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• W2950567243 abstract "Review21 June 2019free access Central metabolic interactions of immune cells and microbes: prospects for defeating infections Ana Traven Corresponding Author [email protected] orcid.org/0000-0001-6252-3104 Infection and Immunity Program and the Department of Biochemistry & Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Vic., Australia Search for more papers by this author Thomas Naderer Corresponding Author [email protected] orcid.org/0000-0003-2691-0283 Infection and Immunity Program and the Department of Biochemistry & Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Vic., Australia Search for more papers by this author Ana Traven Corresponding Author [email protected] orcid.org/0000-0001-6252-3104 Infection and Immunity Program and the Department of Biochemistry & Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Vic., Australia Search for more papers by this author Thomas Naderer Corresponding Author [email protected] orcid.org/0000-0003-2691-0283 Infection and Immunity Program and the Department of Biochemistry & Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Vic., Australia Search for more papers by this author Author Information Ana Traven *,1 and Thomas Naderer *,1 1Infection and Immunity Program and the Department of Biochemistry & Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Vic., Australia *Corresponding author. Tel: +61 3 99029219; E-mail: [email protected] *Corresponding author. Tel: +61 3 9902 9517; E-mail: [email protected] EMBO Rep (2019)20:e47995https://doi.org/10.15252/embr.201947995 See the Glossary for abbreviations used in this article. PDFDownload PDF of article text and main figures.AM PDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract Antimicrobial drug resistance is threatening to take us to the “pre-antibiotic era”, where people are dying from preventable and treatable diseases and the risk of hospital-associated infections compromises the success of surgery and cancer treatments. Development of new antibiotics is slow, and alternative approaches to control infections have emerged based on insights into metabolic pathways in host–microbe interactions. Central carbon metabolism of immune cells is pivotal in mounting an effective response to invading pathogens, not only to meet energy requirements, but to directly activate antimicrobial responses. Microbes are not passive players here—they remodel their metabolism to survive and grow in host environments. Sometimes, microbes might even benefit from the metabolic reprogramming of immune cells, and pathogens such as Candida albicans, Salmonella Typhimurium and Staphylococcus aureus can compete with activated host cells for sugars that are needed for essential metabolic pathways linked to inflammatory processes. Here, we discuss how metabolic interactions between innate immune cells and microbes determine their survival during infection, and ways in which metabolism could be manipulated as a therapeutic strategy. Glossary AA amino acids ADP adenosine diphosphate ATP adenosine triphosphate BCG bacillus Calmette–Guérin (vaccine) cGAS GMP-AMP synthase CoA coenzyme A ER endoplasmatic reticulum ETC electron transport chain FA fatty acids GABA γ-aminobutyric acid GAL4 galactose-induced gene 4 GFP green fluorescent protein GlcN glucosamine HDACi histone deacetylase inhibitors HIF hypoxia-inducible factor ICD isocitrate dehydrogenase ICL isocitrate lyase IDH isocitrate dehydrogenase IDO indoleamine 2,3-dioxygenase IFN interferon IL interleukin IRF interferon regulatory factor IRG immune-responsive gene KDM lysine-specific demethylase LPS lipopolysaccharide MPLA monophosphoryl lipid A mROS mitochondrial reactive oxygen species MS malate synthase mTOR mechanistic target of rapamycin NAD nicotinamide adenine dinucleotide NADPH nicotinamide adenine dinucleotide phosphate NLRP NACHT, LRR and PYD domain-containing protein NMN nicotinamide mononucleotide NO nitric oxide NOS nitric oxide synthase Nrf2 nuclear factor erythroid 2-related factor 2 OXPHOS oxidative phosphorylation PARP poly(ADP-ribose) polymerase PBMCs peripheral blood mononuclear cells PFK phosphofructokinase PPAR peroxisome proliferator-activated receptors PYK pyruvate kinase QPRT quinolinate phosphoribosyltransferase ROS reactive oxygen species SDH succinate dehydrogenase SIRT sirtuin (silent mating type information regulation 2 homolog) STING stimulator of interferon genes TCA cycle tricarboxylic acid cycle TF transcription factor TLR Toll-like receptor UDP-GlcNAc uridine diphosphate N-acetyl glucosamine Challenges in treating infectious diseases The discovery of antibiotics in the 20th century is often heralded as one of the major, if not the biggest medical breakthrough in history. Antibiotics save lives from common infections and support medical interventions that require invasive and immunosuppressive approaches, such as surgery, organ and stem cell transplantation and