bims-imicid 2021-10-31 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2021–10–31
nineteen papers selected by
Dylan Ryan, University of Cambridge

Fueling T-cell Antitumor Immunity: Amino Acid Metabolism Revisited.
Mitochondrial Metabolism in Macrophages.
Metabolic regulation of RA macrophages is distinct from RA fibroblasts and blockade of glycolysis alleviates inflammatory phenotype in both cell types.
Multilayer omics analysis reveals a non-classical retinoic acid signaling axis that regulates hematopoietic stem cell identity.
Impact of intracellular innate immune receptors on immunometabolism.
Metabolic Rewiring in the Tumor Microenvironment to Support Immunotherapy: A Focus on Neutrophils, Polymorphonuclear Myeloid-Derived Suppressor Cells and Natural Killer Cells.
Macrophage polarization state affects lipid composition and the channelling of exogenous fatty acids into endogenous lipid pools.
Lactate Alters Metabolism in Human Macrophages and Improves Their Ability to Kill Mycobacterium tuberculosis.
β2-adrenergic receptor signaling regulates metabolic pathways critical to myeloid-derived suppressor cell function within the TME.
6-Phosphogluconate dehydrogenase (6PGD), a key checkpoint in reprogramming of regulatory T cells metabolism and function.
Emerging roles of peroxisomes in viral infections.
Mitochondrial metabolism coordinates stage-specific repair processes in macrophages during wound healing.
Chromatin accessibility analysis identifies the transcription factor ETV5 as a suppressor of adipose tissue macrophage activation in obesity.
Parasitic nematode fatty acid- and retinol-binding proteins compromise host immunity by interfering with host lipid signaling pathways.
Aconitate decarboxylase 1 suppresses cerebral ischemia-reperfusion injury in mice.
Glutamate metabolism directs energetic trade-offs to shape host-pathogen susceptibility in Drosophila.
Genome-scale metabolic modeling reveals SARS-CoV-2-induced metabolic changes and antiviral targets.
Rapamycin recruits SIRT2 for FKBP12 deacetylation during mTOR activity modulation in innate immunity.
Mitophagy antagonism by ZIKV reveals Ajuba as a regulator of PINK1 signaling, PKR-dependent inflammation, and viral invasion of tissues.

Cancer Immunol Res. 2021 Oct 29.

Fueling T-cell Antitumor Immunity: Amino Acid Metabolism Revisited.

Chenfeng Han, Minmin Ge, Ping-Chih Ho, Lianjun Zhang.

T cells are the key players in eliminating malignant tumors. Adoptive transfer of tumor antigen-specific T cells and immune checkpoint blockade has yielded durable antitumor responses in the clinic, but not all patients respond initially and some that do respond eventually have tumor progression. Thus, new approaches to enhance the utility of immunotherapy are needed. T-cell activation and differentiation status are tightly controlled at the transcriptional, epigenetic, and metabolic levels. Amino acids are involved in multiple steps of T-cell antitumor immunity, including T-cell activation, proliferation, effector function, memory formation as well as functional exhaustion. In this review, we briefly discuss how amino acid metabolism is linked to T-cell fate decisions and summarize how amino acid deprivation or accumulation of certain amino acid metabolites within the tumor microenvironment diminishes T-cell functionality. Furthermore, we discuss potential strategies for immunotherapy via modulating amino acid metabolism either in T cells intrinsically or extrinsically to achieve therapeutic efficacy.

DOI: https://doi.org/10.1158/2326-6066.CIR-21-0459
Am J Physiol Cell Physiol. 2021 Oct 27.

Mitochondrial Metabolism in Macrophages.

Mohamed Zakaria Nassef, Jasmin E Hanke, Karsten Hiller.

  Mitochondria are considered to be the powerhouse of the cell. Normal functioning of the mitochondria is not only essential for cellular energy production but also for several immunomodulatory processes. Macrophages operate in metabolic niches and rely on rapid adaptation to specific metabolic conditions such as hypoxia, nutrient limitations or reactive oxygen species to neutralize pathogens. In this regard, the fast reprogramming of mitochondrial metabolism is indispensable to provide the cells with the necessary energy and intermediates to efficiently mount the inflammatory response. Moreover, mitochondria act as a physical scaffold for several proteins involved in immune signaling cascades and their dysfunction is immediately associated with a dampened immune response. In this review, we put special focus on mitochondrial function in macrophages and highlight how mitochondrial metabolism is involved in macrophage activation.

Keywords:  Itaconic acid; Macrophages; Metabolism; Mitochondira

DOI:  https://doi.org/10.1152/ajpcell.00126.2021
Cell Mol Life Sci. 2021 Oct 27.

