bims-imicid 2024-06-02 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2024‒06‒02
28 papers selected by
Dylan Ryan, University of Cambridge

13C metabolite tracing reveals glutamine and acetate as critical in vivo fuels for CD8 T cells.
CPT2 mediated fatty acid oxidation is dispensable for humoral immunity.
Rapid metabolic regulation of a novel arginine methylation of KCa3.1 attenuates T cell exhaustion.
Targeting metabolism to enhance immunotherapy within tumor microenvironment.
Ablation of Atp5if1 impairs metabolic reprogramming and proliferation of T lymphocytes and compromises mouse survival.
Quercetin induces itaconic acid-mediated M1/M2 alveolar macrophages polarization in respiratory syncytial virus infection.
LncRNA TUG1 mediates microglial inflammatory activation by regulating glucose metabolic reprogramming.
Pro-inflammatory macrophage activation does not require inhibition of mitochondrial respiration.
Multifaceted mitochondria in innate immunity.
Staphylococcus aureus Conquers Host by Hijacking Mitochondria via PFKFB3 in Epithelial Cells.
Gut microbiota-derived butyrate induces epigenetic and metabolic reprogramming in myeloid-derived suppressor cells to alleviate primary biliary cholangitis.
Legumain-deficient macrophages regulate inflammation and lipid metabolism in adipose tissues to protect against diet-induced obesity.
IDO1 promotes CSFV replication by mediating tryptophan metabolism to inhibit NF-κB signaling.
Metabolic Modulation-Mediated Antibiotic and Immune Activation for Treatment of Chronic Lung Infections.
Loss of Bcl-3 regulates macrophage polarization by promoting macrophage glycolysis.
Salmonella Typhimurium expansion in the inflamed murine gut is dependent on aspartate derived from ROS-mediated microbiota lysis.
An IFNγ-dependent immune-endocrine circuit lowers blood glucose to potentiate the innate antiviral immune response.
Impaired tryptophan metabolism by type 2 inflammation in epithelium worsening asthma.
IL-4 Licenses B Cell Activation Through Cholesterol Synthesis.
Islet cell stress induced by insulin-degrading enzyme deficiency promotes regeneration and protection from autoimmune diabetes.
AMPK Drives both Glycolytic and Oxidative Metabolism in Murine and Human T Cells During Graft-versus-host Disease.
FLI1 promotes IFN-γ-induced kynurenine production to impair anti-tumor immunity.
Inflammation causes insulin resistance in mice via interferon regulatory factor 3 (IRF3)-mediated reduction in FAHFA levels.
Hyperglycemia enhances brain susceptibility to lipopolysaccharide-induced neuroinflammation via astrocyte reprogramming.
Glycolysis inhibition induces anti-tumor central memory CD8+T cell differentiation upon combination with microwave ablation therapy.
Metabolic predictors of COVID-19 mortality and severity: a survival analysis.
Caspase-11 drives macrophage hyperinflammation in models of Polg-related mitochondrial disease.
Mycobacterium tuberculosis produces D-serine under hypoxia to limit CD8+ T cell-dependent immunity in mice.

Sci Adv. 2024 May 31. 10(22): eadj1431

13C metabolite tracing reveals glutamine and acetate as critical in vivo fuels for CD8 T cells.

Eric H Ma, Michael S Dahabieh, Lisa M DeCamp, Irem Kaymak, Susan M Kitchen-Goosen, Brandon M Oswald, Joseph Longo, Dominic G Roy, Mark J Verway, Radia M Johnson, Bozena Samborska, Lauren R Duimstra, Catherine A Scullion, Mya Steadman, Matthew Vos, Thomas P Roddy, Connie M Krawczyk, Kelsey S Williams, Ryan D Sheldon, Russell G Jones.

Infusion of 13C-labeled metabolites provides a gold standard for understanding the metabolic processes used by T cells during immune responses in vivo. Through infusion of 13C-labeled metabolites (glucose, glutamine, and acetate) in Listeria monocytogenes-infected mice, we demonstrate that CD8 T effector (Teff) cells use metabolites for specific pathways during specific phases of activation. Highly proliferative early Teff cells in vivo shunt glucose primarily toward nucleotide synthesis and leverage glutamine anaplerosis in the tricarboxylic acid (TCA) cycle to support adenosine triphosphate and de novo pyrimidine synthesis. In addition, early Teff cells rely on glutamic-oxaloacetic transaminase 1 (Got1)-which regulates de novo aspartate synthesis-for effector cell expansion in vivo. CD8 Teff cells change fuel preference over the course of infection, switching from glutamine- to acetate-dependent TCA cycle metabolism late in infection. This study provides insights into the dynamics of Teff metabolism, illuminating distinct pathways of fuel consumption associated with CD8 Teff cell function in vivo.

DOI: https://doi.org/10.1126/sciadv.adj1431
bioRxiv. 2024 May 18. pii: 2024.05.15.594133. [Epub ahead of print]

CPT2 mediated fatty acid oxidation is dispensable for humoral immunity.

Meilu Li, Xian Zhou, Xingxing Zhu, Yanfeng Li, Taro Hitosugi, Yuzhen Li, Hu Zeng.

B cell activation is accompanied by dynamic metabolic reprogramming, supported by a multitude of nutrients that include glucose, amino acids and fatty acids. While several studies have indicated that fatty acid mitochondrial oxidation is critical for immune cell functions, contradictory findings have been reported. Carnitine palmitoyltransferase II (CPT2) is a critical enzyme for long-chain fatty acid oxidation in mitochondria. Here, we test the requirement of CPT2 for humoral immunity using a mouse model with a lymphocyte specific deletion of CPT2. Stable 13 C isotope tracing reveals highly reduced fatty acid-derived citrate production in CPT2 deficient B cells. Yet, CPT2 deficiency has no significant impact on B cell development, B cell activation, germinal center formation, and antibody production upon either thymus-dependent or -independent antigen challenges. Together, our findings indicate that CPT2 mediated fatty acid oxidation is dispensable for humoral immunity, highlighting the metabolic flexibility of lymphocytes.

DOI: https://doi.org/10.1101/2024.05.15.594133
bioRxiv. 2024 May 14. pii: 2024.05.09.593421. [Epub ahead of print]

Rapid metabolic regulation of a novel arginine methylation of KCa3.1 attenuates T cell exhaustion.

Piyush Sharma, Ao Guo, Suresh Poudel, Emilio Boada-Romero, Katherine C Verbist, Gustavo Palacios, Kalyan Immadisetty, Mark J Chen, Dalia Haydar, Ashutosh Mishra, Junmin Peng, M Madan Babu, Giedre Krenciute, Evan S Glazer, Douglas R Green.

