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Review
. 2024 Sep 16;25(18):9977.
doi: 10.3390/ijms25189977.

Interactions of SARS-CoV-2 with Human Target Cells-A Metabolic View

Wolfgang Eisenreich  1 , Julian Leberfing  1 , Thomas Rudel  2 , Jürgen Heesemann  3 , Werner Goebel  3
Affiliations
Review

Interactions of SARS-CoV-2 with Human Target Cells-A Metabolic View

Wolfgang Eisenreich et al. Int J Mol Sci. .

Abstract

Viruses are obligate intracellular parasites, and they exploit the cellular pathways and resources of their respective host cells to survive and successfully multiply. The strategies of viruses concerning how to take advantage of the metabolic capabilities of host cells for their own replication can vary considerably. The most common metabolic alterations triggered by viruses affect the central carbon metabolism of infected host cells, in particular glycolysis, the pentose phosphate pathway, and the tricarboxylic acid cycle. The upregulation of these processes is aimed to increase the supply of nucleotides, amino acids, and lipids since these metabolic products are crucial for efficient viral proliferation. In detail, however, this manipulation may affect multiple sites and regulatory mechanisms of host-cell metabolism, depending not only on the specific viruses but also on the type of infected host cells. In this review, we report metabolic situations and reprogramming in different human host cells, tissues, and organs that are favorable for acute and persistent SARS-CoV-2 infection. This knowledge may be fundamental for the development of host-directed therapies.

Keywords: COVID-19; SARS-CoV-2; host-directed therapies; long COVID; metabolic reprogramming; persistence.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
(Created with BioRender.com): (A) Metabolic program of SARS-CoV-2-infected cells suitable for viral replication (as derived from the discussed studies on SARS-CoV-2 replication in established cell lines and tissue cells). The major metabolic reactions supporting this program are marked by the virus symbol and broad orange arrows, and they include the following: (a) increased glucose uptake via the induction of glucose transporters, especially GLUT1 and GLUT3; (b) enhanced (aerobic) glycolysis due to increased PKM2, combined with increased lactate dehydrogenase A (LDH-A) activity, to regenerate NAD for the maintenance of glucose oxidation via glycolysis, which is necessary for the increased production of ATP, glucose-6-phosphate (G6P) (required for the initiation of PPP), and 3-phosphoglycerate (synthesis of serine/glycine, erythrose-4-phosphate); (c) activation of PPP with both arms to generate ribose-5-phosphate (R5P) and NADPH; (d) reduced OXPHOS via the inhibition of the pyruvate dehydrogenase (PDH)-mediated mitochondrial acetyl-CoA formation, which could be achieved either through the inhibition of the mitochondrial pyruvate carrier complex (MPC), which would block the entry of pyruvate (Pyr) into the mitochondria, or through the activation of pyruvate dehydrogenase kinase (PDHK), which would block the conversion of Pyr into acetyl-CoA; (e) specific metabolites normally produced in the TCA cycle and indispensable for SARS-CoV-2 replication, with α-KG, OAA, acetyl-CoA, citrate (Cit), and Suc-CoA especially able to be delivered via active TCA-cycle enzymes or various anaplerotic reactions, as α-KG can be provided via glutaminolysis, OAA via ATP-dependent PC and ATP-dependent Cit lyase (ACL), acetyl-CoA via fatty acid oxidation (FAO), Cit either via TCA-cycle enzymes from acetyl-CoA and OAA or reverse TCA-cycle reactions through the reduced carboxylation of α-KG and Suc-CoA via the TCA cycle enzyme α-KG dehydrogenase; (f) in the case of a glucose shortage, FAO is an alternative route for ATP generation. (B) Viral reprogramming of cellular regulators that modify metabolic fluxes in favor of SARS-CoV-2 replication. Metabolic reactions that are positively or negatively regulated through viral mechanisms are shown in orange boxes. Viral factors partaking in host-cell control are shown in orange, oval boxes indicated by a virus particle. For details and a further legend, see also Figures S1 and S2.
Figure 1
Figure 1
(Created with BioRender.com): (A) Metabolic program of SARS-CoV-2-infected cells suitable for viral replication (as derived from the discussed studies on SARS-CoV-2 replication in established cell lines and tissue cells). The major metabolic reactions supporting this program are marked by the virus symbol and broad orange arrows, and they include the following: (a) increased glucose uptake via the induction of glucose transporters, especially GLUT1 and GLUT3; (b) enhanced (aerobic) glycolysis due to increased PKM2, combined with increased lactate dehydrogenase A (LDH-A) activity, to regenerate NAD for the maintenance of glucose oxidation via glycolysis, which is necessary for the increased production of ATP, glucose-6-phosphate (G6P) (required for the initiation of PPP), and 3-phosphoglycerate (synthesis of serine/glycine, erythrose-4-phosphate); (c) activation of PPP with both arms to generate ribose-5-phosphate (R5P) and NADPH; (d) reduced OXPHOS via the inhibition of the pyruvate dehydrogenase (PDH)-mediated mitochondrial acetyl-CoA formation, which could be achieved either through the inhibition of the mitochondrial pyruvate carrier complex (MPC), which would block the entry of pyruvate (Pyr) into the mitochondria, or through the activation of pyruvate dehydrogenase kinase (PDHK), which would block the conversion of Pyr into acetyl-CoA; (e) specific metabolites normally produced in the TCA cycle and indispensable for SARS-CoV-2 replication, with α-KG, OAA, acetyl-CoA, citrate (Cit), and Suc-CoA especially able to be delivered via active TCA-cycle enzymes or various anaplerotic reactions, as α-KG can be provided via glutaminolysis, OAA via ATP-dependent PC and ATP-dependent Cit lyase (ACL), acetyl-CoA via fatty acid oxidation (FAO), Cit either via TCA-cycle enzymes from acetyl-CoA and OAA or reverse TCA-cycle reactions through the reduced carboxylation of α-KG and Suc-CoA via the TCA cycle enzyme α-KG dehydrogenase; (f) in the case of a glucose shortage, FAO is an alternative route for ATP generation. (B) Viral reprogramming of cellular regulators that modify metabolic fluxes in favor of SARS-CoV-2 replication. Metabolic reactions that are positively or negatively regulated through viral mechanisms are shown in orange boxes. Viral factors partaking in host-cell control are shown in orange, oval boxes indicated by a virus particle. For details and a further legend, see also Figures S1 and S2.
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