Metabolic regulation of RA macrophages is distinct from RA fibroblasts and blockade of glycolysis alleviates inflammatory phenotype in both cell types.

Sadiq Umar, Karol Palasiewicz, Michael V Volin, Bianca Romay, Rani Rahat, Chandana Tetali, Shiva Arami, Monica Guma, Christian Ascoli, Nadera Sweiss, Ryan K Zomorrodi, Luke A J O'Neill, Shiva Shahrara.

  Recent studies have shown the significance of metabolic reprogramming in immune and stromal cell function. Yet, the metabolic reconfiguration of RA macrophages (MΦs) is incompletely understood during active disease and in crosstalk with other cell types in experimental arthritis. This study elucidates a distinct regulation of glycolysis and oxidative phosphorylation in RA MΦs compared to fibroblast (FLS), although PPP (Pentose Phosphate pathway) is similarly reconfigured in both cell types. 2-DG treatment showed a more robust impact on impairing the RA M1 MΦ-mediated inflammatory phenotype than IACS-010759 (IACS, complexli), by reversing ERK, AKT and STAT1 signaling, IRF8/3 transcription and CCL2 or CCL5 secretion. This broader inhibitory effect of 2-DG therapy on RA M1 MΦs was linked to dysregulation of glycolysis (GLUT1, PFKFB3, LDHA, lactate) and oxidative PPP (NADP conversion to NADPH), while both compounds were ineffective on oxidative phosphorylation. Distinctly, in RA FLS, 2-DG and IACS therapies constrained LPS/IFNγ-induced AKT and JNK signaling, IRF5/7 and fibrokine expression. Disruption of RA FLS metabolic rewiring by 2-DG or IACS therapy was accompanied by a reduction of glycolysis (HIF1α, PFKFB3) and suppression of citrate or succinate buildup. We found that 2-DG therapy mitigated CIA pathology by intercepting joint F480+iNOS+MΦ, Vimentin+ fibroblast and CD3+T cell trafficking along with downregulation of IRFs and glycolytic intermediates. Surprisingly, IACS treatment was inconsequential on CIA swelling, cell infiltration, M1 and Th1/Th17 cytokines (IFN-γ/IL-17) and joint glycolytic mediators. Collectively, our results indicate that blockade of glycolysis is more effective than inhibition of complex 1 in CIA, in part due to its effectiveness on the MΦ inflammatory phenotype.

Keywords:  Glycolysis; Mitochondrial oxidative phosphorylation and CIA; RA FLS; RA macrophages

DOI:  https://doi.org/10.1007/s00018-021-03978-5
Cell Stem Cell. 2021 Oct 20. pii: S1934-5909(21)00414-8. [Epub ahead of print]

Multilayer omics analysis reveals a non-classical retinoic acid signaling axis that regulates hematopoietic stem cell identity.

Katharina Schönberger, Nadine Obier, Mari Carmen Romero-Mulero, Pierre Cauchy, Julian Mess, Polina V Pavlovich, Yu Wei Zhang, Michael Mitterer, Jasmin Rettkowski, Maria-Eleni Lalioti, Karin Jäcklein, Jonathan D Curtis, Betty Féret, Pia Sommerkamp, Claudia Morganti, Keisuke Ito, Norbert B Ghyselinck, Eirini Trompouki, Joerg M Buescher, Erika L Pearce, Nina Cabezas-Wallscheid.

  Hematopoietic stem cells (HSCs) rely on complex regulatory networks to preserve stemness. Due to the scarcity of HSCs, technical challenges have limited our insights into the interplay between metabolites, transcription, and the epigenome. In this study, we generated low-input metabolomics, transcriptomics, chromatin accessibility, and chromatin immunoprecipitation data , revealing distinct metabolic hubs that are enriched in HSCs and their downstream multipotent progenitors. Mechanistically, we uncover a non-classical retinoic acid (RA) signaling axis that regulates HSC function. We show that HSCs rely on Cyp26b1, an enzyme conventionally considered to limit RA effects in the cell. In contrast to the traditional view, we demonstrate that Cyp26b1 is indispensable for production of the active metabolite 4-oxo-RA. Further, RA receptor beta (Rarb) is required for complete transmission of 4-oxo-RA-mediated signaling to maintain stem cells. Our findings emphasize that a single metabolite controls stem cell fate by instructing epigenetic and transcriptional attributes.

