Studies in the immunometabolism field have identified important connections between the cell metabolic status and innate immunity functions. The detection of viral components by pattern recognition receptors (PRRs) induces intracellular signaling that results in the activation of antiviral defenses but also triggers in-depth metabolic reprogramming that is essential to support immunological functions. Conversely, chronic metabolic disorders such as obesity or non-alcoholic fatty liver disease (NAFLD) are characterized by impaired innate antiviral defenses and deleterious chronic inflammation. This led to the concept of immunometabolic pathologies that are associated with poor outcomes in viral infections such as SARS-CoV-2 (1). Therefore, innate immunity and metabolic pathways interact in a reciprocal manner. Besides, viruses which are intracellular parasites have developed diverse strategies to hijack the cellular machinery to fulfill their needs in energy and molecular blocks to replicate. Recent studies suggest that the manipulation of cellular metabolism by viruses is also an evolutionarily selected strategy to control the innate immune response of infected cells (2). Deciphering the mechanisms involved should provide key information to design innovative antiviral therapies targeting immunometabolic regulations.

The liver is a central organ in metabolic homeostasis, controlling levels of macronutrients such as glucose, lipids and cholesterol. This role is mainly devoted to hepatocytes, which are the primary epithelial cell population in the liver. The liver is also involved in the endocrine control of growth signaling pathways and supports the immune response through the secretion of acute phase proteins and cytokines. This organ is therefore a hub where metabolic and innate immune processes connect. Hepatitis viruses such as HBV, HCV and HDV infect specifically hepatocytes and often establish chronic viral infections of the liver, escaping viral immunity for years. These infections promote metabolic disorders associated with chronic inflammation that lead to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Metabolic reprogramming associated with immunological alterations are key drivers in disease progression, but interactions between these two components are still poorly understood. Here, we first summarize our current understanding of functional connections between metabolism and innate immunity pathways at the cellular level. We then present the impact of hepatitis viruses on hepatocyte metabolism, and then discuss potential consequences on innate immunity. Finally, we show that understanding immunometabolic interactions in hepatocytes opens perspectives in the development of dual-effect antiviral therapies that would simultaneously starve viruses for key metabolites and stimulate the innate antiviral response.

Cellular metabolism can greatly vary during activation of the innate immune response and it has been widely observed that reprogramming of cell metabolism can reallocate cellular resources for the achievement of specific immune functions (3). Indeed, cells are using carbohydrates, especially glucose that is degraded by glycolysis into pyruvate, to produce ATP and metabolic precursors for other pathways ( Figure 1 ). Pyruvate is converted to acetyl-CoA into the mitochondria, fueling the tricarboxylic acid cycle (TCA) cycle, which is coupled to the respiratory chain and oxidative phosphorylation (OXPHOS) in the presence of oxygen, generating up to 36 molecules of ATP per molecule of glucose. Although glycolysis is producing only 2 molecules of ATP per molecule of glucose, it can be more rapidly engaged and increased to meet the energetic demand of activated proinflammatory immune cells. Furthermore, intermediate metabolites of glycolysis are fueling several anabolic pathways for the synthesis of lipids, carbohydrates, nucleosides, amino acids and other metabolites that are essential to cellular functions including innate immunity.

