktoria Liss Tatjana Reuter Michael Hensel Blocks in Tricarboxylic Acid Cycle of <named-content content-type="genus-species">Salmonella enterica</named-content> Cause Global Perturbation of Carbon Storage, Motility, and Host-Pathogen Interaction
description	ABSTRACT The tricarboxylic acid (TCA) cycle is a central metabolic hub in most cells. Virulence functions of bacterial pathogens such as facultative intracellular Salmonella enterica serovar Typhimurium (S. Typhimurium) are closely connected to cellular metabolism. During systematic analyses of mutant strains with defects in the TCA cycle, a strain deficient in all fumarase isoforms (ΔfumABC) elicited a unique metabolic profile. Alongside fumarate, S. Typhimurium ΔfumABC accumulates intermediates of the glycolysis and pentose phosphate pathway. Analyses by metabolomics and proteomics revealed that fumarate accumulation redirects carbon fluxes toward glycogen synthesis due to high (p)ppGpp levels. In addition, we observed reduced abundance of CheY, leading to altered motility and increased phagocytosis of S. Typhimurium by macrophages. Deletion of glycogen synthase restored normal carbon fluxes and phagocytosis and partially restored levels of CheY. We propose that utilization of accumulated fumarate as carbon source induces a status similar to exponential- to stationary-growth-phase transition by switching from preferred carbon sources to fumarate, which increases (p)ppGpp levels and thereby glycogen synthesis. Thus, we observed a new form of interplay between metabolism of S. Typhimurium and cellular functions and virulence. IMPORTANCE We performed perturbation analyses of the tricarboxylic acid cycle of the gastrointestinal pathogen Salmonella enterica serovar Typhimurium. The defect of fumarase activity led to accumulation of fumarate but also resulted in a global alteration of carbon fluxes, leading to increased storage of glycogen. Gross alterations were observed in proteome and metabolome compositions of fumarase-deficient Salmonella. In turn, these changes were linked to aberrant motility patterns of the mutant strain and resulted in highly increased phagocytic uptake by macrophages. Our findings indicate that basic cellular functions and specific virulence functions in Salmonella critically depend on the proper function of the primary metabolism.
format	article
author	Janina Noster Nicole Hansmeier Marcus Persicke Tzu-Chiao Chao Rainer Kurre Jasmin Popp Viktoria Liss Tatjana Reuter Michael Hensel
author_facet	Janina Noster Nicole Hansmeier Marcus Persicke Tzu-Chiao Chao Rainer Kurre Jasmin Popp Viktoria Liss Tatjana Reuter Michael Hensel
author_sort	Janina Noster
title	Blocks in Tricarboxylic Acid Cycle of <named-content content-type="genus-species">Salmonella enterica</named-content> Cause Global Perturbation of Carbon Storage, Motility, and Host-Pathogen Interaction
title_short	Blocks in Tricarboxylic Acid Cycle of <named-content content-type="genus-species">Salmonella enterica</named-content> Cause Global Perturbation of Carbon Storage, Motility, and Host-Pathogen Interaction
title_full	Blocks in Tricarboxylic Acid Cycle of <named-content content-type="genus-species">Salmonella enterica</named-content> Cause Global Perturbation of Carbon Storage, Motility, and Host-Pathogen Interaction
title_fullStr	Blocks in Tricarboxylic Acid Cycle of <named-content content-type="genus-species">Salmonella enterica</named-content> Cause Global Perturbation of Carbon Storage, Motility, and Host-Pathogen Interaction
title_full_unstemmed	Blocks in Tricarboxylic Acid Cycle of <named-content content-type="genus-species">Salmonella enterica</named-content> Cause Global Perturbation of Carbon Storage, Motility, and Host-Pathogen Interaction
title_sort	blocks in tricarboxylic acid cycle of <named-content content-type="genus-species">salmonella enterica</named-content> cause global perturbation of carbon storage, motility, and host-pathogen interaction
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/d1b75ac4f2264b5facceadbf5eefda27
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Blocks in Tricarboxylic Acid Cycle of <named-content content-type="genus-species">Salmonella enterica</named-content> Cause Global Perturbation of Carbon Storage, Motility, and Host-Pathogen Interaction

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