Keywords:  4-oxo-RA; Cyp26b1; Rarb; at-RA; epigenetics; hematopoietic stem cells; metabolites; self-renewal; vitamin A

DOI:  https://doi.org/10.1016/j.stem.2021.10.002
Cell Mol Immunol. 2021 Oct 25.

Impact of intracellular innate immune receptors on immunometabolism.

Wei-Chun Chou, Elena Rampanelli, Xin Li, Jenny P-Y Ting.

  Immunometabolism, which is the metabolic reprogramming of anaerobic glycolysis, oxidative phosphorylation, and metabolite synthesis upon immune cell activation, has gained importance as a regulator of the homeostasis, activation, proliferation, and differentiation of innate and adaptive immune cell subsets that function as key factors in immunity. Metabolic changes in epithelial and other stromal cells in response to different stimulatory signals are also crucial in infection, inflammation, cancer, autoimmune diseases, and metabolic disorders. The crosstalk between the PI3K-AKT-mTOR and LKB1-AMPK signaling pathways is critical for modulating both immune and nonimmune cell metabolism. The bidirectional interaction between immune cells and metabolism is a topic of intense study. Toll-like receptors (TLRs), cytokine receptors, and T and B cell receptors have been shown to activate multiple downstream metabolic pathways. However, how intracellular innate immune sensors/receptors intersect with metabolic pathways is less well understood. The goal of this review is to examine the link between immunometabolism and the functions of several intracellular innate immune sensors or receptors, such as nucleotide-binding and leucine-rich repeat-containing receptors (NLRs, or NOD-like receptors), absent in melanoma 2 (AIM2)-like receptors (ALRs), and the cyclic dinucleotide receptor stimulator of interferon genes (STING). We will focus on recent advances and describe the impact of these intracellular innate immune receptors on multiple metabolic pathways. Whenever appropriate, this review will provide a brief contextual connection to pathogenic infections, autoimmune diseases, cancers, metabolic disorders, and/or inflammatory bowel diseases.

Keywords:  AKT-mTOR; Immunometabolism; NLRP3/AIM2 inflammasomes; NLRs; STING; innate sensors/receptors

DOI:  https://doi.org/10.1038/s41423-021-00780-y
Vaccines (Basel). 2021 Oct 14. pii: 1178. [Epub ahead of print]9(10):

Metabolic Rewiring in the Tumor Microenvironment to Support Immunotherapy: A Focus on Neutrophils, Polymorphonuclear Myeloid-Derived Suppressor Cells and Natural Killer Cells.

Andrea De Lerma Barbaro, Maria Teresa Palano, Martina Cucchiara, Matteo Gallazzi, Lorenzo Mortara, Antonino Bruno.

  Leukocytes often undergo rapid changes in cell phenotype, for example, from a resting to an activated state, which places significant metabolic demands on the cell. These rapid changes in metabolic demand need to be tightly regulated to support immune cell effector functions during the initiation and downregulation of an immune response. Prospects for implementing cancer immunotherapy also rest on the idea of optimizing the metabolic profile of immune cell effectors. Here, we examine this issue by focusing on neutrophils and NK cells as cells of increasing interest in cancer immunology and tumor immunometabolism, because they can be targeted or, in the case of NK, used as effectors in immunotherapy. In addition, neutrophils and NK cells have been shown to functionally interact. In the case of neutrophils, we also extended our interest to polymorphonuclear MDSC (PMN-MDSCs), since the granulocytic subset of MDSCs share many phenotypes and are functionally similar to pro-tumor neutrophils. Finally, we reviewed relevant strategies to target tumor metabolism, focusing on neutrophils and NK cells.

Keywords:  PMN-MDSCs; natural killer cells; neutrophils; tumor metabolism; tumor microenvironment

DOI:  https://doi.org/10.3390/vaccines9101178
J Biol Chem. 2021 Oct 22. pii: S0021-9258(21)01147-9. [Epub ahead of print] 101341

Macrophage polarization state affects lipid composition and the channelling of exogenous fatty acids into endogenous lipid pools.

Pooranee K Morgan, Kevin Huynh, Gerard Pernes, Paula M Miotto, Natalie A Mellett, Corey Giles, Peter J Meikle, Andrew J Murphy, Graeme I Lancaster.