The stimulation of PRRs triggers cell signaling events resulting, among other consequences, in metabolic reprogramming supporting innate immune response. This has been best studied in immune cells although the molecular mechanisms have not been completely elucidated and greatly vary according to species and cell type. In macrophages and myeloid dendritic cells (DCs), Toll-like receptors (TLRs) stimulation modulates central carbon metabolism ( Figure 1 ), resulting in increased glycolytic activity to support a pro-inflammatory phenotype (4–8). Glycolysis inhibition by 2-deoxy-glucose (2-DG) reduces the secretion of cytokines, the motility and the expression of costimulatory molecules that characterize mature DCs (5, 6, 8, 9). In murine macrophages and DCs, TLR4 stimulation by LPS is associated with a metabolic shift from OXPHOS to glycolysis despite the presence of oxygen (6, 10, 11). This shift is comparable to the Warburg-like effect in tumor cells. In human plasmacytoid DCs (pDCs), which are of lymphoid origin, TLR7 and TLR9 activation also stimulates glycolysis to support the production of type-I interferon (IFN-I) (11, 12). However, a recent study suggests that OXPHOS is also increased in these cells as opposed to myeloid DCs and necessary to support IFN-I production upon TLR7/9 engagement (13, 14). TLR4-induced type I IFN-β expression, was found to be dependent on the glycolysis and pentose phosphate pathway (15). Glycolysis activation mainly occurs via the upregulation of glycolytic enzymes, such as hexokinase 1 and 2 (HK1, HK2), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and pyruvate kinase isoenzyme M2 (PKM2). TLR engagement also increases the surface expression of the glucose transporter GLUT1 (16–18). This metabolic adaptation of macrophages, DCs and pDCs, is likely to support the synthesis of metabolites that are essential to immune functions, to satisfy energy needs for cell activation, and to allow immune cells to be functional even in oxygen-deprived environments. Moreover, glycolysis fuels the PPP to generate biosynthetic precursors for nucleotides, amino acids, and fatty acid synthesis (FAS), thereby supporting anabolic growth and cytokine secretion (19). Furthermore, the NADPH produced is used for the rapid production of microbicidal reactive oxygen species (ROS) by NADPH oxidase, and for glutathione regeneration, to maintain the redox balance.

Hexokinase (HK) activity is the rate-limiting enzyme controlling glucose entry into glycolysis ( Figure 1 ). The glucose-6-phosphate produced can be either degraded by the glycolysis or serve as a precursor for ribose synthesis via the pentose phosphate pathway or glycogen production. TLR4 cell signaling induces both HK2 expression and phosphorylation in DCs by at least 2 pathways (20). In murine bone-marrow-derived DCs (BMDCs), TLR4 stimulation is known to induce the secretion of pro-inflammatory cytokines through p38-mitogen activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK), nuclear factor kappa-B (NF-κB), but also activates TANK binding kinase 1 (TBK1)/inhibitor of NF-κB kinase subunit epsilon (IKKϵ) and protein kinase B/Akt that phosphorylates HK2 (5). This phosphorylation promotes HK2 binding to voltage-dependent anion channel (VDAC). Mitochondrial binding of HK2 is associated with enhanced glycolysis, reduced OXPHOS and resistance to apoptotic signals (21). The subcellular localization of HK2 dynamically regulates the catabolic versus anabolic fate of glucose-6-phosphate, promoting glycolysis when bound to the mitochondria and glycogen synthesis when located in the cytosol (22). LPS stimulation of murine BMDCs and macrophages through TLR4 also results, as a consequence of OXPHOS inhibition, in a broken TCA cycle. This leads to intracellular succinate accumulation that favors hypoxia induced factor (HIF)-1α stabilization (23, 24). HIF-1α induces the transcription of genes such as glycolytic enzymes, inducible nitric oxide synthase (iNOS) and pro-IL-1β. NO production by iNOS contributes to OXPHOS inhibition (4, 25). In human monocyte-derived DCs, p38-MAPK activation upon TLR4 engagement results in HIF-1α accumulation, enhancing the expression of glycolytic enzymes such as HK2 (8). Additionally, phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Akt and mechanistic target of rapamycin (mTOR) signaling pathways are important modulators of cellular metabolism, sustaining anabolic metabolism and protein translation (26).