cancer chemotherapy. Unfortunately, less than a 100 years later, we are again in a crisis situation 1. We have overused and misused antibiotics and antifungals not only to treat humans, but also to support food production of animals and plants for our ever-increasing population. Microbes can rapidly increase cell populations and possess adaptive mechanisms, such as genome rearrangements that promote drug resistance 2 and the appearance of so-called “mutator” strains 3, 4. This means that the evolution of antimicrobial drug resistance can be fast in all classes of pathogens (bacteria, fungi and parasites) 1, 5-7. Development of new antimicrobial drugs has not been particularly successful, and pharmaceutical companies are pulling out from developing new antimicrobial agents because of reduced profit margins. A 2016 review sponsored by the UK Department of Health and the Wellcome Trust suggested that in the next three decades, deaths from drug-resistant infections could be 10 million per year and thereby surpass deaths from cancer 8. While this assertion has been disputed 9, it is nevertheless clear that the threat from infectious diseases is not decreasing, but rather it is increasing. This is not just a problem of the developing world, but concerns all countries where opportunistic infections threaten many procedures of modern medicine, which we take for granted, and which make us feel that we can conquer any disease. Given that developing new antibiotics is challenging, we need to consider diverse facets of the host–microbe interface, to hopefully develop a range of complementary strategies to manipulate this interaction to benefit the host at the expense of the pathogen. Developing alternative strategies to manage infections critically depends on understanding both sides of the host–microbe interaction. Antimicrobial immunity on the one hand, and immune evasion by microbes on the other, rely on appropriate regulation of transcriptional and signalling networks. These are in turn driven by chemical and physical principles and interactions. Therefore, not surprisingly, it has transpired that host–pathogen interactions are fundamentally regulated by an interplay between host and microbial metabolic pathways and the levels of metabolites in infection microenvironments. Humans face microbes not only in infection but, as is true for any other multicellular organism, they have evolved to coexist commensally with bacteria, fungi or parasites. This is likely to have shaped the metabolic adaptations of host and microbes alike. Commensal microbes generate nutrients essential to maintain human health, but also deplete nutrients to suppress growth of pathogenic microbes. Microbial metabolites also control immunity, by being sensed and metabolised by immune cells. Despite these beneficial interactions with microbiota, commensals and also bona fide pathogens can cause bacteraemia, fungaemia, sepsis, organ failure and mortality. Therefore, a functional epithelial layer and immunity are critically important for maintaining the commensal state of microbiota and defending us from infections. As we will review here, recent advances gave birth to a field of research commonly referred to as “immunometabolism”, which aims to understand how responses of innate immune phagocytes are shaped by cellular metabolism, metabolites and available nutrients. The metabolic adaptations are particularly evident in innate immune cells as they rapidly respond to changing environments, but metabolism also controls responses to infections in T cells and epithelial cells 10. As a counterpart to immunometabolism, microbes reshape their metabolic pathways to match host environments, and could also be employing metabolic tactics to counter immune attack by competing with immune cells for nutrients that are essential for effective antimicrobial responses. Here, we discuss what is known about the reprogramming of host and pathogen metabolic pathways in infection, the plasticity (or otherwise) of host and pathogen metabolism, and how the metabolic interplay controls the host–pathogen interaction. We will focus predominantly on macrophages, as they have been studied extensively in the context of microbial interactions, but several of the mechanisms are also relevant to other immune and non-immune cell types. Finally, we will assess the potential of nutritional approaches and metabolic manipulations in aiding anti-infective therapy. Metabolism of macrophages Macrophages come in different forms reflecting their diverse roles during infections, inflammation, wound repair and tissue homeostasis. While each macrophage is likely able to fulfil many, if not all, of these roles, tissue-resident and recruited macrophages, as well as blood monocytes and neutrophils that accumulate at sites of infection and sterile inflammation, employ distinct immune responses. Macrophage responses may also differ within the same cell population due to concentration gradients