bims-imicid 2025-01-19 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2025–01–19
ten papers selected by
Dylan Ryan, University of Cambridge

In vivo itaconate tracing reveals degradation pathway and turnover kinetics.
Calcium-mediated mitochondrial fission and mitophagy drive glycolysis to facilitate arterivirus proliferation.
Itaconate transporter SLC13A3 confers immunotherapy resistance via alkylation-mediated stabilization of PD-L1.
IL-7 promotes integrated glucose and amino acid sensing during homeostatic CD4+ T cell proliferation.
Two-photon NAD(P)H-FLIM reveals unperturbed energy metabolism of Ascaris suum larvae, in contrast to host macrophages upon artemisinin derivatives exposure.
La dolce vita: fueling chimeric antigen receptor (CAR) T cells with Glut1 to improve therapeutic efficacy.
Vaccinia growth factor-dependent modulation of the mTORC1-CAD axis upon nutrient restriction.
Triglyceride metabolism controls inflammation and APOE4 -associated disease states in microglia.
Increased SOAT2 expression in aged regulatory T cells is associated with altered cholesterol metabolism and reduced anti-tumor immunity.
Tracheal tuft cells release ATP and link innate to adaptive immunity in pneumonia.

bioRxiv. 2025 Jan 02. pii: 2025.01.02.629617. [Epub ahead of print]

In vivo itaconate tracing reveals degradation pathway and turnover kinetics.

Hanna F Willenbockel, Alexander T Williams, Alfredo Lucas, Birte Dowerg, Pedro Cabrales, Christian M Metallo, Thekla Cordes.

Itaconate is an immunomodulatory metabolite that alters mitochondrial metabolism and immune cell function. This organic acid is endogenously synthesized via tricarboxylic acid (TCA) metabolism downstream of TLR signaling. Itaconate-based treatment strategies are being explored to mitigate numerous inflammatory conditions. However, little is known about the turnover rate of itaconate in circulation, the kinetics of its degradation, and the broader consequences on metabolism. By combining mass spectrometry and in vivo 13 C itaconate tracing, we demonstrate that itaconate is rapidly eliminated from plasma, excreted via urine, and fuels TCA cycle metabolism specifically in the liver and kidneys. These studies further revealed that itaconate is converted into acetyl-CoA, mesaconate, and citramalate in mitochondria. Itaconate administration also influenced branched-chain amino acid metabolism and succinate levels, indicating a functional impact on succinate dehydrogenase (SDH) and methylmalonyl-CoA mutase (MUT) activity. Our findings uncovered a previously unknown aspect of the itaconate metabolism, highlighting its rapid catabolism in vivo that contrasts findings in cultured cells.

DOI: https://doi.org/10.1101/2025.01.02.629617
PLoS Pathog. 2025 Jan 13. 21(1): e1012872

Calcium-mediated mitochondrial fission and mitophagy drive glycolysis to facilitate arterivirus proliferation.

Zhe Sun, Zicheng Ma, Wandi Cao, Chenlong Jiang, Lei Guo, Kesen Liu, Yanni Gao, Juan Bai, Jiang Pi, Ping Jiang, Xing Liu.

