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Review
. 2022 Nov 17:13:1033314.
doi: 10.3389/fimmu.2022.1033314. eCollection 2022.

What role for cellular metabolism in the control of hepatitis viruses?

Olivier Diaz  1 , Pierre-Olivier Vidalain  1 , Christophe Ramière  1   2 , Vincent Lotteau  1 , Laure Perrin-Cocon  1
Affiliations
Review

What role for cellular metabolism in the control of hepatitis viruses?

Olivier Diaz et al. Front Immunol. .

Abstract

Hepatitis B, C and D viruses (HBV, HCV, HDV, respectively) specifically infect human hepatocytes and often establish chronic viral infections of the liver, thus escaping antiviral immunity for years. Like other viruses, hepatitis viruses rely on the cellular machinery to meet their energy and metabolite requirements for replication. Although this was initially considered passive parasitism, studies have shown that hepatitis viruses actively rewire cellular metabolism through molecular interactions with specific enzymes such as glucokinase, the first rate-limiting enzyme of glycolysis. As part of research efforts in the field of immunometabolism, it has also been shown that metabolic changes induced by viruses could have a direct impact on the innate antiviral response. Conversely, detection of viral components by innate immunity receptors not only triggers the activation of the antiviral defense but also induces in-depth metabolic reprogramming that is essential to support immunological functions. Altogether, these complex triangular interactions between viral components, innate immunity and hepatocyte metabolism may explain why chronic hepatitis infections progressively lead to liver inflammation and progression to cirrhosis, fibrosis and hepatocellular carcinoma (HCC). In this manuscript, we first present a global overview of known connections between the innate antiviral response and cellular metabolism. We then report known molecular mechanisms by which hepatitis viruses interfere with cellular metabolism in hepatocytes and discuss potential consequences on the innate immune response. Finally, we present evidence that drugs targeting hepatocyte metabolism could be used as an innovative strategy not only to deprive viruses of key metabolites, but also to restore the innate antiviral response that is necessary to clear infection.

Keywords: cellular metabolism; hepatitis virus; hepatocyte; immunometabolism; inflammation; innate immunity; liver diseases.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Interconnexion between innate immunity signaling pathways and central carbon metabolism of the cell. Hexokinase (HK) activity is the rate-limiting enzyme controlling glucose entry into glycolysis. Intermediary metabolites of glycolysis are precursors of anabolic pathways (pentose phosphate pathway, hexosamine pathway, glycerol-phospholipids and amino acids biosynthesis). Pyruvate is converted to acetyl-CoA into the mitochondria, fueling the tricarboxylic acid cycle (TCA) cycle. This cycle is coupled to oxidative phosphorylation by the succinate dehydrogenase (SDH) which is the complex II of the electron transfer chain (ETC). Under aerobic conditions, electron transport through the ETC (Complex I to V) generates ATP by oxidative phosphorylation. HCV and HBV have been described as modulators of the central carbon metabolism by different mechanisms, targeting glycolysis, lactate production, mitochondrial usage of pyruvate, fatty acid oxidation or synthesis. Thereby these viruses can rewire the flow of metabolites in these connected metabolic pathways. Viral RNA and DNA are detected by retinoic acid-inducible gene I (RIG-I) and cGAS respectively. RIG-I signaling is mediated by mitochondrial antiviral signaling protein (MAVS) polymerization at the mitochondrial membrane, triggering TANK-binding kinase 1 (TBK1)/ inhibitor of NF-κB kinase subunit epsilon (IKKε) activation. The stimulator of IFN genes protein (STING) is an essential signal transducer of cGAS and it also functions as an adapter in the sensing of RNA viruses via RIG-I. Infected cells also produce danger signals such as high mobility group box 1 (HMGB1) which is a ligand of Toll-like receptor (TLR) 4. TLR4 stimulation results in the activation of nuclear factor-κB (NFκB), c-Jun N-terminal kinase (JNK), p38-mitogen activated protein kinase (MAPK), inducing the secretion of pro-inflammatory cytokines, and of TBK1/IKKε inducing interferon response factors (IRFs)-dependent type I interferon secretion and phosphorylation of protein kinase B/Akt. Hexokinase-2 (HK2) phosphorylation at Thr473 by Akt promotes HK2 binding to mitochondrial voltage-dependent anion channel (VDAC), where it also interacts with MAVS, the signaling adaptor of RIG-I. Mitochondrial binding of HK2 is associated with enhanced glycolytic and reduced oxidative phosphorylation activities. In human monocyte-derived DCs, p38-MAPK activation results in hypoxia-induced factor (HIF)-1α accumulation, enhancing the expression of metabolic enzymes such as HK2, inducible nitric oxide synthase (iNOS) and pro-IL-1β. Nitric oxide (NO) radical produced by iNOS can inhibit the mitochondrial respiratory chain. When succinate accumulates in the cell, this metabolite inhibits prolyl-hydroxylase domain (PHD) enzymes that degrade HIF-1α thus favoring its accumulation. Adenine nucleotide translocase (ANT), fatty acid (FA), fatty acid transporter (FATP), glucose transporter (GLUT), monocarboxylic acid transporter (MCT), triglyceride (TG).
Figure 2
Figure 2
Using drugs targeting host metabolic pathways as an antiviral strategy. Modifying host cell metabolism using drugs will alter the balance in several metabolite pools. This can primarily prevent viral replication by depletion in essential metabolites. These metabolic changes can be detected by cellular metabolic sensors and have an impact on both the innate immunity response and the cellular machinery. Stalled cellular machinery could both enhance the antiviral immune response and prevent viral propagation.
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