bims-imicid 2025-08-03 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2025–08–03
35 papers selected by
Dylan Ryan, University of Cambridge

NAD + metabolism and function in innate and adaptive immune cells.
Immunometabolism of macrophages in the bone microenvironment: a new perspective for bone healing therapy.
Itaconic Acid: A Regulator of Immune Responses and Inflammatory Metabolism.
Regulation of airway fumarate by host and pathogen promotes Staphylococcus aureus pneumonia.
Pseudomonas aeruginosa-derived extracellular vesicles enhance macrophage aerobic glycolysis that fuels inflammation.
Phosphoglycerate mutase regulates Treg differentiation through control of serine synthesis and one-carbon metabolism.
How lactate and lactylation shape the immunity system in atherosclerosis (Review).
Macrophages in chronic infections: regulation and remodeling.
The source of dietary fat influences anti-tumour immunity in obese mice.
CARMIL2 deficiency disrupts activation-induced metabolic reprogramming in T cells, and is partially rescued by glutamine supplementation.
High-fat diet impairs microbial metabolite production and aggravates influenza A infection.
Metabolic Reprogramming in Respiratory Viral Infections: A Focus on SARS-CoV-2, Influenza, and Respiratory Syncytial Virus.
Polyamines regulate adaptive antitumor immunity by functional specialization of regulatory T cells.
Linking mitochondria, fatty acids and HSC expansion during infection: implications for aging and metabolic diseases.
IDO1-AhR axis increases T regulatory cells in Plasmodium vivax malaria infection.
Ginkgolic acid inhibits CD8+ T cell activation and induces ferroptosis by lactate dehydrogenase A to exert immunosuppressive effect.
Single-Cell RNA-Seq Revealed the Immune Microenvironment Reprogramming by Dexmedetomidine Treatment in Ischemic Stroke.
Dual Isotopologue Profiling of Bacterial Pathogens and their Host Cells: Metabolic Adaptation of Human Macrophages and Fallopian Tube Cells to Intracellular Chlamydia trachomatis.
ACLY inhibition promotes tumour immunity and suppresses liver cancer.
The RNA-binding protein RRP1 brakes macrophage one-carbon metabolism to suppress autoinflammation.
Gasdermin-D-mediated epithelial-immune circuit synchronizes nutrient absorption and host defense in the small intestine.
Host-microbe interactions in NAD+ metabolism.
Tryptophan metabolism and the intestinal microbiota: Implications for inflammatory bowel disease.
Lactylation and viral infections: A novel link between metabolic reprogramming and immune regulation.
Research progress on immunometabolism and gut microbiota in cryptococcal meningitis: mechanisms and therapeutic implications.
Metabolic and Epigenetic Control of CD8+ T Cell Exhaustion: The Acetate-to-Citrate Switch.
Microglia-specific Ido2 deficiency attenuates ictogenesis in the TMEV model of viral encephalitis.
Gut substrate trap of D-lactate from microbiota improves blood glucose and fatty liver disease in obese mice.
Manipulation of the nucleotide pool in human, bacterial and plant immunity.
Metabolomic stratification of shock: pathophysiological insights for personalized critical care.
Metabolic diseases and Kupffer cell's plasticity.
PFKFB2-Driven Glycolysis Promotes Dendritic Cell Maturation and Exacerbates Acute Lung Injury.
An untargeted metabolomics analysis in feces and brain of Orthoflaviviruses-infected mice.
Dietary lipids induce PPARd and BCL6 to repress macrophage IL-23 induction after intestinal injury and LPS exposure.
Multi-omics profiling reveals infectious bursal disease virus-induced alterations in gene expression and metabolism in chicken bursa of fabricius.

J Inflamm (Lond). 2025 Aug 01. 22(1): 30

NAD + metabolism and function in innate and adaptive immune cells.

Rebecca Mann, Victoria Stavrou, Sarah Dimeloe.

Nicotinamide adenine dinucleotide (NAD+) plays a central role in cellular metabolism and energy production, supporting many biological processes. Recent studies highlight the significance of NAD + in regulation of immune cell function, with implications for our understanding of immune homeostasis, inflammation, and disease. This review reports our current understanding on the role of NAD + in the immune system, specifically in macrophages and T cells, facilitating their metabolic reprogramming during differentiation and activation. It offers an overview of NAD + biosynthesis within these immune cells, describes its role in the modulation of immune cell metabolism and effector function, and highlights potential therapeutic applications of NAD + modulation in immunological disorders including autoimmune diseases and cancer.

DOI: https://doi.org/10.1186/s12950-025-00457-7
J Adv Res. 2025 Jul 29. pii: S2090-1232(25)00576-4. [Epub ahead of print]

Immunometabolism of macrophages in the bone microenvironment: a new perspective for bone healing therapy.

Chenyu Wang, Qihang Wu, Luyao Zhuang, Yiqi Chen, Qiu Zhang, Yinuo Wu, Mingyang Jin, Jiansen Miao, Xiangyang Wang, Jiake Xu, Haiming Jin.

   BACKGROUND: Immunometabolism, the regulation of immune cell function through metabolic pathways, has emerged as a key focus in regenerative medicine. Traditional bone healing therapies primarily target the osteoblast-osteoclast regulatory axis, overlooking the metabolic reprogramming of immune cells (e.g., macrophages) and limiting regenerative efficiency. Macrophages orchestrate bone healing through dynamic shifts between proinflammatory (M1-like) and reparative (M2-like) metabolic phenotypes. Recent studies have shown that their immunometabolic transitions govern the sequential phases of bone healing. Therefore, targeting macrophage immunometabolism may offer a novel therapeutic paradigm for bone regeneration.
AIM OF REVIEW: This review summarizes recent advances in understanding how macrophage metabolism regulates bone healing, emphasizing the critical role of immunometabolism in resolving inflammation and regenerating tissue throughout the repair process. By integrating insights from the fields of cellular metabolism, microenvironmental signals, and biomaterial science, this review aims to offer an integrative perspective on how targeting macrophage metabolic control could serve as a therapeutic strategy to enhance bone regeneration.
KEY SCIENTIFIC CONCEPTS OF REVIEW: This review addresses five core concepts. First, it delineates the spatiotemporal roles and phenotypic shifts of macrophages in the different phases of bone healing. Second, it explores how the reprogrammed metabolism of glucose, lipids, and amino acids underlies macrophage polarization and function. Third, it emphasizes how microenvironmental cues, including cytokines, metabolic intermediates, and microbiota-derived metabolites, modulate macrophage immunometabolism. Fourth, it summarizes emerging therapeutic strategies designed to regulate macrophage metabolism for bone regeneration, such as cell-based therapies, immunomodulatory hydrogels, and nanotechnologies. Finally, it identifies major challenges in this field. These include the temporal-spatial complexity of immunometabolism, the lack of human-relevant models, the emerging concepts of cross-system regulation, and the technological limitations in targeted regulation. Together, these insights provide a conceptual basis for future precision immunometabolic interventions in bone repair.

Keywords:  Bone healing; Bone regeneration; Immunometabolism; Macrophages; Metabolic reprogramming; Microenvironment

DOI:  https://doi.org/10.1016/j.jare.2025.07.046
Curr Issues Mol Biol. 2025 Jul 09. pii: 534. [Epub ahead of print]47(7):

Itaconic Acid: A Regulator of Immune Responses and Inflammatory Metabolism.

Kai Ma, Pei Zhou, Wei Zhang, Liwu Zeng, Kaixiong Tao, Peng Zhang.

  This article reviews the multifaceted roles of itaconate in immune regulation and inflammatory metabolism. Itaconic acid is a dicarboxylic acid with anti-inflammatory, antioxidant, and anti-tumor properties. It is initially produced by the heating decomposition of citric acid and is closely related to the tricarboxylic acid cycle. In immune regulation, itaconate regulates macrophage function through a variety of mechanisms, including metabolic reprogramming, polarization regulation, inhibition of cytokine production, and regulation of oxidative stress. It can also affect the function of T cells and B cells. In terms of inflammatory metabolism, itaconate can regulate the production of inflammatory factors, inhibit the activity of succinate dehydrogenase, and affect cellular energy metabolism and lipid metabolism. Its mechanism of action involves the inhibition of succinate dehydrogenase, covalent modification of proteins, influence on epigenetic modification, and playing a role through the G protein-coupled receptor OXGR1 (Oxoglutarate Receptor 1). Itaconic acid derivatives have shown good effects in anti-inflammation and anti-oxidation and have broad application prospects in clinical treatment, including the treatment of inflammatory diseases, anti-tumor and anti-microbial infection. However, the long-term safety and side effects of itaconic acid as a therapeutic agent still need to be further studied. Future studies will further explore the synthesis and function of itaconic acid in different cell types, its physiological effects in non-inflammatory conditions, and its potential application in clinical treatment in order to develop new therapeutic strategies and improve the treatment effect of chronic inflammatory and metabolism-related diseases.

