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Metabolic Adaptations of Intracellullar Bacterial Pathogens and their Mammalian Host Cells during Infection (“Pathometabolism”)

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  • Authors: Wolfgang Eisenreich1, Jürgen Heesemann2, Thomas Rudel3, Werner Goebel4
  • Editors: Tyrrell Conway5, Paul Cohen6
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Lehrstuhl für Biochemie, Technische Universität München, Germany; 2: Max von Pettenkofer-Institut für Hygiene und Medizinische Mikrobiologie, Ludwig-Maximilians-Universität München, Germany; 3: Lehrstuhl für Mikrobiologie, Biozentrum Universität Würzburg, Germany; 4: Max von Pettenkofer-Institut für Hygiene und Medizinische Mikrobiologie, Ludwig-Maximilians-Universität München, Germany; 5: Oklahoma State University, Stillwater, OK; 6: University of Rhode Island, Kingston, RI
  • Source: microbiolspec June 2015 vol. 3 no. 3 doi:10.1128/microbiolspec.MBP-0002-2014
  • Received 30 December 2013 Accepted 14 April 2014 Published 11 June 2015
  • Wolfgang Eisenreich, wolfgang.eisenreich@ch.tum.de
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  • Abstract:

    Several bacterial pathogens that cause severe infections in warm-blooded animals, including humans, have the potential to actively invade host cells and to efficiently replicate either in the cytosol or in specialized vacuoles of the mammalian cells. The interaction between these intracellular bacterial pathogens and the host cells always leads to multiple physiological changes in both interacting partners, including complex metabolic adaptation reactions aimed to promote proliferation of the pathogen within different compartments of the host cells. In this chapter, we discuss the necessary nutrients and metabolic pathways used by some selected cytosolic and vacuolar intracellular pathogens and - when available - the links between the intracellular bacterial metabolism and the expression of the virulence genes required for the intracellular bacterial replication cycle. Furthermore, we address the growing evidence that pathogen-specific factors may also trigger metabolic responses of the infected mammalian cells affecting the carbon and nitrogen metabolism as well as defense reactions. We also point out that many studies on the metabolic host cell responses induced by the pathogens have to be scrutinized due to the use of established cell lines as model host cells, as these cells are (in the majority) cancer cells that exhibit a dysregulated primary carbon metabolism. As the exact knowledge of the metabolic host cell responses may also provide new concepts for antibacterial therapies, there is undoubtedly an urgent need for host cell models that more closely reflect the infection conditions.

  • Citation: Eisenreich W, Heesemann J, Rudel T, Goebel W. 2015. Metabolic Adaptations of Intracellullar Bacterial Pathogens and their Mammalian Host Cells during Infection (“Pathometabolism”). Microbiol Spectrum 3(3):MBP-0002-2014. doi:10.1128/microbiolspec.MBP-0002-2014.

Key Concept Ranking

Aromatic Amino Acids
0.45418146
Type III Secretion System
0.43148986
Type IV Secretion Systems
0.42629468
Aromatic Amino Acid Biosynthesis
0.42080596
0.45418146

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/content/journal/microbiolspec/10.1128/microbiolspec.MBP-0002-2014
2015-06-11
2017-11-20

Abstract:

Several bacterial pathogens that cause severe infections in warm-blooded animals, including humans, have the potential to actively invade host cells and to efficiently replicate either in the cytosol or in specialized vacuoles of the mammalian cells. The interaction between these intracellular bacterial pathogens and the host cells always leads to multiple physiological changes in both interacting partners, including complex metabolic adaptation reactions aimed to promote proliferation of the pathogen within different compartments of the host cells. In this chapter, we discuss the necessary nutrients and metabolic pathways used by some selected cytosolic and vacuolar intracellular pathogens and - when available - the links between the intracellular bacterial metabolism and the expression of the virulence genes required for the intracellular bacterial replication cycle. Furthermore, we address the growing evidence that pathogen-specific factors may also trigger metabolic responses of the infected mammalian cells affecting the carbon and nitrogen metabolism as well as defense reactions. We also point out that many studies on the metabolic host cell responses induced by the pathogens have to be scrutinized due to the use of established cell lines as model host cells, as these cells are (in the majority) cancer cells that exhibit a dysregulated primary carbon metabolism. As the exact knowledge of the metabolic host cell responses may also provide new concepts for antibacterial therapies, there is undoubtedly an urgent need for host cell models that more closely reflect the infection conditions.