T cell exhaustion is linked to persistent antigen exposure and perturbed activation events, correlating with poor disease prognosis. Tumor-mediated T cell exhaustion is well documented; however, how the nutrient-deprived tumor niche affects T cell receptor (TCR) activation is largely unclear. We show that methionine metabolism licenses optimal TCR signaling by regulating the protein arginine methylome, and limiting methionine availability during early TCR signaling promotes subsequent T cell exhaustion. We discovered a novel arginine methylation of a Ca 2+ -activated potassium transporter, KCa3.1, prevention of which results in increased Ca 2+ -mediated NFAT1 activation, NFAT1 promoter occupancy, and T cell exhaustion. Furthermore, methionine supplementation reduces nuclear NFAT1 in tumor-infiltrating T cells and augments their anti-tumor activity. These findings demonstrate metabolic regulation of T cell exhaustion determined during TCR engagement.

DOI: https://doi.org/10.1101/2024.05.09.593421
Acta Pharmacol Sin. 2024 May 29.

Targeting metabolism to enhance immunotherapy within tumor microenvironment.

Xiao-Hui Liang, Xin-Yi Chen, Yue Yan, Ao-Yu Cheng, Jia-Yi Lin, Yi-Xin Jiang, Hong-Zhuan Chen, Jin-Mei Jin, Xin Luan.

  Cancer metabolic reprogramming has been considered an emerging hallmark in tumorigenesis and the antitumor immune response. Like cancer cells, immune cells within the tumor microenvironment or premetastatic niche also undergo extensive metabolic reprogramming, which profoundly impacts anti-tumor immune responses. Numerous evidence has illuminated that immunosuppressive TME and the metabolites released by tumor cells, including lactic acid, Prostaglandin E2 (PGE2), fatty acids (FAs), cholesterol, D-2-Hydroxyglutaric acid (2-HG), adenosine (ADO), and kynurenine (KYN) can contribute to CD8+ T cell dysfunction. Dynamic alterations of these metabolites between tumor cells and immune cells can similarly initiate metabolic competition in the TME, leading to nutrient deprivation and subsequent microenvironmental acidosis, which impedes immune response. This review summarizes the new landscape beyond the classical metabolic pathways in tumor cells, highlighting the pivotal role of metabolic disturbance in the immunosuppressive microenvironment, especially how nutrient deprivation in TME leads to metabolic reprogramming of CD8+ T cells. Likewise, it emphasizes the current therapeutic targets or strategies related to tumor metabolism and immune response, providing therapeutic benefits for tumor immunotherapy and drug development in the future. Cancer metabolic reprogramming has been considered an emerging hallmark in tumorigenesis and the antitumor immune response. Dynamic alterations of metabolites between tumor cells and immune cells initiate metabolic competition in the TME, leading to nutrient deprivation and subsequent microenvironmental acidosis, which impedes immune response.

Keywords:  dynamic interplay; immune response; metabolic reprogramming; targeted strategies; tumor microenvironment

DOI:  https://doi.org/10.1038/s41401-024-01304-w
iScience. 2024 Jun 21. 27(6): 109863

Ablation of Atp5if1 impairs metabolic reprogramming and proliferation of T lymphocytes and compromises mouse survival.

Inés Romero-Carramiñana, Sonia Dominguez-Zorita, Pau B Esparza-Moltó, José M Cuezva.

  T cells experience metabolic reprogramming to an enhanced glycolysis upon activation. Herein, we have investigated whether ATPase Inhibitory Factor 1 (IF1), the physiological inhibitor of mitochondrial ATP synthase, participates in rewiring T cells to a particular metabolic phenotype. We show that the activation of naive CD4+ T lymphocytes both in vitro and in vivo is accompanied by a sharp upregulation of IF1, which is expressed only in Th1 effector cells. T lymphocytes of conditional CD4+-IF1-knockout mice display impaired glucose uptake and flux through glycolysis, reducing the biogenesis of mitochondria and cellular proliferation after activation. Consequently, mice devoid of IF1 in T lymphocytes cannot mount an effective Th1 response against bacterial infection compromising their survival. Overall, we show that the inhibition of a fraction of ATP synthase by IF1 regulates metabolic reprogramming and functionality of T cells, highlighting the essential role of IF1 in adaptive immune responses.

Keywords:  Biological sciences; Immunology; Molecular biology; Physiology

DOI:  https://doi.org/10.1016/j.isci.2024.109863
Phytomedicine. 2024 May 21. pii: S0944-7113(24)00420-3. [Epub ahead of print]130 155761

Quercetin induces itaconic acid-mediated M1/M2 alveolar macrophages polarization in respiratory syncytial virus infection.

Li An, Qianwen Zhai, Keyu Tao, Yingcai Xiong, Weiying Ou, Ziwei Yu, Xingyu Yang, Jianjian Ji, Mengjiang Lu.

  BACKGROUND: Quercetin has received extensive attention for its therapeutic potential treating respiratory syncytial virus (RSV) infection diseases. Recent studies have highlighted quercetin's ability of suppressing alveolar macrophages (AMs)-derived lung inflammation. However, the anti-inflammatory mechanism of quercetin against RSV infection still remains elusive.PURPOSE: This study aims to elucidate the mechanism about quercetin anti-inflammatory effect on RSV infection.
METHODS: BALB/c mice were intranasally infected with RSV and received quercetin (30, 60, 120 mg/kg/d) orally for 3 days. Additionally, an in vitro infection model utilizing mouse alveolar macrophages (MH-S cells) was employed to validate the proposed mechanism.
RESULTS: Quercetin exhibited a downregulatory effect on glycolysis and tricarboxylic acid (TCA) cycle metabolism in RSV-infected AMs. However, it increased itaconic acid production, a metabolite derived from citrate through activating immune responsive gene 1 (IRG1), and further inhibiting succinate dehydrogenase (SDH) activity. While the suppression of SDH activity orchestrated a cascading downregulation of Hif-1α/NLRP3 signaling, ultimately causing AMs polarization from M1 to M2 phenotypes.
CONCLUSION: Our study demonstrated quercetin stimulated IRG1-mediated itaconic acid anabolism and further inhibited SDH/Hif-1α/NLRP3 signaling pathway, which led to M1 to M2 polarization of AMs so as to ameliorate RSV-induced lung inflammation.

Keywords:  Alveolar macrophages polarization; Itaconic acid; Lung inflammation; Quercetin; Respiratory syncytial virus; SDH/Hif-1α/NLRP3 signaling pathway

DOI:  https://doi.org/10.1016/j.phymed.2024.155761
Sci Rep. 2024 05 27. 14(1): 12143

LncRNA TUG1 mediates microglial inflammatory activation by regulating glucose metabolic reprogramming.

Chunxiang He, Ze Li, Wenjing Yu, Rongsiqing Luo, Jinyong Zhou, Jiawei He, Qi Chen, Zhenyan Song, Shaowu Cheng.