Keywords:  IRG1; NLRP3; Nrf2; SDH; immunomodulation; macrophages

DOI:  https://doi.org/10.3390/cimb47070534
Nat Commun. 2025 Aug 01. 16(1): 7050

Regulation of airway fumarate by host and pathogen promotes Staphylococcus aureus pneumonia.

Ying-Tsun Chen, Zihua Liu, Dario Fucich, Stefano G Giulieri, Zhe Liu, Ridhima Wadhwa, Gustavo Rios, Henning Henschel, Nupur Tyagi, Françios A B Olivier, Ian R Monk, Shivang S Shah, Shwetha H Sridhar, Marija Drikic, Colleen Bianco, Gaurav K Lohia, Ayesha Z Beg, Paul J Planet, Ian A Lewis, Robert Sebra, Ana Traven, Abderrahman Hachani, Timothy P Stinear, Benjamin P Howden, Jeffrey M Boyd, Sebastian A Riquelme, Chu Wang, Alice Prince, Tania Wong Fok Lung.

Staphylococcus aureus is a leading cause of healthcare-associated pneumonia, contributing significantly to morbidity and mortality worldwide. As a ubiquitous colonizer of the upper respiratory tract, S. aureus must undergo substantial metabolic adaptation to achieve persistent infection in the distinctive microenvironment of the lung. We observed that fumC, which encodes the enzyme that converts fumarate to malate, is highly conserved with low mutation rates in S. aureus isolates from chronic lung infections. Fumarate, a pro-inflammatory metabolite produced by macrophages during infection, is regulated by the host fumarate hydratase (FH) to limit inflammation. Here, we demonstrate that fumarate, which accumulates in the chronically infected lung, is detrimental to S. aureus, blocking primary metabolic pathways such as glycolysis and oxidative phosphorylation (OXPHOS). This creates a metabolic bottleneck that drives staphylococcal FH (FumC) activity for airway adaptation. FumC not only degrades fumarate but also directs its utilization into critical pathways including the tricarboxylic acid (TCA) cycle, gluconeogenesis and hexosamine synthesis to maintain metabolic fitness and form a protective biofilm. Itaconate, another abundant immunometabolite in the infected airway enhances FumC activity, in synergy with fumarate. In a mouse model of pneumonia, a ΔfumC mutant displays significant attenuation compared to its parent and complemented strains, particularly in fumarate- and itaconate-replete conditions. Our findings underscore the pivotal role of immunometabolites in promoting S. aureus pulmonary adaptation.

DOI: https://doi.org/10.1038/s41467-025-62453-y
Front Microbiol. 2025 ;16 1619101

Pseudomonas aeruginosa-derived extracellular vesicles enhance macrophage aerobic glycolysis that fuels inflammation.

Chun Li, Jing Peng, Lihua Xiao, Haiying Wu, Jing Chen, Nian Chen.

  Outer membrane vesicles (OMVs) derived from Pseudomonas aeruginosa drive inflammation by metabolically reprogramming macrophages to favor aerobic glycolysis. This study shows that OMVs trigger this metabolic shift via Toll-like receptors 2 and 4 (TLR2/4)-dependent activation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway. OMV-stimulated macrophages exhibited increased glucose uptake, lactate production, and expression of key glycolytic enzymes, resulting in a higher extracellular acidification rate and a lower oxygen consumption rate. Inhibition of the PI3K/Akt pathway reversed these metabolic changes. Crucially, this metabolic reprogramming was required for OMV-induced secretion of pro-inflammatory cytokines, as inhibition of glycolysis via 2-deoxy-D-glucose treatment attenuated the inflammatory response both in vitro and in vivo. These findings reveal that P. aeruginosa OMVs control metabolism in macrophages through the TLR2/4-PI3K/Akt axis to promote a pro-inflammatory state and identifies glycolysis as a potential therapeutic target for bacteria-associated inflammatory diseases.

Keywords:  Pseudomonas aeruginosa; aerobic glycolysis; inflammation; outer membrane vesicle; toll-like receptor

DOI:  https://doi.org/10.3389/fmicb.2025.1619101
Elife. 2025 Jul 28. pii: RP104423. [Epub ahead of print]14

Phosphoglycerate mutase regulates Treg differentiation through control of serine synthesis and one-carbon metabolism.

Wesley H Godfrey, Judy J Lee, Shruthi Shanmukha, Kaho Cho, Xiaojing Deng, Chandra Shekar R Ambati, Vasanta Putluri, Abu Hena Mostafa Kamal, Paul M Kim, Nagireddy Putluri, Michael D Kornberg.

  The differentiation and suppressive functions of regulatory CD4 T cells (Tregs) are supported by a broad array of metabolic changes, providing potential therapeutic targets for immune modulation. In this study, we focused on the regulatory role of glycolytic enzymes in Tregs and identified phosphoglycerate mutase (PGAM) as being differentially overexpressed in Tregs and associated with a highly suppressive phenotype. Pharmacologic or genetic inhibition of PGAM reduced Treg differentiation and suppressive function while reciprocally inducing markers of a pro-inflammatory, T helper 17 (Th17)-like state. The regulatory role of PGAM was dependent on the contribution of 3-phosphoglycerate (3 PG), the PGAM substrate, to de novo serine synthesis. Blocking de novo serine synthesis from 3 PG reversed the effect of PGAM inhibition on Treg polarization, while exogenous serine directly inhibited Treg polarization. Additionally, altering serine levels in vivo with a serine/glycine-free diet increased peripheral Tregs and attenuated autoimmunity in a murine model of multiple sclerosis. Mechanistically, we found that serine limits Treg polarization by contributing to one-carbon metabolism and methylation of Treg-associated genes. Inhibiting one-carbon metabolism increased Treg polarization and suppressive function both in vitro and in vivo in a murine model of autoimmune colitis. Our study identifies a novel physiologic role for PGAM and highlights the metabolic interconnectivity between glycolysis, serine synthesis, one-carbon metabolism, and epigenetic regulation of Treg differentiation and suppressive function.

Keywords:  PGAM; T cell biology; Treg; glycolysis; immunology; immunometabolism; inflammation; mouse; phosphoglycerate mutase; serine synthesis

DOI:  https://doi.org/10.7554/eLife.104423
Int J Mol Med. 2025 Oct;pii: 163. [Epub ahead of print]56(4):

How lactate and lactylation shape the immunity system in atherosclerosis (Review).

Yan Xiong, Jie Zhou, Junru Wang, Hui Huang.

  Atherosclerosis is a leading cause of cardiovascular diseases, causing significant morbidity and mortality. This review article examines the role of lactate and lactylation in atherosclerosis, a chronic inflammatory disease closely linked to lipid metabolism and immune system activation. Lactate, a metabolic byproduct and signaling molecule, has emerged as a key regulator of immune cell functions and epigenetic modifications. The article explores the mechanisms through which lactate and lactylation influence macrophage polarization, T‑cell differentiation and B‑cell metabolism, highlighting their complex dual roles in the progression of atherosclerosis. By modulating metabolic reprogramming, functional polarization and epigenetic regulation, lactate and lactylation significantly impact plaque formation and stability. These findings provide a foundation for developing novel therapeutic strategies targeting lactate metabolism and lactylation pathways.

Keywords:  atherosclerosis; epigenetic modifications; immune system; lactate; lactylation; metabolic reprogramming

DOI:  https://doi.org/10.3892/ijmm.2025.5604
Front Immunol. 2025 ;16 1594988

Macrophages in chronic infections: regulation and remodeling.

Hongle Cui, Min Wang, Sitan Jiao, Sirui Tian, Hui Liu, Bo Luo.

  Macrophages, as a critical component of innate immune cells, exhibit significant plasticity. When confronted with danger signals such as pathogens or microenvironmental alterations, macrophages can differentiate into various phenotypes and functions to safeguard the host. However, numerous pathogens manipulate macrophage metabolic pathways to modify their functional expression, facilitating immune evasion and ensuring long-term survival during chronic infections. Therefore, the role of macrophage metabolic reprogramming in chronic infections has received growing attention. This review elucidates the primary metabolic pathways of macrophages and their association with polarization. It examines how pathogens modulate macrophage functional expression through metabolic reprogramming to sustain chronic infection. Additionally, it delineates how macrophage metabolic reprogramming in chronic infections reconfigures the microenvironment through interaction with other immune cells and its contribution to trained immunity.