  Adipose tissue-resident macrophages (ATMs) maintain metabolic homeostasis but also contribute to obesity-induced adipose tissue inflammation and metabolic dysfunction. Central to these contrasting effects of ATMs on metabolic homeostasis is the interaction of macrophages with fatty acids. Fatty acid levels are increased within adipose tissue in various pathological and physiological conditions, but appear to initiate inflammatory responses only upon interaction with particular macrophage subsets within obese adipose tissue. The molecular basis underlying these divergent outcomes is likely due to phenotypic differences between ATM subsets, although how macrophage polarization state influences the metabolism of exogenous fatty acids is relatively unknown. Herein, using stable isotope-labelled and non-labelled fatty acids in combination with mass spectrometry lipidomics, we show marked differences in the utilisation of exogenous fatty acids within inflammatory macrophages (M1 macrophaghes) and macrophages involved in tissue homeostasis (M2 macrophages). Specifically, the accumulation of exogenous fatty acids within triacylglycerols and cholesterol esters is significantly higher in M1 macrophages, while there is an increased enrichment of exogenous fatty acids within glycerophospholipids, ether lipids, and sphingolipids in M2 macrophages. Finally, we show that functionally distinct ATM populations in vivo have distinct lipid compositions. Collectively, this study identifies new aspects of the metabolic reprogramming that occur in distinct macrophage polarization states. The channelling of exogenous fatty acids into particular lipid synthetic pathways may contribute to the sensitivity/resistance of macrophage subsets to the inflammatory effects of increased environmental fatty acid levels.

Keywords:  cell metabolism; fatty acid metabolism; macrophage; phospholipid metabolism; sphingolipid

DOI:  https://doi.org/10.1016/j.jbc.2021.101341
Front Immunol. 2021 ;12 663695

Lactate Alters Metabolism in Human Macrophages and Improves Their Ability to Kill Mycobacterium tuberculosis.

Cilian Ó Maoldomhnaigh, Donal J Cox, James J Phelan, Morgane Mitermite, Dearbhla M Murphy, Gina Leisching, Lorraine Thong, Seónadh M O'Leary, Karl M Gogan, Kate McQuaid, Amy M Coleman, Stephen V Gordon, Sharee A Basdeo, Joseph Keane.

  In order to mount an appropriate immune response to infection, the macrophage must alter its metabolism by increasing aerobic glycolysis and concomitantly decreasing oxidative phosphorylation; a process known as the Warburg effect. Consequently, lactate, the end-product of glycolysis, accumulates in the extracellular environment. The subsequent effect of lactate on surrounding macrophages is poorly understood. Mycobacterium tuberculosis (Mtb), the causative organism of Tuberculosis (TB), is phagocytosed by macrophages in the airways. Mtb infected macrophages upregulate aerobic glycolysis and effector functions to try to kill the bacteria. Our lab has previously shown that human macrophages produce lactate in response to infection with Mtb. Although lactate has largely been considered a waste product of aerobic glycolysis, we hypothesised that the presence of extracellular lactate would impact subsequent immunometabolic responses and modulate macrophage function. We demonstrate that the presence of exogenous lactate has an immediate effect on the cellular metabolism of resting human macrophages; causing a decrease in extracellular acidification rate (ECAR; analogous to the rate of glycolysis) and an increase in the oxygen consumption rate (OCR; analogous to oxidative phosphorylation). When lactate-treated macrophages were stimulated with Mtb or LPS, glycolysis proceeds to increase immediately upon stimulation but oxidative phosphorylation remains stable compared with untreated cells that display a decrease in OCR. This resulted in a significantly reduced ECAR/OCR ratio early in response to stimulation. Since altered metabolism is intrinsically linked to macrophage function, we examined the effect of lactate on macrophage cytokine production and ability to kill Mtb. Lactate significantly reduced the concentrations of TNF and IL-1β produced by human macrophages in response to Mtb but did not alter IL-10 and IL-6 production. In addition, lactate significantly improved bacillary clearance in human macrophages infected with Mtb, through a mechanism that is, at least in part, mediated by promoting autophagy. These data indicate that lactate, the product of glycolysis, has a negative feedback effect on macrophages resulting in an attenuated glycolytic shift upon subsequent stimulation and reduced pro-inflammatory cytokine production. Interestingly, this pro-resolution effect of lactate is associated with increased capacity to kill Mtb.

Keywords:  cytokine; glycolysis; human; lactate; macrophage; metabolism; seahorse; tuberculosis

DOI:  https://doi.org/10.3389/fimmu.2021.663695
Cell Rep. 2021 Oct 26. pii: S2211-1247(21)01353-X. [Epub ahead of print]37(4): 109883

β2-adrenergic receptor signaling regulates metabolic pathways critical to myeloid-derived suppressor cell function within the TME.

Hemn Mohammadpour, Cameron R MacDonald, Philip L McCarthy, Scott I Abrams, Elizabeth A Repasky.

