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Regulating the Intersection of Metabolism and Pathogenesis in Gram-positive Bacteria

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  • Authors: Anthony R. Richardson†1, Greg A. Somerville†2, Abraham L. Sonenshein†3
  • Editors: Tyrrell Conway4, Paul Cohen5
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC; 2: School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE; 3: Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA; 4: Oklahoma State University, Stillwater, OK; 5: University of Rhode Island, Kingston, RI
    • Source: microbiolspec June 2015 vol. 3 no. 3 doi:10.1128/microbiolspec.MBP-0004-2014
  • Received 28 January 2014 Accepted 06 May 2014 Published 11 June 2015
  • Greg Somerville, [email protected]
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  • Abstract:

    Pathogenic bacteria must contend with immune systems that actively restrict the availability of nutrients and cofactors, and create a hostile growth environment. To deal with these hostile environments, pathogenic bacteria have evolved or acquired virulence determinants that aid in the acquisition of nutrients. This connection between pathogenesis and nutrition may explain why regulators of metabolism in nonpathogenic bacteria are used by pathogenic bacteria to regulate both metabolism and virulence. Such coordinated regulation is presumably advantageous because it conserves carbon and energy by aligning synthesis of virulence determinants with the nutritional environment. In Gram-positive bacterial pathogens, at least three metabolite-responsive global regulators, CcpA, CodY, and Rex, have been shown to coordinate the expression of metabolism and virulence genes. In this chapter, we discuss how environmental challenges alter metabolism, the regulators that respond to this altered metabolism, and how these regulators influence the host-pathogen interaction.

  • Citation: Richardson† A, Somerville† G, Sonenshein† A. 2015. Regulating the Intersection of Metabolism and Pathogenesis in Gram-positive Bacteria. Microbiol Spectrum 3(3):MBP-0004-2014. doi:10.1128/microbiolspec.MBP-0004-2014.

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/content/journal/microbiolspec/10.1128/microbiolspec.MBP-0004-2014
2015-06-11
2021-03-01

Abstract:

Pathogenic bacteria must contend with immune systems that actively restrict the availability of nutrients and cofactors, and create a hostile growth environment. To deal with these hostile environments, pathogenic bacteria have evolved or acquired virulence determinants that aid in the acquisition of nutrients. This connection between pathogenesis and nutrition may explain why regulators of metabolism in nonpathogenic bacteria are used by pathogenic bacteria to regulate both metabolism and virulence. Such coordinated regulation is presumably advantageous because it conserves carbon and energy by aligning synthesis of virulence determinants with the nutritional environment. In Gram-positive bacterial pathogens, at least three metabolite-responsive global regulators, CcpA, CodY, and Rex, have been shown to coordinate the expression of metabolism and virulence genes. In this chapter, we discuss how environmental challenges alter metabolism, the regulators that respond to this altered metabolism, and how these regulators influence the host-pathogen interaction.

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Regulating the Intersection of Metabolism and Pathogenesis in Gram-positive Bacteria
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Citation: Richardson† A, Somerville† G, Sonenshein† A. 2015. Regulating the intersection of metabolism and pathogenesis in gram-positive bacteria. microbiolspec 3(3): doi:10.1128/microbiolspec.MBP-0004-2014
/content/microbiolspec/10.1128/microbiolspec.MBP-0004-2014.fig1
FIGURE 1
A simplified view of bacterial physiology. The 13 biosynthetic intermediates discussed in this chapter are all derived from the three metabolic pathways of central metabolism. Alterations in the availability of these biosynthetic intermediates always affect virulence factor synthesis.
microbiolspec/3/3/MBP-0004-2014-fig1_thmb.gif
microbiolspec/3/3/MBP-0004-2014-fig1.gif
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FIGURE 1

A simplified view of bacterial physiology. The 13 biosynthetic intermediates discussed in this chapter are all derived from the three metabolic pathways of central metabolism. Alterations in the availability of these biosynthetic intermediates always affect virulence factor synthesis.

Source: microbiolspec June 2015 vol. 3 no. 3 doi:10.1128/microbiolspec.MBP-0004-2014
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FIGURE 2
Synergistic repression of toxin synthesis by CodY and CcpA. Responding independently to different nutritional signals, CcpA and CodY both bind to the regulatory region of the gene, repressing production of the alternative sigma factor necessary for high-level toxin gene ( and ) expression.
microbiolspec/3/3/MBP-0004-2014-fig2_thmb.gif
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FIGURE 2

Synergistic repression of toxin synthesis by CodY and CcpA. Responding independently to different nutritional signals, CcpA and CodY both bind to the regulatory region of the gene, repressing production of the alternative sigma factor necessary for high-level toxin gene ( and ) expression.