Keywords:  chronic infection; immune regulation; macrophages; metabolic reprogramming; polarization

DOI:  https://doi.org/10.3389/fimmu.2025.1594988
Nat Metab. 2025 Jul 25.

The source of dietary fat influences anti-tumour immunity in obese mice.

Britta Kunkemoeller, Hannah Prendeville, Claire McIntyre, Ayantu Temesgen, Rόisín M Loftus, Conghui Yao, Lydia Dyck, Linda V Sinclair, Christina Rollings, Aaron Douglas, Gerard Pernes, Kathleen A J Mitchelson, Cathal Harmon, Mathilde Raverdeau, Ross Ward, Harry Kane, Jaclyn Kline, Katie L O'Brien, Martin Brennan, Frances Smith, Brenneth Stevens, Helen M Roche, Ed C Lavelle, David K Finlay, Doreen A Cantrell, Edward T Chouchani, Susan Kaech, Evanna L Mills, Marcia Haigis, Lydia Lynch.

Obesity increases the risk of many cancers and impairs the anti-tumour immune response. However, little is known about whether the source or composition of dietary fat affects tumour growth or anti-tumour immunity in obesity. Here, we show that high-fat diets (HFDs) derived from lard, beef tallow or butter accelerate tumour growth in a syngeneic model of melanoma, but HFDs based on coconut oil, palm oil or olive oil do not, despite equivalent obesity. Using butter-based and palm oil-based HFDs as examples, we find that these dietary fat sources differentially regulate natural killer and CD8 T cell infiltration and function within the tumour microenvironment, governed by distinct effects on the plasma metabolome and intracellular metabolism. We identify diet-related lipid intermediates, namely long-chain acylcarnitine species, as immunosuppressive metabolites enriched in mice fed butter compared to palm oil HFD. Together, these results highlight the significance of diet in maintaining a healthy immune system and suggest that modifying dietary fat may improve cancer outcomes in obesity.

DOI: https://doi.org/10.1038/s42255-025-01330-w
J Allergy Clin Immunol. 2025 Jul 28. pii: S0091-6749(25)00806-1. [Epub ahead of print]

CARMIL2 deficiency disrupts activation-induced metabolic reprogramming in T cells, and is partially rescued by glutamine supplementation.

Mona Kabha, Maya Liaks-Bohnick, Fadia Zagairy, Orna Atar, Mira Hamed, Michael Ziv, Nada Danial-Farran, Morad Khayat, Orly Ishach, Yael Dinur-Schejter, Vered Molho-Pessach, Ido Somekh, Shirly Frizinsky, Efrat Bar-Ilan, Shoshana Greenberger, NaserEddin Adeeb, Raz Somech, Polina Stepansky, Noga Ron-Harel, Eran Cohen-Barak.

   BACKGROUND: T-cell activation requires signaling through the T-cell receptor and costimulatory molecules, including CD28, triggering metabolic reprogramming to support growth and proliferation of the activating T -cell. CARMIL2, a scaffold protein, facilitates CD28-mediated signaling. Individuals with CARMIL2 mutations experience inborn errors of immunity, leading to T-cell dysfunction and severe infectious and inflammatory comorbidities. However, how CARMIL2 deficiency impacts T cell metabolic reprogramming remains unknown.
OBJECTIVE: To investigate how CARMIL2 deficiency affects activation-induced metabolic reprogramming in T-cells.
METHODS: CD4+ T-cells were isolated from patients with CARMIL2 deficiency and matched healthy controls (HC). Transcriptomic profile was analyzed by bulk RNA sequencing and whole-cell metabolomics by liquid chromatography-mass spectrometry (LC-MS/MS). Activation markers and signaling pathways were measured by flow cytometry. These approaches informed identification of specific amino acids for rescue experiments.
RESULTS: Nine patients with CARMIL2 deficiency and sixteen age-and sex-matched healthy controls were recruited. RNA sequencing of CD4+ T-cells revealed decreased expression of genes associated with metabolic activity, including mTOR signaling, glycolysis, one-carbon metabolism, and glutamine metabolism. Whole cell metabolomics reinforced these results and highlighted glutamine deficiency as a potential driver of the observed metabolic phenotype. Glutamine supplementation restored NF-kB and mTOR activity, as measured by p-65 and RPS phosphorylation, respectively, and upregulated the expression of IL17A in CARMIL2-mutated CD4+ T cells.
CONCLUSIONS: CARMIL2 deficiency disrupts T-cell metabolic reprogramming and was partially rescued ex-vivo with glutamine supplementation. These findings highlight a potential therapeutic approach targeting metabolism to improve immune function in individuals with CARMIL2 deficiency.

Keywords:  CARMIL2; Glutamine; Metabolism; T -cell; mTOR

DOI:  https://doi.org/10.1016/j.jaci.2025.07.018
Cell Commun Signal. 2025 Jul 31. 23(1): 359

High-fat diet impairs microbial metabolite production and aggravates influenza A infection.

Franziska Hornung, Harini K SureshKumar, Laura Klement, Yasmina Reisser, Christoph Wernike, Vivien Nischang, Paul M Jordan, Oliver Werz, Carsten Hoffmann, Bettina Löffler, Stefanie Deinhardt-Emmer.

   BACKGROUND: Alterations in the gut microbiom can significantly impact various regions in the human body, including the pulmonary tract. This study investigates alterations in the gut microbiome during a high-fat diet (HFD), particularly short-chain fatty acids (SCFAs), and how these metabolites affect lung infection caused by Influenza A virus (IAV).
METHODS: We used a HFD-mouse model to evaluate gut microbiota composition, SCFA levels, and pulmonary outcomes following IAV infection. Microbial changes were analyzed via taxonomic and functional profiling and SCFA levels were measured from non-obese and obese serum donors. Ultimately, acetate's effects were tested ex vivo in human precision-cut lung slices (PCLS) and in vitro in pulmonary epithelial cells. Mechanistic studies investigated the involvement of the SCFA receptor free fatty acid receptor 2 (FFAR2) and intracellular antiviral pathways.
RESULTS: Our data indicates an increased Firmicutes/Bacteroidetes ratio of the gut microbiome and an altered carbohydrate metabolism, leading to reduced SCFA production. Infected HFD mice showed increased IAV titers and sustained microbial alterations. Interestingly, acetate demonstrated antiviral effects in both the human PCLS model and pulmonary cells with an reduced viral replication. These effects depended on FFAR2, which also acts as an IAV co-receptor, as acetate treatment led to FFAR2 internalization and influenced host cell metabolism in our in vitro data.
CONCLUSION: HFD alters the SCFA production, reducing acetate levels in the gut microbiome. This reduction may lead to higher viral loads and worsened disease in HFD mice infected with IAV. Our findings indicate that acetate has antiviral effects during IAV infection in both a human ex vivo lung model and pulmonary epithelial cells. Here, acetate prevents viral entry and affects the cellular metabolic state and antiviral response. Understanding these mechanisms could provide new targets for preventing and treating viral infections in individuals with diet-related health issues.

Keywords:  Acetate; FFAR2; Gut-lung-axis; High-fat diet; Influenza A virus; Interferon response; Microbial metabolites; Short-chain fatty acids

DOI:  https://doi.org/10.1186/s12964-025-02367-w
Biomolecules. 2025 Jul 16. pii: 1027. [Epub ahead of print]15(7):

Metabolic Reprogramming in Respiratory Viral Infections: A Focus on SARS-CoV-2, Influenza, and Respiratory Syncytial Virus.

Jordi Camps, Simona Iftimie, Andrea Jiménez-Franco, Antoni Castro, Jorge Joven.

  Respiratory infections caused by severe acute respiratory syndrome coronavirus 2, influenza virus, and respiratory syncytial virus pose significant global health challenges, leading to high morbidity and mortality, particularly in vulnerable populations. Despite their distinct virological characteristics, these viruses exploit host cellular metabolism to support replication, modulate immune responses, and promote disease progression. Emerging evidence shows that they induce metabolic reprogramming, shifting cellular energy production toward glycolysis to meet the bioenergetic demands of viral replication. Additionally, alterations in lipid metabolism, including enhanced fatty acid synthesis and disrupted cholesterol homeostasis, facilitate viral entry, replication, and immune evasion. The dysregulation of mitochondrial function and oxidative stress pathways also contributes to disease severity and long-term complications, such as persistent inflammation and immune exhaustion. Understanding these metabolic shifts is crucial for identifying new therapeutic targets and novel biomarkers for early disease detection, prognosis, and patient stratification. This review provides an overview of the metabolic alterations induced by severe acute respiratory syndrome coronavirus 2, influenza virus, and respiratory syncytial virus, highlighting shared and virus-specific mechanisms and potential therapeutic interventions.