Intricate interactions between hepatitis viruses and TLRs have been reported with both activating and inhibiting effects (27, 28). At steady state, in primary human hepatocytes (PHH), only the expression of TLR3, 4 and 5 could be detected at the protein level. However, a much larger panel of TLRs was assessed in PHH by mRNA detection and activation by their cognate ligands, indicating that more TLRs are functional (29–31). In particular, it has been shown that HBV particles activate PHH through TLR2 (32), and HBV-infected PHH respond to TLR1/2 stimulation by the ligand Pam3CSK4 with an increasing sensitivity with time, suggesting a feedforward mechanism (33). HCV components can also be sensed by TLRs such as HCV Core that is recognized by human TLR2 (34). Conversely, hepatitis viruses have evolved countermeasures to block TLR signaling (28). For example, the NS3/4A protease of HCV is able to cleave TRIF, the signaling adaptor recruited by TLR3 (35). Another example is HBsAg from HBV that inhibits TLR3 and TLR4 activation in liver cells by their cognate ligands (36) and alters TLR2 response in macrophages (37). Finally, these complex interactions between hepatitis virus and TLR signaling can be manipulated for therapeutic purposes. For example, TLR1/2 and 3 ligands are investigated as a therapeutic approach to block HBV with direct antiviral effects on infected hepatocytes, whereas TLR7 and 8 ligands like GS-9620 and GS-9688 would act indirectly through the stimulation of other liver cell types such as pDC and macrophages (38). These interactions of hepatitis viruses with TLR signaling pathways probably have a direct impact on hepatocyte metabolism, but literature is surprisingly limited. Indeed, HBV interaction with TLR2 has been shown to increase LDL uptake and to induce the expression of low-density lipoprotein receptor (LDLR) and 3-hydroxy-3-methylglutharyl-coenzyme A reductase (HMGCR) in the hepatocyte cell line HepG2 via TLR2 (39). Interestingly, TLR2 also participates in metabolic reprogramming of CD8+ T cells and B cells in the woodchuck hepatitis virus (WHV) model and upon HBV stimulation (40, 41). Enhanced immune functions were associated to increased glucose consumption, lactate secretion and glutaminolysis, supporting a key role of this metabolic switch in the induction of an effective antiviral immune response. Altogether, this supports further studies to better explore the consequences of TLR engagement on liver metabolism in the context of hepatitis virus infections.

Detection of viral components by cytosolic PRRs also triggers metabolic reprogramming in liver cell types (29, 30). In particular, PHH are functional for cytosolic RNA sensors of the RIG-like receptor (RLR) family, retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5), that trigger the downstream signaling molecule mitochondrial antiviral signaling protein (MAVS). RIG-I and MDA5 are essential in the sensing of HCV and HDV in hepatocytes (42–45). Several reports have recently established functional links between glucose metabolism and signaling pathways downstream of these receptors (46–48), which are usually associated with antiviral responses. On the one hand, glucose metabolism supports RIG-I and MDA5 signaling by feeding the hexosamine biosynthesis pathway that is required for the O-GlcNAcylation of MAVS (46). On the other hand, lactate produced by glycolysis inhibits RLR signaling by direct binding to MAVS (47). Besides, HK isoenzymes more directly interfere with RLR signaling in hepatocytes. Indeed, results obtained by Zhang W. et al. (47) indicated that HK2 interacts with both VDAC and MAVS. This mitochondrial localization stimulates HK2 activity and by increasing lactate production, inhibits MAVS signaling and restrains RIG-I-induced IFN-β secretion. Interestingly, RIG-I activation by viral RNAs dissociates HK2 from MAVS and thus reduces glycolysis and lactate production (47). Therefore, the reciprocal negative interactions between RLRs and HK2 form a toggle switch controlling innate immunity. Accordingly, we showed that HK2 expression but not HK4 (or GCK), the liver-specific hexokinase, inhibits RIG-I-induced IFN response in hepatocytic cell lines (49). In the infected liver, the situation is even more complex because hepatitis viruses have evolved mechanisms to block this pathway. The HBV X protein (HBx) binds MAVS and blocks IFN-β induction in response to RIG-I/MDA5 ligands (50–52). Upon HCV infection, the NS3-NS4A cleaves MAVS but also the E3 ubiquitin ligase Riplet that activates RIG-I (53–58). The consequence of these viral countermeasures on the metabolic reprogramming induced by the RLR/MAVS pathway in the context of HCV, HBV and HDV infections are largely unexplored.

