bims-imicid 2025-04-06 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2025–04–06
39 papers selected by
Dylan Ryan, University of Cambridge

Gang of 3: How the Krebs cycle-linked metabolites itaconate, succinate, and fumarate regulate macrophages and inflammation.
A Self-Assembled Metabolic Regulator Reprograms Macrophages to Combat Cytokine Storm and Boost Sepsis Immunotherapy.
Metabolic Reprogramming in Stromal and Immune Cells in Rheumatoid Arthritis and Osteoarthritis: Therapeutic Possibilities.
Development of Itaconate Polymers Microparticles for Intracellular Regulation of Pro-Inflammatory Macrophage Activation.
Iron and energy metabolic interactions in Treg-mediated immune regulation.
Metabolic reprogram and T cell differentiation in inflammation: current evidence and future perspectives.
The metabolic drivers of IFN-γ release: glycolysis and acetyl CoA ride in the front seat.
The role of metabolite sensors in metabolism-immune interaction: New targets for immune modulation.
ABHD11 inhibition drives sterol metabolism to modulate T cell effector function and alleviate autoimmunity.
Mitochondria-dependent innate immunity: A potential therapeutic target in Flavivirus infection.
Crosstalk between metabolism and epigenetics during macrophage polarization.
Hexokinase2-engineered T cells display increased anti-tumor function.
The serine protease KLK7 promotes immune cell infiltration in visceral adipose tissue in obesity.
Foot-and-mouth disease virus activates glycolysis and hijacks HK2 to inhibit innate immunity and promote viral replication.
Role of metabolic transformation in cancer immunotherapy resistance: molecular mechanisms and therapeutic implications.
SOSTDC1 downregulation in CD4+ T cells confers protection against obesity-induced insulin resistance.
Spermidine restricts neonatal inflammation via metabolic shaping of polymorphonuclear myeloid-derived suppressor cells.
Impact of rosuvastatin on the memory potential and functionality of CD8+ T cells from people with HIV.
Srsf3-Dependent APA Drives Macrophage Maturation and Limits Atherosclerosis.
IgA2 ACPA Drives a Hyper-Inflammatory Phenotype in Macrophages via ATP Synthase and COX2.
Pathogen adaptation to lung metabolites.
RVG engineered extracellular vesicles-transmitted miR-137 improves autism by modulating glucose metabolism and neuroinflammation.
Lipid Metabolism and Immune Function: Chemical Tools for Insights into T-Cell Biology.
Restoring immune tolerance in pre-RA: immunometabolic dialogue between gut microbiota and regulatory T cells.
Gut microbial metabolite 4-hydroxybenzeneacetic acid drives colorectal cancer progression via accumulation of immunosuppressive PMN-MDSCs.
Immunometabolic analysis of primary murine group 2 innate lymphoid cells: a robust step-by-step approach.
Protein succinylome analysis identifies citrate synthase as a central regulator of osteoclast metabolic activity.
SIRT1 and SIRT3 Impact Host Mitochondrial Function and Host Salmonella pH Balance during Infection.
The Metabolomic Mind: Microbial Metabolite Programming of Microglia.
Metabolic reprogramming of tumor microenviroment by engineered bacteria.
Commensal-derived Trehalose Monocorynomycolate Triggers γδ T Cell-driven Protective Ocular Barrier Immunity.
Fusobacterium nucleatum Derived 3-Indolepropionic acid Promotes Colorectal Cancer Progression via Aryl Hydrocarbon Receptor Activation in Macrophages.
Cancer-cell-derived cGAMP limits the activity of tumor-associated CD8+ T cells.
Mycoplasma gallisepticum (MG) infection inhibits mitochondrial respiratory function in a wild songbird.
PGC-1α mediates migrasome secretion accelerating macrophage-myofibroblast transition and contributing to sepsis-associated pulmonary fibrosis.
Polyunsaturated Fatty Acid Imbalance-A Contributor to SARS CoV-2 Disease Severity.
Modulation of Host Immunity by Microbiome-Derived Indole-3-Propionic Acid and Other Bacterial Metabolites.
Retinoic acid enhances γδ T cell cytotoxicity in nasopharyngeal carcinoma by reversing immune exhaustion.
Metabolic adaptability and nutrient scavenging in Toxoplasma gondii: insights from ingestion pathway-deficient mutants.