Keywords:  infectious diseases; influenza; metabolism; respiratory infections; respiratory syncytial virus; severe acute respiratory syndrome coronavirus 2; viral infections

DOI:  https://doi.org/10.3390/biom15071027
Immunity. 2025 Jul 25. pii: S1074-7613(25)00316-4. [Epub ahead of print]

Polyamines regulate adaptive antitumor immunity by functional specialization of regulatory T cells.

Georg Bündgen, Alexander Ulges, Jan Pietruschka, Natalia Truong-Andrievici, Matthias Klein, Karolina Romaniuk, Fabian Schmitt, Mathias Hagen, Joachim G Seebass, Lenart Zezlina, Lara Stein, Hans Christian Probst, Ute Distler, Stefan Tenzer, Michael Lohoff, Addi J Romero-Olmedo, Henrik Mei, Toszka Bohn, Michael Delacher, Thierry Schmidlin, Matthias M Gaida, Ivan Dikic, Charles Imbusch, Hansjörg Schild, Tobias Bopp.

  In cancer, metabolic changes and uncontrolled tumor growth alter nutrient availability, impacting antitumor immune responses. Regulatory T (Treg) cells are a subset of T cells with immunosuppressive properties that can also influence tissue homeostasis and repair. However, it is not known how these functions are molecularly controlled and whether they are influenced by tumor metabolism. Here, we report that excessive release of polyamines in the tumor microenvironment directs the functional polarization of Treg cells toward immunosuppression in a protein kinase CK2 (CK2)-dependent manner. Polyamine deprivation as well as genetic or pharmacological inhibition of CK2 activity in Treg cells induced tissue reparative properties in Treg cells that orchestrated efficient antitumor type 2 immune responses and coordinated tissue repair mechanisms to support tumor eradication. These findings suggest that targeted modulation of Treg cell functions could be leveraged as a potential avenue for cancer therapy.

Keywords:  FOXP3; cancer; immune evasion; immunometabolism; kinase; metabolism; polyamines; regulatory T cells; tissue repair; tumor immunology

DOI:  https://doi.org/10.1016/j.immuni.2025.07.007
Stem Cells. 2025 Jul 29. pii: sxaf053. [Epub ahead of print]

Linking mitochondria, fatty acids and HSC expansion during infection: implications for aging and metabolic diseases.

Katherine Hampton, Alyssa Polski-Delve, Charlotte Hellmich, Stuart A Rushworth.

  In steady state, hematopoietic stem cells (HSCs) reside quiescently in their hypoxic niche with minimal mitochondrial activity, maintaining characteristically low levels of reactive oxygen species (ROS) and instead favoring glycolysis to meet their low energy requirements. However, stress, such as acute infection, triggers a state of emergency hematopoiesis during which HSCs expand more rapidly to produce up to ten-fold more downstream differentiated immune cells. To cope with this demand, HSCs increase their energy production by switching from low ATP-yielding glycolysis to high ATP-yielding mitochondrial oxidative phosphorylation. It is this metabolic switch that enables rapid HSC expansion and differentiation into downstream progeny to increase the immune cell pool and effectively clear the infection. This metabolic switch relies on the sufficient availability of healthy mitochondria as well as fuel in the form of free fatty acids to drive the necessary production of cellular components. This concise review aims to focus on how HSCs increase their mitochondrial content and fuel ATP production via fatty acid oxidation and the impact of HSC dysfunction during aging and other metabolic diseases.

Keywords:  Acute myelogenous leukemia (AML); Adult haematopoietic stem cells; Bone marrow; Stem cell expansion; adipose

DOI:  https://doi.org/10.1093/stmcls/sxaf053
Front Immunol. 2025 ;16 1474447

IDO1-AhR axis increases T regulatory cells in Plasmodium vivax malaria infection.

Rafaella Oliveira Dos Santos, Nani Oliveira Carvalho, Thiago Barros do Nascimento de Morais, Wlademir Braga Salgado Sobrinho, Maria Geuziane Soares da Cruz, Elaine Speziali de Faria, Fernanda Fortes de Araújo, Vanessa Peruhype Magalhães, Stefanie Costa Pinto Lopes, Adriana Malheiros, Adolfo José da Mota, Helton da Costa Santiago, Paulo Afonso Nogueira, Andréa Teixeira de Carvalho, Marcus Vinícius Guimarães de Lacerda, Pritesh Lalwani.

   Introduction: Malaria remains a significant public health challenge in Brazil, where Plasmodium vivax (P. vivax) is the predominant species. Dysregulated immune responses contribute substantially to malaria pathogenesis. Indoleamine 2,3-dioxygenase (IDO) mediates the catabolism of tryptophan (TRP) into kynurenine (KYN), an immunosuppressive metabolite implicated in immune tolerance. This study aimed to investigate the role of TRP catabolism and regulatory T cells (Tregs) during P. vivax infection.
Methods: Peripheral blood mononuclear cells (PBMCs) were stimulated in vitro with P. vivax-infected erythrocyte (Pv-iE) lysate to assess IDO-1 expression, KYN/TRP ratio, cytokine production, and Treg frequency. The effects of pharmacological inhibition of IDO, MyD88, and aryl hydrocarbon receptor (AhR) pathways were evaluated. Additionally, plasma KYN/TRP ratio, Treg frequencies, and cytokine levels were measured in patients with acute P. vivax infection and compared between individuals experiencing their first malaria episode and those with previous infections.
Results: Stimulation with Pv-iE lysate increased IDO-1 expression in CD14+ cells, elevated KYN/TRP ratio, and induced pro-inflammatory cytokine production. IDO inhibition reduced KYN/TRP ratio and Treg frequencies upon Pv-iE stimulation. MyD88 inhibition decreased both IDO-1 expression and KYN/TRP ratio. IDO and AhR inhibition reduced Treg frequencies and CD4+ T cell proliferation. Patients with acute P. vivax malaria exhibited elevated KYN/TRP ratios and increased Treg frequencies, with a positive correlation between these parameters. Individuals with prior malaria episodes showed lower Treg frequencies, plasma IFN-γ, and KYN/TRP ratios compared to those with primary infections.
Discussion: These findings highlight the role of IDO-mediated TRP catabolism and innate immune signaling in promoting a tolerogenic phenotype during P. vivax infection. The study provides novel insights into mechanisms that may contribute to immune regulation, chronic inflammation, and tolerance during malaria, with potential implications for therapeutic interventions.

Keywords:  Plasmodium vivax; aryl hydrocarbon receptor; immune tolerance; indoleamine 2,3-dioxygenase; kynurenine; malaria; regulatory T cells; tryptophan catabolism

DOI:  https://doi.org/10.3389/fimmu.2025.1474447
J Pharm Anal. 2025 Jul;15(7): 101233

Ginkgolic acid inhibits CD8+ T cell activation and induces ferroptosis by lactate dehydrogenase A to exert immunosuppressive effect.

Sai Zhang, Zhuyuan Si, Mingkun Liu, Wenjuan Hao, Tong Xia, Zeyang Liu, Gang Du, Bin Jin.

  In the context of the development of transplant oncology, it is of great clinical significance to find a drug with both antitumor and immunosuppressive effects for liver transplantation patients with hepatocellular carcinoma (HCC). The antitumor effect of ginkgolic acid (GA) has been confirmed, and some studies suggest that GA may also have an immunosuppressive effect. The immunosuppressive effect of GA was evaluated by histopathology, T-cell subpopulation, and cytokine detection in rat liver transplantation and mouse cardiac transplantation models, and transcriptomic and metabolomic analysis was used to explore the underlying mechanism of the GA immunosuppressive effect. Metabolites, activation, and ferroptosis markers of CD8+ T cells were detected in vivo and in vitro. Based on rat liver transplantation and mouse cardiac transplantation models, the immunosuppressive effect of GA was first confirmed by histopathology, T-cell subpopulation, and cytokine detection. In the mouse cardiac transplantation model, transcriptomics combined with metabolomics demonstrated for the first time that GA inhibited lactate dehydrogenase A (LDHA) expression and pyruvate metabolism in CD8+ T cells. It was confirmed in vivo and in vitro that GA inhibited pyruvate metabolism of CD8+ T cells through LDHA, inhibiting their activation and inducing ferroptosis. Overexpression of LDHA partially reversed the effect of GA on the metabolism, activation, and ferroptosis of CD8+ T cells in vitro. GA mediates metabolic reprogramming through LDHA to inhibit the activation and induce ferroptosis of CD8+ T cells to exert an immunosuppressive effect, which lays an experimental foundation for the future clinical application of its immunosuppressive effect.