  Myeloid-derived suppressor cells (MDSCs) impede antitumor immunity; however, the precise mechanisms that regulate their suppressive function remain unresolved. Identifying these mechanisms could lead to therapeutic interventions to boost cancer immunotherapy efficacy. Here, we reveal that β2 adrenergic receptor (β2-AR) expression on MDSCs increases with tumor growth and that the β2-AR stress pathway drives the immune suppressive activity of MDSCs by altering their metabolism. We show that β2-AR signaling decreases glycolysis and increases oxidative phosphorylation and fatty acid oxidation (FAO). It also increases expression of the fatty acid transporter CPT1A, which is necessary for the FAO-mediated immunosuppressive function of MDSCs. Moreover, we show that β2-AR signaling increases autophagy and activates the arachidonic acid cycle, both required for increasing the release of the immunosuppressive mediator, PGE2. Our data reveal that β2-AR signaling triggered by stress is an important physiological regulator of key metabolic pathways in MDSCs, driving their immunosuppressive function.

Keywords:  MDSCs; autophagy; cancer; fatty acid oxidation; immune suppression; metabolism; oxidative phosphorylation; prostaglandin E2; stress; β-adrenergic signaling

DOI:  https://doi.org/10.1016/j.celrep.2021.109883
Elife. 2021 Oct 28. pii: e67476. [Epub ahead of print]10

6-Phosphogluconate dehydrogenase (6PGD), a key checkpoint in reprogramming of regulatory T cells metabolism and function.

Saeed Daneshmandi, Teresa Cassel, Richard M Higashi, Teresa W-M Fan, Pankaj Seth.

  Cellular metabolism has key roles in T cells differentiation and function. CD4+ T helper-1 (Th1), Th2, and Th17 subsets are highly glycolytic while regulatory T cells (Tregs) use glucose during expansion but rely on fatty acid oxidation for function. Upon uptake, glucose can enter pentose phosphate pathway (PPP) or be used in glycolysis. Here, we showed that blocking 6-phosphogluconate dehydrogenase (6PGD) in the oxidative PPP resulted in substantial reduction of Tregs suppressive function and shifts toward Th1, Th2, and Th17 phenotypes which led to the development of fetal inflammatory disorder in mice model. These in turn improved anti-tumor responses and worsened the outcomes of colitis model. Metabolically, 6PGD blocked Tregs showed improved glycolysis and enhanced non-oxidative PPP to support nucleotide biosynthesis. These results uncover critical role of 6PGD in modulating Tregs plasticity and function, which qualifies it as a novel metabolic checkpoint for immunotherapy applications.

Keywords:  6PGD; cell biology; glucose; immunoregulation; metabolism; mouse; pentose phosphate pathway; regulatory T cell

DOI:  https://doi.org/10.7554/eLife.67476
Trends Cell Biol. 2021 Oct 22. pii: S0962-8924(21)00199-9. [Epub ahead of print]

Emerging roles of peroxisomes in viral infections.

Ana Rita Ferreira, Mariana Marques, Bruno Ramos, Jonathan C Kagan, Daniela Ribeiro.

  Peroxisomes, essential subcellular organelles that fulfill important functions in lipid and reactive oxygen species metabolism, have recently emerged as key players during viral infections. Their importance for the establishment of the cellular antiviral response has been highlighted by numerous reports of specific evasion of peroxisome-dependent signaling by different viruses. Recent data demonstrate that peroxisomes also assume important proviral functions. Here, we review and discuss the recent advances in the study of the diverse roles of peroxisomes during viral infections, from animal to plant viruses, and from basic to translational perspectives. We further discuss the future development of this emerging area and propose that peroxisome-related mechanisms represent a promising target for the development of novel antiviral strategies.

Keywords:  cellular antiviral immunity; cellular metabolism; peroxisomes; viral infections; virus–host interactions

DOI:  https://doi.org/10.1016/j.tcb.2021.09.010
Cell Metab. 2021 Oct 25. pii: S1550-4131(21)00482-4. [Epub ahead of print]

Mitochondrial metabolism coordinates stage-specific repair processes in macrophages during wound healing.

Sebastian Willenborg, David E Sanin, Alexander Jais, Xiaolei Ding, Thomas Ulas, Julian Nüchel, Milica Popović, Thomas MacVicar, Thomas Langer, Joachim L Schultze, Alexander Gerbaulet, Axel Roers, Edward J Pearce, Jens C Brüning, Aleksandra Trifunovic, Sabine A Eming.