Mitochondria, recognized as the "powerhouse" of cells, play a vital role in generating cellular energy through dynamic processes such as fission and fusion. Viruses have evolved mechanisms to hijack mitochondrial function for their survival and proliferation. Here, we report that infection with the swine arterivirus porcine reproductive and respiratory syndrome virus (PRRSV), manipulates mitochondria calcium ions (Ca2+) to induce mitochondrial fission and mitophagy, thereby reprogramming cellular energy metabolism to facilitate its own replication. Mechanistically, PRRSV-induced mitochondrial fission is caused by elevated levels of mitochondria Ca2+, derived from the endoplasmic reticulum (ER) through inositol 1,4,5-triphosphate receptor (IP3R)-voltage-dependent anion channel 1 (VDAC1)-mitochondrial calcium uniporter (MCU) channels. This process is associated with increased mitochondria-associated membranes (MAMs), mediated by the upregulated expression of sigma non-opioid intracellular receptor 1 (SIGMAR1). Elevated mitochondria Ca2+ further activates the Ca2+/CaM-dependent protein kinase kinase β (CaMKKβ)-AMP-activated protein kinase (AMPK)-dynamin-related protein 1 (DRP1) signaling pathway, which interacts with mitochondrial fission protein 1 (FIS1) and mitochondrial dynamics proteins of 49 kDa (MiD49) to promote mitochondrial fission. PRRSV infection, alongside mitochondrial fission, triggers mitophagy via the PTEN-induced putative kinase 1 (PINK1)-Parkin RBR E3 ubiquitin (Parkin) pathway, promoting cellular glycolysis and excessive lactate production to facilitate its own replication. This study reveals the mechanism by which mitochondrial Ca2+ regulates mitochondrial function during PRRSV infection, providing new insights into the interplay between the virus and host cell metabolism.

DOI: https://doi.org/10.1371/journal.ppat.1012872
Cell Metab. 2025 Jan 03. pii: S1550-4131(24)00480-7. [Epub ahead of print]

Itaconate transporter SLC13A3 confers immunotherapy resistance via alkylation-mediated stabilization of PD-L1.

Yizeng Fan, Weichao Dan, Yuzhao Wang, Zhiqiang Ma, Yanlin Jian, Tianjie Liu, Mengxing Li, Zixi Wang, Yi Wei, Bo Liu, Peng Ding, Yuzeshi Lei, Chendong Guo, Jin Zeng, Xiaolong Yan, Wenyi Wei, Lei Li.

  Itaconate is a metabolite catalyzed by cis-aconitate decarboxylase (ACOD1), which is mainly produced by activated macrophages and secreted into the extracellular environment to exert complex bioactivity. In the tumor microenvironment, itaconate is concentrated and induces an immunosuppressive response. However, whether itaconate can be taken up by tumor cells and its mechanism of action remain largely unclear. Here, we identified solute carrier family 13 member 3 (SLC13A3) as a key protein transporting extracellular itaconate into cells, where it elevates programmed cell death ligand 1 (PD-L1) protein levels and decreases the expression of immunostimulatory molecules, thereby promoting tumor immune evasion. Mechanistically, itaconate alkylates the cysteine 272 residue on PD-L1, antagonizing PD-L1 ubiquitination and degradation. Consequently, SLC13A3 inhibition enhances the efficacy of anti-CTLA-4 (cytotoxic T lymphocyte-associated antigen-4) immunotherapy and improves the overall survival rate in syngeneic mouse tumor models. Collectively, our findings identified SLC13A3 as a key transporter of itaconate and revealed its immunomodulatory role, providing combinatorial strategies to overcome immunotherapy resistance in tumors.

Keywords:  IRG1; PD-L1; SLC13A3; immunotherapy; itaconate

DOI:  https://doi.org/10.1016/j.cmet.2024.11.012
Cell Rep. 2025 Jan 11. pii: S2211-1247(24)01550-X. [Epub ahead of print]44(1): 115199

IL-7 promotes integrated glucose and amino acid sensing during homeostatic CD4+ T cell proliferation.

Seema Bachoo, Nancy Gudgeon, Rebecca Mann, Victoria Stavrou, Emma L Bishop, Audrey Kelly, Alejandro Huerta Uribe, Jordan Loeliger, Corina Frick, Oliver D K Maddocks, Paul Lavender, Christoph Hess, Sarah Dimeloe.

