TY - JOUR
AU - Cassol, Edana
AB - Abstract Several studies over the last decade have identified intimate links between cellular metabolism and macrophage function. Metabolism has been shown to both drive and regulate macrophage function by producing bioenergetic and biosynthetic precursors as well as metabolites (and other bioactive molecules) that regulate gene expression and signal transduction. Many studies have focused on lipopolysaccharide-induced reprogramming, assuming that it is representative of most inflammatory responses. However, emerging evidence suggests that diverse pathogen-associated molecular patterns (PAMPs) are associated with unique metabolic profiles, which may drive pathogen specific immune responses. Further, these metabolic pathways and processes may act as a rheostat to regulate the magnitude of an inflammatory response based on the biochemical features of the local microenvironment. In this review, we will discuss recent work examining the relationship between cellular metabolism and macrophage responses to viral PAMPs and describe how these processes differ from lipopolysaccharide-associated responses. We will also discuss how an improved understanding of the specificity of these processes may offer new insights to fine-tune macrophage function during viral infections or when using viral PAMPs as therapeutics. immunometabolism, macrophage, antiviral responses, pattern recognition receptors, pathogen-associated molecular patterns, mitochondria 1 Introduction A host’s response to a viral infection is a complex and multifaceted set of processes that attempts to limit viral replication and spread and to circumvent the immunological countermeasures designed to prevent viral takeover.1 On the front lines against infection, macrophages are responsible for sensing and immediately responding to invading viruses in most tissues of the body.2,3 To initiate early responses, they possess a series of pathogen recognition receptors (PRRs) that can detect conserved viral pathogen-associated molecular patterns (PAMPs) and host damage-associated molecular patterns (DAMPs) released by dying cells during infection.2–5 This recognition initiates cellular activation, phagocytic processes and intracellular killing, inflammatory cytokine production, and antigen processing and presentation to activate adaptive immune responses.2,6,7 If the body is successful in clearing the pathogen, macrophages then assist in re-establishing tissue homeostasis by expressing anti-inflammatory cytokines to quell inflammation. They also take up apoptotic debris and support tissue remodeling and repair processes.6–9 These diverse functions are tightly regulated and are dynamically modulated to limit excess inflammation and tissue damage. Increasing evidence suggests cellular metabolism plays a central role in regulating macrophage function.10–12 Alterations in metabolism are required to produce the necessary building blocks to support macromolecule biosynthesis and energy production.10,11 Metabolic enzymes, metabolites, and bioactive molecules have also been shown to regulate gene transcription, epigenetics, and signaling cascades, which contribute to immune cell differentiation, maturation, and activation.13–16 Many of the initial studies exploring the specific metabolic processes associated with macrophage function focused on responses to the Gram-negative bacterial ligand lipopolysaccharide (LPS), under the assumption that most inflammatory responses engage similar pathways. However, as this work expands, it is becoming increasingly clear that metabolic reprogramming is pathogen specific and highly dependent on the tissue microenvironment. To that end, this review will explore the current literature pertaining to the role of cellular metabolism in regulating macrophage responses to viral ligands and during viral infections. 2 Innate sensing and recognition of viruses Early initiation of immune responses during infection is dependent on a variety of extracellular and intracellular PRRs that sense an assortment of PAMPs and DAMPs in the environment.3,17,18 The pathways activated depend on whether a cell is infected (infected vs. bystander cells) and the mechanism by which the virus enters the cell (membrane fusion, phagocytosis, endocytosis, micropinocytosis). Several classes of PRRs have been identified that recognize viruses, among the most important are toll-like receptors (TLRs) and retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs).4,5 2.1 Toll-like receptors (TLRs) The best characterized class of PRRs are TLRs. Each member is a single-pass type I membrane protein with an N-terminal ectodomain of leucine-rich repeats and a cytosolic C-terminal Toll/Interleukin-1 receptor (TIR) domain.4 Mammals possess up to 12 distinct TLRs that can be categorized by their ligand specificity and location (10 in humans, 12 in mice). Bacterial PAMPs are generally detected by surface TLRs such as TLR1/2/6 (lipoproteins from Gram-positive bacteria), TLR4 (LPS or monophosphoryl lipid A [MPLA] of Gram-negative bacteria), and TLR5 (flagellin).19–24 Viral PAMPs are detected by TLRs that reside mainly in endosomal compartments including TLR3 (dsRNA) and TLR7/8 (ssRNA).25–27 TLR9 is also found in endosomes and detects both bacterial and viral unmethylated CpG DNA motifs.28,29 PAMP engagement of TLR results in their dimerization (homo- and heterodimers) and the initiation of downstream signaling through either myeloid differentiation primary response 88 (MyD88) or TIR-domain-containing adapter-inducing interferon-β (TRIF).17 MyD88-dependent signaling recruits interleukin (IL)-1 receptor-associated kinase (IRAK) proteins to activate tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6).30 TRAF6 then activates the nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-κB) inhibitor (IκB) kinase (IKK) complex, which phosphorylates IκBα. This phosphorylation results in the detachment of IκBα from NF-κB, allowing NF-κB to translocate into the nucleus inducing the transcription of inflammatory cytokines.31 Both TLR3 and TLR4 activate the TRIF-dependent pathway.30 For TLR3, TRIF triggers the activation of TRAF6-mediated NF-κB and TANK-binding kinase 1 (TBK1)/IKKε-mediated interferon (IFN) regulatory factor 3/7 (IRF3/7) signaling.17 Conversely, TRIF activation following TLR4 engagement only results in the activation of TBK1/IKKε-mediated IRF3/7 signaling.32 The phosphorylation and dimerization of IRF3 and IRF7 triggers the expression of type I IFNs, which play a central role in antiviral immune responses.17,33 2.2 RIG-I-like receptors (RLRs) RLRs are a family of DExD/H box RNA helicases found in the cytosol and are responsible for the detection of cytosolic viral dsRNA during infection.34 They possess a C-terminal domain and catalytic helicase core responsible for binding viral RNA. They also contain an N-terminal caspase active recruitment domains (CARD), which drives downstream signaling.34–36 The RLR family is composed of two major receptors responsible for triggering effector responses: RIG-I and melanoma differentiation-associated protein 5 (MDA5). These receptors detect dsRNA of specific lengths. RIG-I preferentially recognize short RNA strands (<1 kb), whereas MDA5 recognizes longer RNA strands (>2 kb).36,37 This differs from the TLR family, where one receptor (TLR3) is responsible for recognizing all endosomal dsRNA irrespective of length.26 Following engagement, both receptors form filaments along their preferred dsRNA strands, leading to the polymerization of their respective CARD domains.38–41 These oligomeric formations then bind to the mitochondrial antiviral signaling protein (MAVS), forming the MAVS signalosome on the outer membrane of mitochondria.39,42–45 Additional MAVS proteins are also recruited to the signalosome site, leading to signal amplification.45 This complex drives activation of NF-κB-mediated inflammation and the IRF3/7-driven antiviral response via the recruitment of the IKK complex and TBK1/IKKε, respectively.34 2.3 Other sensors of viral nucleic acids In addition to these PRRs, there are several lesser-known sensors of viral nucleic acids. Among these, DExD/H-box RNA helicases, such as DEAD-box polypeptide 3 (DDX3), are capable of sensing viral nucleic acids and inducing type I IFN production (Fig. 1).46 First identified in 1997, DDX3 senses viral RNA and mediates MAVS-mediated activation of antiviral responses.47,48 Further, it can serve as a co-activator and a phosphorylation target of TBK1/IKKε. These interactions lead to IKKε autophosphorylation and self-activation (Fig. 1).49 Several viruses, such as the Vaccinia virus (VACV), hepatitis B virus (HBV), and hepatitis C virus (HCV), have evolved mechanisms to limit the antiviral effects of DDX3. The VACV K7 and HBV Pol proteins can bind to DDX3 and prevent its interaction with IKKε and IRF3 and subsequent induction of IFN-β production.49,50 On the other hand, the HCV core protein prevents DDX3 interactions with MAVS to limit IFN responses.51 Interestingly, DDX3 has also been shown to support the replication of some viruses. In human immunodeficiency virus (HIV) infection, DDX3 is involved in the cytoplasmic translation and nucleocytoplasmic export of viral RNA.52–56 Further, pharmacological targeting of DDX3 results in a reduction of HIV latent reservoir in CD4+ T cells.57 Fig. 1. Open in new tabDownload slide Other sensors of viral nucleic acids. Cytosolic sensors can trigger either MAVS- or STING-mediated activation of NF-κB and IRF signaling cascades. Image created with BioRender.com. Other viral PRRs include the family of absent in melanoma (AIM)-like receptors (ALRs), such as AIM2, PYHIN1, and IFI16, which are found in cytosolic and nuclear compartments (Fig. 1). Mice have 13 different genes that encode for ALRs, whereas humans have only four.58 These phylogenetically conserved hematopoietic IFN-inducible nuclear domains contain 200-amino acid repeat (HIN200) domains at their C-terminus, which recognize viral DNA.59 Upon recognition of viral or host dsDNA, ALR proteins form inflammasomes via associations with pro-caspase 1 and ASC (apoptosis-associated speck-like protein containing a CARD), mediating the cleavage and secretion of inflammatory cytokines IL-1β and IL-18 (Fig. 1).60–62 IFI16 and PYHIN-1 can also interact with the endoplasmic reticulum (ER)-bound stimulator of type I interferon genes (STING).58,61,63 to induce STING dimerization and activation (Fig. 1).64 Once activated, STING translocates to perinuclear foci via the Golgi, where it interacts and activates TBK1, driving the activation of IRF3 and NF-κB signaling (Fig. 1).64,65 Interestingly, Grey et al. (2016) found that all mouse ALR genes as well as IFI16 in humans were not required for IFN responses against transfected DNA, lentivirus and both mouse and human CMV, which suggests that this may be a reductant IFN-related pathway.66 STING can also interact with other dsDNA sensors, such as cyclic GMP-AMP synthase (cGAS) during viral infections to activate IFN signaling (Fig. 1). Upon binding with long strands of dsDNA, cGAS produces cyclic GMP-AMP (cGAMP), which binds to STING in infected and bystander cells, triggering TBK1-mediated IRF activation (Fig. 1).48 While it was originally thought that cGAS only recognizes long strands of dsDNA in a sequence-independent manner,67 recent work by Bode and colleagues68 found cGAS is also capable of responding to other oligodeoxynucleotides (ODN). Interestingly, activation of the cGAS/STING pathway can also occur via endogenous genomic DNA (gDNA) and mitochondrial DNA (mtDNA) release, triggering a DAMP-driven immune response, further demonstrating the flexibility of the response from this PRR.69,70 RNA polymerase III (RNA Pol III) and the DNA-dependent activator of IFN-regulatory factors (DAI) have also been implicated in viral sensing. RNA Pol III has been shown to recognize DNA from the Epstein-Barr virus (EBV) and herpes simplex virus-1 (HSV-1) (Fig. 1).71,72 RNA Pol III converts dsDNA into 5′ppp RNA, which is detected by RIG-I, leading to the activation of inflammatory and IFN signaling pathways (Fig. 1).72 DAI/ZBP1, on the other hand, is a dsDNA sensor that activates NF-κB and IRF via TBK1 and RIP1/3, respectively (Fig. 1).73–75 However, DAI may either be a reductant pathway or restricted in specific cell types. For example, inhibiting DAI expression has been shown to have minimal