Cell Metab. 2025 Mar 24. pii: S1550-4131(25)00107-X. [Epub ahead of print]

Gang of 3: How the Krebs cycle-linked metabolites itaconate, succinate, and fumarate regulate macrophages and inflammation.

Eva M Pålsson-McDermott, Luke A J O'Neill.

  The reprogramming of metabolic pathways and processes in immune cells has emerged as an important aspect of the immune response. Metabolic intermediates accumulate as a result of metabolic adaptations and mediate functions outside of metabolism in the regulation of immunity and inflammation. In macrophages, there has been a major focus on 3 metabolites linked to the Krebs cycle, itaconate, succinate, and fumarate, which have been shown to regulate multiple processes. Here, we discuss recent progress on these 3 metabolites with regard to their effect on macrophages in host defense and inflammatory diseases. We also consider the therapeutic opportunities presented from the mimicry of these metabolites or by targeting the enzymes that make or metabolize them in order to leverage the body's own anti-inflammatory response.

Keywords:  ETC; Krebs cycle; immunometabolism; immunometabolites; inflammation; therapeutic targets

DOI:  https://doi.org/10.1016/j.cmet.2025.03.004
Research (Wash D C). 2025 ;8 0663

A Self-Assembled Metabolic Regulator Reprograms Macrophages to Combat Cytokine Storm and Boost Sepsis Immunotherapy.

Junyan Zhuang, Yongrui Hai, Xintong Lu, Borui Sun, Renming Fan, Bingjie Zhang, Wenhui Wang, Bingxue Han, Li Luo, Le Yang, Chun Zhang, Minggao Zhao, Gaofei Wei.

Sepsis, a life-threatening inflammatory disorder characterized by multiorgan failure, arises from a dysregulated immune response to infection. Modulating macrophage polarization has emerged as a promising strategy to control sepsis-associated inflammation. The endogenous metabolite itaconate has shown anti-inflammatory potential by suppressing the stimulator of interferon genes (STING) pathway, but its efficacy is inhibited by hyperactive glycolysis, which sustains macrophage overactivation. Here, we revealed a critical crosstalk between the itaconate-STING axis and glycolysis in macrophage-mediated inflammation. Building on this interplay, we developed a novel nanoparticle LDO (lonidamine disulfide 4-octyl-itaconate), a self-assembled metabolic regulator integrating an itaconate derivative with the glycolysis inhibitor Lonidamine. By concurrently targeting glycolysis and STING pathways, LDO reprograms macrophages to restore balanced polarization. In sepsis models, LDO effectively attenuates CCL2-driven cytokine storms, alleviates acute lung injury, and significantly enhances survival via metabolic reprogramming. This study offers a cytokine-regulatory strategy rooted in immunometabolism, providing a foundation for the translational development of immune metabolite-based sepsis therapies.

DOI: https://doi.org/10.34133/research.0663
Eur J Immunol. 2025 Apr;55(4): e202451381

Metabolic Reprogramming in Stromal and Immune Cells in Rheumatoid Arthritis and Osteoarthritis: Therapeutic Possibilities.

Órlaith C Henry, Luke A J O'Neill.