of cytokines and pathogens, as well as between different innate immune cells, as all tissue-resident macrophages likely originate from yolk sac and foetal liver progenitor cells, and are thus distinct from monocyte differentiated macrophages that originate from bone haematopoietic stem cells 11-14. The former population is believed to be long-lived and self-renewing, suggesting different metabolic capabilities. The surrounding tissue cells are also important for macrophage development and function 15. The inflammatory milieu and microbial products further drive the differentiation of macrophages, which impacts their metabolism. For instance, the cytokines IL-4 and IFN-γ have long been used to characterise macrophage populations with distinct functions, which are best characterised by their metabolic state. In general, IL-4 promotes amino acid metabolism via mitochondrial respiration and fatty acid oxidation and upregulates arginase-1 to generate ornithine and urea for polyamine biosynthesis 16. In contrast, IFN-γ-treated mouse macrophages utilise exogenous arginine to generate nitric oxide (NO) radicals via NOS2, thereby inhibiting arginase-1 activity 17. The bacterial cell surface component lipopolysaccharide (LPS) and IFN-γ cause a general reduction in amino acid metabolism due to reduced mitochondrial respiration and the upregulation of catabolic enzymes, such as IDO1 that depletes tryptophan levels. Under these conditions, increased glucose import enhances glycolysis and the pentose phosphate pathway to generate energy (ATP) and oxygen radicals (ROS) via the NADPH oxidase. These metabolic responses promote antimicrobial activities: depletion of tryptophan and the generation of ROS prevent the growth of intracellular microbes, which are dependent on host-derived amino acids and susceptible to ROS. Based on these observations, changes in metabolism were thought to support already committed macrophages to fulfil their diverse functions during infections and tissue homeostasis 17. More recent studies, however, have demonstrated that the metabolic reprogramming that occurs after LPS exposure not only supports, but directly controls and enables immune responses (Fig 1), as inhibition of glycolysis prevents the expression of the pro-inflammatory cytokine IL-1β in primary mouse macrophages 18. This result with LPS was validated with bacterial infection of macrophages with Bordetella pertussis 18. Upregulation of glycolysis in LPS-activated macrophages leads to the secretion of lactate rather than fuelling mitochondrial respiration despite the presence of oxygen 19. This resembles metabolic change in cancer cells and is commonly referred to as Warburg metabolism, which is utilised by rapidly dividing cells or immune cells that need to quickly respond to environmental cues 20. This is in contrast to naïve macrophages, which utilise both glycolysis and mitochondrial metabolism, whereby the latter generates important metabolites for amino acid and fatty acid synthesis, as well as ATP via oxidative phosphorylation (OXPHOS) via the electron transport chain (ETC) 21, 22. Figure 1. Metabolic reprogramming of microbes and macrophages in infectionWhen challenged with stimuli such as the bacterial ligand LPS, IFN-γ, the bacterium M. tuberculosis and the fungus C. albicans, macrophages remodel their metabolism so that glucose import and glycolysis are enhanced, and the TCA cycle is compromised. Increased levels of TCA intermediates citrate and succinate play direct roles in promoting antimicrobial responses. Citrate is a precursor of itaconate, an inhibitor of microbial glyoxylate cycle enzyme isocitrate lyase (ICL) and host succinate dehydrogenase (SDH), while succinate stabilises the transcriptional activator of glucose utilisation genes and antimicrobial cytokines, HIF-1α. Similarly, microbes adapt their metabolism by transcriptionally upregulating the glyoxylate shunt pathway, glycolysis and gluconeogenesis at distinct stages of infection. Reprogramming of microbial metabolism depends on available nutrients, including host-derived lactate and itaconate. Mitochondria and nucleus (labelled orange and blue, respectively) are present in fungi, but not in bacteria. In fungi, the glyoxylate cycle reactions are further compartmentalised in the peroxisome (indicated by yellow shading). Metabolites and enzymes up- and down-regulated during macrophage–microbe interaction are shown in red and purple, respectively. HIF-1α, hypoxia-inducible factor-1α; ICL, isocitrate lyase; ICT/CCL, succinyl-CoA:itaconate CoA transferase/(S)-citramalyl-CoA lyase; IDH, isocitrate dehydrogenase; IRG1, immune-responsive gene 1; MS, malate synthase; SDH, succinate dehydrogenase; TF, transcription factor. Download figure Download PowerPoint After LPS exposure of macrophages, the carbon flux through the TCA cycle is disrupted due to downregulation of isocitrate dehydrogenase (IDH1) and higher levels of the citrate carrier in mitochondria resulting