  Wound healing is a coordinated process that initially relies on pro-inflammatory macrophages, followed by a pro-resolution function of these cells. Changes in cellular metabolism likely dictate these distinct activities, but the nature of these changes has been unclear. Here, we profiled early- versus late-stage skin wound macrophages in mice at both the transcriptional and functional levels. We found that glycolytic metabolism in the early phase is not sufficient to ensure productive repair. Instead, by combining conditional disruption of the electron transport chain with deletion of tgcqmitochondrial aspartyl-tRNA synthetase, followed by single-cell sequencing analysis, we found that a subpopulation of early-stage wound macrophages are marked by mitochondrial ROS (mtROS) production and HIF1α stabilization, which ultimately drives a pro-angiogenic program essential for timely healing. In contrast, late-phase, pro-resolving wound macrophages are marked by IL-4Rα-mediated mitochondrial respiration and mitohormesis. Collectively, we identify changes in mitochondrial metabolism as a critical control mechanism for macrophage effector functions during wound healing.

Keywords:  metabolism; mitochondria; mitochondrial repurposing; mitohormesis; monocyte/macrophage; tissue repair; type 2 immunity; wound healing

DOI:  https://doi.org/10.1016/j.cmet.2021.10.004
Cell Death Dis. 2021 Oct 29. 12(11): 1023

Chromatin accessibility analysis identifies the transcription factor ETV5 as a suppressor of adipose tissue macrophage activation in obesity.

Ren-Dong Hu, Wen Zhang, Liang Li, Zu-Qi Zuo, Min Ma, Jin-Fen Ma, Ting-Ting Yin, Cai-Yue Gao, Shu-Han Yang, Zhi-Bin Zhao, Zi-Jun Li, Gui-Bin Qiao, Zhe-Xiong Lian, Kun Qu.

Activation of adipose tissue macrophages (ATMs) contributes to chronic inflammation and insulin resistance in obesity. However, the transcriptional regulatory machinery involved in ATM activation during the development of obesity is not fully understood. Here, we profiled the chromatin accessibility of blood monocytes and ATMs from obese and lean mice using assay for transposase-accessible chromatin sequencing (ATAC-seq). We found that monocytes and ATMs from obese and lean mice exhibited distinct chromatin accessibility status. There are distinct regulatory elements that are specifically associated with monocyte or ATM activation in obesity. We also discovered several transcription factors that may regulate monocyte and ATM activation in obese mice, specifically a predicted transcription factor named ETS translocation variant 5 (ETV5). The expression of ETV5 was significantly decreased in ATMs from obese mice and its downregulation was mediated by palmitate stimulation. The decrease in ETV5 expression resulted in macrophage activation. Our results also indicate that ETV5 suppresses endoplasmic reticulum (ER) stress and Il6 expression in macrophages. Our work delineates the changes in chromatin accessibility in monocytes and ATMs during obesity, and identifies ETV5 as a critical transcription factor suppressing ATM activation, suggesting its potential use as a therapeutic target in obesity-related chronic inflammation.

DOI: https://doi.org/10.1038/s41419-021-04308-0
PLoS Pathog. 2021 Oct 29. 17(10): e1010027

Parasitic nematode fatty acid- and retinol-binding proteins compromise host immunity by interfering with host lipid signaling pathways.

Sophia C Parks, Susan Nguyen, Shyon Nasrolahi, Chaitra Bhat, Damian Juncaj, Dihong Lu, Raghavendran Ramaswamy, Harpal Dhillon, Hideji Fujiwara, Anna Buchman, Omar S Akbari, Naoki Yamanaka, Martin J Boulanger, Adler R Dillman.

Parasitic nematodes cause significant morbidity and mortality globally. Excretory/secretory products (ESPs) such as fatty acid- and retinol- binding proteins (FARs) are hypothesized to suppress host immunity during nematode infection, yet little is known about their interactions with host tissues. Leveraging the insect parasitic nematode, Steinernema carpocapsae, we describe here the first in vivo study demonstrating that FARs modulate animal immunity, causing an increase in susceptibility to bacterial co-infection. Moreover, we show that FARs dampen key components of the fly immune response including the phenoloxidase cascade and antimicrobial peptide (AMP) production. Our data also reveal that FARs deplete lipid signaling precursors in vivo as well as bind to these fatty acids in vitro, suggesting that FARs elicit their immunomodulatory effects by altering the availability of lipid signaling molecules necessary for an efficient immune response. Collectively, these data support a complex role for FARs in immunosuppression in animals and provide detailed mechanistic insight into parasitism in phylum Nematoda.