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FIGURE 1

Metabolic potential of intracellular bacterial pathogens replicating in the cytosol of host cells. (a) , (b) , and (c) . Solid arrows indicate reversible (double-headed arrows) and essentially irreversible (single-headed arrows) reactions of glycolysis and gluconeogenesis (GL/GN), red arrows), pentose phosphate pathway (PPP, blue arrows), Entner-Doudoroff pathway (ED, orange arrows), the tricarboxylic acid cycle (TCA). The irreversible reactions involved in GN are marked by dotted-framed boxes: fbp for phosphofructo-1,6-bisphosphatase, pps for PEP synthase, and pckA for PEP carboxykinase. Broken black arrows depict anaplerotic reactions: GS for glyoxylate shunt, pycA for pyruvate carboxylase, ppc for PEP carboxylase; pckA for PEP carboxykinase, and maeA (sfcA) for malate enzyme. Yellow boxes and arrows mark major carbon and energy substrates and black-framed boxes mark the biosynthesis of amino acids, vitamins, nucleotides, cell envelope components, and fatty acids/lipids as well as the major sites of ATP production. The major sites for the generation of NADH/H, NADPH/H and FADH are also shown. doi:10.1128/microbiolspec.MBP-0002-2014.f1

Source: microbiolspec June 2015 vol. 3 no. 3 doi:10.1128/microbiolspec.MBP-0002-2014
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FIGURE 2

Metabolic potential of intracellular bacterial pathogens replicating in specialized vacuoles of the host cells. (a) , (b) L, and (c) . See legend of Fig 1 for further explanations and abbreviations. doi:10.1128/microbiolspec.MBP-0002-2014.f2

Source: microbiolspec June 2015 vol. 3 no. 3 doi:10.1128/microbiolspec.MBP-0002-2014
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FIGURE 3

Carbon metabolism and its regulation in mammalian cells. (a) Major carbon sources and their transporters are indicated by yellow boxes and arrows. Main catabolic and anabolic pathways, including glycolysis (GL, red solid arrows) with lactose formation (red broken arrows), pentose-phosphate pathway (PPP, blue arrows) in the cyctosol, TCA cycle in the mitochondria and associated cytosolic reactions (black arrows), and glutaminolysis (purple arrows); catabolic breakdown of amino acids and fatty acids are indicated by dotted arrows. The reactions indicated by the green arrows are two anaplerotic reactions (catalysed by PCK and PYC). The starting points for the biosynthesis of the “non-essential” amino acids, nucleotides and fatty acids/lipids are schematically indicated by broken arrows. (b) Regulation of glucose uptake, glycolysis and pentose-phosphate pathway and (c) of the TCA cycle, glutaminolysis, aerobic respiration, and lactate production by general transcription factors, tumor suppressors, and oncogenes. Activation of the target enzymes (yellow boxes) are shown by green pointed arrows and inhibition by the red symbol. Explanations and abbreviations: Fru-2,6P: fructose 2,6-bisphosphate, the formation of which is catalysed by the fructokinase 2 (PFK2); Fru-2,6P activates fructokinase 1(PFK1); ACL: cytosolic ATP-dependent citrate lyase; ICD-2: cytosolic NADP-dependent isocitrate dehydrogenase; ME: cytosolic malate dehydrogenase (malic enzyme); GLS: glutaminase; HIF-1: hypoxia-inducible factor1; p53: tumor suppressor protein 53 encoded by the gene TP53; TIGAR: TP53-inducible glycolysis and apoptosis regulator; PTEN: phosphatase and tensin homolog; mTORC1: mammalian target of rapamycin complex 1; PI3K/Akt: phosphoinositide-dependent kinase-1/protein kinase B. For further details regarding the complex regulation circuit, see ( 30 , 54 ) and further references cited there. doi:10.1128/microbiolspec.MBP-0002-2014.f3

Source: microbiolspec June 2015 vol. 3 no. 3 doi:10.1128/microbiolspec.MBP-0002-2014
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