Another important PRR that regulates metabolism is the stimulator of IFN genes protein (STING). This protein is a universal receptor for cyclic dinucleotides (cGAMP and cCGMP) which plays a pivotal role in cytosolic DNA sensing cascades and immune activation in response to DNA viruses, mitochondrial damages and genotoxic stress. Cyclic dinucleotides, which are produced by the cyclic GMP-AMP synthase (cGAS) in response to cytosolic DNA, bind to STING at the ER. This promotes the recruitment of TBK1, which phosphorylates the transcription factor IRF3, resulting in the production of IFN-I. Recently, several studies have linked STING activation to metabolic pathways (59). The STING pathway was identified as a key player in mediating obesity-induced chronic low-grade inflammation (60). Interestingly, chronic activation of TBK1 has been shown to inhibit mTORC1 activity, leading to dysregulated cellular metabolism (60). This is suggesting that activation of the STING pathway may inhibit mTORC1 signaling. Conversely, Meade N. et al. have shown that by targeting the mTORC1/mTORC2 regulatory circuit, the F17 protein of poxviruses suppresses STING signaling (61), indicating that the STING pathway is controlled by mTOR and could be regulated by nutrient availability. In the liver, STING is mainly expressed in non-parenchymal cells (including Kupffer cells, sinusoidal endothelial cells and stellate cells) but is virtually absent from hepatocytes (62). As a consequence, HBV DNA sensing is ineffective in hepatocytes because STING expression is too low (63). However, components of the cGAS/STING pathway can be upregulated in obese patients, which could favor the sensing of hepatitis viruses and aggravate inflammatory processes (64). Even though, the virus can also avoid DNA detection by active mechanisms (65). For example, it was shown that HBV polymerase inhibits the sensing of cytosolic DNA by interfering with the ubiquitin-dependent activation of STING (66). Besides, HCV has been shown to inhibit STING-mediated IFN induction through expression of the viral protein NS4B (67, 68).

Although it was observed a long time ago that cellular metabolism increases upon viral infection, especially glucose consumption (69, 70), this phenomenon was little studied for decades. It is only since the 2010s and the advent of metabolomics and fluxomics technologies that the scientific community investigated the interference of viruses with central carbon metabolism at the cellular level. In recent years, many viruses have been shown to stimulate the biosynthetic pathways necessary for their replication (for review see (71)). However, underlying molecular mechanisms are not fully described. Furthermore, even if viral replication can be effectively impaired by specific metabolic inhibitors, whether this also involves indirect effects on antiviral immunity remains an open question. Therefore, the characterization of molecular mechanisms selected by viruses to control metabolism appears as a way to identify new pathways controlling innate immunity.

Hepatotropic viruses are highly adapted to hepatocytes, which have per se a very specific central carbon metabolism to regulate the energy homeostasis of the whole organism. Indeed, hepatocytes control glycemia by storing glucose in the form of glycogen upon insulin signaling (glycogenesis) or by producing glucose through breaking down intracellular glycogen (glycogenolysis) or gluconeogenesis from pyruvate. The liver is also at the center of the lipoproteins metabolism that distributes lipids throughout the organism. Hepatocytes have the ability to produce triglyceride-rich very-low density lipoproteins (VLDL) using lipids that are either neosynthesized from carbon sources or recycled from uptake of circulating lipoproteins. Hepatocytes are supplied by exogenous lipids coming from the intestine through chylomicron uptake during immediate post-prandial phases. Then, hepatocytes redistribute lipids in the form of VLDL that are secreted in the blood during inter-prandial phases. Thus, these cells have intrinsic specific capacities to switch their metabolism from anabolism to catabolism, depending on the body’s energy supply and demand. Therefore, chronic viral infection of hepatocytes requires specific viral strategies to control this unique cellular metabolism. For HCV, the interference with carbohydrate-lipid metabolism is exemplified by the metabolic syndrome developed in chronically infected patients (hypertension, insulin resistance, increased abdominal fat, dyslipidemia, steatosis and overweight). In chimpanzees, the most relevant in vivo model for HCV infection, a modulation of the genes involved in lipid metabolism was observed in animals that developed an acute infection and cleared or transiently cleared the infection (72). This was not the case in the animal that did not show an initial peak of viral replication but developed a persistent infection with a viral load only detected after 10 weeks. Upon HCV infection of hepatocytic cell lines, glucose consumption and STAT3 signaling pathway are increased and lipid peroxidation reduced (73), which correlates with accumulation of very long-chain fatty acids in cells and steatohepatitis in chronically-infected patients. Metabolomic combined with transcriptomic analyses in primary hepatocytes showed that metabolic pathways, including long chain fatty acid metabolism, glycolysis, and glycogen metabolism, are also altered by HBV (74). Although HBV is clearly inducing metabolic modulations in infected hepatocytes, HBV infection is probably not responsible for liver steatosis as opposed to HCV infection (75). It is thus clear that liver viruses interfere with host-specific cell metabolic pathways and we have reviewed below the major pathways that are targeted by HCV or HBV and its satellite virus HDV.