  Microglia are natural immune cells in the central nervous system, and the activation of microglia is accompanied by a reprogramming of glucose metabolism. In our study, we investigated the role of long non-coding RNA taurine-upregulated gene 1 (TUG1) in regulating microglial glucose metabolism reprogramming and activation. BV2 cells were treated with Lipopolysaccharides (LPS)/Interferon-γ (IFN-γ) to establish a microglial activation model. The glycolysis inhibitor 2-Deoxy-D-glucose (2-DG) was used as a control. The expression levels of TUG1 mRNA and proinflammatory cytokines such as Interleukin-1β (IL-1β), Interleukin -6, and Tumor Necrosis Factor-α mRNA and anti-inflammatory cytokines such as IL-4, Arginase 1(Arg1), CD206, and Ym1 were detected by RT-qPCR. TUG1 was silenced using TUG1 siRNA and knocked out using CRISPR/Cas9. The mRNA and protein expression levels of key enzymes involved in glucose metabolism, such as Hexokinase2, Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), Lactate dehydrogenase, Glucose 6 phosphate dehydrogenase, and Pyruvate dehydrogenase (PDH), were determined by RT-qPCR and Western blotting. The glycolytic rate of microglial cells was measured using Seahorse. Differential metabolites were determined by metabolomics, and pathway enrichment was performed using these differential metabolites. Our findings revealed that the expression of TUG1 was elevated in proinflammatory-activated microglia and positively correlated with the levels of inflammatory factors. The expression of anti-inflammatory cytokines such as IL-4, Arg1, CD206, and Ym1 were decreased when induced with LPS/IFN-γ. However, this decrease was reversed by the treatment with 2-DG. Silencing of GAPDH led to an increase in the expression of TUG1 and inflammatory factors. TUG1 knockout (TUG1KO) inhibited the expression of glycolytic key enzymes and promoted the expression of oxidative phosphorylation key enzymes, shifting the metabolic profile of activated microglia from glycolysis to oxidative phosphorylation. Additionally, TUG1KO reduced the accumulation of metabolites, facilitating the restoration of the tricarboxylic acid cycle and enhancing oxidative phosphorylation in microglia. Furthermore, the downregulation of TUG1 was found to reduce the expression of both proinflammatory and anti-inflammatory cytokines under normal conditions. Interestingly, when induced with LPS/IFN-γ, TUG1 downregulation showed a potentially beneficial effect on microglia in terms of inflammation. Downregulation of TUG1 expression inhibits glycolysis and facilitates the shift of microglial glucose metabolism from glycolysis to oxidative phosphorylation, promoting their transformation towards an anti-inflammatory phenotype and exerting anti-inflammatory effects in BV2.

Keywords:  Glucose metabolic reprogramming; Glycolysis; Inflammation; LncRNA TUG1; Microglia

DOI:  https://doi.org/10.1038/s41598-024-62966-4
bioRxiv. 2024 May 14. pii: 2024.05.10.593451. [Epub ahead of print]

Pro-inflammatory macrophage activation does not require inhibition of mitochondrial respiration.

Andréa B Ball, Anthony E Jones, Kaitlyn B Nguyễn, Amy Rios, Nico Marx, Wei Yuan Hsieh, Krista Yang, Brandon R Desousa, Kristen K O Kim, Michaela Veliova, Zena Marie Del Mundo, Orian S Shirihai, Cristiane Benincá, Linsey Stiles, Steven J Bensinger, Ajit S Divakaruni.

Pro-inflammatory macrophage activation is a hallmark example of how mitochondria serve as signaling organelles. Upon classical macrophage activation, oxidative phosphorylation sharply decreases and mitochondria are repurposed to accumulate signals that amplify effector function. However, evidence is conflicting as to whether this collapse in respiration is essential or largely dispensable. Here we systematically examine this question and show that reduced oxidative phosphorylation is not required for pro-inflammatory macrophage activation. Only stimuli that engage both MyD88- and TRIF-linked pathways decrease mitochondrial respiration, and different pro-inflammatory stimuli have varying effects on other bioenergetic parameters. Additionally, pharmacologic and genetic models of electron transport chain inhibition show no direct link between respiration and pro-inflammatory activation. Studies in mouse and human macrophages also reveal accumulation of the signaling metabolites succinate and itaconate can occur independently of characteristic breaks in the TCA cycle. Finally, in vivo activation of peritoneal macrophages further demonstrates that a pro-inflammatory response can be elicited without reductions to oxidative phosphorylation. Taken together, the results suggest the conventional model of mitochondrial reprogramming upon macrophage activation is incomplete.

DOI: https://doi.org/10.1101/2024.05.10.593451
NPJ Metab Health Dis. 2024 ;2(1): 6

Multifaceted mitochondria in innate immunity.

Eloïse Marques, Robbin Kramer, Dylan G Ryan.

  The ability of mitochondria to transform the energy we obtain from food into cell phosphorylation potential has long been appreciated. However, recent decades have seen an evolution in our understanding of mitochondria, highlighting their significance as key signal-transducing organelles with essential roles in immunity that extend beyond their bioenergetic function. Importantly, mitochondria retain bacterial motifs as a remnant of their endosymbiotic origin that are recognised by innate immune cells to trigger inflammation and participate in anti-microbial defence. This review aims to explore how mitochondrial physiology, spanning from oxidative phosphorylation (OxPhos) to signalling of mitochondrial nucleic acids, metabolites, and lipids, influences the effector functions of phagocytes. These myriad effector functions include macrophage polarisation, efferocytosis, anti-bactericidal activity, antigen presentation, immune signalling, and cytokine regulation. Strict regulation of these processes is critical for organismal homeostasis that when disrupted may cause injury or contribute to disease. Thus, the expanding body of literature, which continues to highlight the central role of mitochondria in the innate immune system, may provide insights for the development of the next generation of therapies for inflammatory diseases.

Keywords:  Energy metabolism; Mitochondria

DOI:  https://doi.org/10.1038/s44324-024-00008-3
J Infect Dis. 2024 May 28. pii: jiae263. [Epub ahead of print]

Staphylococcus aureus Conquers Host by Hijacking Mitochondria via PFKFB3 in Epithelial Cells.

Xing Gao, Shiyuan Feng, Binfeng Wu, Laizhen Liu, Yuanyuan Xu, Jinqiu Zhang, Jinfeng Miao.

  Staphylococcus aureus (S. aureus) persists within mammary epithelial cells for an extended duration, exploiting the host metabolic resources to facilitate replication. This study revealed a mechanism by which intracellular S. aureus reprograms host metabolism, with PFKFB3 playing a crucial role in this process. Mechanistically, S. aureus induced mitochondrial damage, leading to increased levels of mitochondrial reactive oxygen species (mROS) and dysfunction in electron transport chain (ETC). Moreover, S. aureus shifted the balance of mitochondrial dynamics from fusion to fission, subsequently activating PINK1-PRKN-dependent mitophagy, causing loss of the sirtuin 3 (SIRT3) to stabilize hypoxic inducible factor 1α (HIF1α), and shifting the host metabolism toward enhanced glycolysis. The inhibition of PFKFB3 reversed the mitochondrial damage and degradation of SIRT3 induced by S. aureus. Overall, our findings elucidate the mechanism by which S. aureus reprograms host metabolism and offer insights into the treatment of S. aureus infection.