Source: microbiolspec June 2015 vol. 3 no. 3 doi:10.1128/microbiolspec.MBP-0004-2014
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FIGURE 3
Examples of oxidative and reductive metabolic pathways in . NADH produced during glycolysis and other oxidative pathways is converted back to NAD by a series of reductive pathways. The proline pathway, catalyzed by proline reductase, appears to be the favored pathway. When proline is available, the other pathways shown are repressed by Rex. Repression by Rex is relieved when the ratio of NAD to NADH indicates the need for increased regeneration of NAD. Additional repression by CcpA and CodY restricts maximal expression of the alternative pathways to conditions in which CcpA and CodY are relatively inactive. The bottom three pathways (effectively, acetyl-CoA to butyrate) are encoded in a single eight-gene operon.
microbiolspec/3/3/MBP-0004-2014-fig3_thmb.gif
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FIGURE 3

Examples of oxidative and reductive metabolic pathways in . NADH produced during glycolysis and other oxidative pathways is converted back to NAD by a series of reductive pathways. The proline pathway, catalyzed by proline reductase, appears to be the favored pathway. When proline is available, the other pathways shown are repressed by Rex. Repression by Rex is relieved when the ratio of NAD to NADH indicates the need for increased regeneration of NAD. Additional repression by CcpA and CodY restricts maximal expression of the alternative pathways to conditions in which CcpA and CodY are relatively inactive. The bottom three pathways (effectively, acetyl-CoA to butyrate) are encoded in a single eight-gene operon.

Source: microbiolspec June 2015 vol. 3 no. 3 doi:10.1128/microbiolspec.MBP-0004-2014
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FIGURE 4
Differences in M1- versus M2-macrophage fueling reactions. In response to inflammatory stimuli, M1-macrophages upregulate a pathway known as aerobic glycolysis. This involves the import of glucose through GLUT-1 and its phosphorylation by Hexokinase-1 (HK-1). The resulting glucose-6-phosphate (G6P) can be shuttled through the pentose phosphate pathway (PPP) for NADPH generation, which fuels immune radical production, including nitric oxide (NO). At the same time, G6P is also oxidized to pyruvate (PYR) for ATP synthesis, and this PYR is primarily reduced to lactate (LAC) to conserve redox balance. Very little PYR enters the Krebs cycle as acetyl-CoA (Ac-CoA) due to the phosphorylation and inactivation of pyruvate dehydrogenase (PDH). Genes activated/repressed by HIF-1α are depicted as green/red. Upon stimulation with anti-inflammatory stimuli, M2-macrophages adopt an oxidative metabolism involving the import of free fatty acids and low-density lipoprotein (LDL)-associated lipids (fatty acids and LDL) by CD36. These fatty acids are linked to carnitine and shuttled to the mitochondria for β-oxidation, yielding ATP. In addition, some of the Ac-CoA is reused to synthesize new fatty acids. Rather than using tissue arginine for NO-production, these cells use the amino acid for proline and polyamine production, the former of which is critical for collagen synthesis. Features activated/repressed by PPAR-γ are depicted in green/red.
microbiolspec/3/3/MBP-0004-2014-fig4_thmb.gif
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FIGURE 4

Differences in M1- versus M2-macrophage fueling reactions. In response to inflammatory stimuli, M1-macrophages upregulate a pathway known as aerobic glycolysis. This involves the import of glucose through GLUT-1 and its phosphorylation by Hexokinase-1 (HK-1). The resulting glucose-6-phosphate (G6P) can be shuttled through the pentose phosphate pathway (PPP) for NADPH generation, which fuels immune radical production, including nitric oxide (NO). At the same time, G6P is also oxidized to pyruvate (PYR) for ATP synthesis, and this PYR is primarily reduced to lactate (LAC) to conserve redox balance. Very little PYR enters the Krebs cycle as acetyl-CoA (Ac-CoA) due to the phosphorylation and inactivation of pyruvate dehydrogenase (PDH). Genes activated/repressed by HIF-1α are depicted as green/red. Upon stimulation with anti-inflammatory stimuli, M2-macrophages adopt an oxidative metabolism involving the import of free fatty acids and low-density lipoprotein (LDL)-associated lipids (fatty acids and LDL) by CD36. These fatty acids are linked to carnitine and shuttled to the mitochondria for β-oxidation, yielding ATP. In addition, some of the Ac-CoA is reused to synthesize new fatty acids. Rather than using tissue arginine for NO-production, these cells use the amino acid for proline and polyamine production, the former of which is critical for collagen synthesis. Features activated/repressed by PPAR-γ are depicted in green/red.

Source: microbiolspec June 2015 vol. 3 no. 3 doi:10.1128/microbiolspec.MBP-0004-2014
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