effects in mouse embryonic fibroblasts (MEFs) and dendritic cells (DCs) but can dampen type I IFN responses in L929 cells.76,77 2.4 Type I interferon (IFN) signaling Type I IFNs are the largest class of IFNs, consisting of IFN-δ, IFN-ε, IFN-κ, IFN-τ, IFN-ω, IFN-β, and 13 different subtypes of IFN-α.78,79 They act in an autocrine and paracrine manner to induce antiviral states in infected and bystander cells in the local microenvironment (Fig. 2). This state is associated with the upregulation of IFN-stimulating genes (ISGs) including antiviral proteins, which prevent further viral propagation and replication. Type I IFNs also regulate antigen presentation and phagocytic activity to support adaptive immune system activation, which is critical for locating and more targeted killing of infected cells.80–82 Fig. 2. Open in new tabDownload slide Activation of JAK/STAT and PI3K/Akt/mTOR pathways during Type I IFN responses. Type I IFNs act through IFNAR1 and IFNAR2, leading to the activation of JAK proteins JAK1 and TYK2. They, in turn, phosphorylate STAT family of transcription factors. STAT proteins can either form homo- or heterodimers and activate GAS-mediated ISG expression. In addition, STAT1 and STAT2 interact with IRF9 to form the ISGF3 complex and drive ISRE-mediated ISG expression. In addition, JAK1/TYK2 phosphorylate insulin receptor substrate 1 and 2 (IRS1/IRS2), which leads to the activation of the PI3K-AKT-mTOR pathway. The activation of mTOR initiates mRNA translation of ISGs and other genes related to energy metabolism, such as HIF-1α and PKM2. Image created with BioRender.com. Type I IFNs interact with either IFN-α receptor 1 or 2 (IFNAR1/2) leading to IFNAR dimerization (Fig. 2).83 This results in the autophosphorylation and activation of the Janus activated kinase (JAK) proteins, JAK1 and tyrosine kinase 2 (TYK2), which are constitutively associated with IFNAR1 and IFNAR2, respectively.83 These kinases then activate the signal transducer and activator of transcription (STAT) proteins STAT1 and STAT2, leading to their subsequent nuclear translocation.84 Two different mechanisms exist resulting in ISG expression. First, STAT1 and STAT2 can bind to IRF9 to form the IFN-stimulated gene factor 3 complex (ISGF3), which recognizes the IFN-stimulated responsive elements (ISREs), resulting in ISG expression.83 Second, phosphorylated STAT proteins can form homo- or heterodimers capable of binding to IFN-γ-associated sites (GAS) elements leading to ISG expression.85 ISGs can have an ISRE site and/or a GAS site, thus a combination of different STAT complex formations may be required for the expression of >1,000 known ISGs.86 In addition to the traditional JAK-STAT pathway, IFNAR engagement can also activate the phosphoinositide 3-kinase (PI3K)-Akt-mechanistic target of rapamycin (mTOR) pathway, critical for the phosphorylation of STAT proteins and the transcription and translation of ISGs.87–89 This pathway is also responsible for the expression of genes related to energy metabolism in activated immune cells, such as hypoxic-inducible factor-1α (HIF-1α) and pyruvate kinase muscle isozyme 2 (PKM2) (Fig. 2).90–92 3 Metabolic regulation of macrophages The last decade of research has placed a spotlight on the central role that cellular metabolism plays in controlling the magnitude and specificity of immune responses.10,11,93,94 It is well recognized that cellular metabolism provides the necessary biosynthetic and bioenergetic requirements to support effector function and survival. Consistent with these findings, initial work done by Warburg and colleagues demonstrated that activated leukocytes and cancer cells were metabolically similar and favored glycolysis as a primary energy producer over the more efficient oxidative phosphorylation (OXPHOS).95–97 This reprioritization quickly provides the essential metabolic precursors for rapid cell division and function. However, an increasing number of studies have shown it may be more complicated and interesting than that. Metabolic enzymes, metabolites, and bioactive molecules also play a central role in regulating gene transcription, epigenetics, and signaling cascades, which contribute to immune cell differentiation, maturation, and activation.13–16 Macrophages are highly plastic and heterogeneous cells that are responsible for a wide range of responses along the inflammatory spectrum.98 Macrophages initiate and suppress inflammation and, as a result, have been classified by their activation status and primary functions.98 The M1 state, induced by inflammatory ligands such as LPS and IFN-γ, is associated with the production of inflammatory cytokines (TNF-α, IL-1β, IL-6) and is required to initiate antimicrobial immune responses and to attract other immune cells to the site of infection (Fig. 3).12,99 M2 macrophages are a diverse population of cells whose activation status has been subclassified into three separate phenotypes based on activating stimuli and their function: M2a, M2b, M2c (Fig. 3).100,101 M2a macrophages arise in response to IL-4 and are involved in the T helper 2 cell-type immune response; M2b macrophages are induced in response to immune complexes and TLR and IL-1 receptor agonists and regulate the magnitude of immune responses; M2c macrophages arise in response to IL-10 or transforming growth factor-β (TGF-β) and are involved in tissue remodeling.100,101 Fig. 3. Open in new tabDownload slide The differences between M1 and M2 macrophages. M1 and M2 are functionally distant macrophage phenotypes. While M1 macrophages are proinflammatory in nature, M2 macrophages are considered anti-inflammatory. These divergent functions are associated with differential metabolic reprogramming supporting their respective functions. M1 macrophages rely on glycolysis for ATP production. M2 macrophages rely on OXPHOS and FAO. Image created with BioRender.com. Interestingly, these activation states are associated with distinct metabolic profiles, which are partially driven by differential mitochondrial function.98 Supported by the Warburg effect, M1 macrophages are heavily reliant on glycolysis as their primary energy source (Fig. 3).95–97 Their mitochondria are reprogrammed from an ATP-producing to a reactive oxygen species (ROS)-generating organelle via reduced succinate dehydrogenase (SDH) activity, driving reverse electron transport (RET), a buildup of electrons at complex I of the electron transport chain (ETC) and subsequent ROS generation.102 Altered SDH activity leads to succinate accumulation, which inhibits prolyl hydroxylases (PHDs) and results in the stabilization of HIF-1α, responsible for the upregulation of glycolytic and inflammatory genes.13,103 Alternatively, M2 macrophages are generally considered dependent on OXPHOS and fatty acid (FA) oxidation (FAO) to support energy production, mediated by nutrient-sensing AMP-activated protein kinase (AMPK) activation (Fig. 3).104,105 FAO represents one of several alternative energy pathways accessible to macrophages that feeds into mitochondria, bypassing any input from glycolysis. In addition to FAO, glutamine and branched-chain amino acids (BCAAs; e.g. leucine, valine, isoleucine) can provide TCA metabolites to fuel OXPHOS to produce ATP.106 The plasticity of macrophages allows them to adapt their phenotype based on their microenvironment. However, this ability is dependent on the degree of mitochondrial impairment in the cell,107,108 highlighting the importance of mitochondria as the dynamic regulator of proper innate immune function. 3.1 Metabolic reprogramming of LPS engagement of TLR4 LPS is a prototypic inducer of M1 activation and has been widely used to model changes in cellular metabolism due to its robust inflammatory response relative to other stimuli.109–111 However, it is increasingly recognized that the metabolic alterations associated with LPS stimulation are not observed in all inflammatory conditions. A plethora of studies have outlined that diverse proinflammatory and anti-inflammatory stimuli induce distinct metabolic profiles suggesting that the M1/M2 dichotomy represents more of a spectrum of macrophage activation states with varying degrees of metabolic reprogramming.7 Further, interpretation of these results is limited by the fact that most studies to date have been performed using mouse cells, and increasing evidence suggests these responses may not be identical in humans.112,113 3.1.1 Reprogramming of glycolysis due to LPS A key feature of LPS-associated metabolic reprogramming is an increased reliance on glycolysis, mediated by HIF-1α and NF-κB.12,114–116 This reprogramming starts within minutes of detecting the stimuli by increasing glucose influx through glucose transporter (GLUT)-1 and GLUT6 (Fig. 4).115,117 This influx is required to initiate inflammatory responses.118 Several different transcription factors are linked to this early response. Balic and colleagues119 recently showed that TRAF6 directly activates STAT3, assisting in the glycolytic burst during early responses. IRF5 activation has also been linked, via ChIP-Seq analysis, to early increases in glycolytic genes such as hexokinase 2 (HK2).120 Interestingly, while MYC is vital for this early burst in metabolic activity by increasing lactate dehydrogenase (LDH) activity and lactate production, it also functions as a rheostat by suppressing IRF4 and placing a cap on the magnitude of the inflammatory response.121 Fig. 4. Open in new tabDownload slide Metabolic reprogramming of LPS-stimulated macrophages. Image created with BioRender.com. To handle the increased influx of glucose and subsequent glycolytic burst, glycolytic genes, such as HK2, LDHA, pyruvate dehydrogenase (PDH) kinase 1 (PDK1), and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB3), are quickly transcribed and translated to produce pyruvate and funnel it toward the production of lactate (Fig. 4).12,122,123 Interestingly, these glycolytic enzymes also participate in secondary “moonlighting” roles to facilitate inflammation. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) has been shown to bind to the mRNAs of inflammatory genes such as IFN-γ and TNF-α, which suppresses their translation under resting conditions (Fig. 4).124–126 Following LPS activation, its malonylation results in its dissociation from these mRNAs, leading to inflammatory cytokine expression.126 Similarly, PKM2 traditionally forms a tetramer to support glycolysis (Fig. 4).127 However, under inflammatory conditions, PKM2 is converted into its dimer form that translocates to the nucleus where it can co-activate HIF-1α and STAT3, increasing IL-1β and IL-6 levels, respectively (Fig. 4).103,128 In addition to rapidly generating ATP,12,129 the intermediary molecules of glycolysis are also used as precursors to critical biomolecules in the regulation of LPS-mediated inflammation. For example, pentose phosphate pathway (PPP) gene expression (e.g. G6PD) and activity is elevated in LPS-stimulated mouse bone marrow-derived macrophages (BMM),130,131 driving the production of nicotinamide adenine dinucleotide phosphate (NADPH), a critical cofactor for ROS-producing NADPH oxidase (NOX) and various enzymes involved in energy metabolism, cholesterol, and FA synthesis (Fig. 4).130 Further, in its dephosphorylated form, NADH serves as the main source of energy transport throughout the macrophage. High levels of NAD+ are also consumed during inflammatory responses to protect against excess ROS-associated DNA damage.132 To maintain a sufficient supply of NAD+, two separate NAD-related pathways are activated during LPS activation: tryptophan-driven de novo NAD+ synthesis133,134 and the NAD+ salvaging pathway (Fig. 4).132,134,135 Both pathways allow for sustained Warburg metabolism during LPS activation. Finally, glycolytic-derived NADH is also funneled into mitochondria using the glycerol 3-phosphate shuttle (GPS), to fuel various vital mitochondrial reactions supporting IL-6 and IL-1β production (Fig. 4).136 3.1.2 Reprogramming of mitochondrial function due to LPS Another central feature of LPS engagement in mouse macrophages is the multifaceted impairment of OXPHOS activity, a feature that is noticeably absent in human macrophages.112 During LPS stimulation, two breaks occur along the TCA cycle: at isocitrate dehydrogenase (IDH) and SDH (Fig. 4).130 LPS-induced IFN-β downregulates the expression of IDH via IL-10 production.137 The resulting