Keywords:   Staphylococcus aureus ; HIF1α; PFKFB3; SIRT3; glycolysis; mitophagy

DOI:  https://doi.org/10.1093/infdis/jiae263
Gastroenterology. 2024 May 27. pii: S0016-5085(24)04936-9. [Epub ahead of print]

Gut microbiota-derived butyrate induces epigenetic and metabolic reprogramming in myeloid-derived suppressor cells to alleviate primary biliary cholangitis.

Rui Wang, Bo Li, Bingyuan Huang, Yikang Li, Qiaoyan Liu, Zhuwan Lyu, Ruiling Chen, Qiwei Qian, Xueying Liang, Xiting Pu, Yi Wu, Yu Chen, Qi Miao, Qixia Wang, Min Lian, Xiao Xiao, Patrick S C Leung, M Eric Gershwin, Zhengrui You, Xiong Ma, Ruqi Tang.

  BACKGROUND & AIMS: Gut dysbiosis and myeloid-derived suppressor cells (MDSCs) are implicated in primary biliary cholangitis (PBC) pathogenesis. However, it remains unknown whether gut microbiota or their metabolites can modulate MDSCs homeostasis to rectify immune dysregulation in PBC.METHODS: We measured fecal short-chain fatty acids (SCFAs) levels by targeted GC-MS and analyzed circulating MDSCs by flow cytometry in two independent PBC cohorts. Human and murine MDSCs were differentiated in vitro in the presence of butyrate, followed by transcriptomic, epigenetic (CUT&Tag-seq and ChIP-qPCR) and metabolic (untargeted LC-MS, mitochondrial stress test, and isotope tracing) analyses. The in vivo role of butyrate-MDSCs was evaluated in 2-octynoic acid-BSA-induced cholangitis murine model.
RESULTS: Decreased butyrate levels and defective MDSCs function were found in patients with incomplete response to ursodeoxycholic acid (UDCA), compared to those with adequate response. Butyrate induced expansion and suppressive activity of MDSCs in a manner dependent on PPARD-driven fatty acid β-oxidation (FAO). Pharmaceutical inhibition or genetic knockdown of the FAO rate-limiting gene CPT1A abolished the effect of butyrate. Furthermore, butyrate inhibited HDAC3 function, leading to enhanced H3K27ac modifications at promoter regions of PPARD and FAO genes in MDSCs. Therapeutically, butyrate administration alleviated immune-mediated cholangitis in mice via MDSCs, and adoptive transfer of butyrate-treated MDSCs also displayed protective efficacy. Importantly, reduced expression of FAO genes and impaired mitochondrial physiology were detected in MDSCs from UDCA non-responders, and their impaired suppressive function was restored by butyrate.
CONCLUSION: We identify a critical role for butyrate in modulation of MDSCs homeostasis by orchestrating epigenetic and metabolic crosstalk, proposing a novel therapeutic strategy for treating PBC.

Keywords:  Autoimmune liver disease; Fatty acid oxidation; Microbial metabolite; Myeloid cells

DOI:  https://doi.org/10.1053/j.gastro.2024.05.014
Mol Cell Endocrinol. 2024 May 28. pii: S0303-7207(24)00139-4. [Epub ahead of print] 112283

Legumain-deficient macrophages regulate inflammation and lipid metabolism in adipose tissues to protect against diet-induced obesity.

Wanyu Zhang, Shuowen Wang, Zhuo Liu, Ping Qian, Yuanyuan Li, Jianxin Wu.

  Adipose tissue macrophages (ATMs) are key players in the development of obesity and associated metabolic inflammation, which contributes to systemic metabolic dysfunction, and understanding the interaction between macrophages and adipocytes is crucial for developing novel macrophage-based strategies against obesity. Here, we found that Legumain (Lgmn), a well-known lysosomal cysteine protease, is expressed mainly in the ATMs of obese mice. To further deﬁne the potential role of Lgmn-expressing macrophages in the generation of an aberrant metabolic state, LgmnF/F; LysMCre mice, which do not express Lgmn in macrophages, were maintained on a high-fat diet (HFD), and metabolic parameters were assessed. Macrophage-specific Lgmn deficiency protects mice against diet-induced obesity, diminishes the quantity of proinflammatory macrophages in obese adipose tissues, and alleviates hepatic steatosis and insulin resistance. By analysing the transcriptome and proteome of murine visceral white adipose tissue (vWAT) after HFD feeding, we determined that macrophage Lgmn deficiency causes changes in lipid metabolism and the inflammatory response. Furthermore, the reciprocity of macrophage-derived Lgmn with integrin α5β1 in adipocytes was tested via colocalization analyses. It is further demonstrated in macrophage and adipocyte coculture system that macrophage derived Lgmn bound to integrin α5β1 in adipocytes, therefore attenuating PKA activation, downregulating lipolysis-related proteins and eventually exacerbating obesity development. Overall, our study identified Lgmn as a previously unrecognized regulator involved in the interaction between ATMs and adipocytes contributing to diet-induced obesity and suggested that Lgmn is a potential target for treating metabolic disorders.

Keywords:  Inflammation; Integrin α5β1; Lgmn; Lipolysis; Macrophage; Obesity

DOI:  https://doi.org/10.1016/j.mce.2024.112283
J Virol. 2024 May 30. e0045824

IDO1 promotes CSFV replication by mediating tryptophan metabolism to inhibit NF-κB signaling.

Feifan Zhao, Yaoyao Huang, Junzhi Ji, Xueyi Liu, Xiaowen Li, Linke Zou, Keke Wu, Xiao di Liu, Sen Zeng, Xinyan Wang, Wenshuo Hu, Yiwan Song, Zhimin Lu, Bolun Zhou, Peng Li, Weijun Wang, Mingqiu Zhao, Jinding Chen, Lin Yi, Shuangqi Fan.

  Tryptophan metabolism plays a crucial role in facilitating various cellular processes essential for maintaining normal cellular function. Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes the conversion of tryptophan (Trp) into kynurenine (Kyn), thereby initiating the degradation of Trp. The resulting Kyn metabolites have been implicated in the modulation of immune responses. Currently, the role of IDO1-mediated tryptophan metabolism in the process of viral infection remains relatively unknown. In this study, we discovered that classical swine fever virus (CSFV) infection of PK-15 cells can induce the expression of IDO1, thereby promoting tryptophan metabolism. IDO1 can negatively regulate the NF-κB signaling by mediating tryptophan metabolism, thereby facilitating CSFV replication. We found that silencing the IDO1 gene enhances the expression of IFN-α, IFN-β, and IL-6 by activating the NF-κB signaling pathway. Furthermore, our observations indicate that both silencing the IDO1 gene and administering exogenous tryptophan can inhibit CSFV replication by counteracting the cellular autophagy induced by Rapamycin. This study reveals a novel mechanism of IDO1-mediated tryptophan metabolism in CSFV infection, providing new insights and a theoretical basis for the treatment and control of CSFV.IMPORTANCEIt is well known that due to the widespread use of vaccines, the prevalence of classical swine fever (CSF) is shifting towards atypical and invisible infections. CSF can disrupt host metabolism, leading to persistent immune suppression in the host and causing significant harm when co-infected with other diseases. Changes in the host's metabolic profiles, such as increased catabolic metabolism of amino acids and the production of immunoregulatory metabolites and their derivatives, can also influence virus replication. Mammals utilize various pathways to modulate immune responses through amino acid utilization, including increased catabolic metabolism of amino acids and the production of immunoregulatory metabolites and their derivatives, thereby limiting viral replication. Therefore, this study proposes that targeting the modulation of tryptophan metabolism may represent an effective approach to control the progression of CSF.