in the accumulation of citrate 21, 23, 24. Increased levels of citrate fuel fatty acid synthesis to generate inflammatory prostaglandins and membrane lipids to promote cytokine secretion 25, 26. In addition, LPS-activated macrophages upregulate immune-responsive gene IRG1, which converts citrate into itaconate 21. Itaconate has antimicrobial effects by inhibiting the microbial glyoxylate shunt that generates essential metabolites for intracellular survival of bacteria and fungi 27. Itaconate also regulates host metabolic and immune responses by inhibiting the TCA enzyme succinate dehydrogenase (SDH), and activating transcription factor Nrf2 to control inflammation 28-32. The increased level of succinate stabilises transcription factor HIF-1α resulting in the upregulation of IL-1β 18, 33, 34. The metabolic changes in inflammatory macrophages, and their consequences for antimicrobial responses, are summarised in Fig 1. Oxidation of succinate via SDH further triggers inflammatory responses via the generation of mitochondrial ROS (mROS), likely due to reverse electron transport. mROS has multiple functions. Firstly, mROS is antimicrobial, delivered by mitochondria that traffic to bacteria-containing phagosomes 35, 36. Secondly, mROS further stabilises HIF-1α, promoting inflammation 33. Thirdly, mROS may activate the NLRP3 inflammasome 37. Finally, excessive mROS may lead to irreversible mitochondria damage resulting in the release of DNA, which can lead to NLRP3 and cGAS/STING-mediated inflammation 38-41. LPS treatment has also recently been shown to cause depletion of NAD+ due to increased activity of NAD-consuming pathways, such poly(ADP-ribose) biosynthesis by PARPs and sirtuins, and downregulation of the NAD biosynthesis gene QPRT, despite upregulation of the initial enzyme IDO1 42. Loss of cellular NAD+ and mitochondrial deacetylase activity of SIRT3 results in the acetylation and inhibition of complex I, thereby reducing oxidative phosphorylation, and triggering increased pro-inflammatory responses in macrophages and mice challenged with LPS 42. We note that many of the studies that we discussed used LPS stimulation as a proxy for bacterial infection, with validation with whole bacteria rarely performed. Nevertheless, challenge of primary mouse macrophages and human peripheral blood mononuclear cells (PBMCs) with the yeast pathogen Candida albicans resulted in similar metabolic changes to those seen with LPS 43, 44. However, differences compared to LPS have been reported in other cases. Specifically, challenge of human monocytes with the synthetic TLR2 receptor ligand Pam3CSK4, or whole-cell lysates prepared from the bacterium Mycobacterium tuberculosis, Staphylococcus aureus or Escherichia coli resulted in upregulation of both glycolysis and mitochondrial oxidative phosphorylation 45. Similarly, both glycolysis and oxidative phosphorylation were increased (while fatty oxidation genes were mostly repressed) in human blood samples from people suffering from bacterial or fungal infection 43. Future experiments using live infections of immune cells with diverse microbial pathogens should broaden our understanding of which metabolic changes in innate immune cells are common, and which are specific to distinct infection agents. In contrast to the situation described above for LPS and IFN-γ, IL-4-mediated transcriptional programmes increase mitochondrial metabolism and respiration in macrophages to promote wound healing mechanisms 17. For instance, inhibiting the reprogramming of mitochondrial respiration prevents anti-inflammatory phenotype and the upregulation of arginase-1, which is required to increase proline levels for collagen synthesis to support the extracellular matrix in wound repair 46, 47. Increased rates of fatty acid oxidation and mitochondrial respiration may directly drive IL-4 activation of macrophages 46, 48, 49. In addition, IL-4 treatment results in increased hexosamine biosynthesis, generating UDP-GlcNAc, which is essential for N-glycosylation of cell surface receptors that are upregulated in these macrophages 21. Hexosamine biosynthesis depends on glucose and glutamine utilisation, and both metabolites are critical to induce the expression of IL-4-dependent genes 21, 48, 50. Besides hexosamine biosynthesis, glucose also feeds into glycolysis, which is upregulated in IL-4-activated macrophages depending on the transcription factor IRF4 48, 50. It is thought that increased glycolysis enables fatty acid biosynthesis, which is upregulated in IL-4-activated macrophages to promote oxidative metabolism. Inhibition of glycolysis and fatty acid biosynthesis prevents the expression of several IL-4-dependent markers 48. However, more recent genetic studies suggest that coenzyme A (CoA) homeostasis, rather than mitochondrial respiration, controls IL-4 activation of macrophages 51. CoA is involved in many cellular processes, ranging from fatty acid synthesis to post translational modification