Metabolic host responses to infection by intracellular bacterial pathogens

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.

Keywords: antibacterial therapy; cancer cells; common (“core”) and specific metabolic host responses; intracellular bacteria; metabolism of mammalian cells; regulation of metabolic pathways; virulence-associated factors.

Figure 1

Model showing possible interactions of common bacterial surface components and pathogen-specific virulence factors with the host cell metabolism in the cytosol (blue lines) and in the mitochondria (orange). The schematic view of the host cell (gray box) metabolism comprises glucose uptake (blue star), glycolysis (GL), pentose-phosphate shunt (PP), tricarboxylic acid cycle (TCA), glutaminolysis (GLNLY), β-oxidation of fatty acids (β-ox), and the electron transport chain (ETC) essential for aerobic respiration. (A) Interaction with non-pathogenic bacteria (green sphere) which may trigger common metabolic host cell responses (green dashed arrows; see text for definition) mainly via cell envelope structures (e.g., PG, LPS, LTA—green triangles). (B) Extracellular bacterial pathogens (red sphere) may trigger in addition to these common responses (green dashed arrows), specific metabolic host cell responses via cell-bound or secreted virulence factors (red triangles and red circles), as well as via specific secretion systems (e.g., T3SS or T4SS; purple boxes) translocated effector proteins (purple circles). (C) Intracellular bacterial pathogens replicating in membrane-surrounded vacuoles within the host cell could trigger metabolic host responses via translocated effector proteins (purple circles). (D) Intracellular bacterial pathogens replicating in the host cell's cytosol could trigger metabolic host responses via secreted or cell-bound virulence factors (red triangles and circles). For abbreviations and further details, see text.

Figure 2

Major catabolic and anabolic pathways in mammalian cells. Glucose uptake by the transporters GLUT or SGLT, glycolysis (GL, red arrows) and gluconeogenesis (GN; specific reactions marked by blue arrows); pentose-phosphate pathway (PPP; broken red arrows); tricarboxylic acid cycle (TCA; green circle); glutaminolysis (GLNLY, magenta arrows) and the associated TCA reactions. β-oxidation (β-Ox) and other catabolic reactions occurring in the mitochondrium and (mainly) in the cytosol are marked by black arrows. Anabolic reactions leading to amino acids, nucleotides, and lipids are indicated by broken thick black arrows. Also indicated are the reactions leading to NADH, NADPH, NAD, and ATP, respectively. Metabolites are marked in black and enzymes in blue. Abbreviations: HK, hexokinase; PFK, phosphofructokinase; FBP, fructose bisphosphatase; PK, pyruvate kinase; PDH, pyruvate dehydrogenase complex; PYC, pyruvate carboxylase; PCK, PEP-carboxylase; LDH, lactate dehydrogenase; CS, citrate synthase; ICD, isocitrate dehydrogenase; ACL, ATP-dependent citrate lyase; ME, malate enzyme; ETC, electron transfer chain for aerobic respiration (small red circle), consisting of complexes I–IV and of ATPase (complex V); small blue box: glutamine transporters SLC1A5 and ASCT2.

Figure 3

Regulation of central metabolic pathways by signaling pathways, proto-oncogenes, and tumor suppressors. The figure provides a rough overview how the major metabolic pathways (GL, PPP, TCA, glutaminolysis, β-oxidation, etc.) are regulated by signaling pathways, protooncogenes, and tumor suppressors, including mainly PI3K/AKT, LKB1/AMPK, HIF-1, mTORC1, MYC, p53, and the p53-controlled regulators TIGAR and PTEN. Interactions between these major players are mediated in part by additional regulatory factors not listed in the figure (Gordan et al., ; Levine and Puzio-Kuter, 2010). Red-boxed regulators repress specific metabolic target reactions (indicated by the red bars) whereas green boxed regulators activate specific reactions (indicated by the green arrows). Inhibition and activation of the indicated enzymes may occur on the transcriptional, translational of post-translational level (see text and Supplementary Material S6 for further details). Black arrows indicate the most relevant metabolic steps. Targeted enzymes are yellow-boxed. For abbreviations, see Figure 2 and text.

Figure 4

Major metabolic pathways in normal differentiated cells and cancer cells. In normal differentiated mammalian cells (A), e.g., epithelial cell or non-activated macrophages, glucose uptake, glycolysis, TCA cycle, and aerobic respiration (indicated by the thick red arrows) are active at low balanced levels. All other less- or non-active catabolic and anabolic pathways are indicated by thin black and broken black arrows, respectively. In mammalian cancer cells (B), carbon metabolism is characterized by enhanced glucose uptake, glycolysis, pentose-phosphate shunt, enhanced conversion of pyruvate to lactate (indicated by the thick red arrows) and reduced conversion to acetyl-CoA by pyruvate dehydrogenase, reduced TCA cycle, gluconeogenesis, and aerobic respiration (indicated by the thin red and black arrows). In some cancer cells, glutaminolysis is also highly induced with the subsequent reactions leading to α-ketoglutarate (α-KG) and malate (Mal) which is converted to pyruvate by the cytosolic malic enzyme (ME) and to citrate (Cit). Cit is transported into the cytosol and converted by ATP-dependent citrate lyase to oxaloacetate (Oxa) and acetyl-CoA (Ac-CoA). These reactions are marked by the thick broken red arrows. Also induced are the anabolic reactions leading to amino acids, nucleotides, and fatty acids/lipids (indicated by the broken thick black arrows). The non-activated metabolic reactions are marked by thin black arrows. For abbreviations, see Figure 2.

Figure 5

Summary overview showing the major metabolic pathways and reactions of a metabolically active mammalian host cell (blue spheres and boxes) and the regulatory network with the major regulators (green box) that control host cell metabolism. Blue arrows indicate exchange of metabolites and intermediates of the different metabolic functional units. Green arrows indicate control of these functional units by specific regulators. The pink sphere indicates an (intracellular) bacterial pathogen with surface components (red triangles), T3SS or T4SS effector proteins and other secreted virulence factors (red bars and circles) that might interact with metabolic targets of the host cell. The red dashed arrows indicate already confirmed or probable interactions (see text for details).