Since cellular metabolism is connected to the innate antiviral response in hepatocytes, this functional interaction gives leverage for developing innovative host-directed therapies. Drugs interfering with nucleoside/nucleotide biosynthesis well illustrate this idea since these antimetabolites enhance the innate antiviral response. A good example is provided by inhibitors of inosine monophosphate dehydrogenase (IMPDH), an enzyme converting inosine monophosphate into xanthine monophosphate in the purine nucleotide biosynthesis pathway. IMPDH inhibition with mycophenolic acid (MPA) has been shown to inhibit HCV replication in Huh7 cells both in vitro and in xenografted mice (174). IMPDH was also identified as a prominent target for inhibiting hepatitis E virus (HEV) replication (175). Indeed, MPA and other IMPDH inhibitors potently restrain the replication of HEV in Huh7 cells. Antiviral properties of MPA were associated to the induction of antiviral interferon-stimulated genes (ISGs) and synergistic effects with IFN-α stimulation (174, 175). Although initially controversial, recent reports showed that this induction of ISGs is reversed by guanosine supplementation of culture medium, thus demonstrating the role of purine depletion in MPA-treated cells (175). Besides, ISG induction is mediated by a non-canonical pathway that is independent of both IFN-I induction and JAK/STAT signaling. It has been suggested that a similar mechanism contributes to the anti-HCV effect of ribavirin, another inhibitor of IMPDH that is acting synergistically with IFN-α (176). However, these observations are apparently specific to transformed cells as a recent report showed that in PHH and in the non-transformed cell line HepaRG, ribavirin does not induce but rather represses and resets the expression of ISGs by chromatin remodeling (177). Besides, this phenomenon appears to be independent of IMPDH inhibition. Whether MPA is also showing the same activity in PHH and HepaRG cells has to be determined. More recently, it has been shown that an excess of guanosine also inhibits HCV replication (178). Indeed, when guanosine is added to the culture medium, intracellular levels of NDPs and NTPs are modified, thus increasing the frequency of mutations in HCV genome during viral replication. Quite unexpectedly, it was also found that the inhibition of enzymes upstream of IMPDH in the purine biosynthesis pathway does not inhibit but rather enhances the replication of HEV (175). Altogether, these results demonstrate that drugs inducing imbalance in the pool of purine nucleoside/nucleotide have an impact on the expression of ISGs, and this clearly contributes to their antiviral effect. However, the mechanisms involved need to be further investigated in primary cell cultures.

Conflicting results have been reported regarding the effect of purine biosynthesis inhibitors on HBV replication. MPA has been shown to enhance the replication of HBV in human hepatocyte cell lines HepG2 and Huh7 (179, 180). This effect is dependent on p38-MAPK and is reversed by the addition of guanosine in the culture medium, demonstrating the role of purine inhibition in this phenomenon (180). Conversely, an inhibitory effect or no effect were reported by other groups when treating HBV-replicating cell lines with MPA or VX-497, another IMPDH inhibitor (181–183). Most importantly, MPA was shown to inhibit HBV replication in PHH that represents the most relevant in vitro model for HBV infection (184). In these cells, the inhibitory effect of MPA was reversed by the addition of guanosine. Besides, MPA showed no antiviral effect in liver transplanted patients with HBV (185). Therefore, the inhibition of purine biosynthesis has variable effects on HBV infection depending on the cellular model and the metabolic status of host cells. Whether modulation of the innate immune response contributes to the impact of MPA on HBV replication has not been investigated yet.