Keywords:  CD8+ T cell; Ferroptosis; Ginkgolic acid; Immunosuppressive; LDHA

DOI:  https://doi.org/10.1016/j.jpha.2025.101233
Mol Neurobiol. 2025 Aug 01.

Single-Cell RNA-Seq Revealed the Immune Microenvironment Reprogramming by Dexmedetomidine Treatment in Ischemic Stroke.

Wenyi Zhang, Xingyun Wang, Bing Zhang, Minjiang Yi, Yinzhong Lu, Shuyan Wang, Junfeng Zhang, Guangming Zhang.

  Prior studies have indicated that the neuroprotective effects of dexmedetomidine (DEX) in cerebral ischemia, yet its mechanisms remain elusive. Using multi-omics approaches (RNA-seq, metabolomics, and single-cell RNA-seq), we discovered that DEX pretreatment significantly reduced cerebral infarct volume and improved neurological function in middle cerebral artery occlusion (MCAO) mice compared to PBS controls. Single-cell analysis revealed that DEX preserved microglial phagocytic function via metabolic regulation, leading to reduced microglial apoptosis and attenuated immune dysregulation-including decreased chemotactic neutrophils, B cells, and antigen-presenting fibroblasts. These cellular changes were corroborated by transcriptomic and metabolic profiles showing suppressed apoptosis and inflammation. Mechanistically, we identified HK2 (hexokinase 2) as a key regulator of microglial homeostasis, with its expression correlating with microglial migration, proliferation, and inflammation, findings validated in oxygen-glucose deprivation models. Collectively, our results demonstrate that DEX protects against cerebral ischemia-reperfusion injury by maintaining immune microenvironment homeostasis through microglial metabolic reprogramming mediated by HK2. This multi-omics study provides mechanistic insights supporting DEX's translational potential in ischemic stroke therapy.

Keywords:  Apoptosis; Dexmedetomidine; MCAO; ScRNA-seq; Stroke

DOI:  https://doi.org/10.1007/s12035-025-05237-1
ACS Chem Biol. 2025 Jul 28.

Dual Isotopologue Profiling of Bacterial Pathogens and their Host Cells: Metabolic Adaptation of Human Macrophages and Fallopian Tube Cells to Intracellular Chlamydia trachomatis.

Sandra Radziej, Adriana Moldovan, Mark Klöpfer, Werner Goebel, Thomas Rudel, Wolfgang Eisenreich.

Chlamydia trachomatis is a Gram-negative bacterium that utilizes multiple host-derived substrates to ensure its intracellular survival. In this study, human fallopian tube (HFT) cells, and human macrophages polarized toward a pro-inflammatory (M1-like) or anti-inflammatory (M2-like) state were infected with C. trachomatis and cocultivated in the presence of [U-13C6]glucose. Samples were analyzed in toto by dual isotopologue profiling with a focus on specific bacterial and host-specific metabolites. Immunofluorescence and ultrastructural analysis, as well as detection of the bacteria-specific metabolites (i.e., the branched-chain iso-C15:0 and anteiso-C15:0 fatty acids, and the cell wall component meso-diaminopimelic acid), confirmed that HFT cells and M2-like, but not M1-like macrophages, allow replication of C. trachomatis. The 13C-labeling patterns in these metabolites reflected their known biosynthetic pathways, but also upstream carbon fluxes via the uptake of host amino acids and glucose phosphate into the intracellular bacteria. Differential analysis of infected vs noninfected host cells showed that, in HFT cells and M2-like macrophages, the chlamydial infection upregulated glucose uptake into the host cells, glucose conversion into pyruvate and lactate via host glycolysis, and release of lactate into the medium. The rates of these processes were higher in HFT cells than in M2-like macrophages. We here establish dual isotopologue profiling as a suitable method to analyze the dynamics of host-intracellular pathogen interactions.

DOI: https://doi.org/10.1021/acschembio.5c00268
Nature. 2025 Jul 30.

ACLY inhibition promotes tumour immunity and suppresses liver cancer.

Jaya Gautam, Jianhan Wu, James S V Lally, Jamie D McNicol, Russta Fayyazi, Elham Ahmadi, Daniela Carmen Oniciu, Spencer Heaton, Roger S Newton, Sonia Rehal, Dipankar Bhattacharya, Fiorella Di Pastena, Binh Nguyen, Celina M Valvano, Logan K Townsend, Suhrid Banskota, Battsetseg Batchuluun, Maria Joy Therese Jabile, Alice Payne, Junfeng Lu, Eric M Desjardins, Naoto Kubota, Evangelia E Tsakiridis, Bejal Mistry, Alex Aganostopoulos, Vanessa Houde, Ann Dansercoer, Koen H G Verschueren, Savvas N Savvides, Joanne A Hammill, Ksenia Bezverbnaya, Paola Muti, Theodoros Tsakiridis, Wenting Dai, Lei Jiang, Yujin Hoshida, Mark Larché, Jonathan L Bramson, Scott L Friedman, Kenneth Verstraete, Dongdong Wang, Gregory R Steinberg.

Immunosuppressive tumour microenvironments are common in cancers such as metabolic dysfunction-associated steatohepatitis (MASH)-driven hepatocellular carcinoma (HCC) (MASH-HCC)1-3. Although immune cell metabolism influences effector function, the effect of tumour metabolism on immunogenicity is less understood4. ATP citrate lyase (ACLY) links substrate availability and mitochondrial metabolism with lipid biosynthesis and gene regulation5-7. Although ACLY inhibition shows antiproliferative effects in various tumours, clinical translation has been limited by challenges in inhibitor development and compensatory metabolic pathways8-12. Here, using a mouse model of MASH-HCC that mirrors human disease, genetic inhibition of ACLY in hepatocytes and tumours reduced neoplastic lesions by over 70%. To evaluate the therapeutic potential of this pathway, a novel small-molecule ACLY inhibitor, EVT0185 (6-[4-(5-carboxy-5-methyl-hexyl)-phenyl]-2,2-dimethylhexanoic acid), was identified via phenotypic screening. EVT0185 is converted to a CoA thioester in the liver by SLC27A2 and structural analysis by cryo-electron microscopy reveals that EVT0185-CoA directly interacts with the CoA-binding site of ACLY. Oral delivery of EVT0185 in three mouse models of MASH-HCC dramatically reduces tumour burden as monotherapy and enhances efficacy of current standards of care including tyrosine kinase inhibitors and immunotherapies. Transcriptomic and spatial profiling in mice and humans linked reduced tumour ACLY with increases in the chemokine CXCL13, tumour-infiltrating B cells and tertiary lymphoid structures. The depletion of B cells blocked the antitumour effects of ACLY inhibition. Together, these findings illustrate how targeting tumour metabolism can rewire immune function and suppress cancer progression in MASH-HCC.

DOI: https://doi.org/10.1038/s41586-025-09297-0
Nat Commun. 2025 Jul 25. 16(1): 6880

The RNA-binding protein RRP1 brakes macrophage one-carbon metabolism to suppress autoinflammation.

Yumei Zhou, Mengxuan Li, Ke Jin, Mingyue Wen, Hua Qin, Yue Xu, Chunmei Wang, Xuan Zhang, Xuetao Cao.

RNA-binding proteins (RBP) are important for the initiation and resolution of inflammation, so better understanding of RBP-RNA interactions and their crosstalk with metabolism may provide alternate targets to controlling inflammation. Here we establish global RNA-protein interactome purification (GRPIp) to profile the RBP landscape in inflammatory primary macrophages and identify ribosomal RNA processing 1 (RRP1) as a suppressor of inflammatory innate responses. Mechanistically, RRP1 binds nuclear thymidylate synthetase (Tyms) transcript and decreases TYMS expression post-transcriptionally in inflammatory macrophages, consequently suppressing folate metabolism cycle and inhibiting one-carbon metabolism-driven inflammation. Myeloid-specific RRP1-deficient mice develop severe experimental arthritis with increased pro-inflammatory cytokines and immunologic injury. Meanwhile, in patients with rheumatoid arthritis, RRP1 expression in peripheral blood monocytes negatively correlates with TYMS expression and serum IL-1β levels. Our results thus suggest that RRP1 acts as an anti-inflammatory factor through braking one-carbon metabolism post-transcriptionally, thereby implicating potential strategies for controlling autoinflammation.

DOI: https://doi.org/10.1038/s41467-025-62173-3
Immunity. 2025 Jul 22. pii: S1074-7613(25)00309-7. [Epub ahead of print]

Gasdermin-D-mediated epithelial-immune circuit synchronizes nutrient absorption and host defense in the small intestine.