  Metabolic reprogramming of stromal cells, including fibroblast-like synoviocytes (FLS) and chondrocytes, as well as osteoclasts (OCs), are involved in the inflammatory and degenerative processes underlying rheumatoid arthritis (RA) and osteoarthritis (OA). In RA, FLS exhibit mTOR activation, enhanced glycolysis and reduced oxidative phosphorylation, fuelling inflammation, angiogenesis, and cartilage degradation. In OA, chondrocytes undergo metabolic rewiring, characterised by mTOR and NF-κB activation, mitochondrial dysfunction, and increased glycolysis, which promotes matrix metalloproteinase production, extracellular matrix (ECM) degradation, and angiogenesis. Macrophage-derived immunometabolites, including succinate and itaconate further modulate stromal cell function, acting as signalling molecules that modulate inflammatory and catabolic processes. Succinate promotes inflammation whilst itaconate is anti-inflammatory, suppressing inflammatory joint disease in models. Itaconate deficiency also correlates inversely with disease severity in RA in humans. Emerging evidence highlights the potential of targeting metabolic processes as promising therapeutic strategies for connective tissue disorders.

Keywords:  arthritis; inflammation; metabolic reprogramming; metabolism; rheumatology

DOI:  https://doi.org/10.1002/eji.202451381
Adv Healthc Mater. 2025 Apr 04. e2405257

Development of Itaconate Polymers Microparticles for Intracellular Regulation of Pro-Inflammatory Macrophage Activation.

Kaitlyn E Woodworth, Zachary S C S Froom, Natasha D Osborne, Christian N Rempe, Brenden Wheeler, Kyle Medd, Neal I Callaghan, Huikang Qian, Abhinav P Acharya, Carlie Charron, Locke Davenport Huyer.

  Itaconate (IA) is an endogenous metabolite and a potent regulator of the innate immune system. It's use in immunomodulatory therapies has faced limitations due to challenges in controlled delivery and requirements of high extracellular concentrations for internalization of the highly polar small molecule to achieve its intracellular therapeutic activity. Microparticle (MP)-based delivery strategies are a promising approach for intracellular delivery of small molecule metabolites through macrophage phagocytosis and subsequent intracellular polymer degradation-based delivery. Toward the goal of intracellular delivery of IA, degradable polyester polymer- (poly(dodecyl itaconate)) based IA polymer microparticles (IA-MPs) are generated using an emulsion method, forming micron-scale (≈1.5 µm) degradable microspheres. IA-MPs are characterized with respect to their material properties and IA release kinetics to inform particle fabrication. Treatment of murine bone marrow-derived macrophages with an optimized particle concentration of 0.1 mg million-1 cells enables phagocytosis-mediated internalization and low levels of cytotoxicity. Flow cytometry demonstrates IA-MP-specific regulation of IA-sensitive inflammatory targets. Metabolic analyses demonstrate that IA-MP internalization inhibits oxidative metabolism and induced glycolytic reliance, consistent with the established mechanism of IA-associated inhibition of succinate dehydrogenase. This development of IA-based polymer microparticles provides a basis for additional innovative metabolite-based microparticle drug delivery systems for the treatment of inflammatory disease.

Keywords:  biomaterials; immunometabolism; inflammation; microparticles; polyester

DOI:  https://doi.org/10.1002/adhm.202405257
Front Immunol. 2025 ;16 1554028

Iron and energy metabolic interactions in Treg-mediated immune regulation.

Frédérique Savagner, Thomas Farge, Zoubida Karim, Meryem Aloulou.

  Immunometabolism, the study of how metabolic processes influence immune cell function, has emerged as a critical field in understanding the regulation of immune tolerance and the pathological mechanisms underlying autoimmune diseases. Intracellular metabolic pathways not only provide the necessary energy for immune cell survival and activity but also shape the differentiation, phenotype, proliferation, and effector functions of immune cells. This is particularly evident in CD4+ Foxp3+ regulatory T cells (Treg), which are pivotal for maintaining immune homeostasis and preventing autoimmune reactions. Strong experimental evidence highlights the profound impact of metabolism on Treg. Their anti-inflammatory function and ability to suppress excessive immune responses depend on the integration of metabolic cues with their transcriptional and signaling networks. Iron metabolism and mitochondrial dynamics are among the key factors influencing Treg function. This review focuses on how iron and mitochondrial metabolism shape Treg biology and function.