of histones and other proteins. Treatment with IL-4 causes accumulation of acetyl-CoA partly due to citrate cleavage and increased uptake of glucose, glutamine and fatty acids, which are catabolised to acetyl-CoA 50. Increased acetyl-CoA levels promote histone acetylation, mediating IL-4-dependent immune responses and arginase-1 expression 50. IL-4-treated macrophages remain metabolically flexible, as they can utilise fatty acids or glucose to fulfil their roles, likely because IRF4-dependent transcription increases mitochondrial metabolism and glycolysis. As such, IL-4-treated macrophages can be reprogrammed by LPS/IFN-γ to express inflammatory markers 49. In contrast, LPS- and IFN-γ-treated macrophages primarily utilise glucose to fuel metabolic pathways and immune responses, are metabolically inflexible and fail to respond to IL-4 48, 49. Immune cell metabolism in sepsis patients Blood-derived immune cells of sepsis patients that are exposed to circulating LPS and other microbial products provide unique opportunities to study the role of metabolic reprogramming during and after human infections. Transcriptional profiling of blood-derived lymphocytes isolated from sepsis patients with acute hyper-inflammation or LPS-induced experimental endotoxemia showed differential expression of glycolysis and mitochondrial respiration genes, with either up- or downregulation of these pathways detected relative to healthy people depending on the condition 43. Several metabolites are increased in the blood of sepsis patients, including lactate, raising the possibility that the metabolic reprogramming of leucocytes during sepsis contributes to the hyperlactaemia 52. Hyperglycaemia is also strongly associated with severe sepsis, due to insulin resistance and impaired degradation of the insulin receptor 53. Increased blood glucose levels trigger glucose transporter-mediated transcriptional reprogramming of epithelial cells, which causes loss of gut barrier integrity and infections 54. Whether increased blood glucose levels are critical to support inflammatory responses of activated macrophages and monocytes remains unknown. The plasma concentrations of most amino acids are altered in sepsis patients compared to healthy controls and may indicate disease severity 52. For instance, glutamine levels are increased, and may fuel succinate synthesis via the GABA shunt and thus promote inflammatory responses 55. Also, sepsis patients show increased arginine levels that may support NO production via NOS2 in inflammatory macrophages. Compared to survivors, arginine levels were reduced in sepsis patients that failed to recover 55. Similarly, several plasma lipid levels, particularly carnitine esters, are increased in sepsis non-survivors relative to controls, together with decreased expression of fatty acid transporters 56. This likely reflects defects in mitochondrial import of fatty acids, which requires carnitine palmitoyltransferase and reduced rates of β-oxidation. Consistent with this, the expression of peroxisome proliferator-activated receptors (PPAR) α, β and δ, which regulate several aspects of β-oxidation, is reduced in severe sepsis patients 57, 58. Collectively, these data support in vitro observations in LPS-treated macrophages showing that increased glycolysis fuels fatty acid synthesis. Conversely, uptake of fatty acid and their catabolism via oxidation into acetate may further enable the accumulation of citrate and succinate in the TCA cycle to drive inflammatory responses. Of note and as mentioned previously, the reduction of mitochondrial respiration, as occurs in LPS-treated macrophages, is not always observed in sepsis patients 43, 52, possibly reflecting the infection site and/or microbes involved, as in vitro experiments showed that activation with ligands such as Pam3CSK4, E. coli and S. aureus does not induce a reduction of mitochondrial respiration in monocytes 45. Current efforts are aimed at identifying the role of individual metabolites in promoting survival of sepsis patients, and how this knowledge could be applied to manipulate metabolism for treatment. The role of metabolism to control macrophage immune responses, however, has largely been studied in ex vivo immune cells or cell lines treated with defined stimuli in rich culture media. Determining the metabolism of tissue-resident macrophages and monocyte-derived macrophages within infection microenvironments remains technically challenging. It is equally difficult to quantify the levels of key immune-related metabolite levels in these niches. While inflammatory responses are critically important to eliminate microbes during sepsis, excessive inflammation contributes to tissue damage, dissemination and increased mortality. As such, timing of nutrient supplementation during sepsis may be critical. Inflammatory macrophages also secrete cytokines to dampen inflammation, including IL-4 59. Consequently, tissue macrophages may not strictly adhere