Qianzhou Yu, Danlu Jiang, Tianming Zhao, Yuelin Guan, Jian Zhang, Dehang Yang, Ruya Sun, Weiwei Yu, Zhen Wang, Sheng Chen, Mobai Li, Tianyi Hu, Qiqi Deng, Xiaoyang Lu, Yidong Yang, Mengfei Chang, Liheng Du, Xue Zhang, Zhexu Chi, Di Wang.

  The small intestine (SI) absorbs nutrients and acts as a barrier against pathogens. Diet enables the absorptive function of the SI while maintaining immune homeostasis. But how the SI transmits nutritional signals to the immune response and adapts to dietary intake remains unclear. Here, we demonstrated that epithelial gasdermin D (GSDMD) in the SI facilitated the absorptive function of enterocytes, subsequently empowering an epithelial-immune cooperation to modulate host defense. Unlike its pyroptotic function, GSDMD determines the absorptive versus the defensive zonation of enterocytes and promotes brush border assembly. This diet-induced, GSDMD-mediated adaptation promoted lipid absorption and subsequently rewired enterocyte metabolism to support intraepithelial γδ T lymphocytes (γδ T-IELs), thereby enhancing barrier function. Impairment of this GSDMD-mediated circuit exacerbated barrier-dysfunction-associated enteritis. Our results reveal how epithelial cells and lymphocytes co-adapt to nutrient signals in the SI, thereby adjusting the equilibrium between nutrient uptake and host defense in response to environmental change.

Keywords:  GSDMD; brush border assembly; enteritis; enterocyte; feeding pattern; host defense; intraepithelial γδ T lymphocytes; nutrient absorption; nutritional imbalance; the small intestine

DOI:  https://doi.org/10.1016/j.immuni.2025.06.019
Trends Mol Med. 2025 Jul 24. pii: S1471-4914(25)00167-4. [Epub ahead of print]

Host-microbe interactions in NAD+ metabolism.

Xiaoyue Wu, Igor Shats, Xiaoling Li.

  Nicotinamide adenine dinucleotide (NAD+) is an essential cofactor for hundreds of biochemical reactions. Targeting NAD+ metabolism has been investigated as a therapeutic strategy for various metabolic, neurogenerative, and inflammatory conditions, including aging and cancer. Here we highlight recent advances in host-microbiome interactions regulating NAD+ metabolism and discuss their therapeutic potential.

Keywords:  anticancer therapy; deamidated NAD(+) biosynthesis; dietary NAD(+) precursors; gut microbiota

DOI:  https://doi.org/10.1016/j.molmed.2025.07.001
Microbiol Res. 2025 Jul 24. pii: S0944-5013(25)00239-3. [Epub ahead of print]300 128280

Tryptophan metabolism and the intestinal microbiota: Implications for inflammatory bowel disease.

Xue Hua, Yongchao Chen, Sujuan Ding, Jun Fang.

  Tryptophan metabolism exerts a pivotal influence on inflammatory bowel disease (IBD) involving intestinal microbiota. Tryptophan (Trp) undergoes several metabolic processes that result in the formation of several bioactive compounds, such as 5-hydroxytryptamine (5-HT), kynurenine (KYN), and indole analogs, and these metabolites have significant roles in maintaining intestinal health and modulating immune function. The components and ability of the intestinal microbiota affect the metabolic balance of tryptophan, and dysbiosis may lead to disorders of tryptophan metabolism, which may exacerbate the condition of IBD. In this paper, we went over how the intestinal microbiota and tryptophan metabolism interact and the mechanism of tryptophan metabolism and its products in IBD, explored the regulatory roles of the aryl hydrocarbon receptor (AhR) signaling pathway, immune cells, and immune factors in this regard, and proposed a strategy for the treatment of IBD based on tryptophan metabolism. We also mentioned that tryptophan metabolites exhibit distinct functions between Crohn's disease (CD) and ulcerative colitis (UC), and vary across different stages of the disease. Looking forward to the future, in-depth study of the interaction between tryptophan metabolism and intestinal microbiota can give new ideas to the clinical management of IBD.

Keywords:  Inflammatory bowel disease; Intestinal microbiota; Mechanism of action; Therapeutic strategies; Tryptophan metabolism

DOI:  https://doi.org/10.1016/j.micres.2025.128280
PLoS Pathog. 2025 Jul;21(7): e1013366

Lactylation and viral infections: A novel link between metabolic reprogramming and immune regulation.

Shanshan Chen, Tongxue Qin, Shengrui Luo, Fengyi Wang, Feirong Chen, Hailun Wei, Yuting Wu, Rongfeng Chen, Wudi Wei, Jingzhen Lai, Hao Liang, Li Ye, Zongxiang Yuan, Junjun Jiang.

Post-translational modifications (PTMs) regulate protein structure, function, and interactions, playing pivotal roles in cellular processes and disease progression. Lactate, a byproduct of the Warburg effect, accumulates excessively during viral infections and functions as a signaling molecule, disrupting mitochondrial antiviral-signaling protein activity and facilitating viral immune evasion. Lactylation, a recently identified PTM derived from lactate metabolism, links cellular metabolism and immune regulation by modulating gene expression and metabolic reprogramming. It also serves as a mechanism for viruses to modulate host immunity. Despite its emerging importance, its role with respect to viruses infecting humans and animals remains poorly understood. Investigating its impact on metabolic, protein modifications, and immune signaling may reveal novel immune evasion strategies and therapeutic targets. This review aims to provide an overview of the fundamental features and regulatory functions of lactylation, explore its association with viral infections, and offer insights into how lactylation influences metabolic and immune responses during virus-host interactions.

DOI: https://doi.org/10.1371/journal.ppat.1013366
Front Neurosci. 2025 ;19 1622349

Research progress on immunometabolism and gut microbiota in cryptococcal meningitis: mechanisms and therapeutic implications.

Sha Wen, Mu Liu, Chengyu Pan, Linhai Zhang, Rong Yan, Zucai Xu.

  Cryptococcal meningitis (CM) is a fatal central nervous system infection caused by Cryptococcus neoformans breaching the blood-brain barrier (BBB), carrying a mortality rate approaching 100% in untreated individuals, while even survivors following treatment often experience neurological complications including optic nerve atrophy, memory impairment, hydrocephalus, and motor dysfunction. Current research has yet to fully elucidate the complex pathological mechanisms of CM, particularly leaving a significant gap in the systemic analysis within the dynamic interaction network of immunity, metabolism, and the gut microbiota. This article systematically integrates the interplay of immune responses, metabolic reprogramming, and the gut microbiome to reveal the pathogenesis of CM across multiple dimensions: in immune regulation, the phagocytic-inflammatory equilibrium in macrophages and CD4 + T cells defends against pathogen invasion, but hyperactivated immune responses may damage the BBB and exacerbate neural injury; metabolically, host iron overload induces ferroptosis, disrupting the BBB via lipid peroxidation, while inositol metabolism provides substrates for cryptococcal capsular synthesis, enhancing its virulence and promoting CNS invasion; the gut microbiota, meanwhile, modulates immune homeostasis via the "gut-brain axis," with its metabolites (e.g., short-chain fatty acids) enhancing BBB integrity and suppressing neuroinflammation through immunomodulation. We propose a combined therapeutic strategy of "immunomodulators + metabolic inhibitors + microbiota intervention," moving beyond traditional single-factor research paradigms to establish a multi-omics integrated framework for the precise treatment of CM-spanning molecular mechanisms to clinical translation-and propelling the field of neuroinfectious diseases towards a host-pathogen-microenvironment systemic regulation paradigm.

Keywords:  cryptococcal meningitis (CM); gut microbiota; gut-brain axis; immunity; metabolism

DOI:  https://doi.org/10.3389/fnins.2025.1622349
MedComm (2020). 2025 Aug;6(8): e70307

Metabolic and Epigenetic Control of CD8+ T Cell Exhaustion: The Acetate-to-Citrate Switch.

Xiaoyi Lei, Wei Zhang, Dunfang Zhang.

DOI: https://doi.org/10.1002/mco2.70307
Brain Behav Immun. 2025 Jul 23. pii: S0889-1591(25)00286-7. [Epub ahead of print]129 839-856

Microglia-specific Ido2 deficiency attenuates ictogenesis in the TMEV model of viral encephalitis.

Zoë A MacDowell Kaswan, Alexandra K Brooks, Myrna Hurtado, Emily Y Chen, Andrew J Steelman, Robert H McCusker.

