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Modulation of Host Cell Metabolism by

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  • Authors: Marion Rother1, Ana Rita Teixeira da Costa4, Rike Zietlow5, Thomas F. Meyer6, Thomas Rudel7
  • Editors: Pascale Cossart8, Craig R. Roy9, Philippe Sansonetti10
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Steinbeis Innovation Center for Systems Biomedicine, 14612 Berlin-Falkensee, Germany; 2: Institute of Experimental Internal Medicine, Otto von Guericke University Magdeburg, 39120 Magdeburg, Germany; 3: Max Planck Institute for Infection Biology, Department of Molecular Biology, 10117 Berlin, Germany; 4: Max Planck Institute for Infection Biology, Department of Molecular Biology, 10117 Berlin, Germany; 5: Max Planck Institute for Infection Biology, Department of Molecular Biology, 10117 Berlin, Germany; 6: Max Planck Institute for Infection Biology, Department of Molecular Biology, 10117 Berlin, Germany; 7: Department of Microbiology, Biocenter, University of Wuerzburg, 97074 Wuerzburg, Germany; 8: Institut Pasteur, Paris, France; 9: Yale University School of Medicine, New Haven, Connecticut; 10: Institut Pasteur, Paris, France
  • Source: microbiolspec May 2019 vol. 7 no. 3 doi:10.1128/microbiolspec.BAI-0012-2019
  • Received 11 July 2018 Accepted 10 January 2019 Published 17 May 2019
  • Thomas F. Meyer, [email protected]; Thomas Rudel [email protected]
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  • Abstract:

    Propagation of the intracellular bacterial pathogen is strictly bound to its host cells. The bacterium has evolved by minimizing its genome size at the cost of being completely dependent on its host. Many of the vital nutrients are synthesized only by the host, and this has complex implications. Recent advances in loss-of-function analyses and the metabolomics of human infected versus noninfected cells have provided comprehensive insight into the molecular changes that host cells undergo during the stage of infection. Strikingly, infected cells acquire a stage of high metabolic activity, featuring distinct aspects of the Warburg effect, a condition originally assigned to cancer cells. This condition is characterized by aerobic glycolysis and an accumulation of certain metabolites, altogether promoting the synthesis of crucial cellular building blocks, such as nucleotides required for DNA and RNA synthesis. The altered metabolic program enables tumor cells to rapidly proliferate as well as -infected cells to feed their occupants and still survive. This program is largely orchestrated by a central control board, the tumor suppressor protein p53. Its downregulation in -infected cells or mutation in cancer cells not only alters the metabolic state of cells but also conveys the prevention of programmed cell death involving mitochondrial pathways. While this points toward common features in the metabolic reprogramming of infected and rapidly proliferating cells, it also forwards novel treatment options against chronic intracellular infections involving well-characterized host cell targets and established drugs.

  • Citation: Rother M, Teixeira da Costa A, Zietlow R, Meyer T, Rudel T. 2019. Modulation of Host Cell Metabolism by . Microbiol Spectrum 7(3):BAI-0012-2019. doi:10.1128/microbiolspec.BAI-0012-2019.

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/content/journal/microbiolspec/10.1128/microbiolspec.BAI-0012-2019
2019-05-17
2019-06-16

Abstract:

Propagation of the intracellular bacterial pathogen is strictly bound to its host cells. The bacterium has evolved by minimizing its genome size at the cost of being completely dependent on its host. Many of the vital nutrients are synthesized only by the host, and this has complex implications. Recent advances in loss-of-function analyses and the metabolomics of human infected versus noninfected cells have provided comprehensive insight into the molecular changes that host cells undergo during the stage of infection. Strikingly, infected cells acquire a stage of high metabolic activity, featuring distinct aspects of the Warburg effect, a condition originally assigned to cancer cells. This condition is characterized by aerobic glycolysis and an accumulation of certain metabolites, altogether promoting the synthesis of crucial cellular building blocks, such as nucleotides required for DNA and RNA synthesis. The altered metabolic program enables tumor cells to rapidly proliferate as well as -infected cells to feed their occupants and still survive. This program is largely orchestrated by a central control board, the tumor suppressor protein p53. Its downregulation in -infected cells or mutation in cancer cells not only alters the metabolic state of cells but also conveys the prevention of programmed cell death involving mitochondrial pathways. While this points toward common features in the metabolic reprogramming of infected and rapidly proliferating cells, it also forwards novel treatment options against chronic intracellular infections involving well-characterized host cell targets and established drugs.