Keywords:  Foxp3; ROS; Treg; immunoregulation; iron; mitochondria

DOI:  https://doi.org/10.3389/fimmu.2025.1554028
Cell Death Discov. 2025 Mar 28. 11(1): 123

Metabolic reprogram and T cell differentiation in inflammation: current evidence and future perspectives.

Yuxin Shi, Hao Zhang, Changhong Miao.

T cell metabolism and differentiation significantly shape the initiation, progression, and resolution of inflammatory responses. Upon activation, T cells undergo extensive metabolic shifts to meet distinct functional demands across various inflammatory stages. These metabolic alterations are not only critical for defining different T cell subsets, but also for sustaining their activity in inflammatory environments. Key signaling pathways-including mTOR, HIF-1α, and AMPK regulate these metabolic adaptions, linking cellular energy states with T cell fate decisions. Insights into the metabolic regulation of T cells offer potential therapeutic strategies to manipulate T cell function, with implications for treating autoimmune diseases, chronic inflammation, and cancer by targeting specific metabolic pathways.

DOI: https://doi.org/10.1038/s41420-025-02403-1
J Immunol. 2025 Apr 03. pii: vkaf045. [Epub ahead of print]

The metabolic drivers of IFN-γ release: glycolysis and acetyl CoA ride in the front seat.

John Henderson, Steven O'Reilly.

  Interferon gamma (IFN-γ) is a pleotropic cytokine which is a central mediator of the immune response to pathogen infection, while also playing important roles in tumour suppression and the pathogenesis of various autoimmune diseases. Consequently, there is potential utility in the treatment of a number of pathological conditions via being able to modify IFN-γ secretion. T cells and natural killer (NK) cells are the primary IFN-γ sources, with metabolic rewiring prior to their activation and IFN-γ secretion in both a unifying feature. The mechanisms by which metabolic changes, particularly increased glycolysis, drive enhanced IFN-γ production are multi-faceted, but are likely focused on epigenetic changes via increased acetyl CoA levels which fuels histone acetylation. Herein, we discuss the mechanisms by which metabolic changes drive altered IFN-γ synthesis by immune cells.

Keywords:  STING; acetyl CoA; glycolysis; immunometabolism; interferon

DOI:  https://doi.org/10.1093/jimmun/vkaf045
Clin Transl Med. 2025 Apr;15(4): e70294

The role of metabolite sensors in metabolism-immune interaction: New targets for immune modulation.

Qiqing Yang, Ce Guo, Long Zhang.

  Recent advancements in immunometabolism have highlighted the critical role of metabolite sensors in regulating immune responses. Metabolites such as lactate, succinate, itaconate, and β-hydroxybutyrate influence immune cell function by interacting with specific sensors. These metabolites act as signaling molecules, linking cellular metabolic changes to immune responses. Lactate, a metabolite commonly produced under hypoxic conditions, has emerged as a major regulator of innate immunity. Key enzymes, including AARS1 and AARS2, function as intracellular lactate sensors, catalyzing lactylation on proteins like cGAS, which plays a central role in DNA sensing and immune activation. The lactylation of cGAS inhibits its activity, modulating immune responses by balancing inflammation and immune tolerance. Metabolite sensors, like MCT1, also contribute to immune modulation, particularly in cancer and chronic inflammatory diseases. Therapeutically, targeting these sensors offers potential for restoring immune function, especially in cancer immunotherapy. However, challenges in specificity, off-target effects, and long-term safety require further investigation. This article explores the emerging role of metabolite sensors in immune regulation, with a focus on lactate sensors, and outlines potential therapeutic strategies to enhance immune responses in metabolic diseases.

Keywords:  immune modulation; inhibitor research and development; lactylation; metabolite sensors

DOI:  https://doi.org/10.1002/ctm2.70294
bioRxiv. 2025 Mar 19. pii: 2025.03.19.643996. [Epub ahead of print]

ABHD11 inhibition drives sterol metabolism to modulate T cell effector function and alleviate autoimmunity.