  Viral encephalitis is a serious condition that causes acute neuroinflammation, neurodegeneration, cognitive deficits and behavioral changes, while putting patients at risk of developing seizures (ictogenesis) and post-encephalitis epilepsy. Intracerebral injection of C57BL/6 mice with Theiler's murine encephalomyelitis virus (TMEV) is a model of viral encephalitis that causes behavioral seizures along with substantial neurodegeneration and neuroinflammation. This model is considered a benchmark preclinical paradigm for the investigation of hippocampal-dependent viral ictogenesis and temporal lobe epilepsy. Inflammation-induced indolealine2,3-deoxygenase (Ido) 1 and 2 initiate the conversion of tryptophan into kynurenine, which is subsequently converted into downstream neuroactive metabolites with the ability to modify behavioral seizures. Ido1 and Ido2 have also been shown to have non-redundant roles in modulating several inflammatory diseases. We have previously shown that Ido1 deficiency increases TMEV-induced behavioral seizure incidence using wild type (WT, C57BL/6J) mice. Here, we extend those findings to Ido2 deficiencies. We find that Ido2KO (knockout) mice have equivalent TMEV-induced behavioral seizure incidence and hippocampal gene expression relative to wild type WT mice. However, while TMEV infection causes an increase in Iba1+ staining throughout the hippocampus (indicating microglial activation) this effect is ameliorated in Ido2KO mice. Microglia, the resident innate immune cells of the brain, are critical for TMEV clearance but may also contribute to ictogenesis. Therefore, based on Ido2-dependent differences in microglia activation, we examined TMEV-induced ictogenesis in mice with microglial-specific Ido1 and Ido2 deficiencies. We found that microglial Ido2, but not Ido1, deficiency reduced ictogenesis but caused minimal changes in hippocampal gene expression. In vitro treatments revealed that microglia respond to TMEV infection via inflammatory signals rather than directly to viral infection itself. In sum, we demonstrate that Ido2 plays a key role in microglial response to TMEV and that, when the effects of Ido2 deficiency are limited to microglia, Ido2 deficiency is protective against ictogenesis.

Keywords:  Encephalitis; Epilepsy; Ictogenesis; Ido1; Ido2; Indoleamine 2,3-dioxygenase; Inflammation; Microglia; Seizures; TMEV; Viral infection

DOI:  https://doi.org/10.1016/j.bbi.2025.07.017
Cell Metab. 2025 Jul 23. pii: S1550-4131(25)00328-6. [Epub ahead of print]

Gut substrate trap of D-lactate from microbiota improves blood glucose and fatty liver disease in obese mice.

Han Fang, Fernando F Anhê, Dana Kukje Zada, Nicole G Barra, Rodrigo Rodrigues E-Lacerda, Breanne T McAlpin, Ryan Wylie, Line Berthiaume, Étienne Audet-Walsh, Conor O'Dwyer, Peyman Ghorbani, Morgan D Fullerton, Claudia Gagnon, André Tchernof, André Marette, Jonathan D Schertzer.

  L-lactate participates in metabolism, including the Cori cycle, but less is known about D-lactate. We found that circulating D-lactate was higher in humans and mice with obesity. D-lactate increased hepatic glycogen, triglycerides, and blood glucose more than equimolar L-lactate in mice. Stable isotope analyses showed that D-lactate is metabolized in mice and in hepatocytes to pyruvate, TCA intermediates, lipids, and glucose. The gut microbiota is the main source of blood D-lactate. Colonization of mice with a bacterial strain that produced D-lactate elevated blood glucose more than an L-lactate producer. Oral delivery of a biocompatible polymer that traps gut D-lactate, forcing fecal excretion, lowered blood glucose and insulin resistance in obese mice in a polymer length- and dose-dependent manner. This D-lactate trap lowered hepatic inflammation and fibrosis in mice with metabolic dysfunction-associated fatty liver disease (MAFLD)/metabolic dysfunction-associated steatohepatitis (MASH). Therefore, microbial-derived D-lactate contributes to host glucose and lipid metabolism and can be trapped to improve metabolic disease during obesity.

Keywords:  diabetes; fibrosis; gut; inflammation; liver; metabolic dysfunction-associated steatotic liver disease; microbiome; obesity; polymer; postbiotics

DOI:  https://doi.org/10.1016/j.cmet.2025.07.001
Nat Rev Immunol. 2025 Jul 29.

Manipulation of the nucleotide pool in human, bacterial and plant immunity.

Dina Hochhauser, Rotem Sorek.

The cell-autonomous innate immune system is responsible for sensing and mitigating viral infection at the level of individual cells. Many of the mechanisms used by the cell-autonomous innate immune system in eukaryotic cells are ancient and have evolutionary roots in bacterial systems that defend against phage infection. Studies from recent years have shown that modification of the free nucleotide pool is central to many of these conserved immune mechanisms. In this Review, we explain how immune pathways manipulate the available pool of nucleotides to deprive viruses of molecules essential for their replication, how immune proteins chemically modify nucleotides to generate immune signalling molecules, and how cell-autonomous innate immune mechanisms produce altered nucleotides that poison viral replication. We also discuss the mechanisms used by viruses to antagonize nucleotide-based immunity. Finally, we explore the evolutionary logic of using nucleotides as building blocks for immune responses.

DOI: https://doi.org/10.1038/s41577-025-01206-w
Ann Intensive Care. 2025 Jul 31. 15(1): 109

Metabolomic stratification of shock: pathophysiological insights for personalized critical care.

Frederic Sangla, Karim Bendjelid, Federico Aletti, Vicente Ribas, Antoine Herpain, Bernardo Bollen Pinto, David Legouis.

   BACKGROUND: Shock, encompassing septic and cardiogenic etiologies, is a life-threatening condition associated with systemic inflammation, metabolic dysregulation, and high mortality in intensive care units. Traditional clinical markers often fail to capture the complexity of this syndrome, limiting personalized therapeutic approaches. Advances in metabolomics enable comprehensive analysis of metabolic disruptions, providing novel insights into shock pathophysiology. This study aimed to cluster critically ill patients with shock into metabolic phenotypes and investigate their associations with clinical severity.
RESULTS: We analyzed metabolomic profiles from 60 critically ill patients with shock at ICU admission using Uniform Manifold Approximation and Projection (UMAP) for dimensionality reduction and Density-Based Spatial Clustering of Applications with Noise (DBSCAN) for clustering. Three distinct clusters were identified: Cluster 1 (n = 13) exhibited the highest severity (median APACHE II: 29) and mortality (54%), with elevated biogenic amines, sugars, and sphingolipids, reflecting intense metabolic activation. Cluster 2 (n = 24), despite having low initial severity (median APACHE II: 25), demonstrated high mortality (38%) and was characterized by elevated glycerophospholipids and sphingolipids as in cluster 1, without enhanced biogenic amines and sugars, indicating inadaptive metabolic responses. Cluster 3 (n = 23) showed the lowest severity (median APACHE II: 22) and mortality (9%), with uniformly reduced metabolite levels, suggesting an adaptive metabolic profile.
CONCLUSIONS: Shock patients exhibit distinct metabolic phenotypes associated with clinical severity and outcomes. Metabolomic profiling offers a promising avenue for precision medicine in critical care by uncovering pathophysiological insights. Future research should validate these findings, identify practical biomarkers, and explore therapeutic interventions tailored to specific metabolic profiles.

Keywords:  55 in-hospital mortality; Cluster analysis; Mass spectrometry; Metabolomics; Septic shock

DOI:  https://doi.org/10.1186/s13613-025-01532-1
Immunometabolism (Cobham). 2025 Jul;7(3): e00066

Metabolic diseases and Kupffer cell's plasticity.

Francesca Fantini, Giuseppe Danilo Norata.

  Macrophages play a crucial role in the innate immune system. They are present in most tissues, where they contribute to maintain homeostasis. Kupffer cells have specialized immunometabolic functions that link immune regulation and metabolic homeostasis directly. This enables them to regulate hepatic metabolism by controlling lipid handling and inflammatory responses. Consequently, there is growing interest in developing strategies to selectively modulate the function, polarity, distribution, behavior, and phenotype of Kupffer cells depending on the pathophysiological context. Given their plasticity and contribution to metabolic dysfunction-associated steatotic liver disease (MASLD), it is of increasing interest to find strategies that can selectively modulate Kupffer cell's plasticity to control their distribution and phenotype depending on the pathophysiological context. This would modify their interaction with other cells in the liver niche, particularly hepatocytes, in the context of both atherosclerosis and MASLD. Future perspectives should focus on understanding how changes in the uptake capacity of Kupffer cells occur under conditions of lipid overload, and on exploring paracrine signals within the liver that can modulate their activation using advanced techniques such as high resolution spatial liver profiling.

Keywords:  Kupffer cells; cell plasticity; immunometabolism

DOI:  https://doi.org/10.1097/IN9.0000000000000066
Adv Sci (Weinh). 2025 Jul 30. e02428

PFKFB2-Driven Glycolysis Promotes Dendritic Cell Maturation and Exacerbates Acute Lung Injury.