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FIGURE 1

Distribution and overrepresentation of validated hits of the human genome-wide RNA interference screen in biological processes of the host cell. Numbers in parentheses indicate the values for each overrepresented biological process (determined with the PANTHER Overrepresentation Test).

Source: microbiolspec May 2019 vol. 7 no. 3 doi:10.1128/microbiolspec.BAI-0012-2019
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Image of FIGURE 2
FIGURE 2

Pathway map representing modulated metabolites and related host factors essential for () infection. See text for explanation. Abbreviations for metabolites: 2OHG, 2-hydroxyglutarate; 3OH-butanoate, D-3-hydroxybutyrate; 3PGA, 3-phosphoglyceric acid; AcCoA, acetyl coenzyme A; AcetAcetCoA, acetoacetyl-CoA; aKg, alpha-ketoglutaric acid; DHAP, dihydroxyacetone phosphate; E4P, erythrose 4-phosphate; F16BP, fructose-1-6-bisphosphate; F6P, fructose-6-phosphate; G6P, glucose-6-phosphate; GA3P, glyceraldehyde 3-phosphate; Glyc3P, glycerol-3-phosphate; GlycPGlyc, glycerophosphoglycerol; GMP, guanosine monophosphate; IMP, inosine monophosphate; OAA, oxaloacetic acid; PE, phosphatidylethanolamine; PEP, phosphoenolpyruvate; PG6, phosphogluconolactone; PRA, 5′-phosphoribosylamine; PRPP, 5-phospho--ribose α-1-pyrophosphate; R5P, ribose-5-phosphate; Ru5P, ribulose-5-phosphate; S7P, -sedo heptulose 7-P; SuccCoA, succinyl coenzyme A; X5P, xylulose 5-phosphate; XMP, xanthine monophosphate. RNA interference screen hits: ALDH1B1, aldehyde dehydrogenase 1 family member B1; BDH1, 3-hydroxybutyrate dehydrogenase, type 1; ETNK1, ethanolamine kinase 1; G6PD, glucose-6-phosphate dehydrogenase; GMPS, guanosine monophosphate synthetase; GPD2, mitochondrial glycerol-3-phosphate dehydrogenase; GPI, glucose-6-phosphate isomerase; IMPDH2, inosine-5′-monophosphate dehydrogenase 2; PDH, pyruvate dehydrogenase; PDK2, pyruvate dehydrogenase kinase isoform 2; PFKM, 6-phosphofructokinase; PPAT, phosphoribosyl pyrophosphate amidotransferase; PRPS2, phosphoribosyl pyrophosphate synthetase 2; TKT, transketolase; TPK1, thiamine pyrophosphokinase 1. Chlamydial metabolic genes: , ATP/ADP translocase; , fructose 1,6-bisphosphate aldolase; , fumarate hydratase; , 6-phosphogluconate dehydrogenase; , malate dehydrogenase; , pyruvate dehydrogenase; , phosphoglycerate mutase; , glucose-6-phosphate isomerase; , pyruvate kinase; , succinate dehydrogenase; , succinyl-CoA ligase; , G6P transporter; , transaldolase; , triosephosphate isomerase; , glucose-6-phosphate 1-dehydrogenase.

Source: microbiolspec May 2019 vol. 7 no. 3 doi:10.1128/microbiolspec.BAI-0012-2019
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Image of FIGURE 3
FIGURE 3

Regulation of glucose metabolism and mitochondrial architecture in -infected cells. Glucose is taken up by the host cell and converted to glucose-6-P (G6P) by hexokinase II (HKII). G6P is then channeled into the PPP and increased nucleotide biosynthesis or is directly taken up by . ATP from the host cell is directly used by as an energy source during active replication. UDP-glucose (UDP-Glu) from the host cell is converted to glycogen in the inclusion lumen and serves as a source for G6P in the EB. PI3 kinase (PI3K)-dependent upregulation of c-Myc and PI3K/miR30-induced downregulation of p53 pathways increase glycolysis and the G6P flux to the host PPP. P53 downregulation also prevents the transcription of Drp1, the major factor involved in mitochondrial fission. Prevention of mitochondrial fragmentation preserves the ATP supply from mitochondria.

Source: microbiolspec May 2019 vol. 7 no. 3 doi:10.1128/microbiolspec.BAI-0012-2019
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