break at IDH forces citrate into two directions. First, it can be transported out of mitochondria to facilitate FA and prostaglandin biosynthesis via increased activity of mitochondrial citrate carrier and ATP citrate lyase (ACLY) (Fig. 4).138,139 Second, citrate can be metabolized by immunoresponsive gene 1 (IRG1), producing the antibacterial and immunosuppressive itaconate.137,140–142 Itaconate targets several different proteins, including NF-E2–related factor 2 (NRF2) (responsible for blocking IL-6 and IL-1β production) and SDH.140,143–147 It is also capable of inducing IFN-β production, creating a feed-forward mechanism to quell inflammation.143 The break at SDH leads to succinate accumulation and the inhibition of PHDs, stabilizing HIF-1α (Fig. 4).13,140,146 However, some SDH activity is required to drive the RET phenomenon, funneling electrons to complex I and ROS generation and further stabilizing HIF-1α by inactivating the iron cofactor of PHDs.102,148–151 RET-generated ROS can be blocked using the diabetic drug Metformin, which inhibits complex I activity and boosts IL-10 expression.152 This antidiabetic drug also blocks glucose uptake and glycolytic activity, which further limits the inflammatory response.153 Accumulating succinate has also been shown to have pro- and anti-inflammatory effects. While two separate studies have shown that interactions between extracellular succinate and the succinate receptor SUCNR1 lead to increased inflammatory cytokine production in DCs and macrophages (Fig. 4),154,155 the succinate/SUCNR1 signaling axis has also been shown to induce macrophages into an anti-inflammatory phenotype in certain disease states, such as cancer and obesity.156,157 Recently, Harber et al.158 found that cell-permeable succinate can suppress the secretion of inflammatory mediators in a SUCNR1-independent manner, while SUCNR1-deficient BMMs possess a hyperinflammatory phenotype in the absence of any exogeneous succinate. This suggests that the inflammatory effects of succinate and SUCNR1 may be dictated by the cellular microenvironment. Other TCA metabolites, such as fumarate and α-ketoglutarate (α-KG), also play a role in driving epigenetic reprograming to augment TNF-α and IL-6 production.159 The presence of α-KG, along with succinate, can dictate the inflammatory nature of macrophages through its relationship to PHD function. Liu and colleagues129 have shown that cell-permeable α-KG dampens proinflammatory cytokine secretion through reduced NF-κB signaling through PHD-mediated hydroxylation and inactivation of IKKβ. In addition to the repurposing of the TCA cycle, the ETC undergoes a considerable rearrangement during LPS activation. Activated macrophages force ETC supercomplex disassembly via optic atrophy 1 (OPA1) downregulation, facilitating the increased reliance on glycolytic energy and amplified inflammatory response observed in LPS-activated macrophages (Fig. 4).148,160 This disassembly of ETC supercomplexes leads to increased mitochondrial ROS (mtROS)-mediated NOD-like receptor (NLR) family pyrin domain containing 3 (NLRP3) activation.148,161 Methylation-controlled J protein (MCJ or DnaJC15) has been shown to regulate ETC supercomplex assembly through its direct interactions with complex I, preventing its association with other ETC complexes and resulting in an increased reliance on glycolysis.162–164 In the absence of MCJ, both RAW264.7 and BMM produce less TNF-α, demonstrating an inverse relationship between the assembly of ETC supercomplexes and inflammatory cytokine production.165 Another mitochondrial fusion protein, mitofusin 2 (MFN2), is also critical for the induction of mtROS and proper proinflammatory and phagocytic functions (Fig. 4).166 The conversion of mitochondria from an energy-producing organelle to a ROS-generating organelle augments the bactericidal activity of macrophages as these oxidative species are recruited to bacteria-containing phagosomes to facilitate bacteria killing.149 Interestingly, BMM deficient in NDUFS4, a complex I subunit, are primed toward a proinflammatory phenotype with increased mtROS, HIF-1α, TNF-α, and IL-1β in the absence of direct activation.167 Furthermore, complex III-derived H2O2 has been shown to cause disulfide bond formation within the IKK complex, activating it and driving NF-κB translation.168,169 To prevent hyperinflammation, uncoupling protein 2 (UCP2) reduces mitochondrial membrane potential (MMP) to lessen mtROS levels.170–172 Although the mitochondrion is not used in its traditional role as a central energy hub, ETC activity still is vital to LPS-driven effector functions. 3.1.3 Reprogramming of amino acid metabolism due to LPS Amino acid metabolism serves diverse roles during LPS activation. This includes the catabolism of glutamine, arginine, serine, and leucine. In LPS-stimulated macrophages, increased expression of glutamine transporter SLC3A2 results in increased glutamine uptake (Fig. 4).13 This increased pool of glutamine is broken down and funneled into the TCA cycle as α-KG via glutaminolysis.130,173 This is done to replenish the carbons lost due to the diversion of citrate and to drive succinate accumulation.13,130 Consistent with these findings, depriving LPS-stimulated BMMs of glutamine or inhibiting glutaminase (GLS) via BPTES results in an increased expression of proinflammatory mediators such as TNF-α, IL-6, and IL-1β, by reducing α-KG/succinate ratio in cells.129 In addition, a portion of glutamate that is derived from this increased pool of glutamine is directly shuttled toward succinate through the γ-aminobutyric acid (GABA) shunt, further elevating succinate levels.13 Arginine transport is also upregulated during LPS activation to support nitric oxide (NO) production through inducible NO synthase (iNOS) (Fig. 4).112,174–176 This feature is unique to mouse macrophages, as iNOS expression in human macrophages under this context were minimal in comparison.176 NO is a powerful bactericide and inhibitor of OXPHOS activity, both of which further contribute to the proinflammatory state.175,176 In addition to inhibiting ETC activity by outcompeting O2 for binding on complex IV or by nitrosylating other ETC proteins, NO also inhibits the function of TCA enzymes aconitase and PDH, which blocks glucose-derived carbon flow through the TCA cycle and ETC.173,177 Citrulline, the other product of the iNOS reaction, is then directed toward the aspartate-arginosuccinate shunt to support arginine generation and further NO production.130 Recently, Mao and colleagues178 found that this depletion of citrulline is required for maintaining the inflammatory response. They found that during LPS stimulation, exogenous citrulline supplementation prevents the STAT1-JAK2-mediated metabolizing of citrulline by argininosuccinate synthetase (ASS1) by directly binding to JAK2 and preventing its phosphorylation of ASS1, subsequently reducing the macrophage inflammatory response.178 Interestingly, arginase 2 (ARG2), which competes against iNOS for arginine, has been shown to be protective against excessive inflammation in macrophages.179 ARG2-/- macrophages are in a hyperinflammatory state with increased HIF-1α, mtROS and IL-1β production. Further, IL-10-induced ARG2 assists in the resolution of immune response by increased OXPHOS activity via increased SDH activity.179 Glucose-derived serine and serine uptake are also critical for IL-1β expression (Fig. 4).180,181 This serine is used to generate glycine, which is required to synthesize glutathione (GSH) and fuel epigenetic modifications of proinflammatory genes such as IL-1β. It does this by increasing de novo ATP synthesis, which is used in the methionine cycle leading to the generation of S-adenosylmethionine (SAM), a key metabolite used in histone methylation.180,181 Interestingly, LPS stimulation has been shown to repress phosphoglycerate dehydrogenase (PHGDH) activity, the first enzyme in the de novo serine/glycine biosynthetic pathway. This inhibition likely limits the flow of glucose-derived carbons out of the glycolytic pathway, highlighting the delicate and complex network involved in a proper immune response.182 Cysteine also plays an important role in GSH synthesis. It is secreted at a higher rate alongside GSH during LPS stimulation to provide surrounding cells with redox molecules and limit bystander oxidative damage (Fig. 4).183 To support this process, LPS-stimulated macrophages take up more cystine, the oxidized dimer form of cysteine, to reduce and produce more cysteine and GSH.183,184 Finally, BCAAs are also used to maintain the inflammatory state, with increased uptake and expression of branched chain amino acid transaminase 1 (BCAT1).185,186 The loss of BCAT1 has been shown to reduce itaconate and IRG1 levels due to decreased glycolytic activity.186,187 This occurs independently of its role in BCAA catabolism and function by driving NRF2-mediated antioxidant response and glucose-derived TCA metabolite production.187 This further demonstrates the delicate balance required across amino acid metabolic networks to provide a robust and complete immune response by macrophages. 3.1.4 Reprogramming of lipid metabolism due to LPS Lipid metabolism also plays a key role in regulating LPS-driven responses in macrophages. LPS-stimulated macrophages have been shown to have reduced cholesterol biosynthesis and support increased cholesterol ester formation in a type I IFN-dependent manner (Fig. 4).188–190 Interestingly, increasing flux through the cholesterol biosynthetic pathway via overexpression of the 3β-hydroxysterol Δ24-reductase (DHCR24) promotes mtROS production and NLRP3-dependent inflammasome activation, thereby supporting the progression of atherosclerosis.191 Autocrine IFN-β signaling also diverts excess cholesterol toward cholesterol 25-hydroxylase (CH25H)-mediated 25-hydroxycholesterol (25-HC) production.188,192 This reduction in cholesterol biosynthesis and the reprogramming of its lipid membrane composition is mediated by MyD88-dependent NRF2 and sterol regulatory element-binding protein (SREBP) signaling and plays an important role in increasing membrane fluidity and phagocytotic capacity.189,193 The oxysterol 25-HC can further control flux through the cholesterol biosynthetic pathway by inducing the proteolytic degradation of the rate-limiting enzyme 3-hydroxy-3-methyl glutaryl coenzyme A reductase (HMGCR), the rate-limiting enzyme in de novo cholesterol biosynthesis.194 Moreover, 25-HC provides resistance against the binding of cholesterol-dependent cytolysins to cellular membranes,195 suppresses IL-1β transcription and inflammasome activation to prevent a hyperinflammatory environment and atherosclerotic plaque formation196,197 and reduces SREBP1 and SREBP2-driven translation, responsible for the expression of cholesterol biosynthetic genes.188 SREBP1 is also upregulated in the later stages of activation to drive anti-inflammatory FA production in a liver X receptor (LXR)-dependent manner.198 Another late expressing protein, sphingosine kinase 2 (SPHK2), is degraded within 6 h of activation to promote inflammation before its induction 24 h post-stimulation to quell inflammation in a STING- and NF-κB-dependent manner.199,200 4 Role of cellular metabolism in viral infections The role of cellular metabolism in regulating macrophage effector function is not limited to antibacterial immune responses. Recent evidence has shown that antiviral immune responses are also supported by the rewiring of metabolic networks1 In addition, some viruses attempt to reprogram these metabolic networks to support viral replication and the survival of infected cells as well as subvert host immune responses.1,201 A better understanding of this complex interplay is required to fully elucidate the metabolic pathways associated with protection vs. pathogenesis across diverse viral infections. 