Ding Yuan, Fang Yang, Linlin Hou, Yan Zhang, Xin Pang, Yuqi Du, Hongyi Yan, Huanzhou Zhu, Yue Cheng, Yue Wu, Pinpin Jiang, Mengnan Guo, Mengying Zhang, Jinjie Guo, Huihui Hao, Yong Jiang, Yi Li, Yanxia Gao.

  Acute lung injury (ALI) is a life-threatening condition with excessive immune activation and dysregulated inflammation. Dendritic cells (DCs) play a pivotal role in immune regulation; however, their exact contribution to ALI pathogenesis remains unclear. This study demonstrates that the upregulation of the glycolytic regulator 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2 (PFKFB2) by hypoxia-inducible factor-1α (HIF-1α) enhances glycolysis, drives DC maturation, and exacerbates inflammation, contributing to the pathogenesis of ALI. The findings reveal that HIF-1α directly binds to the PFKFB2 promoter and drives its transcription, leading to increased glycolysis, accelerated DC maturation, and amplified immune activation. In paraquat (PQ)-ALI and lipopolysaccharide (LPS)-ALI mouse models, DC-specific PFKFB2 knockout and DC-targeted delivery of HIF-1α inhibitor-loaded nanoparticles each significantly suppressed DC maturation and alleviated ALI severity. Analyses of lung tissues from patients with PQ poisoning, secondary bacterial pneumonia (2°BP), and Coronavirus Disease 2019 (COVID-19), as well as from normal controls, confirmed these findings, showing increased PFKFB2 expression and DC maturation during ALI. These findings highlight the HIF-1α-PFKFB2 signaling pathway as a critical regulator of glycolysis-driven DC maturation and immune activation, offering novel insights into immunometabolic regulation and a promising therapeutic target for ALI.

Keywords:  HIF‐1α; PFKFB2; acute lung injury; dendritic cells; glycolysis

DOI:  https://doi.org/10.1002/advs.202502428
BMC Microbiol. 2025 Jul 25. 25(1): 452

An untargeted metabolomics analysis in feces and brain of Orthoflaviviruses-infected mice.

Zhiwei Su, Ningze Sun, Chenghong Yin, Xiaoyan Zheng.

  Annually, millions of people are affected by mosquito-borne Orthoflavivirus infections. These include diseases caused by the Dengue virus (DENV), Japanese encephalitis virus (JEV), and Zika virus (ZIKV), posing a formidable challenge to global public health. This research aims to explore the potential role of the Gut-Brain Axis (GBA) in Orthoflavivirus infection, particularly focusing on key metabolites involved in the process of viral invasion into the central nervous system. Given the advantages of metabolomics technology in metabolite identification. Therefore, we employed an untargeted Liquid Chromatography-Mass Spectrometry (LC-MS) metabolomics platform to examine alterations in metabolite concentrations within the feces and brain tissues of mice infected with DENV, JEV, or ZIKV, as well as uninfected controls. The results showed that 225, 240, and 252 differential metabolites were identified in the fecal metabolome of DENV, JEV, and ZIKV infections, respectively, with amino acid metabolism and lipid metabolism being significantly disrupted. In the brain metabolome, 37, 81, and 18 differential metabolites were identified for DENV, JEV, and ZIKV infections, respectively, with lipid metabolism and purine metabolism being significantly disrupted. Amino acids with low abundance in viral proteins are significantly disrupted in the amino acid metabolism pathway, suggesting that Orthoflaviviruses adapt to its needs for synthesizing viral proteins by regulating the host's amino acid composition. The disruption of purine metabolism also implies the viral genome replication process occurring in the brain. Moreover, the disturbance of lipid metabolism is highly correlated with the biological function of the Orthoflavivirus envelope, where Sphingosine 1-phosphate (S1P) may be the key for Orthoflaviviruses to enter the human central nervous system via the GBA. This research is the first to explore the potential role of GBA in Orthoflavivirus infection through joint metabolomic analysis of fecal and brain tissue samples, providing new insights into viral invasion of the central nervous system. The findings not only elucidate the characteristics of viral infection from complementary perspectives of fecal and brain tissue samples, revealing associated metabolic changes, but also establish a foundation for subsequent identification of biomarkers to diagnose disease states-particularly for predicting central nervous system infection risks. The specific patterns revealed by fecal metabolomics analysis provide the theoretical basis for developing non-invasive predictive approaches to assess brain infection status in the future.

Keywords:   Orthoflavivirus ; Biomarkers; GBA; LC-MS; Metabolomics

DOI:  https://doi.org/10.1186/s12866-025-04192-0
Sci Rep. 2025 Jul 27. 15(1): 27344

Dietary lipids induce PPARd and BCL6 to repress macrophage IL-23 induction after intestinal injury and LPS exposure.

Ashleigh M Gil, Daniel F Zegarra-Ruiz, Wan-Jung Wu, Kendra Norwood, Adrien Assie, Buck S Samuel, Angela M Major, Gretchen E Diehl, Andrea A Hill McAlester.

Unresolved tissue damage is a common feature of Inflammatory Bowel Disease (IBD) that facilitates disease progression. Here, we showed that high animal fat diets (HFD), an environmental risk factor associated with IBD pathogenesis, suppress intestinal macrophage production of critical tissue repair responses after damage. This includes reduced IL-23 production, which drives downstream production of IL-22, which is needed for barrier repair. Indicating that dietary lipids interfere with responses to microbial molecules needed to induce barrier protective functions, we found oleic acid could directly suppress macrophage Il23a induction after lipopolysaccharide (LPS) treatment. Deleting the lipid transporter CD36 on macrophages restored the Il23a and Il22 response, reducing intestinal damage in HFD-fed DSS-treated mice. We found that CD36-mediated intracellular lipid accumulation, mainly oleic acid, in macrophages leads to peroxisome proliferator-activated receptor delta (PPARδ) release of the transcriptional repressor protein B-cell lymphoma 6 (BCL6). BCL6 suppresses Il23a transcription in microbe-exposed macrophages. The studies suggest dietary lipid modulation of the macrophage PPARδ/BCL6 transcriptional repressor complex is a key mechanism of fat-associated defects in intestinal damage repair and immune dysregulation. Overall, our findings provide new insights into dietary lipid contribution to intestinal disease progression and identify new potential therapeutic targets to decrease diet-associated risk for IBD.

DOI: https://doi.org/10.1038/s41598-025-12448-y
Vet Microbiol. 2025 Jul 16. pii: S0378-1135(25)00270-6. [Epub ahead of print]308 110635

Multi-omics profiling reveals infectious bursal disease virus-induced alterations in gene expression and metabolism in chicken bursa of fabricius.

Cuiping Song, Siyu Li, Yanmei Yuan, Wei Gao, Xusheng Qiu, Lei Tan, Yingjie Sun, Ning Tang, Yang Qu, Ying Liao, Chan Ding.

  Infectious Bursal Disease (IBD) is an acute, highly contagious disease caused by IBDV, characterized by inflammation, atrophy of the Bursa of Fabricius, and immunosuppression. This study infected 21-day-old SPF chickens with three IBDV strains (classical YZ, very virulent AH, and variant SD). On day 7 post-infection, bursa samples were collected for transcriptomic and metabolomic analyses. Metabolite profiles were analyzed using multivariate statistics, and KEGG enrichment analysis was used to identify dysregulated pathways, elucidating the transcriptional and metabolic responses in IBDV-infected bursa tissue. Transcriptomic analysis identified 1733 DEGs in the YZ group, 5731 in the AH group, and 84 in the SD group. Gene Ontology clustering of common SDE genes between virus-infected and control groups focused on cellular components, molecular functions, and biological processes；KEGG enrichment showed they were mainly involved in lipid-related metabolic pathways for the three IBDV subtypes. Metabolomic analysis detected 460 significantly changed metabolites per subtype after IBDV infection. Lipid metabolism disorders were associated with IBDV, involving L-carnitine and other substances；KEGG analysis indicated the main pathways were lipid-related, like arachidonic acid (AA) metabolism. Moreover, this study verified mRNA levels of cytokines, NLRP3 protein level, and AA content. IBDV infection induces differential gene expression related to host immune response and metabolic regulation at the transcriptomic level, with metabolomic changes mainly involving lipid metabolism. Integrating transcriptomics and metabolomics provides a comprehensive understanding of the host's response to IBDV infection.

Keywords:  Arachidonic acid; Infectious bursal disease virus; Metabolomics; NLRP3; Transcriptomics

DOI:  https://doi.org/10.1016/j.vetmic.2025.110635