How Viral and Intracellular Bacterial Pathogens Reprogram the Metabolism of Host Cells to Allow Their Intracellular Replication

Abstract

Viruses and intracellular bacterial pathogens (IBPs) have in common the need of suitable host cells for efficient replication and proliferation during infection. In human infections, the cell types which both groups of pathogens are using as hosts are indeed quite similar and include phagocytic immune cells, especially monocytes/macrophages (MOs/MPs) and dendritic cells (DCs), as well as nonprofessional phagocytes, like epithelial cells, fibroblasts and endothelial cells. These terminally differentiated cells are normally in a metabolically quiescent state when they are encountered by these pathogens during infection. This metabolic state of the host cells does not meet the extensive need for nutrients required for efficient intracellular replication of viruses and especially IBPs which, in contrast to the viral pathogens, have to perform their own specific intracellular metabolism to survive and efficiently replicate in their host cell niches. For this goal, viruses and IBPs have to reprogram the host cell metabolism in a pathogen-specific manner to increase the supply of nutrients, energy, and metabolites which have to be provided to the pathogen to allow its replication. In viral infections, this appears to be often achieved by the interaction of specific viral factors with central metabolic regulators, including oncogenes and tumor suppressors, or by the introduction of virus-specific oncogenes. Less is so far known on the mechanisms leading to metabolic reprogramming of the host cell by IBPs. However, the still scant data suggest that similar mechanisms may also determine the reprogramming of the host cell metabolism in IBP infections. In this review, we summarize and compare the present knowledge on this important, yet still poorly understood aspect of pathogenesis of human viral and especially IBP infections.

Keywords: intracellular bacterial pathogens; metabolic adaptation; metabolism of infected and uninfected host cells; reprogamming of host cell metabolism; viruses.

Figure 1

Carbon metabolism of mammalian cells in quiescent and activated states. In the quiescent state (thin blue arrows) a low amount of glucose, the major carbon source under these conditions, is taken up and oxidized mainly via the glycolytic pathway (1) and to a lesser extent by the (2). Pyruvate, the end product of glycolysis is transported to the mitochondria where it is further oxidized to CO₂ through the TCA (3). NADH, NADPH, and FADH₂, generated in (1), (2), and (3), respectively enter the electron transfer chain (ETC) where these electron donors are re-generated to NAD, NADP, and FAD thereby producing ATP by oxidative phosphorylation (OXPHOS) (5). ATP is also produced in the glycolytic pathway (1) by substrate phosphorylation. The anabolic pathways biosynthesizing the non-essential amino acids Ala, Ser, Asp, Asn, Glu, Gln, Pro as well as FAs, lipids, sterols, and nucleotides (green letters) are shut off or are running at a low level. In the activated state (red arrows), induced e.g., by growth factors, cytokines, activation of oncogenes, inactivation of tumor suppressors (see text for details), (1) and (2) are frequently highly induced, whereas (3) and (5) are now running at reduced levels. This metabolic condition is termed aerobic glycolysis or “Warburg effect.” In this state, pyruvate is converted to lactate thereby regenerating NAD which is needed for continuous glucose oxidation. Glutamine (Gln) and FAs may serve as alternative or additional carbon substrate(s) under these conditions. Gln is converted through glutaminolysis (4) to α-KG and FAs through ß-oxidation (6) to acetyl-CoA. Both metabolites can replenish the TCA. Under these conditions anabolic pathways are also activated as metabolites serving as precursors for the biosynthesis of amino acids, FAs/lipids/sterols, and nucleotides are produced in excess. (1): Glycolysis; (2): Pentose-phosphate pathway (PPP); (3): Tricarboxylic acid cycle (TCA); (4): Glutaminolysis; (5): Electron transfer chain/Oxidative phosphorylation (OXPHOS); (6): Fatty acid ß-oxidation (FAO). Ac-CoA, Acetyl-Coenzyme A; OAA, Oxaloacetate; Cit, Citrate; α-KG, α-ketoglutarate; Suc, Succinate; Fum, Fumarate; Mal, Malate. Blue box: Glucose transporters (GLUT-1-4), yellow box: glutamine transporter SLC1A5; ETC electron transfer chain, consisting of complexes I–IV and ATPase (complex V).