4.1 The regulation of antiviral immune responses by cellular metabolism In response to viral infection, macrophages employ countermeasures against the co-opting of cell machinery by the virus.1 Central to these responses is the reprogramming of metabolic networks, such as glycolysis, OXPHOS, amino acid metabolism, and lipid metabolism. These alterations play critical roles in supporting resistance to infection, antigen presentation, and the production of inflammatory and antiviral mediators.86,202–205 4.1.1 Relationship between metabolism and RLR-mediated responses The best characterized viral PPR pathway shown to reprogram cellular metabolism in macrophages are the cytosolic RLRs. This is likely given the intimate link between the signaling of these receptors and the mitochondria. The MAVS protein participates in several interactions that mediate RLR responses. Following RLR engagement, MAVS undergoes O-linked β-N-acetylglucosamine (O-GlcNAc) modifications via O-GlcNAc transferase (OGT), leading to its ubiquitination and aggregation.206 This process is regulated by COX5B, a component of complex IV. COX5B interacts directly with MAVS preventing its aggregation and ROS production, ultimately suppressing antiviral responses.207 This provides a direct link between the homeostatic functions of the ETC and MAVS-mediated signaling. MAVS can also undergo protein geranylgeranylation, a metabolite from the cholesterol-producing mevalonate pathway, causing Rac1 translocation to mitochondria-associated ER membranes (MAMs), which blocks TRIM31-mediated ubiquitination and activation of MAVS.208 In addition, Rac1 also recruits caspase-8 and cFLIPL, which causes the degradation of RIPK1, terminating MAVS-mediated signaling.208 Interestingly, MAVS also interacts with HK2 to support glycolysis.209 Upon RLR activation, this interaction is lost, resulting in reduced glycolytic activity.209 This loss of activity is required to prevent lactate accumulation, which also binds to MAVS and prevents its aggregation and type I IFN production.209 However, the relationship between RLR signaling and glycolysis may be more complex as increased PFKFB3 expression is required for proper type I IFN induction,205 suggesting some activity may be required to mount functional antiviral immune responses. Mitochondria have also been shown to regulate RLR-mediated responses independent of their ability to serve as a scaffold to support cellular signaling. For example, mitochondrial fusion proteins MFN1 and MFN2 have been shown to support RLR-associated responses. MFN1 interacts with MAVS to provide effective RLR signaling.210,211 Alternatively, MFN2 maintains MMP,212,213 which is required to maintain OXPHOS activity and ROS-mediated potentiation of RLR signaling.214,215 To prevent hyperactivation, autophagy related 5 (ATG5)-mediated increases the removal of dysfunctional mitochondria, a large source of mtROS during RLR activation.214 Recently, Huang and colleagues identified dimethylarginine dimethylaminohydrolase 2 (DDAH2) as a negative regulator of RLR-mediated antiviral signaling, which translocates to mitochondria and metabolizes methylarginines, endogenous inhibitors of all NOS isoforms and their NO production.216,217 The clearance of methylarginines and the resulting NO production caused the activation of dynamin-related protein 1 (DRP1), promoting mitochondrial fission and preventing proper activation of MAVS, which can be inhibited by TBK1-mediated phosphorylation of DDAH2.216 4.1.2 TLR3-mediated responses depend on altered metabolic flux Endosomal dsRNA is recognized by TLR3, which activates antiviral immune response. However, less is known regarding the role of cellular metabolism in regulating these responses in macrophages. ROS has emerged as an important regulator of these responses. To et al.218 found that NOX2-generated ROS facilitates the expression of IFN-β, IL-1β, TNF-α, and IL-6 at supraphysiological concentrations of the artificial dsRNA ligand polyinosinic:polycytidylic acid (Poly(I:C) or PIC) (Fig. 5). In addition, increased complex III expression following TLR3 engagement elevates mtROS production (Fig. 5).219 This cytosolic and mitochondrial ROS is essential for the activation of NF-κB, IRF3, and STAT1 signaling.220 Other studies have also shown that TLR3 engagement is accompanied by reduced complex I-associated ATP production, partly linked to an increase in MCJ-mediated ETC supercomplex disassembly, forcing a reliance on glycolysis,148,160,165 highlighting differences between RLR and TLR3 responses (Fig. 5). This dependency on glycolysis is reliant on increased glucose uptake and PFKFB3 activity, which is required to support phagocytotic activity (Fig. 5).205,221 Interestingly, this increase in glycolytic activity is independent of HIF-1α and yet, in association with PKM2, drives NF-κB-mediated inflammation.221 Proteomic analysis has also directly connected the expression of 18 different metabolic proteins to the proper activation of TYK2, a member of the JAK-STAT signaling pathway.222 These include proteins linked to glucose metabolism (e.g. TIM) as well as FA synthesis (e.g. ACLY, ACSL4) and degradation (e.g. ACSL4).138,222 Further, TLR3-associated metabolic reprogramming is associated with the autocrine effects of type I IFN signaling. This includes the IFN-mediated induction of IRG-1 and increased itaconate production, which acts as a feedback mechanism to limit further type I IFN production (Fig. 5).147 Another suppressor of TLR3-associated responses is histone deacetylase 6 (HDAC6), which limits TBK1 activity and subsequent IFN-β production while enhancing Akt activation and IL-10 production.223 Fig. 5. Open in new tabDownload slide The metabolic regulation of macrophages stimulated by the viral-sensing TLRs. Image created with BioRender.com. As shown in Grunert et al.,222 lipid metabolism also plays an important role in regulating TLR3-mediated responses. After TLR3 engagement, activated macrophages significantly reduce the levels of saturated and unsaturated long-chain FAs as well as cholesterol in the plasma membrane and thus rely on lipid import rather than de novo synthesis regulated by SREBP (Fig. 5).204 This partly leads to a redirecting of cholesterol toward the generation of 25-HC, via increased expression of CH25H, which replaces cholesterol in the plasma membrane and prevents viral entry.192,224,225 It also regulates the magnitude of the inflammatory response by repressing IL-1β expression,196 yet amplifying the expression of other inflammatory mediators such as IL-6 and iNOS via activator protein 1 (AP-1) and STAT1.226,227 TRIF-induced type I IFN signaling also promotes reprogramming of lipid membrane composition distinct from MyD88-mediated signaling with a divergent accumulation of phosphatidylcholines, triglycerides (TAGs), and TLR3-specific accumulation of cholesterol esters, facilitated by an increased uptake and cycling of and their incorporation into TAGs and other lipids (Fig. 5).193,228 By comparison, little is known regarding the regulatory role of amino acids during TLR3 activation. The little known is from studies using supraphysiological levels of poly(I:C) (20–100μg/mL) and resulted in increased consumption of arginine by iNOS to produce NO. This was associated with IκB degradation and subsequent NF-κB activation of the inflammatory response as well as upregulation of Src-mediated TLR3 phosphorylation and prolonged IFN-β production.229,230 4.1.3 The metabolic reprogramming induced by other viral sensing TLRs The role of metabolism in regulating responses to other viral sensing TLR requires further investigation. To date, most of the work done on these ligands has been performed on other cell types.176,192,231–235 or has been conducted as an accessory to global TLR studies or used as a comparison to TLR4-focused studies. The ssRNA-sensing TLR7/8 is engaged by a few different artificial ligands including imidazoquinolinones (Imiquimod/R837, Resiquimod/R848, CL097).236–238 While NOX2-derived ROS is produced during TLR7 activation, it has been shown to repress cytokine production, and the use of apocynin (NOX2 inhibitor) has been shown to enhance cytokine secretion in a MyD88-dependent manner (Fig. 5).218 Consistent with these findings, proteomic analysis of R848-treated macrophages found 27 differentially expressed proteins, including several antioxidant proteins (SOD2, GPX, PRDX1/6).168 Stimulation of macrophages with imidazoquinolinone also inhibits complex I activity, leading to increased mtROS and ROS-mediated NLRP3 activation, suggesting that mtROS, but not cytosolic ROS, may be key in modulating TLR7/8 responses (Fig. 5).239,240 This inhibition contributes to the M1-like phenotype observed in R837 stimulated macrophages and is associated with elevated glycolytic function driven by HIF-1α and GLUT1-mediated inflammation.241 Consistent with these findings, the increased expression of inflammatory mediators IL-1β, IL-6, and IL-12 can be abrogated with 2-deoxyglucose (2-DG).241 Like other viral ligand receptors, activation of TLR7/8 has also been shown to alter macrophage lipid metabolism to protect the cell against infection. This occurs via MyD88-dependent lipid membrane recomposition by NRF2 and SREBP, which facilitates inflammatory cytokine production as well as increased cholesterol synthesis and import (Fig. 5).193,195,242 However, uncontrolled TLR7/8-mediated inflammation can result in foam cell formation due to excess cellular lipid accumulation.243 A key modulator of this homeostatic balance is SPHK2, which is degraded in the early phase of activation but induced in the late phase to quell inflammation.199 Another immunosuppressive molecule produced during TLR7/8 activation is itaconate, which assists in preventing hyperinflammation (Fig. 5).145 Even less is known about the role of cellular metabolism in regulating the activation of the DNA-sensing TLR9. Like TLR3 and TLR4, TLR9 activation with CpG oligonucleotides has been shown to induce ETC supercomplex disassembly, upregulation of MFN2 and MFN2-driven mtROS, as well as increased dependency on glycolysis for energy (Fig. 5).160,166,244 However, TLR9-activated macrophages also possessed increased OXPHOS activity,245 which is dependent on other energy sources for proper activation. Recently, Liu et al.246 found that CpG activation can reduce glucose input into the TCA cycle in order to favor carbons from glutaminolysis. Furthermore, the lysosomal amino acid transporter, SLC15A4, plays a central role in balancing the nutrient input into mitochondria during CpG activation by elevating mitochondrial pyruvate flux into the TCA cycle via PDH and by limiting glutamine’s incorporation into the TCA cycle via glutaminolysis (Fig. 5).247 This is done through a possible “moonlighting” role as a scaffold for AMPK and mTORC1 activation.247 TCA metabolites are also shunted toward de novo lipid biosynthesis via increased carnitine palmitoyltransferase I (CPT1A) and ACLY activity (Fig. 5).242,246 This is to increase their incorporation into the plasma membrane akin to other MyD88-dependent TLRs (TLR3/7/8)193 and to use newly generated lipids to support FAO’s energy contribution.246 Like other MyD88-dependent TLRs, TLR9 activation is also associated with increased cholesterol biosynthesis,195 though its role in the overall immune response has yet to be elucidated as the prevailing theory is that the presence of cholesterol in the plasma membrane leaves the cells more vulnerable for infection.248 4.1.4 The role of cellular metabolism in regulating the activation of other viral nucleic acid sensors It is also unclear what role cellular metabolism plays in regulating DDX3, ALR, STING, RNA Pol III, and DAI responses. He and colleagues249 found that sirtuin 5 (SIRT5) is critical to driving antiviral responses through its interaction and demalonylation of DDX3, which facilitates TBK1/IFR3 interactions. Malonylation is a recently identified post-translational modification that has been associated with the regulation of TNF-α expression via the malonylation of GAPDH and its subsequent release from TNF-α mRNA strands.126 A recent study by Tao et al.250 also found that ROS release during herpesvirus infection can regulate the STING-mediated sensing of cytoplasmic DNA by directly oxidizing cysteine residues to prevent receptor polymerization and activation. Further, STING activation has been shown to require a glutathione peroxidase 4 (GPX4)-mediated thwarting of lipid peroxidation, which, if present, prevents its trafficking from the ER to the Golgi.251 STING-mediated type I IFN responses can also be inhibited by de novo cholesterol biosynthesis or by replenishment of free cholesterol.204 Excess cholesterol in an inflammatory environment can also reduce mitochondrial respiration and mtDNA release, leading to mtDNA-induced AIM2 inflammasome activation as well as IL-1β cleavage and secretion.188,252 4.2 Virus-mediated hijacking of