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      Metabolic host responses to infection by intracellular bacterial pathogens

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          Abstract

          The interaction of bacterial pathogens with mammalian hosts leads to a variety of physiological responses of the interacting partners aimed at an adaptation to the new situation. These responses include multiple metabolic changes in the affected host cells which are most obvious when the pathogen replicates within host cells as in case of intracellular bacterial pathogens. While the pathogen tries to deprive nutrients from the host cell, the host cell in return takes various metabolic countermeasures against the nutrient theft. During this conflicting interaction, the pathogen triggers metabolic host cell responses by means of common cell envelope components and specific virulence-associated factors. These host reactions generally promote replication of the pathogen. There is growing evidence that pathogen-specific factors may interfere in different ways with the complex regulatory network that controls the carbon and nitrogen metabolism of mammalian cells. The host cell defense answers include general metabolic reactions, like the generation of oxygen- and/or nitrogen-reactive species, and more specific measures aimed to prevent access to essential nutrients for the respective pathogen. Accurate results on metabolic host cell responses are often hampered by the use of cancer cell lines that already exhibit various de-regulated reactions in the primary carbon metabolism. Hence, there is an urgent need for cellular models that more closely reflect the in vivo infection conditions. The exact knowledge of the metabolic host cell responses may provide new interesting concepts for antibacterial therapies.

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          TIGAR, a p53-Inducible Regulator of Glycolysis and Apoptosis

          The p53 tumor-suppressor protein prevents cancer development through various mechanisms, including the induction of cell-cycle arrest, apoptosis, and the maintenance of genome stability. We have identified a p53-inducible gene named TIGAR (TP53-induced glycolysis and apoptosis regulator). TIGAR expression lowered fructose-2,6-bisphosphate levels in cells, resulting in an inhibition of glycolysis and an overall decrease in intracellular reactive oxygen species (ROS) levels. These functions of TIGAR correlated with an ability to protect cells from ROS-associated apoptosis, and consequently, knockdown of endogenous TIGAR expression sensitized cells to p53-induced death. Expression of TIGAR may therefore modulate the apoptotic response to p53, allowing survival in the face of mild or transient stress signals that may be reversed or repaired. The decrease of intracellular ROS levels in response to TIGAR may also play a role in the ability of p53 to protect from the accumulation of genomic damage.
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            Gut inflammation provides a respiratory electron acceptor for Salmonella

            Salmonella enterica serotype Typhimurium (S. Typhimurium) causes acute gut inflammation by using its virulence factors to invade the intestinal epithelium and survive in mucosal macrophages. The inflammatory response enhances the transmission success of S. Typhimurium by promoting its outgrowth in the gut lumen through unknown mechanisms. Here we show that reactive oxygen species generated during inflammation reacted with endogenous, luminal sulphur compounds (thiosulfate) to form a new respiratory electron acceptor, tetrathionate. The genes conferring the ability to utilize tetrathionate as an electron acceptor produced a growth advantage for S. Typhimurium over the competing microbiota in the lumen of the inflamed gut. We conclude that S. Typhimurium virulence factors induce host-driven production of a new electron acceptor that allows the pathogen to use respiration to compete with fermenting gut microbes. Thus, the ability to trigger intestinal inflammation is crucial for the biology of this diarrhoeal pathogen.
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              The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes.

              Cells from some tumors use an altered metabolic pattern compared with that of normal differentiated adult cells in the body. Tumor cells take up much more glucose and mainly process it through aerobic glycolysis, producing large quantities of secreted lactate with a lower use of oxidative phosphorylation that would generate more adenosine triphosphate (ATP), water, and carbon dioxide. This is the Warburg effect, which provides substrates for cell growth and division and free energy (ATP) from enhanced glucose use. This metabolic switch places the emphasis on producing intermediates for cell growth and division, and it is regulated by both oncogenes and tumor suppressor genes in a number of key cancer-producing pathways. Blocking these metabolic pathways or restoring these altered pathways could lead to a new approach in cancer treatments.
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                Author and article information

                Journal
                Front Cell Infect Microbiol
                Front Cell Infect Microbiol
                Front. Cell. Infect. Microbiol.
                Frontiers in Cellular and Infection Microbiology
                Frontiers Media S.A.
                2235-2988
                09 July 2013
                2013
                : 3
                : 24
                Affiliations
                [1] 1Lehrstuhl für Biochemie, Center of Isotopologue Profiling, Technische Universität München Garching, Germany
                [2] 2Max von Pettenkofer-Institut für Hygiene und Medizinische Mikrobiologie, Ludwig-Maximilians-Universität München München, Germany
                [3] 3Lehrstuhl für Mikrobiologie, Biozentrum Universität Würzburg Würzburg, Germany
                Author notes

                Edited by: Alain Charbit, University Paris Descartes, France

                Reviewed by: Alain Charbit, University Paris Descartes, France; Jaiyanth Daniel, University of Central Florida, USA

                *Correspondence: Werner Goebel, Max von Pettenkofer-Institut für Hygiene und Medizinische Mikrobiologie, Ludwig-Maximilians-Universität München, Pettenkoferstraße 9a, D-80336 München, Germany e-mail: goebel@ 123456biozentrum.uni-wuerzburg.de
                Article
                10.3389/fcimb.2013.00024
                3705551
                23847769
                c7edf355-f804-40fe-9e95-c015caf0ecc9
                Copyright © 2013 Eisenreich, Heesemann, Rudel and Goebel.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.

                History
                : 30 April 2013
                : 11 June 2013
                Page count
                Figures: 5, Tables: 0, Equations: 0, References: 196, Pages: 22, Words: 18201
                Categories
                Microbiology
                Review Article

                Infectious disease & Microbiology
                metabolism of mammalian cells,regulation of metabolic pathways,cancer cells,intracellular bacteria,common (“core”) and specific metabolic host responses,virulence-associated factors,antibacterial therapy

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