Figure 2

Major regulators controlling catabolic pathways by activating (green arrows) or inhibiting (red arrows) key enzymes (yellow boxes) and/or nutrient transporters. See text for details. Abbreviations of enzymes: HK-1(2), Hexokinase-1 and−2; PFK-1, Phosphofructokinase-1; FBP, fructose 1,6-bisphosphatase; ENO, phosphopyruvate hydratase (enolase); PK, pyruvate kinase; PDH, pyruvate dehydrogenase; LDH, lactate dehydrogenase A; ACL, ATP-dependent citrate lyase; GLS, glutaminase; ß-FAO, fatty acid ß-oxidation. For further abbreviations see Figure 1.

Figure 3

Metabolic pathways activated by viruses supporting their replication. (Left box) Viruses activating glucose uptake, glycolysis (1), PPP (2), and lactate production/secretion in their host cells; (Right upper box) Viruses activating biosynthesis of FAs/lipids or cholesterol and nucleotides, respectively in their host cells; (Right lower box) Viruses activating glutamine uptake and glutaminolysis (4). Abbreviations of viruses: ADV, Adenovirus; DENV, Dengue Virus; EBV, Ebstein-Barr Virus; HCMV, Human Cytomegalovirus; HCV, Hepatitis C Virus; HIV, Human Immunodeficiency Virus; HPV, Human Papillomavirus; HSV-1, Herpes Simplex Virus type 1; KSHV, Kaposi HSV-1, Herpes Simplex Herpesvirus; PolioV, Poliovirus; VACV, Vaccinia Virus. For further abbreviations see Figure 1 and text.

Figure 4

Viruses influence the activity of central metabolic regulators. Viral factors (see text and Tables 1, 2 for details) activate components of the PI3K/Akt/mTOR cascade or HIF-1α (see Figure 3) or inactivate the tumor suppressor p53. These interactions lead in general to enhanced glucose uptake, increased aerobic glycolysis and enhanced PPP activity as well as to activation of anabolic pathways in the infected host cells. Activation of Myc by some viral factors enhances especially Gln uptake and glutaminolysis. For abbreviations see Figures 1, 2.

Figure 5

Some viruses activate HIF-1 by stabilization or increased expression of HIF-1α. The transcription factor HIF-1 is a heterodimer consisting of HIF-1α and the constitutively expressed HIF-1ß. Under normoxic conditions HIF-1α is hydroxylated by prolylhydroxylase (PHD) at conserved proline residues making HIF-1α recognizable for the Von Hippel-Lindau E3 ubiquitin ligase (VHL) complex which leads to rapid degradation by the proteasome. Some viruses are able to inhibit proteasomal degradation of HIF-1α even under normoxic conditions by inhibiting PHD or blocking association of HIF-1α with VHL; others may enhance expression of HIF-α.

Figure 6

Intracellular bacterial pathogens (IBPs) influence the activity of central metabolic regulators of their host cells. Bacterial factors activate components of the PI3K/Akt/mTOR cascade and Myc, or alter the concentration and/or activity of p53 and HIF-1 (see text and Table 3 for details). Most of these interactions lead to enhanced glucose uptake, increased aerobic glycolysis and enhanced PPP activity as well as to activation of anabolic pathways in the infected host cells. Activation of Myc by some IBPs also enhances Gln uptake and glutaminolysis. Lm, Listeria monocytogenes; Sf, Shigella flexneri; St, Salmonella enterica; Lp, Legionella pneumophila; Mt, Mycobacterium tuberculosis; Ba, Brucella abortus; Bh, Bartonella henselae; Cb, Coxiella burnettii; Ct, Chlamydia trachomatis; Ft, Francisella tularensis. For other abbreviations, see Figures 1, 2.