Keywords:  autophagy; classical swine fever virus; indoleamine 2,3-dioxygenase 1 (IDO1); kynurenine; nuclear factor kappa-B (NF-κB); tryptophan

DOI:  https://doi.org/10.1128/jvi.00458-24
ACS Nano. 2024 May 27.

Metabolic Modulation-Mediated Antibiotic and Immune Activation for Treatment of Chronic Lung Infections.

Weijun Xiu, Heng Dong, Xiaolong Chen, Ling Wan, Liang Lu, Kaili Yang, Lihui Yuwen, Qiang Li, Meng Ding, Yu Zhang, Yongbin Mou, Lianhui Wang.

  The Pseudomonas aeruginosa biofilm in recalcitrant chronic lung infections not only develops high antimicrobial tolerance but also induces an aberrant host inflammatory response. The metabolic condition plays a vital role in both the antimicrobial susceptibility of bacteria and the inflammatory response of immune cells, thereby offering a potential therapeutic target. Herein, we described a metabolic modulation strategy by using ultrasound-responsive liposomal nanoparticles containing a sonosensitizer and a hypoxia-activated prodrug against biofilm-associated chronic lung infections. Under ultrasound stimulation, the sonosensitizer generates antibacterial reactive oxygen species by oxygen consumption. Subsequently, the oxygen consumption-mediated hypoxia not only induces the anaerobic metabolism of bacteria for antibiotic activation but also triggers the glycolysis pathway of immune cells for inflammatory activation. Such metabolic modulation strategy demonstrated efficient therapeutic efficacy for P. aeruginosa biofilm-induced chronic lung infections in mice models and provides a promising way for combating biofilm-associated chronic infections.

Keywords:  bacterial biofilm infection; immune; liposomal nanoparticles; metabolism; ultrasound

DOI:  https://doi.org/10.1021/acsnano.4c03527
Immunol Cell Biol. 2024 May 28.

Loss of Bcl-3 regulates macrophage polarization by promoting macrophage glycolysis.

Shengnan Liu, Hao Wang, Jiaoyang Li, Jingtao Gao, Li Yu, Xiaofei Wei, Mengchao Cui, Yuxin Zhao, Yinming Liang, Hui Wang.

  M1/M2 macrophage polarization plays an important role in regulating the balance of the microenvironment within tissues. Moreover, macrophage polarization involves the reprogramming of metabolism, such as glucose and lipid metabolism. Transcriptional coactivator B-cell lymphoma-3 (Bcl-3) is an atypical member of the IκB family that controls inflammatory factor levels in macrophages by regulating nuclear factor kappa B pathway activation. However, the relationship between Bcl-3 and macrophage polarization and metabolism remains unclear. In this study, we show that the knockdown of Bcl-3 in macrophages can regulate glycolysis-related gene expression by promoting the activation of the nuclear factor kappa B pathway. Furthermore, the loss of Bcl-3 was able to promote the interferon gamma/lipopolysaccharide-induced M1 macrophage polarization by accelerating glycolysis. Taken together, these results suggest that Bcl-3 may be a candidate gene for regulating M1 polarization in macrophages.

Keywords:  Bcl‐3; glucose metabolism; inflammation; macrophages; polarization

DOI:  https://doi.org/10.1111/imcb.12785
Cell Host Microbe. 2024 May 17. pii: S1931-3128(24)00142-2. [Epub ahead of print]

Salmonella Typhimurium expansion in the inflamed murine gut is dependent on aspartate derived from ROS-mediated microbiota lysis.

Woongjae Yoo, Nicolas G Shealy, Jacob K Zieba, Teresa P Torres, Madi Baltagulov, Julia D Thomas, Catherine D Shelton, Anna G McGovern, Nora J Foegeding, Erin E Olsan, Mariana X Byndloss.

  Inflammation boosts the availability of electron acceptors in the intestinal lumen, creating a favorable niche for pathogenic Enterobacteriaceae. However, the mechanisms linking intestinal inflammation-mediated changes in luminal metabolites and pathogen expansion remain unclear. Here, we show that mucosal inflammation induced by Salmonella enterica serovar Typhimurium (S. Tm) infection increases intestinal levels of the amino acid aspartate. S. Tm used aspartate-ammonia lyase (aspA)-dependent fumarate respiration for growth in the murine gut only during inflammation. AspA-dependent growth advantage was abolished in the gut of germ-free mice and restored in gnotobiotic mice colonized with members of the classes Bacteroidia and Clostridia. Reactive oxygen species (ROS) produced during the host response caused lysis of commensal microbes, resulting in the release of microbiota-derived aspartate that was used by S. Tm, in concert with nitrate-dependent anaerobic respiration, to outcompete commensal Enterobacteriaceae. Our findings demonstrate the role of microbiota-derived amino acids in driving respiration-dependent S. Tm expansion during colitis.

Keywords:  Enterobacteriaceae; Salmonella Typhimurium; amino acids; colonization resistance; intestinal inflammation; microbe-microbe interactions; microbial metabolism; microbiome

DOI:  https://doi.org/10.1016/j.chom.2024.05.001
Nat Immunol. 2024 May 29.

An IFNγ-dependent immune-endocrine circuit lowers blood glucose to potentiate the innate antiviral immune response.

Marko Šestan, Sanja Mikašinović, Ante Benić, Stephan Wueest, Christoforos Dimitropoulos, Karlo Mladenić, Mia Krapić, Lea Hiršl, Yossef Glantzspiegel, Ana Rasteiro, Maria Aliseychik, Đurđica Cekinović Grbeša, Tamara Turk Wensveen, Marina Babić, Irit Gat-Viks, Henrique Veiga-Fernandes, Daniel Konrad, Felix M Wensveen, Bojan Polić.

Viral infection makes us feel sick as the immune system alters systemic metabolism to better fight the pathogen. The extent of these changes is relative to the severity of disease. Whether blood glucose is subject to infection-induced modulation is mostly unknown. Here we show that strong, nonlethal infection restricts systemic glucose availability, which promotes the antiviral type I interferon (IFN-I) response. Following viral infection, we find that IFNγ produced by γδ T cells stimulates pancreatic β cells to increase glucose-induced insulin release. Subsequently, hyperinsulinemia lessens hepatic glucose output. Glucose restriction enhances IFN-I production by curtailing lactate-mediated inhibition of IRF3 and NF-κB signaling. Induced hyperglycemia constrained IFN-I production and increased mortality upon infection. Our findings identify glucose restriction as a physiological mechanism to bring the body into a heightened state of responsiveness to viral pathogens. This immune-endocrine circuit is disrupted in hyperglycemia, possibly explaining why patients with diabetes are more susceptible to viral infection.