cellular metabolism Viruses are obligate intracellular microorganisms that use the host cell machinery to support their life cycle. To do this, they hijack the host cell’s metabolism to build the macromolecules required to promote viral replication and assembly as well as to support the survival of infected cells.1 Viral replication requires an immense amount of energy and requires a rapid and robust induction of energy production.201 One key metabolic pathway that provides this rapid energy and the production of macromolecule precursors is glycolysis. Accordingly, human cytomegaloviruses (HCMV) increase glucose uptake and consumption in infected cells by promoting the expression of GLUT4, which has a much higher affinity (∼3×) for glucose than GLUT1.253 This increases glucose-derived TCA metabolite flux, providing the building blocks to facilitate virus production.254 Airway macrophages infected with influenza A (IAV) also support elevated glycolytic activity linked to increased IRF5-mediated HK2 expression.120 Metabolomic analysis of IAV-infected macrophages revealed that this upregulation in glycolysis driven by the virus results in augmented glycolytic-derived citrate and succinate. These metabolites drive FA synthesis for viral envelope assembly, increase HIF-1α accumulation to enhance glycolytic activity, and provide building blocks for nucleotide synthesis.255 In addition to IAV, HIV, HCV, and SARS-CoV-2 have been shown to upregulate HIF-1α to boost glucose uptake and glycolysis.256–265 Consistent with these findings, LDH and GLUT1 have been identified as prognostic markers of disease severity for COVID-19 and HIV, respectively.266–268 During HIV infection, HIF-1α expression is elevated in both infected and bystander cells to promote a proinflammatory state and viral replication.269 Further, individuals who live with HIV for longer than 10 yrs with a normal CD4+ T cell count or those on antiretroviral therapy (ART) possess a lower proportion of GLUT1+ monocytes and T cells resulting in less TNF-α and IL-6 production, suggesting that increased glucose uptake in immune cells is associated with HIV progression.270–272 Alternatively, adenovirus and HSV upregulate glycolysis to drive intermediates to PPP and boost nucleotide synthesis to support viral genome replication.273–275 Targeting glycolysis, using the hexokinase inhibitor 2-deoxyglucose (2-DG), has shown to be effective in reducing HSV glycosylation of viral glycoproteins, decreasing HSV-induced cell fusion, preventing cell-to-cell spread of HSV, and attenuating HSV viral replication.276–278 2-DG is being explored as a potential therapeutic against certain cancers as well as an adjunct to the standard of care for those individuals infected with COVID-19.279,280 Viruses also employ strategies to alter mitochondrial function to support viral replication. These often include increased mtROS production and altered cellular redox status. For instance, dengue virus (DENV) infection is associated with increased mtROS and blocked mitochondrial fusion, which drives mitochondrial damage and DNA release resulting in an increased dependence on glycolysis to support the production of biomolecular precursors required for viral replication.69,213,281 Alternatively, HBV infection increases DRP1 activation while promoting MFN2 degradation and favoring mitochondrial fission and mitophagy in order to prevent apoptosis.282 On the other hand, HCV expresses several proteins that alter mitochondrial function by either reducing the levels of complex IV subunits,283,284 inhibiting complex I activity to induce mtROS,285,286 or by altering mitochondrial fusion/fission.287 Similarly, supplementing macrophages with pyruvate during IAV infection has been shown to be protective against mitochondrial superoxide-associated damage and to amplify OXPHOS-specific ATP production.288 However, this supplementation impairs inflammatory cytokine production without preventing IAV replication,288 suggesting that while these complex processes support viral replication, they are also required to support inflammatory responses. At the level of cellular redox status, transcriptomic analysis of the peripheral mononuclear blood cells (PMBCs) of severe COVID-19 patients has shown suppressed NRF2-dependent antioxidant gene expression, including heme oxygenase 1 (HMOX1) and NAD(P)H quinone dehydrogenase 1 (NQO1), which may promote a hyperinflammatory environment that favors viral replication and propagation.289 Similarly, HIV possesses several proteins that may interfere with cellular redox balance by either inhibiting GSH production or amplifying ROS production,290–295 leading to oxidative stress-induced HIV-1 promoter activation via HIF-1α and MAPK.256,296,297 Interestingly, HIV-1 selectively infects high energy CD4+ T cells irrespective of their activation phenotype.298 However, HIV-infected macrophages that survive the initial infection have reduced ATP production and increased mtROS, suggesting differential cell type machinery adaptation to ensure viral survival.295,299–302 Viral replication is an energy-intensive process and uses multiple bioenergetic pathways to support viral propagation. Adenovirus and HCV infections cause increased glutaminolysis and glutamine dependence to support robust viral replication and cell growth.273,303 In addition, HIV-infected macrophages have an increased reliance on glutamine as an energy source.299 VACV viral infection preferentially increases intracellular glutamine levels as it is the primary energy source during viral replication.304 This dependency on glutamine for energy has the added benefit of maintaining TCA cycle metabolites to generate amino acids for viral protein synthesis.304 Conversely, HIV-infected macrophages secrete glutamine and glutamate into the extracellular milieu, which may contribute to glutamate-facilitated neurological impairments seen in HIV-infected individuals.262 Further, work by Wu and colleagues305,306 has shown that GLS-driven glutaminolysis and its end-product, α-KG, are essential drivers of extracellular vesicle release from infected cells. Another amino acid associated with HIV infection is tryptophan. Increased expression of indoleamine 2,3-dioxygenase (IDO), and tryptophan catabolism during viral infection307 has been shown to increase kynurenine and quinolinic acid, which can promote HIV-1 infection by activating aryl hydrocarbon receptor (AHR) to initiate viral transcription.308 The progression of a viral infection also alters lipid and cholesterol metabolism to further infection. DENV-infected cells increase FAO via AMPK activation to provide energy to cells.309 Yet a DENV component protein can recruit FA synthase (FASN) to sites of viral particle replication and stimulate its activity.310 Other viruses preferentially use lipids to support viral replication and assembly. For example, HIV uses lipid rafts as an entry point into the cell and promotes FA and cholesterol biosynthesis to support viral propagation.311–315 Productive HCMV infection requires the expression of multiple acyl-CoA synthetases and FA elongases to produce very long chain FAs (C26-C34).316 Furthermore, monocytes actively uptake cholesterol in the early phases of HIV infection. Over the course of disease, rate of uptake lessens as cholesterol accumulation results in foam cell formation.317 HCMV also induces lipogenesis via SREBP1 and SREBP2 upregulation,318 while IAV increases FA synthesis and decreases FAO in order to funnel lipids toward the production of more viruses.319,320 Targeting de novo FA biosynthesis during VACV infection reduced viral load.321 HCV infection boosts lipid metabolism by activating SREBP protein translation and increasing its proteolytic cleavage into its mature form.322–325 As a result, host immune cells must enact defense strategies to counteract the reprogramming driven by viruses, and central to these strategies is the ability of cellular metabolism to manipulate the degree and magnitude of the host response. Most studies in this context have focused on the downstream effects of the viral interactions with the macrophages and the subsequent metabolic requirements of the virus and the host cell. Yet very little work has examined many of the upstream functions involved in the virus–cell interactions such as viral uptake or membrane fusion events. Furthermore, the relationships between specific aspects of the virus life cycle have been linked to specific metabolic pathways but the mechanisms underlying these processes have been incompletely investigated. While DeVito and colleagues found that HCMV increased pyrimidine biosynthesis in order to elevate the production of UDP-sugars, required for the synthesis of its viral envelope protein gB and its ability to bind to host cells,326 more work is required in order to dissect the needs from each metabolic pathway for each stage of the viral life cycle as that increased understanding will undoubtedly leads to advancements in potential new therapeutics. 5 Applications of innate sensing as therapeutics An increased understanding of the associations between metabolism and macrophage effector functions has provided researchers with novel therapeutic opportunities to optimize immune responses. While viruses rewire the host cell’s metabolism to support viral replication and propagation, immune cells also undergo metabolic reprogramming to elicit robust immune responses. To target these pathways effectively, we need a clear understanding of the specific role of each component over the course of an infection.1 We also need a full understanding of the differences between mouse and human responses. There are two potential avenues for development: (1) inhibiting metabolic pathways that are advantageous to the virus or (2) activating pathways that support functional antiviral immune responses. Required for this process will be a detailed understanding of the metabolic mechanisms underlying type I IFN responses as well as the specific features of type I IFN responses (e.g. ISGs) that interfere with the metabolic requirements of viral replication, dissemination, and the long-term survival of infected cells.86,327 It will also be important to understand how altered metabolic processes during viral infections contribute to immunopathology and tissue damage linked through such mechanisms as excess ROS production.1 This becomes particularly important in the context of chronic infections as metabolic perturbations and dysregulated immune responses linked to altered type I IFN signaling drive disease pathogenesis.328,329 There is also an increasing interest in using PRR ligands, including viral ligands as adjuvants to enhance the immunogenicity of vaccines and other immunotherapies.330 A PubMed and Scopus search identified 26 studies in the last 10 years that are at various stages of developing or using PPR ligands (i.e. LPS,331–334 Poly(I:C),332–344 and CpG335,336,339,340,344–347 as adjuvants or immune modulators to treat communicable and noncommunicable diseases (Table 1). Targeting metabolism may also represent a powerful tool to optimize these immune responses across tissue types (e.g. lung, liver, intestine) and diverse populations (e.g. elderly, diabetics). Further, there has been a significant increase in the use of oncolytic viruses (OVs) to treat various cancers. Understanding how metabolic processes regulate OV associated antitumor immune responses and how the tumor microenvironments affect these processes may provide important insights to optimize these therapies.356 Table 1. Literature from the last 10 years investigating the use of PRR ligands as part of possible immunotherapies as identified using PubMed and Scopus. . Title . Year . Database/Type of Study . PPR Ligand . Application . Treatment . Ref . 