  Interleukin (IL)-7 promotes T cell expansion during lymphopenia. We studied the metabolic basis in CD4+ T cells, observing increased glucose usage for nucleotide synthesis and oxidation in the tricarboxylic acid (TCA) cycle. Unlike other TCA metabolites, glucose-derived citrate does not accumulate upon IL-7 exposure, indicating diversion into other processes. In agreement, IL-7 promotes glucose-dependent histone acetylation and chromatin accessibility, notable at the loci of the amino acid-sensing Ragulator complex. Consistently, the expression of its subunit late endosomal/lysosomal adaptor, MAPK and mTOR activator 5 (LAMTOR5) is promoted by IL-7 in a glucose-dependent manner, and glucose availability determines amino acid-dependent mechanistic target of rapamycin (mTOR) activation, confirming integrated nutrient sensing. LAMTOR5 deletion impairs IL-7-mediated T cell expansion, establishing that glycolysis in the absence of Ragulator activation is insufficient to support this. Clinically, CD4+ T cells from stem cell transplant recipients demonstrate coordinated upregulation of glycolytic and TCA cycle enzymes, amino acid-sensing machinery, and mTOR targets, highlighting the potential to therapeutically target this pathway to fine-tune lymphopenia-induced T cell proliferation.

Keywords:  IL-7; Immunology; Metabolism; T cell; T lymphocyte; mTOR; metabolism; nutrient sensing; proliferation

DOI:  https://doi.org/10.1016/j.celrep.2024.115199
Sci Rep. 2025 Jan 15. 15(1): 2056

Two-photon NAD(P)H-FLIM reveals unperturbed energy metabolism of Ascaris suum larvae, in contrast to host macrophages upon artemisinin derivatives exposure.

Zaneta D Musimbi, Arkadi Kundik, Jürgen Krücken, Anja E Hauser, Sebastian Rausch, Peter H Seeberger, Raluca Niesner, Ruth Leben, Susanne Hartmann.

Soil-transmitted helminths (STH) are widespread, with Ascaris lumbricoides infecting millions globally. Malaria and STH co-infections are common in co-endemic regions. Artemisinin derivatives (ARTs)-artesunate, artemether, and dihydroartemisinin-are standard malaria treatments and are also known to influence the energy metabolism of parasites, tumors, and immune cells. Herein, we explore the potential of ARTs to influence ascariasis either by directly targeting larvae or indirectly by modifying macrophage responses. Ascaris suum third-stage larvae and porcine IL-4 polarized (M2-like) macrophages were exposed to ARTs in vitro, and their metabolism was evaluated using two-photon NAD(P)H-FLIM. Both larvae and M2-like macrophages exhibited a steady-state bioenergetic profile of high oxidative phosphorylation and low anaerobic glycolysis. In A. suum larvae, two metabolically distinct regions were identified, with particularly high DUOX activity in the pharynx compared to the midgut; however, ARTs did not alter these profiles. In contrast, exposure of M2-like macrophages to ARTs induced a metabolic shift towards high anaerobic glycolysis and reduced metabolic activity, suggesting a possible indirect effect of ARTs on the helminth infection. Overall, two-photon NAD(P)H-FLIM proved to be a powerful tool for studying specific metabolic pathways in Ascaris larvae and host macrophages, offering valuable insights into the metabolic mechanisms of drug action on both parasite and host.

DOI: https://doi.org/10.1038/s41598-025-85780-y
Immunometabolism (Cobham). 2025 Jan;7(1): e00055

La dolce vita: fueling chimeric antigen receptor (CAR) T cells with Glut1 to improve therapeutic efficacy.

Karen Slattery, David K Finlay, Phillip K Darcy.

  The approval of chimeric antigen receptor (CAR) T cell therapies for the treatment of hematological cancers has marked a new era in cancer care, with seven products being FDA approved since 2017. However, challenges remain, and while profound effects are observed initially in myeloma, the majority of patients relapse, which is concomitant with poor CAR T cell persistence. Similarly, the efficacy of CAR T cell therapy is limited in solid tumors, largely due to tumor antigen heterogeneity, immune evasion mechanisms, and poor infiltration and persistence. In this recent study, Guerrero et al endeavor to improve the efficacy of human CAR T cells by overexpressing the glucose transporter GLUT1 and show that GLUT1 overexpressing CAR T cells have improved capacity to persist and control tumor burden in vivo.

Keywords:  Glut1; cancer; chimeric antigen receptor T cells; cytokines; glucose; glycolysis; metabolism; tumor

DOI:  https://doi.org/10.1097/IN9.0000000000000055
J Virol. 2025 Jan 16. e0211024

Vaccinia growth factor-dependent modulation of the mTORC1-CAD axis upon nutrient restriction.