DOI: https://doi.org/10.1371/journal.ppat.1010027
Exp Neurol. 2021 Oct 23. pii: S0014-4886(21)00310-1. [Epub ahead of print] 113902

Aconitate decarboxylase 1 suppresses cerebral ischemia-reperfusion injury in mice.

Thomas M Vigil, Ryan A Frieler, KiAundra L Kilpatrick, Michael M Wang, Richard M Mortensen.

  Immunometabolic changes have been shown to be a key factor in determining the immune cell response in disease models. The immunometabolite, itaconate, is produced by aconitate decarboxylase 1 (Acod1) and has been shown to inhibit inflammatory signaling in macrophages. In this study, we explore the role of Acod1 and itaconate in cerebral ischemia/reperfusion injury. We assessed the effect of global Acod1 knockout (Acod1KO, loss of endogenous itaconate) in a transient ischemia/reperfusion occlusion stroke model. Mice received a transient 90-min middle cerebral artery occlusion followed with 24-h of reperfusion. Stroke lesion volume was measured by MRI analysis and brain tissues were collected for mRNA gene expression analysis. Acod1KO mice showed significant increases in lesion volume compared to control mice, however no differences in pro-inflammatory mRNA levels were observed. Cell specific knockout of Acod1 in myeloid cells (LysM-Cre), microglia cells (CX3CR1, Cre-ERT2) and Endothelial cells (Cdh5(PAC), Cre-ERT2) did not reproduce lesion volume changes seen in global Acod1KO, indicating that circulating myeloid cells, resident microglia and endothelial cell populations are not the primary contributors to the observed phenotype. These effects however do not appear to be driven by changes in inflammatory gene regulation. These data suggests that endogenous Acod1 is protective in cerebral ischemia/reperfusion injury.

Keywords:  Acod1; Immunometabolism; Inflammation; Irg1; Itaconate; Stroke

DOI:  https://doi.org/10.1016/j.expneurol.2021.113902
Cell Metab. 2021 Oct 22. pii: S1550-4131(21)00481-2. [Epub ahead of print]

Glutamate metabolism directs energetic trade-offs to shape host-pathogen susceptibility in Drosophila.

Xiao Zhao, Jason Karpac.

  Individual hosts within populations often show inter-individual variation in their susceptibility to bacterial pathogen-related diseases. Utilizing Drosophila, we highlight that phenotypic variation in host-pathogen susceptibility within populations is driven by energetic trade-offs, facilitated by infection-mediated changes in glutamate metabolism. Furthermore, host-pathogen susceptibility is conditioned by life history, which adjusts immunometabolic sensing in muscles to direct vitamin-dependent reallocation of host energy substrates from the adipose tissue (i.e., a muscle-adipose tissue axis). Life history conditions inter-individual variation in the activation strength of intra-muscular NF-κB signaling. Limited intra-muscular NF-κB signaling activity allows for enhanced infection-mediated mitochondrial biogenesis and function, which stimulates glutamate dehydrogenase-dependent synthesis of glutamate. Muscle-derived glutamate acts as a systemic metabolite to promote lipid mobilization through modulating vitamin B enzymatic cofactor transport and function in the adipose tissue. This energy substrate reallocation improves pathogen clearance and boosts host survival. Finally, life history events that adjust energetic trade-offs can shape inter-individual variation in host-pathogen susceptibility after infection.

Keywords:  Smvt; glutamate; glutamate dehydrogenase; immunometabolism; innate immunity; life history; lipid metabolism; mitochondria; muscle; vitamin

DOI:  https://doi.org/10.1016/j.cmet.2021.10.003
Mol Syst Biol. 2021 Nov;17(11): e10260

Genome-scale metabolic modeling reveals SARS-CoV-2-induced metabolic changes and antiviral targets.

Kuoyuan Cheng, Laura Martin-Sancho, Lipika R Pal, Yuan Pu, Laura Riva, Xin Yin, Sanju Sinha, Nishanth Ulhas Nair, Sumit K Chanda, Eytan Ruppin.

  Tremendous progress has been made to control the COVID-19 pandemic caused by the SARS-CoV-2 virus. However, effective therapeutic options are still rare. Drug repurposing and combination represent practical strategies to address this urgent unmet medical need. Viruses, including coronaviruses, are known to hijack host metabolism to facilitate viral proliferation, making targeting host metabolism a promising antiviral approach. Here, we describe an integrated analysis of 12 published in vitro and human patient gene expression datasets on SARS-CoV-2 infection using genome-scale metabolic modeling (GEM), revealing complicated host metabolism reprogramming during SARS-CoV-2 infection. We next applied the GEM-based metabolic transformation algorithm to predict anti-SARS-CoV-2 targets that counteract the virus-induced metabolic changes. We successfully validated these targets using published drug and genetic screen data and by performing an siRNA assay in Caco-2 cells. Further generating and analyzing RNA-sequencing data of remdesivir-treated Vero E6 cell samples, we predicted metabolic targets acting in combination with remdesivir, an approved anti-SARS-CoV-2 drug. Our study provides clinical data-supported candidate anti-SARS-CoV-2 targets for future evaluation, demonstrating host metabolism targeting as a promising antiviral strategy.