1 Intravaginal TLR agonists increase local vaccine-specific CD8 T cells and human papillomavirus-associated genital-tumor regression in mice 2013 Scopus; Comparative study w/control TLR3 (poly(I:C)) and/or TLR9 (CpG-ODN) Cancer vaccine: Human papillomaviruses (HPV)-related cervical cancer Intravaginal (IVAG) after with HPV E7 oncogene-specific therapeutic vaccine 335 2 The efficacy versus toxicity profile of combination virotherapy and TLR immunotherapy highlights the danger of administering TLR agonists to oncolytic virus-treated mice 2013 Scopus; Comparative study TLR4 (LPS) Vesicular stomatitis virus (VSV) as oncolytic virus vaccine (B16ova tumors model) In combination with vaccine 331 3 Combinations of TLR ligands: A promising approach in cancer immunotherapy 2013 Scopus; Comparative study TLR3 (Poly(I:C)), TLR7/8 (R848) and/or TLR4 (LPS + Taxol) Colorectal cancer (CRC) Monotherapy and in combinations with other TLRs 332 4 Administration of a toll-like receptor 9 agonist decreases the proviral reservoir in virologically suppressed HIV-infected patients 2013 PubMed; Clinical Trial TLR-9 (CPG 7909) HIV Combination with pneumococcal vaccines 345 5 Local administration of TLR ligands rescues the function of tumor-infiltrating CD8 T cells and enhances the antitumor effect of lentivector immunization 2013 Scopus; Comparative study w/control TLR3 (poly(I:C)) and/or TLR9 (CpG) Cancer vaccines Local administration of TLR ligands 336 6 Induction of antigen-specific immunity with a vaccine targeting NY-ESO-1 to the dendritic cell receptor DEC-205 2014 PubMed; Clinical Trial TLR7/8 (Resiquimod) and TLR3 (Poly-ICLC) Cancer vaccines: Patients w/advanced malignancies refractory to available therapies. With CDX-1401 vaccine 337 7 Comparing the effect of toll-like receptor agonist adjuvants on the efficiency of a DNA vaccine 2014 PubMed; Comparative Study TLR3 (Poly(I:C) and TLR7 (Resiquimod) Vaccine adjuvants against tumors expressing the human papilloma virus 16 (HPV-16) E7 protein Combination with HPV-16 E7 DNA vaccine 338 8 The combination of ISCOMATRIX adjuvant and TLR agonists induces regression of established solid tumors in vivo 2015 Scopus; Comparative study w/control TLR3 (Poly(I:C)), TLR9 (CpG) Solid tumors in vivo (B16-OVA melanoma, Panc-OVA pancreatic, and TRAMP-C1 prostate cancer) As adjuvants to ISCOMATRIX vaccines 339 9 TLR agonist augments prophylactic potential of acid inducible antigen Rv3203 against mycobacterium tuberculosis H37Rv in experimental animals 2016 Scopus; Comparative study with control TLR2/6 (zymosan) Mycobacterium tuberculosis With Rv3203 (a cell wall associated protein with lipolytic activity) 348 10 Encapsulation of two different TLR ligands into liposomes confer protective immunity and prevent tumor development 2017 Scopus; Comparative study w/control TLR3 (poly(I:C)), and/or TLR9 (CpG ODN) Cancer vaccine Immunoadjuvants with protein antigen in a liposomal carrier system 340 11 Phase Ib trial of the toll-like receptor 8 agonist, Motolimod (VTX-2337), Combined with Cetuximab in patients with recurrent or metastatic SCCHN 2017 PubMed; Clinical Trial Phase Ib TLR8 (Motolimod) Recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) Combination with cetuximab 349 12 Effect of TLR ligands co-encapsulated with multiepitopic antigen in nanoliposomes targeted to human DCs via Fc receptor for cancer vaccines 2017 Scopus; Comparative study with control TLRR7/8 (R848), TLR3 (Poly(I:C)), TLR4 (LPS), and TLR2 (PAM3CSK4) Cancer vaccines: androgen-responsive prostate cancer Adjuvants of peptide-based liposome vaccine 333 13 Combination immunotherapy with TLR agonists and checkpoint inhibitors suppresses head and neck cancer 2017 Scopus; Comparative study with control TLR7 (1V270), TLR9 (SD-101/CpG ODN) Recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) In combination with checkpoint inhibitors with anti-PD-1 346 14 Co-delivery of nucleoside-modified mRNA and TLR agonists for cancer immunotherapy: Restoring the immunogenicity of immunosilent mRNA 2017 Scopus; Comparative study with control TLR4 (MPLA) Therapeutic cancer mRNA vaccination In combination with nucleoside-modified mRNA 350 15 Combination therapy with proteasome inhibitors and TLR agonists enhances tumour cell death and IL-1β production article/96/21 2018 Scopus; Comparative study with control TLR5 (flagellin), TLR7/8 (R848), TLR1/2 (Pam3CSK4), TLR9 (CpG ODN), or TLR4 (MPLA) Haematological malignancies (myeloid tumour cells); anti-tumor activity Combination with proteasome inhibitor (bortezomib) 347 16 A multipeptide vaccine plus toll-like receptor agonists LPS or polyICLC in combination with incomplete Freund’s adjuvant in melanoma patients 2019 PubMed; Clinical Trial TLR3 (polyICLC) or TLR4 (LPS) Peptide vaccine adjuvants for resected stage IIB-IV melanoma A mixture of 12 short melanoma peptides (12MP) + a tetanus helper peptide + TLR agonists +/- treatment arms with IFA. 334 17 Immune adjuvant therapy using Bacillus Calmette-Guérin cell wall skeleton (BCG-CWS) in advanced malignancies: A phase 1 study of safety and immunogenicity assessments 2019 PubMed; Clinical Trial Phase I TLR2/4 and CLRs ligand (BCG cell wall skeleton (BCG-CWS)) Advanced WT1-expressing cancers refractory to standard anticancer therapies Combination with WT1 peptide 351 18 TLR agonist rHP-NAP as an adjuvant of dendritic cell-based vaccine to enhance anti-melanoma response 2020 Scopus; Comparative study with control TLR agonist (Recombinant HP-NAP (rHP-NAP)) and TLR4 (LPS) An adjuvant of DC-based vaccine in anti-melanoma treatment. As an adjuvant of a vaccine 352 19 Induction of immune response against metastatic tumors via vaccination of Mannan-BAM, TLR ligands, and anti-CD40 antibody (MBTA) 2020 Scopus; Comparative study TLR7/8 (R848), TLR3 (poly(I:C)), and TLR2 (LTA) Metastatic tumors (colon carcinoma model) MBTA therapy with irradiated whole tumor cells 341 20 Potential of TLR agonist as an adjuvant in Leishmania vaccine against visceral leishmaniasis in BALB/c mice 2021 Scopus; Comparative study with control TLR7 (Gardiquimod) Visceral leishmaniasis Used as an adjuvant in Leishmania vaccine (heat-killed antigen) 353 21 Combinatorial delivery of antigen and TLR agonists via PLGA nanoparticles modulates Leishmania major-infected-macrophages activation 2021 Scopus; Comparative study TLR1/2 (Pam3CSK4) and TLR7/8 (R848) Leishmania major-infected-macrophages Combinatorial delivery of antigen and TLR agonists via PLGA nanoparticles 354 22 Enhanced humoral immune response by high density TLR agonist presentation on hyperbranched polymers 2021 Scopus; Comparative study TLR7/8 (R848) Humoral immunity TLR7/8 agonists are covalently attached to highly dense end-groups of hyperbranched polymers 355 23 Phase I/II trial of a long peptide vaccine (LPV7) plus toll-like receptor (TLR) agonists with or without incomplete Freund’s adjuvant (IFA) for resected high-risk melanoma 2021 Scopus; Clinical Trial: Phase I/II TLR3 (polyICLC) and/or TLR7/8 (R848) Resected high-risk melanoma Adjuvant to long peptide vaccine (with/without combinations of IFA) 342 24 Mannan-BAM, TLR ligands, and anti-CD40 immunotherapy in established murine pancreatic adenocarcinoma: understanding therapeutic potentials and limitations 2021 Scopus; Comparative study with control TLR7/8 (R848), TLR3(poly(I:C)) and TLR2/6 (lipoteichoic acid (LTA)) Subcutaneous pancreatic adenocarcinoma (Panc02) tumors Mannan-BAM, R-848, poly(I:C), and LTA together with anti-CD40 antibody (called MBTA therapy) 343 25 TLR ligand loaded exosome mediated immunotherapy of established mammary tumor in mice 2021 Scopus; Comparative study TLR9 (K-type CpG ODN) and TLR3 (poly(I:C)) Tumor-derived exosomes (TEXs) as immunotherapeutic cancer vaccines Loaded in Tumor-derived exosomes (4T1/Her2 cell-derived exosomes) 344 . Title . Year . Database/Type of Study . PPR Ligand . Application . Treatment . Ref . 1 Intravaginal TLR agonists increase local vaccine-specific CD8 T cells and human papillomavirus-associated genital-tumor regression in mice 2013 Scopus; Comparative study w/control TLR3 (poly(I:C)) and/or TLR9 (CpG-ODN) Cancer vaccine: Human papillomaviruses (HPV)-related cervical cancer Intravaginal (IVAG) after with HPV E7 oncogene-specific therapeutic vaccine 335 2 The efficacy versus toxicity profile of combination virotherapy and TLR immunotherapy highlights the danger of administering TLR agonists to oncolytic virus-treated mice 2013 Scopus; Comparative study TLR4 (LPS) Vesicular stomatitis virus (VSV) as oncolytic virus vaccine (B16ova tumors model) In combination with vaccine 331 3 Combinations of TLR ligands: A promising approach in cancer immunotherapy 2013 Scopus; Comparative study TLR3 (Poly(I:C)), TLR7/8 (R848) and/or TLR4 (LPS + Taxol) Colorectal cancer (CRC) Monotherapy and in combinations with other TLRs 332 4 Administration of a toll-like receptor 9 agonist decreases the proviral reservoir in virologically suppressed HIV-infected patients 2013 PubMed; Clinical Trial TLR-9 (CPG 7909) HIV Combination with pneumococcal vaccines 345 5 Local administration of TLR ligands rescues the function of tumor-infiltrating CD8 T cells and enhances the antitumor effect of lentivector immunization 2013 Scopus; Comparative study w/control TLR3 (poly(I:C)) and/or TLR9 (CpG) Cancer vaccines Local administration of TLR ligands 336 6 Induction of antigen-specific immunity with a vaccine targeting NY-ESO-1 to the dendritic cell receptor DEC-205 2014 PubMed; Clinical Trial TLR7/8 (Resiquimod) and TLR3 (Poly-ICLC) Cancer vaccines: Patients w/advanced malignancies refractory to available therapies. With CDX-1401 vaccine 337 7 Comparing the effect of toll-like receptor agonist adjuvants on the efficiency of a DNA vaccine 2014 PubMed; Comparative Study TLR3 (Poly(I:C) and TLR7 (Resiquimod) Vaccine adjuvants against tumors expressing the human papilloma virus 16 (HPV-16) E7 protein Combination with HPV-16 E7 DNA vaccine 338 8 The combination of ISCOMATRIX adjuvant and TLR agonists induces regression of established solid tumors in vivo 2015 Scopus; Comparative study w/control TLR3 (Poly(I:C)), TLR9 (CpG) Solid tumors in vivo (B16-OVA melanoma, Panc-OVA pancreatic, and TRAMP-C1 prostate cancer) As adjuvants to ISCOMATRIX vaccines 339 9 TLR agonist augments prophylactic potential of acid inducible antigen Rv3203 against mycobacterium tuberculosis H37Rv in experimental animals 2016 Scopus; Comparative study with control TLR2/6 (zymosan) Mycobacterium tuberculosis With Rv3203 (a cell wall associated protein with lipolytic activity) 348 10 Encapsulation of two different TLR ligands into liposomes confer protective immunity and prevent tumor development 2017 Scopus; Comparative study w/control TLR3 (poly(I:C)), and/or TLR9 (CpG ODN) Cancer vaccine Immunoadjuvants with protein antigen in a liposomal carrier system 340 11 Phase Ib trial of the toll-like receptor 8 agonist, Motolimod (VTX-2337), Combined with Cetuximab in patients with recurrent or metastatic SCCHN 2017 PubMed; Clinical Trial Phase Ib TLR8 (Motolimod) Recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) Combination with cetuximab 349 12 Effect of TLR ligands co-encapsulated with multiepitopic antigen in nanoliposomes targeted to human DCs via Fc receptor for cancer vaccines 2017 Scopus; Comparative study with control TLRR7/8 (R848), TLR3 (Poly(I:C)), TLR4 (LPS), and TLR2 (PAM3CSK4) Cancer vaccines: androgen-responsive prostate cancer Adjuvants of peptide-based liposome vaccine 333 13 Combination immunotherapy with TLR agonists and checkpoint inhibitors suppresses head and neck cancer 2017 Scopus; Comparative study with control TLR7 (1V270), TLR9 (SD-101/CpG ODN) Recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) In combination with checkpoint inhibitors with anti-PD-1 346 14 Co-delivery of nucleoside-modified mRNA and TLR agonists for cancer immunotherapy: Restoring the immunogenicity of immunosilent mRNA 2017 Scopus; Comparative study with control TLR4 (MPLA) Therapeutic cancer mRNA vaccination In combination with nucleoside-modified mRNA 350 15 Combination therapy with proteasome inhibitors and TLR agonists enhances tumour cell death and IL-1β production article/96/21 2018 Scopus; Comparative study with control TLR5 (flagellin), TLR7/8 (R848), TLR1/2 (Pam3CSK4), TLR9 (CpG ODN), or TLR4 (MPLA) Haematological malignancies (myeloid tumour cells); anti-tumor activity Combination with proteasome inhibitor (bortezomib) 347 16 A multipeptide vaccine plus toll-like receptor agonists LPS or polyICLC in combination with incomplete Freund’s adjuvant in melanoma patients 2019 PubMed; Clinical Trial TLR3 (polyICLC) or TLR4 (LPS) Peptide vaccine adjuvants for resected stage IIB-IV melanoma A mixture of 12 short melanoma peptides (12MP) + a tetanus helper peptide + TLR agonists +/- treatment arms with IFA. 334 17 Immune adjuvant therapy using Bacillus Calmette-Guérin cell wall skeleton (BCG-CWS) in advanced malignancies: A phase 1 study of safety and immunogenicity assessments 2019 PubMed; Clinical Trial Phase I TLR2/4 and CLRs ligand (BCG cell