Lara Dsouza, Anil Pant, Blake Pope, Zhilong Yang.

  The molecular mechanisms by which vaccinia virus (VACV), the prototypical member of the poxviridae family, reprograms host cell metabolism remain largely unexplored. Additionally, cells sense and respond to fluctuating nutrient availability, thereby modulating metabolic pathways to ensure cellular homeostasis. Understanding how VACV modulates metabolic pathways in response to nutrient signals is crucial for understanding viral replication mechanisms, with the potential for developing antiviral therapies. In this study, we establish the importance of de novo pyrimidine synthesis during VACV infection. We report the significance of vaccinia growth factor (VGF), a viral early protein and a homolog of cellular epidermal growth factor (EGF), in enabling VACV to phosphorylate the key enzyme CAD of the de novo pyrimidine pathway at serine 1859, a site known to positively regulate CAD activity. Although nutrient-poor conditions typically inhibit mTORC1 activation, VACV activates CAD via the mTORC1-S6K1 signaling axis in a VGF-dependent manner, especially upon glutamine and asparagine limitation. However, unlike its cellular homolog EGF, the VGF peptide alone, in the absence of VACV infection, has minimal ability to activate CAD. This suggests the involvement of other viral factors yet to be identified. Our research provides a foundation for understanding the regulation of a significant metabolic pathway, de novo pyrimidine synthesis during VACV infection, shedding new light on viral regulation under distinct nutritional environments. This study not only has the potential to contribute to the advancement of antiviral treatments but also improve the development of VACV as an oncolytic agent and vaccine vector.IMPORTANCEViruses often reprogram host cell metabolism to facilitate replication. How poxviruses, such as the prototype member, vaccinia virus (VACV), modulate host cell metabolism is not well understood. Understanding how VACV affects these metabolic pathways is key to learning about viral replication and developing antiviral treatments. This study highlights the importance of de novo pyrimidine synthesis during VACV infection. We found that the vaccinia growth factor (VGF), a viral protein similar to the cellular epidermal growth factor (EGF), helps VACV activate the enzyme CAD of the de novo pyrimidine pathway. Upon nutrient limitation, VGF is needed for the activation of CAD through mTORC1-S6K signaling. VGF peptide alone is unable to activate this pathway independent of infection, suggesting the involvement of other viral factor(s). Our research not only sheds light on how VACV regulates metabolism but also holds promise for improving VACV as a cancer treatment and vaccine.

Keywords:  CAD; asparagine; glutamine; mTORC1; metabolism; nutrient stress; nutrition; poxvirus; pyrimidine; vaccinia virus

DOI:  https://doi.org/10.1128/jvi.02110-24
bioRxiv. 2024 Apr 13. pii: 2024.04.11.589145. [Epub ahead of print]

Triglyceride metabolism controls inflammation and APOE4 -associated disease states in microglia.

Roxan A Stephenson, Kory R Johnson, Linling Cheng, Linda G Yang, Jessica T Root, Jaanam Gopalakrishnan, Han-Yu Shih, Priyanka S Narayan.

Microglia modulate their cell state in response to various stimuli. Changes to cellular lipids often accompany shifts in microglial cell state, but the functional significance of these metabolic changes remains poorly understood. In human induced pluripotent stem cell-derived microglia, we observed that both extrinsic activation (by lipopolysaccharide treatment) and intrinsic triggers (the Alzheimer's disease-associated APOE4 genotype) result in accumulation of triglyceride-rich lipid droplets. We demonstrate that lipid droplet accumulation is not simply concomitant with changes in cell state but rather necessary for microglial activation. We discovered that both triglyceride biosynthesis and catabolism are needed for the transcription and secretion of proinflammatory cytokines and chemokines in response to extrinsic stimuli. Additionally, we reveal that triglyceride biosynthesis and catabolism are necessary for the activation-associated phagocytosis of multiple substrates including the disease-associated amyloid-beta peptide. In microglia harboring the Alzheimer's disease risk APOE4 genotype, triglyceride-rich lipid droplets accumulate even in the absence of any external stimuli. Inhibiting triglyceride biosynthesis in APOE4 microglia not only modifies the transcription of immune response genes but also attenuates disease-associated transcriptional states. This work establishes that triglyceride metabolism is necessary for microglia to respond to extrinsic activation. In APOE4 microglia, this metabolic process modulates both immune signaling and a disease-associated transcriptional state. Importantly, our work identifies metabolic pathways that can be used to tune microglial immunometabolism in APOE4- associated disease.