Keywords:  RNAi screen; SARS-CoV-2; antiviral target; genome-scale metabolic modeling; remdesivir

DOI:  https://doi.org/10.15252/msb.202110260
iScience. 2021 Nov 19. 24(11): 103177

Rapamycin recruits SIRT2 for FKBP12 deacetylation during mTOR activity modulation in innate immunity.

Lin Hu, Fuxian Chen, Chao Wu, Jun Wang, Si-Si Chen, Xiang-Rong Li, Jing Wang, Linpeng Wu, Jian-Ping Ding, Jian-Chuan Wang, Chao Huang, Hui Zheng, Yu Rao, Yu Sun, Zhijie Chang, Wei Deng, Cheng Luo, Y Eugene Chin.

  The mammalian target of rapamycin (mTOR) is a serine-threonine kinase involved in cellular innate immunity, metabolism, and senescence. FK506-binding protein 12 (FKBP12) inhibits mTOR kinase activity via direct association. The FKBP12-mTOR association can be strengthened by the immunosuppressant rapamycin, but the underlying mechanism remains elusive. We show here that the FKBP12-mTOR association is tightly regulated by an acetylation-deacetylation cycle. FKBP12 is acetylated on the lysine cluster (K45/K48/K53) by CREB-binding protein (CBP) in mammalian cells in response to nutrient treatment. Acetyl-FKBP12 associates with CBP acetylated Rheb. Rapamycin recruits SIRT2 with a high affinity for FKBP12 association and deacetylation. SIRT2-deacetylated FKBP12 then switches its association from Rheb to mTOR. Nutrient-activated mTOR phosphorylates IRF3S386 for the antiviral response. In contrast, rapamycin strengthening FKBP12-mTOR association blocks mTOR antiviral activity by recruiting SIRT2 to deacetylate FKBP12. Hence, on/off mTOR activity in response to environmental nutrients relies on FKBP12 acetylation and deacetylation status in mammalian cells.

Keywords:  Biochemistry; Molecular biology; Protein

DOI:  https://doi.org/10.1016/j.isci.2021.103177
Cell Rep. 2021 Oct 26. pii: S2211-1247(21)01358-9. [Epub ahead of print]37(4): 109888

Mitophagy antagonism by ZIKV reveals Ajuba as a regulator of PINK1 signaling, PKR-dependent inflammation, and viral invasion of tissues.

Sanket S Ponia, Shelly J Robertson, Kristin L McNally, Gayatri Subramanian, Gail L Sturdevant, Matthew Lewis, Forrest Jessop, Catherine Kendall, Dylan Gallegos, Arielle Hay, Cindi Schwartz, Rebecca Rosenke, Greg Saturday, Catherine M Bosio, Craig Martens, Sonja M Best.

  Dysregulated inflammation dominated by chemokine expression is a key feature of disease following infection with the globally important human pathogens Zika virus (ZIKV) and dengue virus, but a mechanistic understanding of how pro-inflammatory responses are initiated is lacking. Mitophagy is a quality-control mechanism that regulates innate immune signaling and cytokine production through selective degradation of damaged mitochondria. Here, we demonstrate that ZIKV nonstructural protein 5 (NS5) antagonizes mitophagy by binding to the host protein Ajuba and preventing its translocation to depolarized mitochondria where it is required for PINK1 activation and downstream signaling. Consequent mitophagy suppression amplifies the production of pro-inflammatory chemokines through protein kinase R (PKR) sensing of mitochondrial RNA. In Ajuba-/- mice, ZIKV induces early expression of pro-inflammatory chemokines associated with significantly enhanced dissemination to tissues. This work identifies Ajuba as a critical regulator of mitophagy and demonstrates a role for mitophagy in limiting systemic inflammation following infection by globally important human viruses.

Keywords:  PINK1; PKR; Parkin; Zika virus; chemokines; flavivirus; mitochondria; mitophagy; mtRNA; pathogenesis

DOI:  https://doi.org/10.1016/j.celrep.2021.109888