DOI: https://doi.org/10.1038/s41590-024-01848-3
iScience. 2024 Jun 21. 27(6): 109923

Impaired tryptophan metabolism by type 2 inflammation in epithelium worsening asthma.

Yushan Miao, Caiming Zhong, Shujun Bao, Kunchen Wei, Wei Wang, Na Li, Chong Bai, Wei Chen, Hao Tang.

  Previous researches indicate that tryptophan metabolism is critical to allergic inflammation and that indoleamine 2,3-dioxygenase 1 (IDO1), as a key enzyme, is known for its immunosuppressive properties. Therefore, we are aimed to explore whether tryptophan metabolism, especially IDO1, influences allergic asthma and clarify specific mechanism. With the analysis of clinical data, exploration in cell experiments, and verifying in HDM-induced asthma mice models, we finally found that in allergic asthma, low level of T1 cytokines along with high level of T2 cytokines inhibited the expression of IDO1 in airway epithelium, hampering the kynurenine pathway in tryptophan metabolism and decreasing the level of intracellular kynurenine (Kyn). As an endogenous ligand of aryl hydrocarbon receptor, Kyn regulated the expression of cystathionine-γ-lyase (CTH). Notably, in asthma models, enhancing either IDO1 or H2S relieved asthma, while inhibiting the activity of CTH exacerbated it. IDO1-Kyn-CTH pathway could be a potential target for treatment for allergic asthma.

Keywords:  Immunology; Molecular biology; Physiology

DOI:  https://doi.org/10.1016/j.isci.2024.109923
bioRxiv. 2024 May 15. pii: 2024.05.13.593964. [Epub ahead of print]

IL-4 Licenses B Cell Activation Through Cholesterol Synthesis.

Holly R Steach, Autumn G York, Mathias H Skadow, Shuting Chen, Jun Zhao, Kevin J Williams, Quan Zhou, Weu-Yuan Hsieh, J Richard Brewer, Rihao Qu, Justin A Shyer, Christian Harman, Esen Sefik, Walter K Mowell, Will Bailis, Can Cui, Yuval Kluger, Steven J Bensinger, Joe Craft, Richard A Flavell.

Lymphocyte activation involves a transition from quiescence and associated catabolic metabolism to a metabolic state with noted similarities to cancer cells such as heavy reliance on aerobic glycolysis for energy demands and increased nutrient requirements for biomass accumulation and cell division 1-3 . Following antigen receptor ligation, lymphocytes require spatiotemporally distinct "second signals". These include costimulatory receptor or cytokine signaling, which engage discrete programs that often involve remodeling of organelles and increased nutrient uptake or synthesis to meet changing biochemical demands 4-6 . One such signaling molecule, IL-4, is a highly pleiotropic cytokine that was first identified as a B cell co-mitogen over 30 years ago 7 . However, how IL-4 signaling mechanistically supports B cell proliferation is incompletely understood. Here, using single cell RNA sequencing we find that the cholesterol biosynthetic program is transcriptionally upregulated following IL-4 signaling during the early B cell response to influenza virus infection, and is required for B cell activation in vivo . By limiting lipid availability in vitro , we determine cholesterol to be essential for B cells to expand their endoplasmic reticulum, progress through cell cycle, and proliferate. In sum, we demonstrate that the well-known ability of IL-4 to act as a B cell growth factor is through a previously unknown rewiring of specific lipid anabolic programs, relieving sensitivity of cells to environmental nutrient availability.

DOI: https://doi.org/10.1101/2024.05.13.593964
iScience. 2024 Jun 21. 27(6): 109929

Islet cell stress induced by insulin-degrading enzyme deficiency promotes regeneration and protection from autoimmune diabetes.

Shuaishuai Zhu, Emmanuelle Waeckel-Énée, Masaya Oshima, Anna Moser, Marie-Andrée Bessard, Abdelaziz Gdoura, Kevin Roger, Nina Mode, Joanna Lipecka, Ayse Yilmaz, Barbara Bertocci, Julien Diana, Benjamin Saintpierre, Ida Chiara Guerrera, Raphael Scharfmann, Stefania Francesconi, François-Xavier Mauvais, Peter van Endert.

  Tuning of protein homeostasis through mobilization of the unfolded protein response (UPR) is key to the capacity of pancreatic beta cells to cope with variable demand for insulin. Here, we asked how insulin-degrading enzyme (IDE) affects beta cell adaptation to metabolic and immune stress. C57BL/6 and autoimmune non-obese diabetic (NOD) mice lacking IDE were exposed to proteotoxic, metabolic, and immune stress. IDE deficiency induced a low-level UPR with islet hypertrophy at the steady state, rapamycin-sensitive beta cell proliferation enhanced by proteotoxic stress, and beta cell decompensation upon high-fat feeding. IDE deficiency also enhanced the UPR triggered by proteotoxic stress in human EndoC-βH1 cells. In Ide-/- NOD mice, islet inflammation specifically induced regenerating islet-derived protein 2, a protein attenuating autoimmune inflammation. These findings establish a role of IDE in islet cell protein homeostasis, demonstrate how its absence induces metabolic decompensation despite beta cell proliferation, and UPR-independent islet regeneration in the presence of inflammation.

Keywords:  Molecular biology; Physiology; Proteomics; Transcriptomics

DOI:  https://doi.org/10.1016/j.isci.2024.109929
Blood Adv. 2024 May 29. pii: bloodadvances.2023010740. [Epub ahead of print]

AMPK Drives both Glycolytic and Oxidative Metabolism in Murine and Human T Cells During Graft-versus-host Disease.

Archana Ramgopal, Erica Braverman, Lee-Kai Sun, Darlene Monlish, Christopher James Wittmann, Felicia Kemp, Mengtao Qin, Manda J Ramsey, Richard Thomas Cattley, William Hawse, Craig Byersdorfer.

Allogeneic T cells reprogram their metabolism during acute graft-versus-host disease (GVHD) in a process involving the cellular energy sensor AMP-activated protein kinase (AMPK). Deletion of AMPK in donor T cells limits GVHD but still preserves homeostatic reconstitution and graft-versus-leukemia (GVL) effects. In the current studies, murine AMPK KO T cells decreased oxidative metabolism at early timepoints post-transplant and lacked a compensatory increase in glycolysis following inhibition of the electron transport chain. Immunoprecipitation using an antibody specific to phosphorylated targets of AMPK determined that AMPK modified interactions of several glycolytic enzymes including aldolase, enolase, pyruvate kinase M (PKM), and glyceraldehyde 3-phosphate dehydrogenase (GAPDH), and enzyme assays indicated impaired aldolase and GAPDH activity in AMPK KO T cells. Importantly, these changes in glycolysis correlated with both an impaired ability of AMPK KO T cells to produce significant amounts of interferon gamma (IFNγ) upon antigenic re-stimulation and a decrease in the total number of donor CD4 T cells recovered at later time points post-transplant. Human T cells lacking AMPK gave similar results, with glycolytic compensation impaired both in vitro and following expansion in vivo. GVHD results also mirrored those of the murine model, with reduced CD4/CD8 ratios and a significant improvement in disease severity. Together these data highlight a significant role for AMPK in controlling oxidative and glycolytic metabolism in both murine and human T cells and endorse further study of AMPK inhibition as a potential clinical target for future GVHD therapies.