DOI: https://doi.org/10.1101/2024.04.11.589145
Nat Commun. 2025 Jan 13. 16(1): 630

Increased SOAT2 expression in aged regulatory T cells is associated with altered cholesterol metabolism and reduced anti-tumor immunity.

Mingjiong Zhang, Jiahua Cui, Haoyan Chen, Yifan Cheng, Qiaoyu Chen, Feng Zong, Xiao Lu, Lang Qin, Yu Han, Xingwang Kuai, Yuxing Zhang, Minjie Chu, Shuangshuang Wu, Jianqing Wu.

Immune functions decline with aging, leading to increased susceptibility to various diseases including tumors. Exploring aging-related molecular targets in elderly patients with cancer is thus highly sought after. Here we find that an ER transmembrane enzyme, sterol O-acyltransferase 2 (SOAT2), is overexpressed in regulatory T (Treg) cells from elderly patients with lung squamous cell carcinoma (LSCC), while radiomics analysis of LSCC patients associates increased SOAT2 expression with reduced immune infiltration and poor prognosis. Mechanically, ex vivo human and mouse Treg cell data and in vivo mouse tumor models suggest that SOAT2 overexpression in Treg cells promotes cholesterol metabolism by activating the SREBP2-HMGCR-GGPP pathway, leading to enhanced Treg suppresser functions but reduced CD8+ T cell proliferation, migration, homeostasis and anti-tumor immunity. Our study thus identifies a potential mechanism responsible for altered Treg function in the context of immune aging, and also implicates SOAT2 as a potential target for tumor immunotherapy.

DOI: https://doi.org/10.1038/s41467-025-56002-w
Nat Commun. 2025 Jan 10. 16(1): 584

Tracheal tuft cells release ATP and link innate to adaptive immunity in pneumonia.

Noran Abdel Wadood, Monika I Hollenhorst, Mohamed Ibrahem Elhawy, Na Zhao, Clara Englisch, Saskia B Evers, Mahana Sabachvili, Stephan Maxeiner, Amanda Wyatt, Christian Herr, Ann-Kathrin Burkhart, Elmar Krause, Daniela Yildiz, Anja Beckmann, Soumya Kusumakshi, Dieter Riethmacher, Markus Bischoff, Sandra Iden, Sören L Becker, Brendan J Canning, Veit Flockerzi, Thomas Gudermann, Vladimir Chubanov, Robert Bals, Carola Meier, Ulrich Boehm, Gabriela Krasteva-Christ.

Tracheal tuft cells shape immune responses in the airways. While some of these effects have been attributed to differential release of either acetylcholine, leukotriene C4 and/or interleukin-25 depending on the activating stimuli, tuft cell-dependent mechanisms underlying the recruitment and activation of immune cells are incompletely understood. Here we show that Pseudomonas aeruginosa infection activates mouse tuft cells, which release ATP via pannexin 1 channels. Taste signaling through the Trpm5 channel is essential for bacterial tuft cell activation and ATP release. We demonstrate that activated tuft cells recruit dendritic cells to the trachea and lung. ATP released by tuft cells initiates dendritic cell activation, phagocytosis and migration. Tuft cell stimulation also involves an adaptive immune response through recruitment of IL-17A secreting T helper cells. Collectively, the results provide a molecular framework defining tuft cell dependent regulation of both innate and adaptive immune responses in the airways to combat bacterial infection.

DOI: https://doi.org/10.1038/s41467-025-55936-5