to an IFN-γ/IL-4 dichotomy, but rather follow a broad spectrum of activation states 60. This warrants further studies to determine the metabolism of other activated macrophages and individual lymphocytes isolated from sepsis patients 45. Immune cell tolerance and paralysis during severe sepsis In severe sepsis patients, macrophages and monocytes often fail to respond appropriately to microbial and inflammatory signals, resulting in an immune tolerant state that can develop into immune paralysis. The absence of a functional innate immune system may lead to increased infection and mortality rates commonly observed in severe sepsis patients. The underlying mechanisms that lead to immune tolerance, however, remain poorly understood. In vitro studies have shown that LPS-treated macrophages fail to respond to subsequent LPS exposure, and this is likely driven by epigenetic modifications of histones and changes to gene transcription. In particular, prolonged LPS exposure of macrophages increases cellular levels of NAD+, and NAD+-dependent sirtuins (SIRT1 and SIRT6) downregulate glycolysis and increase β-oxidation 61. SIRT6 targets HIF-1α promoter sites to decrease acetylation of lysine 9 of histone H3 (H3K9Ac), causing reduced expression of genes encoding glycolytic enzymes 62. NAD+ levels are also increased in immunotolerant monocytes from sepsis patients 43. Here, epigenetic changes at H3K9 similarly correlate with reduced rates of glycolysis in immunotolerant monocytes 43. Tolerant monocytes show reduced mitochondrial and fatty acid metabolism, further compounding their inability to respond to LPS. Nevertheless, immunotolerant monocytes secrete 10-fold more IL-10 compared to LPS-treated control cells 43. IL-10 is thought to contribute to immunotolerance in macrophages by inhibiting glycolysis and inducing the degradation of damaged mitochondria (mitophagy) via mTOR signalling 63. Loss of IL-10 increases inflammation, partly due to activation of the NLRP3 inflammasome mediated by increased glycolysis and mitochondrial ROS 63. IL-10 secretion, as well as defects in metabolism and immune response, is reversed in patients who have recovered from severe sepsis 43. The molecular pathways involved in the resolution of immunotolerance, however, remain to be described. Metabolic aspects of trained immunity Immunotolerance likely acts as a mechanism to dampen excessive inflammation and appears to be chiefly mediated by reducing leucocyte metabolism. In a contrasting scenario, innate immune cells can be reprogrammed to respond to a secondary signal more quickly and vigorously compared to the first time. This suggests that innate immune cells are capable of memory, which is referred to as “innate immune memory” or “trained immunity” 64. Trained immunity is not restricted to a particular stimulus, and it confers cross-protection against diverse infections 65. Similar to macrophages activated by the bacterial cell surface component LPS, the cell wall component from fungal cells, β-glucan, increases macrophage glycolysis and reduces mitochondrial respiration. Inhibiting glycolysis reduces macrophage immune responses to β-glucan, as described for LPS 66. In contrast, however, β-glucan-mediated metabolic reprogramming lasts for weeks and months, whereas LPS activation leads to metabolic dysfunction and immune tolerance within 6 days 66, 67. It is thought that these different metabolic responses are due to changes in the epigenetic state of chromatin and therefore gene expression, including histone acetylation and methylation 66-68. Epigenetic modifications are triggered by cellular metabolites, which in turn enhance the expression of metabolic pathways. For instance, β-glucan is sensed by the cell surface receptor dectin-1 that signals via Akt/mTOR/HIF-1α to induce metabolic reprogramming due changes in the TCA cycle and the accumulation of fumarate 66, 68. Fumarate inhibits the KDM5 demethylase and causes the accumulation of the H3K4 trimethylation mark 69. It also has a further effect on H3K27 acetylation and HIF-1α levels and was associated with increased expression of glycolytic enzymes 69. Epigenetic modifications underpin the long-lasting changes in the metabolism of innate immune cells, as activation of histone deacetylases reduces trained immunity and promotes immunotolerance 66. This is observed in animals and humans, whereby clearance of initial fungal infections or vaccinations induce permanent changes in the cellular metabolism of innate immune cells 64. Activated monocytes are thought to be short-lived" @default.
• W2950567243 created "2019-06-27" @default.
• W2950567243 creator A5017073551 @default.
• W2950567243 creator A5087713515 @default.
• W2950567243 date "2019-06-21" @default.
• W2950567243 modified "2023-10-17" @default.
• W2950567243 title "Central metabolic interactions of immune cells and microbes: prospects for defeating infections" @default.
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