The pyrimidine biosynthesis pathway was also involved in the replication of hepatitis viruses. Dihydroorotate dehydrogenase (DHODH) is the fourth rate-limiting enzyme in the de novo pyrimidine biosynthesis pathway and represents a prime target for pharmacological drugs. DHODH inhibition has been shown to block the replication of HCV in Huh7.5 or Huh7.5.1 cells (186, 187). Quite similarly, DHODH inhibition impaired the replication of HEV in Huh7 cells (175). Interestingly, DHODH inhibition with different pharmacological drugs has been shown to induce the expression of several ISGs through an IFN-independent and JAK/STAT-independent pathway (175). This induction was reversed by the addition of uridine, thus demonstrating that pyrimidine depletion is responsible for this induction of innate antiviral genes. The inhibition of orotidine-5’-monophosphate decarboxylase (ODCase), an enzyme that is two steps downstream of DHODH in the de novo pyrimidine biosynthesis pathway, showed a similar effect on ISG induction and HEV inhibition (175). In a similar fashion, the pyrimidine biosynthesis inhibitor Gemcitabine also impaired the replication of HEV through the activation of STAT1 and the induction of ISGs through a non-canonical pathway (188). Surprisingly, DHODH inhibitors Leflunomide and FK778 were initially reported to enhance the replication of HBV when tested in HepG2 and Huh7 cells, and this was confirmed in a recent report (179). However, the inhibition of the carbamoyl-phosphate synthetase 2, aspartate transcarbamylase and dihydroorotase (CAD) enzyme, which is upstream of DHODH in the pyrimidine biosynthesis pathway, showed no effect on HBV replication in HepAD38 or HepG2 cell lines (189). As above, this suggests that inhibitors of pyrimidine biosynthesis have variable effects on HBV that are highly context and cell type dependent. Finally, the same report showed that the CAD inhibitor PALA suppresses the replication of HDV both in Huh-106 and PHH (189). This antiviral effect of PALA is reversed by the addition of uridine to culture medium, thus demonstrating that it depends on pyrimidine biosynthesis inhibition. It is thus expected that DHODH inhibitors would also be able to inhibit HDV replication, but this has not yet been experimentally validated.

Besides nucleoside/nucleotide biosynthesis pathways, glucose metabolism also represents a therapeutic target to enhance the immune response against hepatitis viruses. Besides the already described O-GlcNAcylation of MAVS (46), hexosamine biosynthetic pathway positively regulates host antiviral response against HBV in vitro and in vivo through O-GlcNAc modification of sterile alpha motif and histidine/aspartic acid domain-containing protein 1 (SAMHD1) (190). Indeed, SAMHD1 is an interferon-induced deoxynucleotide triphosphate triphosphohydrolase (dNTPase) that restricts the replication of DNA viruses including HBV by degrading the intracellular pool of dNTPs. The O-GlcNAcylation of SAMHD1 stabilizes the expression of this restriction factor and increases its antiviral activity. These results reveal a link between the hexosamine pathway derived from the fructose-6-phosphate of the glycolytic pathway and innate antiviral immunity.

Other lipid-related factors that are targeted for antiviral purposes in the liver include components of the bile acid pathways, especially the bile acid transporter NTCP and the nuclear receptor FXR. Some links have been unraveled between bile acids metabolism and innate immunity. NTCP is a membrane transporter for bile acid but also an entry receptor for HBV and HDV that share the same surface glycoprotein HBs. Bulevirtide, a NTCP inhibitor derived from the preS1 peptide of HBs, is now used in the treatment of chronic HDV infection. Interestingly, it has been shown that by binding NTCP, Bulevirtide reverts the inhibitory effect of bile acids on the interferon response. This suggests that Bulevirtide inhibits HDV propagation not only by interfering with viral entry but also by restoring innate immunity (191). Since it has been proposed that FXR is hijacked by HBV to regulate viral transcription in cooperation with PGC-1α and SIRT1 (192), FXR modulators are now developed as HBV inhibitors and are evaluated in clinical trials. Whether the antiviral activity of FXR ligands on HBV infection implies a modulation of the immune response remains to be determined, but recent studies showed that FXR regulates inflammation. A direct interaction between FXR and NF-κB has been described resulting in a negative crosstalk between FXR and NF-κB signaling pathways. It has also been shown that treatment with FXR agonists inhibit the expression of inflammatory mediators in response to NF-κB activation in both HepG2 cells and in vitro cultured primary hepatocytes (193, 194). This nuclear receptor is also a negative regulator of NLRP3 inflammasome with trans-repressive effects on NF-κB and AP-1 target gene expression (195). Therefore, FXR ligands may have dual effects both on the virus and the innate immune response, and should help control the inflammatory response associated with chronic hepatitis. Like bile acids, vitamin D biosynthesis depends on cholesterol metabolism. Interestingly, vitamin D exhibits antiviral effects on HCV and this activity is associated with the induction and the amplification of IFN-I signaling (196, 197). Another cholesterol derivative and female sex hormone, 17β-estradiol, has been shown to protect cells from HCV infection and this antiviral effect depends on IFN-I induction (198). Altogether, these observations suggest that cholesterol metabolism in the liver could be targeted to inhibit hepatitis viruses through the modulation of innate immunity pathways.