Benjamin J Jenkins, Yasmin R Jenkins, Fernando M Ponce-Garcia, Chloe Moscrop, Iain A Perry, Matthew D Hitchings, Alejandro H Uribe, Federico Bernuzzi, Simon Eastham, James G Cronin, Ardena Berisha, Alexandra Howell, Joanne Davies, Julianna Blagih, Douglas J Veale, Luke C Davies, Micah Niphakis, David K Finlay, Linda V Sinclair, Benjamin F Cravatt, Andrew E Hogan, James A Nathan, Ursula Fearon, David Sumpton, Johan Vande Voorde, Goncalo Dias do Vale, Jeffrey G McDonald, Gareth W Jones, James A Pearson, Emma E Vincent, Nicholas Jones.

Chronic inflammation in autoimmunity is driven by T cell hyperactivation. This unregulated response to self is fuelled by heightened metabolic programmes, which offers a promising new direction to uncover novel treatment strategies. α/β-hydrolase domain-containing protein 11 (ABHD11) is a mitochondrial hydrolase that maintains the catalytic function of α-ketoglutarate dehydrogenase (α-KGDH), and its expression in CD4+ T cells has been linked to remission status in rheumatoid arthritis (RA). However, the importance of ABHD11 in regulating T cell metabolism and function - and thus, the downstream implication for autoimmunity - is yet to be explored. Here, we show that pharmacological inhibition of ABHD11 dampens cytokine production by human and mouse T cells. Mechanistically, the anti-inflammatory effects of ABHD11 inhibition are attributed to increased 24,25-epoxycholesterol (24,25-EC) biosynthesis and subsequent liver X receptor (LXR) activation, which arise from a compromised TCA cycle. The impaired cytokine profile established by ABHD11 inhibition is extended to two patient cohorts of autoimmunity. Importantly, using a murine model of accelerated type 1 diabetes (T1D), we show that targeting ABHD11 suppresses cytokine production in antigen-specific T cells and delays the onset of diabetes in vivo . Collectively, our work provides pre-clinical evidence that ABHD11 is an encouraging drug target in T cell-mediated autoimmunity.

DOI: https://doi.org/10.1101/2025.03.19.643996
Int Immunopharmacol. 2025 Mar 28. pii: S1567-5769(25)00541-7. [Epub ahead of print]154 114551

Mitochondria-dependent innate immunity: A potential therapeutic target in Flavivirus infection.

Saurabh Losarwar, Bhaskaranand Pancholi, Raja Babu, Debapriya Garabadu.

  Mitochondria, known as the powerhouse of cells, play a crucial role in host innate immunity during flavivirus infections such as Dengue, Zika, West Nile, and Japanese Encephalitis Virus. Mitochondrial antiviral signaling protein (MAVS) resides on the outer mitochondrial membrane which is triggered by viral RNA recognition by RIG-I-like receptors (RLRs). This activation induces IRF3 and NF-κB signaling, resulting in type I interferon (IFN) production and antiviral responses. Upon flavivirus infection, mitochondrial stress and dysfunction may lead to the release of mitochondrial DNA (mtDNA) into the cytoplasm, which serves as a damage-associated molecular pattern (DAMP). Cytosolic mtDNA is sensed by cGAS (cyclic GMP-AMP synthase), leading to the activation of the STING (Stimulator of Interferon Genes) pathway to increase IFN production and expand inflammation. Flaviviral proteins control mitochondrial morphology by controlling mitochondrial fission (MF) and fusion (MFu), disrupting mitochondrial dynamics (MD) to inhibit MAVS signaling and immune evasion. Flaviviral proteins also cause oxidative stress, resulting in the overproduction of reactive oxygen species (ROS), which triggers NLRP3 inflammasome activation and amplifies inflammation. Additionally, flaviviruses drive metabolic reprogramming by shifting host cell metabolism from oxidative phosphorylation (OxPhos) to glycolysis and fatty acid synthesis, creating a pro-replicative environment that supports viral replication and persistence. Thus, the present review explores the complex interaction between MAVS, mtDNA, and the cGAS-STING pathway, which is key to the innate immune response against flavivirus infections. Understanding these mechanisms opens new avenues in therapeutic interventions in targeting mitochondrial pathways to enhance antiviral immunity and mitigate viral infection.