wall skeleton (BCG-CWS)) Advanced WT1-expressing cancers refractory to standard anticancer therapies Combination with WT1 peptide 351 18 TLR agonist rHP-NAP as an adjuvant of dendritic cell-based vaccine to enhance anti-melanoma response 2020 Scopus; Comparative study with control TLR agonist (Recombinant HP-NAP (rHP-NAP)) and TLR4 (LPS) An adjuvant of DC-based vaccine in anti-melanoma treatment. As an adjuvant of a vaccine 352 19 Induction of immune response against metastatic tumors via vaccination of Mannan-BAM, TLR ligands, and anti-CD40 antibody (MBTA) 2020 Scopus; Comparative study TLR7/8 (R848), TLR3 (poly(I:C)), and TLR2 (LTA) Metastatic tumors (colon carcinoma model) MBTA therapy with irradiated whole tumor cells 341 20 Potential of TLR agonist as an adjuvant in Leishmania vaccine against visceral leishmaniasis in BALB/c mice 2021 Scopus; Comparative study with control TLR7 (Gardiquimod) Visceral leishmaniasis Used as an adjuvant in Leishmania vaccine (heat-killed antigen) 353 21 Combinatorial delivery of antigen and TLR agonists via PLGA nanoparticles modulates Leishmania major-infected-macrophages activation 2021 Scopus; Comparative study TLR1/2 (Pam3CSK4) and TLR7/8 (R848) Leishmania major-infected-macrophages Combinatorial delivery of antigen and TLR agonists via PLGA nanoparticles 354 22 Enhanced humoral immune response by high density TLR agonist presentation on hyperbranched polymers 2021 Scopus; Comparative study TLR7/8 (R848) Humoral immunity TLR7/8 agonists are covalently attached to highly dense end-groups of hyperbranched polymers 355 23 Phase I/II trial of a long peptide vaccine (LPV7) plus toll-like receptor (TLR) agonists with or without incomplete Freund’s adjuvant (IFA) for resected high-risk melanoma 2021 Scopus; Clinical Trial: Phase I/II TLR3 (polyICLC) and/or TLR7/8 (R848) Resected high-risk melanoma Adjuvant to long peptide vaccine (with/without combinations of IFA) 342 24 Mannan-BAM, TLR ligands, and anti-CD40 immunotherapy in established murine pancreatic adenocarcinoma: understanding therapeutic potentials and limitations 2021 Scopus; Comparative study with control TLR7/8 (R848), TLR3(poly(I:C)) and TLR2/6 (lipoteichoic acid (LTA)) Subcutaneous pancreatic adenocarcinoma (Panc02) tumors Mannan-BAM, R-848, poly(I:C), and LTA together with anti-CD40 antibody (called MBTA therapy) 343 25 TLR ligand loaded exosome mediated immunotherapy of established mammary tumor in mice 2021 Scopus; Comparative study TLR9 (K-type CpG ODN) and TLR3 (poly(I:C)) Tumor-derived exosomes (TEXs) as immunotherapeutic cancer vaccines Loaded in Tumor-derived exosomes (4T1/Her2 cell-derived exosomes) 344 Open in new tab Table 1. Literature from the last 10 years investigating the use of PRR ligands as part of possible immunotherapies as identified using PubMed and Scopus. . Title . Year . Database/Type of Study . PPR Ligand . Application . Treatment . Ref . 1 Intravaginal TLR agonists increase local vaccine-specific CD8 T cells and human papillomavirus-associated genital-tumor regression in mice 2013 Scopus; Comparative study w/control TLR3 (poly(I:C)) and/or TLR9 (CpG-ODN) Cancer vaccine: Human papillomaviruses (HPV)-related cervical cancer Intravaginal (IVAG) after with HPV E7 oncogene-specific therapeutic vaccine 335 2 The efficacy versus toxicity profile of combination virotherapy and TLR immunotherapy highlights the danger of administering TLR agonists to oncolytic virus-treated mice 2013 Scopus; Comparative study TLR4 (LPS) Vesicular stomatitis virus (VSV) as oncolytic virus vaccine (B16ova tumors model) In combination with vaccine 331 3 Combinations of TLR ligands: A promising approach in cancer immunotherapy 2013 Scopus; Comparative study TLR3 (Poly(I:C)), TLR7/8 (R848) and/or TLR4 (LPS + Taxol) Colorectal cancer (CRC) Monotherapy and in combinations with other TLRs 332 4 Administration of a toll-like receptor 9 agonist decreases the proviral reservoir in virologically suppressed HIV-infected patients 2013 PubMed; Clinical Trial TLR-9 (CPG 7909) HIV Combination with pneumococcal vaccines 345 5 Local administration of TLR ligands rescues the function of tumor-infiltrating CD8 T cells and enhances the antitumor effect of lentivector immunization 2013 Scopus; Comparative study w/control TLR3 (poly(I:C)) and/or TLR9 (CpG) Cancer vaccines Local administration of TLR ligands 336 6 Induction of antigen-specific immunity with a vaccine targeting NY-ESO-1 to the dendritic cell receptor DEC-205 2014 PubMed; Clinical Trial TLR7/8 (Resiquimod) and TLR3 (Poly-ICLC) Cancer vaccines: Patients w/advanced malignancies refractory to available therapies. With CDX-1401 vaccine 337 7 Comparing the effect of toll-like receptor agonist adjuvants on the efficiency of a DNA vaccine 2014 PubMed; Comparative Study TLR3 (Poly(I:C) and TLR7 (Resiquimod) Vaccine adjuvants against tumors expressing the human papilloma virus 16 (HPV-16) E7 protein Combination with HPV-16 E7 DNA vaccine 338 8 The combination of ISCOMATRIX adjuvant and TLR agonists induces regression of established solid tumors in vivo 2015 Scopus; Comparative study w/control TLR3 (Poly(I:C)), TLR9 (CpG) Solid tumors in vivo (B16-OVA melanoma, Panc-OVA pancreatic, and TRAMP-C1 prostate cancer) As adjuvants to ISCOMATRIX vaccines 339 9 TLR agonist augments prophylactic potential of acid inducible antigen Rv3203 against mycobacterium tuberculosis H37Rv in experimental animals 2016 Scopus; Comparative study with control TLR2/6 (zymosan) Mycobacterium tuberculosis With Rv3203 (a cell wall associated protein with lipolytic activity) 348 10 Encapsulation of two different TLR ligands into liposomes confer protective immunity and prevent tumor development 2017 Scopus; Comparative study w/control TLR3 (poly(I:C)), and/or TLR9 (CpG ODN) Cancer vaccine Immunoadjuvants with protein antigen in a liposomal carrier system 340 11 Phase Ib trial of the toll-like receptor 8 agonist, Motolimod (VTX-2337), Combined with Cetuximab in patients with recurrent or metastatic SCCHN 2017 PubMed; Clinical Trial Phase Ib TLR8 (Motolimod) Recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) Combination with cetuximab 349 12 Effect of TLR ligands co-encapsulated with multiepitopic antigen in nanoliposomes targeted to human DCs via Fc receptor for cancer vaccines 2017 Scopus; Comparative study with control TLRR7/8 (R848), TLR3 (Poly(I:C)), TLR4 (LPS), and TLR2 (PAM3CSK4) Cancer vaccines: androgen-responsive prostate cancer Adjuvants of peptide-based liposome vaccine 333 13 Combination immunotherapy with TLR agonists and checkpoint inhibitors suppresses head and neck cancer 2017 Scopus; Comparative study with control TLR7 (1V270), TLR9 (SD-101/CpG ODN) Recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) In combination with checkpoint inhibitors with anti-PD-1 346 14 Co-delivery of nucleoside-modified mRNA and TLR agonists for cancer immunotherapy: Restoring the immunogenicity of immunosilent mRNA 2017 Scopus; Comparative study with control TLR4 (MPLA) Therapeutic cancer mRNA vaccination In combination with nucleoside-modified mRNA 350 15 Combination therapy with proteasome inhibitors and TLR agonists enhances tumour cell death and IL-1β production article/96/21 2018 Scopus; Comparative study with control TLR5 (flagellin), TLR7/8 (R848), TLR1/2 (Pam3CSK4), TLR9 (CpG ODN), or TLR4 (MPLA) Haematological malignancies (myeloid tumour cells); anti-tumor activity Combination with proteasome inhibitor (bortezomib) 347 16 A multipeptide vaccine plus toll-like receptor agonists LPS or polyICLC in combination with incomplete Freund’s adjuvant in melanoma patients 2019 PubMed; Clinical Trial TLR3 (polyICLC) or TLR4 (LPS) Peptide vaccine adjuvants for resected stage IIB-IV melanoma A mixture of 12 short melanoma peptides (12MP) + a tetanus helper peptide + TLR agonists +/- treatment arms with IFA. 334 17 Immune adjuvant therapy using Bacillus Calmette-Guérin cell wall skeleton (BCG-CWS) in advanced malignancies: A phase 1 study of safety and immunogenicity assessments 2019 PubMed; Clinical Trial Phase I TLR2/4 and CLRs ligand (BCG cell wall skeleton (BCG-CWS)) Advanced WT1-expressing cancers refractory to standard anticancer therapies Combination with WT1 peptide 351 18 TLR agonist rHP-NAP as an adjuvant of dendritic cell-based vaccine to enhance anti-melanoma response 2020 Scopus; Comparative study with control TLR agonist (Recombinant HP-NAP (rHP-NAP)) and TLR4 (LPS) An adjuvant of DC-based vaccine in anti-melanoma treatment. As an adjuvant of a vaccine 352 19 Induction of immune response against metastatic tumors via vaccination of Mannan-BAM, TLR ligands, and anti-CD40 antibody (MBTA) 2020 Scopus; Comparative study TLR7/8 (R848), TLR3 (poly(I:C)), and TLR2 (LTA) Metastatic tumors (colon carcinoma model) MBTA therapy with irradiated whole tumor cells 341 20 Potential of TLR agonist as an adjuvant in Leishmania vaccine against visceral leishmaniasis in BALB/c mice 2021 Scopus; Comparative study with control TLR7 (Gardiquimod) Visceral leishmaniasis Used as an adjuvant in Leishmania vaccine (heat-killed antigen) 353 21 Combinatorial delivery of antigen and TLR agonists via PLGA nanoparticles modulates Leishmania major-infected-macrophages activation 2021 Scopus; Comparative study TLR1/2 (Pam3CSK4) and TLR7/8 (R848) Leishmania major-infected-macrophages Combinatorial delivery of antigen and TLR agonists via PLGA nanoparticles 354 22 Enhanced humoral immune response by high density TLR agonist presentation on hyperbranched polymers 2021 Scopus; Comparative study TLR7/8 (R848) Humoral immunity TLR7/8 agonists are covalently attached to highly dense end-groups of hyperbranched polymers 355 23 Phase I/II trial of a long peptide vaccine (LPV7) plus toll-like receptor (TLR) agonists with or without incomplete Freund’s adjuvant (IFA) for resected high-risk melanoma 2021 Scopus; Clinical Trial: Phase I/II TLR3 (polyICLC) and/or TLR7/8 (R848) Resected high-risk melanoma Adjuvant to long peptide vaccine (with/without combinations of IFA) 342 24 Mannan-BAM, TLR ligands, and anti-CD40 immunotherapy in established murine pancreatic adenocarcinoma: understanding therapeutic potentials and limitations 2021 Scopus; Comparative study with control TLR7/8 (R848), TLR3(poly(I:C)) and TLR2/6 (lipoteichoic acid (LTA)) Subcutaneous pancreatic adenocarcinoma (Panc02) tumors Mannan-BAM, R-848, poly(I:C), and LTA together with anti-CD40 antibody (called MBTA therapy) 343 25 TLR ligand loaded exosome mediated immunotherapy of established mammary tumor in mice 2021 Scopus; Comparative study TLR9 (K-type CpG ODN) and TLR3 (poly(I:C)) Tumor-derived exosomes (TEXs) as immunotherapeutic cancer vaccines Loaded in Tumor-derived exosomes (4T1/Her2 cell-derived exosomes) 344 . Title . Year . Database/Type of Study . PPR Ligand . Application . Treatment . Ref . 