DOI: https://doi.org/10.1182/bloodadvances.2023010740
Nat Commun. 2024 May 30. 15(1): 4590

FLI1 promotes IFN-γ-induced kynurenine production to impair anti-tumor immunity.

Enni Chen, Jiawei Wu, Jiajia Huang, Wancui Zhu, Haohui Sun, Xiaonan Wang, Dagui Lin, Xiaodi Li, Dingbo Shi, Zhiqiao Liu, Jinsheng Huang, Miao Chen, Fangyun Xie, Wuguo Deng.

Nasopharyngeal carcinoma (NPC)-mediated immunosuppression within the tumor microenvironment (TME) frequently culminates in the failure of otherwise promising immunotherapies. In this study, we identify tumor-intrinsic FLI1 as a critical mediator in impairing T cell anti-tumor immunity. A mechanistic inquiry reveals that FLI1 orchestrates the expression of CBP and STAT1, facilitating chromatin accessibility and transcriptional activation of IDO1 in response to T cell-released IFN-γ. This regulatory cascade ultimately leads to augmented IDO1 expression, resulting in heightened synthesis of kynurenine (Kyn) in tumor cells. This, in turn, fosters CD8+ T cell exhaustion and regulatory T cell (Treg) differentiation. Intriguingly, we find that pharmacological inhibition of FLI1 effectively obstructs the CBP/STAT1-IDO1-Kyn axis, thereby invigorating both spontaneous and checkpoint therapy-induced immune responses, culminating in enhanced tumor eradication. In conclusion, our findings delineate FLI1-mediated Kyn metabolism as an immune evasion mechanism in NPC, furnishing valuable insights into potential therapeutic interventions.

DOI: https://doi.org/10.1038/s41467-024-48397-9
Nat Commun. 2024 May 30. 15(1): 4605

Inflammation causes insulin resistance in mice via interferon regulatory factor 3 (IRF3)-mediated reduction in FAHFA levels.

Shuai Yan, Anna Santoro, Micah J Niphakis, Antonio M Pinto, Christopher L Jacobs, Rasheed Ahmad, Radu M Suciu, Bryan R Fonslow, Rachel A Herbst-Graham, Nhi Ngo, Cassandra L Henry, Dylan M Herbst, Alan Saghatelian, Barbara B Kahn, Evan D Rosen.

Obesity-induced inflammation causes metabolic dysfunction, but the mechanisms remain elusive. Here we show that the innate immune transcription factor interferon regulatory factor (IRF3) adversely affects glucose homeostasis through induction of the endogenous FAHFA hydrolase androgen induced gene 1 (AIG1) in adipocytes. Adipocyte-specific knockout of IRF3 protects male mice against high-fat diet-induced insulin resistance, whereas overexpression of IRF3 or AIG1 in adipocytes promotes insulin resistance on a high-fat diet. Furthermore, pharmacological inhibition of AIG1 reversed obesity-induced insulin resistance and restored glucose homeostasis in the setting of adipocyte IRF3 overexpression. We, therefore, identify the adipocyte IRF3/AIG1 axis as a crucial link between obesity-induced inflammation and insulin resistance and suggest an approach for limiting the metabolic dysfunction accompanying obesity.

DOI: https://doi.org/10.1038/s41467-024-48220-5
J Neuroinflammation. 2024 May 27. 21(1): 137

Hyperglycemia enhances brain susceptibility to lipopolysaccharide-induced neuroinflammation via astrocyte reprogramming.

Kyung-Seo Lee, Sung-Hyun Yoon, Inhwa Hwang, Jeong-Hwa Ma, Euimo Yang, Rebekah Hyeyoon Kim, Eosu Kim, Je-Wook Yu.

  Hyperglycemia has been shown to modulate the immune response of peripheral immune cells and organs, but the impact of hyperglycemia on neuroinflammation within the brain remains elusive. In the present study, we provide evidences that streptozotocin (STZ)-induced hyperglycemic condition in mice drives a phenotypic switch of brain astrocytes to a proinflammatory state, and increases brain vulnerability to mild peripheral inflammation. In particular, we found that hyperglycemia led to a significant increase in the astrocyte proliferation as determined by flow cytometric and immunohistochemical analyses of mouse brain. The increased astrocyte proliferation by hyperglycemia was reduced by Glut1 inhibitor BAY-876. Transcriptomic analysis of isolated astrocytes from Aldh1l1CreERT2;tdTomato mice revealed that peripheral STZ injection induced astrocyte reprogramming into proliferative, and proinflammatory phenotype. Additionally, STZ-induced hyperglycemic condition significantly enhanced the infiltration of circulating myeloid cells into the brain and the disruption of blood-brain barrier in response to mild lipopolysaccharide (LPS) administration. Systemic hyperglycemia did not alter the intensity and sensitivity of peripheral inflammation in mice to LPS challenge, but increased the inflammatory potential of brain microglia. In line with findings from mouse experiments, a high-glucose environment intensified the LPS-triggered production of proinflammatory molecules in primary astrocyte cultures. Furthermore, hyperglycemic mice exhibited a significant impairment in cognitive function after mild LPS administration compared to normoglycemic mice as determined by novel object recognition and Y-maze tasks. Taken together, these results demonstrate that hyperglycemia directly induces astrocyte reprogramming towards a proliferative and proinflammatory phenotype, which potentiates mild LPS-triggered inflammation within brain parenchymal regions.

Keywords:  Astrocytes; Cognitive function; Hyperglycemia; Lipopolysaccharide; Microglia; Neuroinflammation; RNA-sequencing

DOI:  https://doi.org/10.1186/s12974-024-03136-1
Nat Commun. 2024 May 31. 15(1): 4665

Glycolysis inhibition induces anti-tumor central memory CD8+T cell differentiation upon combination with microwave ablation therapy.

Xinyu Tang, Xinrui Mao, Peiwen Ling, Muxin Yu, Hua Pan, Jiaming Wang, Mingduo Liu, Hong Pan, Wen Qiu, Nan Che, Kai Zhang, Feifan Bao, Hongwei Peng, Qiang Ding, Shui Wang, Wenbin Zhou.