Other metabolic pathways have been implicated in the regulation of antiviral immunity against several viruses. Although their impact on hepatitis viral infections has not been investigated yet, their broad antiviral activity deserves attention. This includes itaconate and its isomers metaconate and citraconate that were recently reported to inhibit the production of influenza virus particles by A549 infected cells (199). Immunomodulatory properties of itaconate have been extensively reviewed elsewhere (200). Interestingly, the TCA cycle intermediate succinate was also described to inhibit influenza virus infection both in vitro and in vivo by succinylation of the viral nucleoprotein (201). The potential impact of these metabolites on hepatitis virus infections deserves to be analyzed. Other metabolic pathways of prime interest include the tryptophan/kynurenine pathway. Although kynurenine is a well-known immunosuppressive metabolite, its degradation by kynurenine-3-monooxygenase (KMO) and downstream enzymes produces quinolinic acid that shows potent antiviral effects. Quinolinic acid has been shown to activate the N-methyl-D-aspartate receptor (NMDAR), which triggers Ca2+ influx, the phosphorylation of calcium/calmodulin-dependent protein kinase II (CaMKII) and IRF3, and finally leads to IFN-I production (202). This study shows that quinolinic acid produced from tryptophan has broad antiviral activity against HSV-1, adenovirus 5, VSV, influenza virus, ZIKV, DENV and SARS-CoV2. Whether it could also inhibit hepatitis viruses was not investigated.

The development of drugs targeting host cellular metabolism as antivirals is an attractive strategy to deprive viruses of the metabolites they need and, more generally, to make the cellular environment inappropriate for viral replication ( Figure 2 ). Targeting metabolism can also induce cellular stress that shuts down basic machinery such as protein translation, with indirect inhibitory effects on viral replication. As discussed in this review, a third possibility is that altered metabolism is detected by metabolic sensors that activate the innate immune response ( Figure 2 ). This fits the interesting concept of “homeostasis-altering molecular processes” (HAMPs) developed by A. Liston and S.L. Masters in the context of inflammasome activation (203). Indeed, metabolic imbalance induced by specific viruses and drugs can be viewed as HAMPs, and quite similarly to PAMPs (pathogen-associated molecular patterns) and DAMPs (damage-associated molecular patterns), stimulate the immune response. Thus, targeting metabolic pathways to stimulate host innate immunity now appears to be a valuable strategy for controlling the replication of viruses. Modulators of nucleotide biosynthesis pathways have proven, for example, their ability to inhibit hepatitis viruses while stimulating the innate immune response. The exact contribution of immunity factors in the antiviral effect of these drugs needs to be further explored, and whether this general concept can be translated in vivo has to be determined. Lipid and cholesterol biosynthesis pathways are also considered as therapeutic targets in the treatment of HBV based on observations that drugs inhibiting these pathways decrease the production of subviral and/or viral particles (75, 204). Interestingly, serum lipid profiles change in HCV-infected patients treated with direct-acting antivirals (DAA) and this correlates with viral clearance (205, 206). Although direct evidence is missing, it is tempting to speculate that modulation of lipid metabolism associated to DAA contributes to viral clearance (207). In the case of HBV and HDV, metabolism could be manipulated on purpose with drugs to improve viral inhibition, to restore the immune response and finally to achieve functional cure. This will deserve attention in the near future and viral hepatitis, because of the close connection between viral replication, metabolism and innate immunity in the liver, is clearly an appropriate field to explore this concept.

OD, P-OV, CR, VL, LP-C wrote sections of the manuscript. All authors contributed to the article and approved the submitted version.

This work was supported by the Agence Nationale de Recherches sur le Sida et les Hépatites Virales Grants ASA21007CRA, ECTZ72972, ECTZ136480 and the Fondation pour la Recherche Médicale Grant DEQ20160334893.

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.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.