1 Intravaginal TLR agonists increase local vaccine-specific CD8 T cells and human papillomavirus-associated genital-tumor regression in mice 2013 Scopus; Comparative study w/control TLR3 (poly(I:C)) and/or TLR9 (CpG-ODN) Cancer vaccine: Human papillomaviruses (HPV)-related cervical cancer Intravaginal (IVAG) after with HPV E7 oncogene-specific therapeutic vaccine 335 2 The efficacy versus toxicity profile of combination virotherapy and TLR immunotherapy highlights the danger of administering TLR agonists to oncolytic virus-treated mice 2013 Scopus; Comparative study TLR4 (LPS) Vesicular stomatitis virus (VSV) as oncolytic virus vaccine (B16ova tumors model) In combination with vaccine 331 3 Combinations of TLR ligands: A promising approach in cancer immunotherapy 2013 Scopus; Comparative study TLR3 (Poly(I:C)), TLR7/8 (R848) and/or TLR4 (LPS + Taxol) Colorectal cancer (CRC) Monotherapy and in combinations with other TLRs 332 4 Administration of a toll-like receptor 9 agonist decreases the proviral reservoir in virologically suppressed HIV-infected patients 2013 PubMed; Clinical Trial TLR-9 (CPG 7909) HIV Combination with pneumococcal vaccines 345 5 Local administration of TLR ligands rescues the function of tumor-infiltrating CD8 T cells and enhances the antitumor effect of lentivector immunization 2013 Scopus; Comparative study w/control TLR3 (poly(I:C)) and/or TLR9 (CpG) Cancer vaccines Local administration of TLR ligands 336 6 Induction of antigen-specific immunity with a vaccine targeting NY-ESO-1 to the dendritic cell receptor DEC-205 2014 PubMed; Clinical Trial TLR7/8 (Resiquimod) and TLR3 (Poly-ICLC) Cancer vaccines: Patients w/advanced malignancies refractory to available therapies. With CDX-1401 vaccine 337 7 Comparing the effect of toll-like receptor agonist adjuvants on the efficiency of a DNA vaccine 2014 PubMed; Comparative Study TLR3 (Poly(I:C) and TLR7 (Resiquimod) Vaccine adjuvants against tumors expressing the human papilloma virus 16 (HPV-16) E7 protein Combination with HPV-16 E7 DNA vaccine 338 8 The combination of ISCOMATRIX adjuvant and TLR agonists induces regression of established solid tumors in vivo 2015 Scopus; Comparative study w/control TLR3 (Poly(I:C)), TLR9 (CpG) Solid tumors in vivo (B16-OVA melanoma, Panc-OVA pancreatic, and TRAMP-C1 prostate cancer) As adjuvants to ISCOMATRIX vaccines 339 9 TLR agonist augments prophylactic potential of acid inducible antigen Rv3203 against mycobacterium tuberculosis H37Rv in experimental animals 2016 Scopus; Comparative study with control TLR2/6 (zymosan) Mycobacterium tuberculosis With Rv3203 (a cell wall associated protein with lipolytic activity) 348 10 Encapsulation of two different TLR ligands into liposomes confer protective immunity and prevent tumor development 2017 Scopus; Comparative study w/control TLR3 (poly(I:C)), and/or TLR9 (CpG ODN) Cancer vaccine Immunoadjuvants with protein antigen in a liposomal carrier system 340 11 Phase Ib trial of the toll-like receptor 8 agonist, Motolimod (VTX-2337), Combined with Cetuximab in patients with recurrent or metastatic SCCHN 2017 PubMed; Clinical Trial Phase Ib TLR8 (Motolimod) Recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) Combination with cetuximab 349 12 Effect of TLR ligands co-encapsulated with multiepitopic antigen in nanoliposomes targeted to human DCs via Fc receptor for cancer vaccines 2017 Scopus; Comparative study with control TLRR7/8 (R848), TLR3 (Poly(I:C)), TLR4 (LPS), and TLR2 (PAM3CSK4) Cancer vaccines: androgen-responsive prostate cancer Adjuvants of peptide-based liposome vaccine 333 13 Combination immunotherapy with TLR agonists and checkpoint inhibitors suppresses head and neck cancer 2017 Scopus; Comparative study with control TLR7 (1V270), TLR9 (SD-101/CpG ODN) Recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) In combination with checkpoint inhibitors with anti-PD-1 346 14 Co-delivery of nucleoside-modified mRNA and TLR agonists for cancer immunotherapy: Restoring the immunogenicity of immunosilent mRNA 2017 Scopus; Comparative study with control TLR4 (MPLA) Therapeutic cancer mRNA vaccination In combination with nucleoside-modified mRNA 350 15 Combination therapy with proteasome inhibitors and TLR agonists enhances tumour cell death and IL-1β production article/96/21 2018 Scopus; Comparative study with control TLR5 (flagellin), TLR7/8 (R848), TLR1/2 (Pam3CSK4), TLR9 (CpG ODN), or TLR4 (MPLA) Haematological malignancies (myeloid tumour cells); anti-tumor activity Combination with proteasome inhibitor (bortezomib) 347 16 A multipeptide vaccine plus toll-like receptor agonists LPS or polyICLC in combination with incomplete Freund’s adjuvant in melanoma patients 2019 PubMed; Clinical Trial TLR3 (polyICLC) or TLR4 (LPS) Peptide vaccine adjuvants for resected stage IIB-IV melanoma A mixture of 12 short melanoma peptides (12MP) + a tetanus helper peptide + TLR agonists +/- treatment arms with IFA. 334 17 Immune adjuvant therapy using Bacillus Calmette-Guérin cell wall skeleton (BCG-CWS) in advanced malignancies: A phase 1 study of safety and immunogenicity assessments 2019 PubMed; Clinical Trial Phase I TLR2/4 and CLRs ligand (BCG cell wall skeleton (BCG-CWS)) Advanced WT1-expressing cancers refractory to standard anticancer therapies Combination with WT1 peptide 351 18 TLR agonist rHP-NAP as an adjuvant of dendritic cell-based vaccine to enhance anti-melanoma response 2020 Scopus; Comparative study with control TLR agonist (Recombinant HP-NAP (rHP-NAP)) and TLR4 (LPS) An adjuvant of DC-based vaccine in anti-melanoma treatment. As an adjuvant of a vaccine 352 19 Induction of immune response against metastatic tumors via vaccination of Mannan-BAM, TLR ligands, and anti-CD40 antibody (MBTA) 2020 Scopus; Comparative study TLR7/8 (R848), TLR3 (poly(I:C)), and TLR2 (LTA) Metastatic tumors (colon carcinoma model) MBTA therapy with irradiated whole tumor cells 341 20 Potential of TLR agonist as an adjuvant in Leishmania vaccine against visceral leishmaniasis in BALB/c mice 2021 Scopus; Comparative study with control TLR7 (Gardiquimod) Visceral leishmaniasis Used as an adjuvant in Leishmania vaccine (heat-killed antigen) 353 21 Combinatorial delivery of antigen and TLR agonists via PLGA nanoparticles modulates Leishmania major-infected-macrophages activation 2021 Scopus; Comparative study TLR1/2 (Pam3CSK4) and TLR7/8 (R848) Leishmania major-infected-macrophages Combinatorial delivery of antigen and TLR agonists via PLGA nanoparticles 354 22 Enhanced humoral immune response by high density TLR agonist presentation on hyperbranched polymers 2021 Scopus; Comparative study TLR7/8 (R848) Humoral immunity TLR7/8 agonists are covalently attached to highly dense end-groups of hyperbranched polymers 355 23 Phase I/II trial of a long peptide vaccine (LPV7) plus toll-like receptor (TLR) agonists with or without incomplete Freund’s adjuvant (IFA) for resected high-risk melanoma 2021 Scopus; Clinical Trial: Phase I/II TLR3 (polyICLC) and/or TLR7/8 (R848) Resected high-risk melanoma Adjuvant to long peptide vaccine (with/without combinations of IFA) 342 24 Mannan-BAM, TLR ligands, and anti-CD40 immunotherapy in established murine pancreatic adenocarcinoma: understanding therapeutic potentials and limitations 2021 Scopus; Comparative study with control TLR7/8 (R848), TLR3(poly(I:C)) and TLR2/6 (lipoteichoic acid (LTA)) Subcutaneous pancreatic adenocarcinoma (Panc02) tumors Mannan-BAM, R-848, poly(I:C), and LTA together with anti-CD40 antibody (called MBTA therapy) 343 25 TLR ligand loaded exosome mediated immunotherapy of established mammary tumor in mice 2021 Scopus; Comparative study TLR9 (K-type CpG ODN) and TLR3 (poly(I:C)) Tumor-derived exosomes (TEXs) as immunotherapeutic cancer vaccines Loaded in Tumor-derived exosomes (4T1/Her2 cell-derived exosomes) 344 Open in new tab 6 Conclusions While it was largely thought that all inflammatory responses were similar, increasing evidence suggests that metabolic reprogramming of macrophages is ligand/pathogen specific and may serve to fine-tune specific antimicrobial responses. This is important given that most PRRs activate the same families of transcription factors but need to induce distinct inflammatory and antiviral responses. This reprogramming contributes to fine-tuning by providing the required biosynthetic and bioenergetic precursors but also by regulating gene transcription, epigenetics, and signaling cascades.13–15,134,142 To target these processes to treat viral infections and/or optimize immune responses, we need a detailed understanding of the specific metabolic features of these diverse responses. Authorship DA and EC outlined the manuscript. DA, MD, and EC wrote, edited, and revised the manuscript. DA designed and prepared the figures with the assistance of EC. MD put together the table. Acknowledgments The figures in this article are created with BioRender.com. Funding Funding provided by a research development grant provide by Carleton and an NSERC Discovery grant. References 1 Fritsch SD , Weichhart T. 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Mol Ther . 2020 : 28 ( 6 ): 1417 – 1421 . https://doi.org/10.1016/j.ymthe.2020.03.014 Google Scholar OpenURL Placeholder Text WorldCat Abbreviations 25-HC 25-hydroxycholesterol 2-DG 2-deoxyglucose ACLY ATP-citrate lyase AHR Aryl hydrocarbon receptor AIM Absent in melanoma ALR AIM-like receptors AMPK AMP-activated protein kinase AP-1 Activator protein 1 ARG2 Arginase 2 ASC Apoptosis-associated speck-like protein containing a CARD ASS1 Argininosuccinate synthetase BCAA Branched-chain amino acid BCAT1 Branched-chain aminotransferase 1 BMM Mouse Bone marrow-derived macrophages CARD Caspase active recruitment domain cGAMP Cyclic GMP-AMP cGAS Cyclic GMP-AMP synthase CH25H Cholesterol 25-hydroxylase CPT1A Carnitine palmitoyltransferase I DAI DNA-dependent activator of IFN-regulatory factors DAMP Damage/Danger-associated molecular pattern DC Dendritic cell DDAH2 Dimethylarginine dimethylaminohydrolase 2 DDX3 DEAD-box polypeptide 3 DENV Dengue virus DHCR24 3β-hydroxysterol Δ24-reductase DRP1 Dynamin-related protein 1 EBV Epstein-Barr virus ER Endoplasmic reticulum ETC Electron transport chain FA Fatty acid FAO Fatty acid oxidation FASN Fatty acid synthase GABA γ-aminobutyric acid GAPDH Glyceraldehyde 3-phosphate dehydrogenase GAS IFN-γ-associated sites gDNA Genomic DNA GLS Glutaminase GLUT Glucose transporter GPS Glycerol 3-phosphate shuttle GPX Glutathione peroxidase GSH Glutathione HBV Hepatitis B virus HCMV Human cytomegaloviruses HCV Hepatitis C virus HDAC Histone deacetylase 6 HIF-1α Hypoxic-inducible factor 1α HIN200 Hematopoietic IFN-inducible nuclear domains contain 200-amino acid repeat domain HIV Human immunodeficiency virus HK2 Hexokinase 2 HMGCR 3-hydroxy-3-methyl glutaryl coenzyme A reductase HMOX Heme oxygenase HSV Herpes Simplex Virus IAV Influenza A virus IDH Isocitrate dehydrogenase IDO Indoleamine 2,3-dioxygenase IFN Interferon IFNAR IFN-α receptor IKK Inhibitor of NF-κB kinase IL Interleukin iNOS Inducible nitric oxide synthase IRAK IL-1 receptor-associated kinase IRF Interferon regulatory factor IRG1 Immunoresponsive gene 1 ISG Interferon stimulating genes ISGF3 IFN-stimulated gene factor 3 ISRE IFN-stimulated responsive elements IκB Inhibitor of NF-Κb JAK Janus activated kinase LDH Lactate dehydrogenase LPS Lipopolysaccharide LXR Liver X receptor MAVS Mitochondrial antiviral signaling protein MAM Mitochondria-associated ER membrane MCJ Methylation-controlled J protein MDA5 Melanoma differentiation-associated protein 5 MEF Mouse embryonic fibroblasts MFN Mitofusin MMP Mitochondrial membrane potential MPLA Monophosphoryl lipid A mtDNA Mitochondrial DNA mTOR Mechanistic target of rapamycin mtROS Mitochondrial ROS NADH Nicotinamide adenine dinucleotide NADPH Nicotinamide adenine dinucleotide phosphate NF-κB Nuclear factor of kappa light polypeptide gene enhancer in B-cells NLR NOD-like receptor NLRP3 NLR family pyrin domain containing 3 NO Nitric Oxide NOX NADPH oxidase NQO1 NADPH quinone dehydrogenase 1 NRF2 NF-E2–related factor 2 ODN Oligodeoxynucleotides O-GlcNAc O-linked β-N-acetylglucosamine OGT O-GlcNAc transferase OPA1 Optic atrophy 1 OV Oncolytic virus OXPHOS Oxidative phosphorylation PAMP Pathogen-associated molecular pattern PBMC Peripheral blood mononuclear cells PDH Pyruvate dehydrogenase PDK Pyruvate dehydrogenase kinase PFKFB3 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase PHD Prolyl hydroxylase PHGDH Phosphoglycerate dehydrogenase PI3K Phosphoinositide 3-kinase PKM2 Pyruvate kinase, muscle isozyme 2 Poly(I:C)/PIC Polyinosinic:polycytidylic acid PPP Pentose phosphate pathway PRDX Peroxiredoxin 1 PRR Pathogen recognition receptor RET Reverse electron transport RIG-I Retinoic acid-inducible gene I RIPK1 Receptor-interacting serine/threonine-protein kinase 1 RLR RIG-I-like receptor RNA Pol III RNA polymerase III ROS Reactive oxygen species SAM S-adenosylmethionine SDH Succinate dehydrogenase SIRT Sirtuin SOD Superoxide dismutase SPHK2 Sphingosine kinase 2 SREBP Sterol regulatory element-binding protein STAT Signal transducer and activator of transcription STING Stimulator of type I IFN genes TAG Triglyceride TBK1 TANK-binding kinase 1 TGF-β Transforming growth factor-β TIR Toll/Interleukin-1 receptor TLR Toll-like receptor TNF Tumour necrosis factor TRAF6 TNF receptor-associated factor 6 TRIF TIR-domain-containing adapter-inducing interferon-β TYK2 Tyrosine kinase 2 UCP Uncoupling protein UDP Uridine diphosphate VACV Vaccinia virus α-KG α-ketoglutarate Author notes Conflict of interest The authors declare that they have no conflicts of interest. © The Author(s) 2023. 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TI - Innate sensing and cellular metabolism: role in fine tuning antiviral immune responses
JF - Journal of Leukocyte Biology
DO - 10.1093/jleuko/qiac011
DA - 2023-01-16
UR - https://www.deepdyve.com/lp/oxford-university-press/innate-sensing-and-cellular-metabolism-role-in-fine-tuning-antiviral-0BEHtXGsbc
SP - 1
EP - 1
VL - Advance Article
IS - 
DP - DeepDyve
ER -