Minimally invasive thermal therapy is a successful alternative treatment to surgery in solid tumors with high complete ablation rates, however, tumor recurrence remains a concern. Central memory CD8+ T cells (TCM) play important roles in protection from chronic infection and cancer. Here we find, by single-cell RNA analysis of human breast cancer samples, that although the memory phenotype of peripheral CD8+ T cells increases slightly after microwave ablation (MWA), the metabolism of peripheral CD8+ T cells remains unfavorable for memory phenotype. In mouse models, glycolysis inhibition by 2-deoxy-D-glucose (2DG) in combination with MWA results in long-term anti-tumor effect via enhancing differentiation of tumor-specific CD44hiCD62L+CD8+ TCM cells. Enhancement of CD8+ TCM cell differentiation determined by Stat-1, is dependent on the tumor-draining lymph nodes (TDLN) but takes place in peripheral blood, with metabolic remodeling of CD8+ T cells lasting the entire course of the the combination therapy. Importantly, in-vitro glycolysis inhibition in peripheral CD8+ T cells of patients with breast or liver tumors having been treated with MWA thrice leads to their differentiation into CD8+ TCM cells. Our work thus offers a potential strategy to avoid tumor recurrence following MWA therapy and lays down the proof-of-principle for future clinical trials.

DOI: https://doi.org/10.1038/s41467-024-49059-6
Front Immunol. 2024 ;15 1353903

Metabolic predictors of COVID-19 mortality and severity: a survival analysis.

Abdallah Musa Abdallah, Asmma Doudin, Theeb Osama Sulaiman, Omar Jamil, Rida Arif, Fatima Al Sada, Hadi M Yassine, Mohamed A Elrayess, Abdel-Naser Elzouki, Mohamed M Emara, Nagendra Babu Thillaiappan, Farhan S Cyprian.

  Introduction: The global healthcare burden of COVID-19 pandemic has been unprecedented with a high mortality. Metabolomics, a powerful technique, has been increasingly utilized to study the host response to infections and to understand the progression of multi-system disorders such as COVID-19. Analysis of the host metabolites in response to SARS-CoV-2 infection can provide a snapshot of the endogenous metabolic landscape of the host and its role in shaping the interaction with SARS-CoV-2. Disease severity and consequently the clinical outcomes may be associated with a metabolic imbalance related to amino acids, lipids, and energy-generating pathways. Hence, the host metabolome can help predict potential clinical risks and outcomes.Methods: In this prospective study, using a targeted metabolomics approach, we studied the metabolic signature in 154 COVID-19 patients (males=138, age range 48-69 yrs) and related it to disease severity and mortality. Blood plasma concentrations of metabolites were quantified through LC-MS using MxP Quant 500 kit, which has a coverage of 630 metabolites from 26 biochemical classes including distinct classes of lipids and small organic molecules. We then employed Kaplan-Meier survival analysis to investigate the correlation between various metabolic markers, disease severity and patient outcomes.
Results: A comparison of survival outcomes between individuals with high levels of various metabolites (amino acids, tryptophan, kynurenine, serotonin, creatine, SDMA, ADMA, 1-MH and carnitine palmitoyltransferase 1 and 2 enzymes) and those with low levels revealed statistically significant differences in survival outcomes. We further used four key metabolic markers (tryptophan, kynurenine, asymmetric dimethylarginine, and 1-Methylhistidine) to develop a COVID-19 mortality risk model through the application of multiple machine-learning methods.
Conclusions: Metabolomics analysis revealed distinct metabolic signatures among different severity groups, reflecting discernible alterations in amino acid levels and perturbations in tryptophan metabolism. Notably, critical patients exhibited higher levels of short chain acylcarnitines, concomitant with higher concentrations of SDMA, ADMA, and 1-MH in severe cases and non-survivors. Conversely, levels of 3-methylhistidine were lower in this context.

Keywords:  COVID-19; biomarkers; critical; metabolites; mortality; severe

DOI:  https://doi.org/10.3389/fimmu.2024.1353903
bioRxiv. 2024 May 25. pii: 2024.05.11.593693. [Epub ahead of print]

Caspase-11 drives macrophage hyperinflammation in models of Polg-related mitochondrial disease.

Jordyn J VanPortfliet, Yuanjiu Lei, Camila Guerra Martinez, Jessica Wong, Kathryn Pflug, Raquel Sitcheran, Stephen C Kneeland, Stephen A Murray, Peter J McGuire, Carolyn L Cannon, A Phillip West.

Mitochondrial diseases (MtD) represent a significant public health challenge due to their heterogenous clinical presentation, often severe and progressive symptoms, and the lack of effective therapies. Environmental exposures, such bacterial and viral infection, can further compromise mitochondrial function and exacerbate the progression of MtD. Infections in MtD patients more frequently progress to sepsis, pneumonia, and other detrimental inflammatory endpoints. However, the underlying immune alterations that enhance immunopathology in MtD remain unclear, constituting a key gap in knowledge that complicates treatment and increases mortality in this population. Here we employ in vitro and in vivo approaches to clarify the molecular and cellular basis for innate immune hyperactivity in models of polymerase gamma (Polg)-related MtD. We reveal that type I interferon (IFN-I)-mediated upregulation of caspase-11 and guanylate-binding proteins (GBPs) increase macrophage sensing of the opportunistic microbe Pseudomonas aeruginosa (PA) in Polg mutant mice. Furthermore, we show that excessive macrophage cytokine secretion and pyroptotic cell death contribute to lung inflammation and morbidity after infection with PA. Our work sheds new light on innate immune dysregulation in MtD and reveals potential targets for limiting infection- and inflammation-related complications in Polg-related MtD.

DOI: https://doi.org/10.1101/2024.05.11.593693
Nat Microbiol. 2024 May 28.

Mycobacterium tuberculosis produces D-serine under hypoxia to limit CD8+ T cell-dependent immunity in mice.

Hongyu Cheng, Zhe Ji, Yang Wang, Shenzhi Li, Tianqi Tang, Fei Wang, Cheng Peng, Xiangyang Wu, Yuanna Cheng, Zhonghua Liu, Mingtong Ma, Jie Wang, Xiaochen Huang, Lin Wang, Lianhua Qin, Haipeng Liu, Jianxia Chen, Ruijuan Zheng, Carl G Feng, Xia Cai, Di Qu, Lilin Ye, Hua Yang, Baoxue Ge.

Adaptation to hypoxia is a major challenge for the survival of Mycobacterium tuberculosis (Mtb) in vivo. Interferon (IFN)-γ-producing CD8+ T cells contribute to control of Mtb infection, in part by promoting antimicrobial activities of macrophages. Whether Mtb counters these responses, particularly during hypoxic conditions, remains unknown. Using metabolomic, proteomic and genetic approaches, here we show that Mtb induced Rv0884c (SerC), an Mtb phosphoserine aminotransferase, to produce D-serine. This activity increased Mtb pathogenesis in mice but did not directly affect intramacrophage Mtb survival. Instead, D-serine inhibited IFN-γ production by CD8+ T cells, which indirectly reduced the ability of macrophages to restrict Mtb upon co-culture. Mechanistically, D-serine interacted with WDR24 and inhibited mTORC1 activation in CD8+ T cells. This decreased T-bet expression and reduced IFN-γ production by CD8+ T cells. Our findings suggest an Mtb evasion mechanism where pathogen metabolic adaptation to hypoxia leads to amino acid-dependent suppression of adaptive anti-TB immunity.

DOI: https://doi.org/10.1038/s41564-024-01701-1