Keywords:  Flavivirus; Innate immunity; Mitochondria; Mitochondrial antiviral signaling protein (MAVS); Mitochondrial dynamics (MD); RIG-I-like receptors (RLRs)

DOI:  https://doi.org/10.1016/j.intimp.2025.114551
Epigenetics Chromatin. 2025 Mar 29. 18(1): 16

Crosstalk between metabolism and epigenetics during macrophage polarization.

Kangling Zhang, Chinnaswamy Jagannath.

  Macrophage polarization is a dynamic process driven by a complex interplay of cytokine signaling, metabolism, and epigenetic modifications mediated by pathogens. Upon encountering specific environmental cues, monocytes differentiate into macrophages, adopting either a pro-inflammatory (M1) or anti-inflammatory (M2) phenotype, depending on the cytokines present. M1 macrophages are induced by interferon-gamma (IFN-γ) and are characterized by their reliance on glycolysis and their role in host defense. In contrast, M2 macrophages, stimulated by interleukin-4 (IL-4) and interleukin-13 (IL-13), favor oxidative phosphorylation and participate in tissue repair and anti-inflammatory responses. Metabolism is tightly linked to epigenetic regulation, because key metabolic intermediates such as acetyl-coenzyme A (CoA), α-ketoglutarate (α-KG), S-adenosylmethionine (SAM), and nicotinamide adenine dinucleotide (NAD+) serve as cofactors for chromatin-modifying enzymes, which in turn, directly influences histone acetylation, methylation, RNA/DNA methylation, and protein arginine methylation. These epigenetic modifications control gene expression by regulating chromatin accessibility, thereby modulating macrophage function and polarization. Histone acetylation generally promotes a more open chromatin structure conducive to gene activation, while histone methylation can either activate or repress gene expression depending on the specific residue and its methylation state. Crosstalk between histone modifications, such as acetylation and methylation, further fine-tunes macrophage phenotypes by regulating transcriptional networks in response to metabolic cues. While arginine methylation primarily functions in epigenetics by regulating gene expression through protein modifications, the degradation of methylated proteins releases arginine derivatives like asymmetric dimethylarginine (ADMA), which contribute directly to arginine metabolism-a key factor in macrophage polarization. This review explores the intricate relationships between metabolism and epigenetic regulation during macrophage polarization. A better understanding of this crosstalk will likely generate novel therapeutic insights for manipulating macrophage phenotypes during infections like tuberculosis and inflammatory diseases such as diabetes.

Keywords:  Acetylation; Epigenetics; Glucose metabolism; Histones; IFN-γ; IL-13; IL-4; IL10; M1; M2; Macrophage polarization; Macrophages; Metabolism; Methylation; Sirtuins

DOI:  https://doi.org/10.1186/s13072-025-00575-9
Front Immunol. 2025 ;16 1477929

Hexokinase2-engineered T cells display increased anti-tumor function.

Raphaëlle Toledano Zur, Shiran Didi Zurinam, Maria Radman, Elia Funaro Balouka, Tatiana Borodianskiy-Shteinberg, Dieter Saur, Cyrille J Cohen.

   Background: T cells face significant metabolic challenges in the tumor microenvironment (TME), where cancer cells monopolize critical nutrients like glucose and amino acids. This metabolic competition supports tumor growth while impairing T-cell anti-tumor responses, partly by reducing glycolytic function. Hexokinase 2 (HK2), a key enzyme in glycolysis, plays a pivotal role in maintaining T-cell functionality.
Methods: To enhance T-cell function, primary human T cells were genetically engineered to overexpress HK2 alongside a tumor-specific receptor. These engineered T cells were tested in vitro and in vivo to evaluate their metabolic and therapeutic efficacy.
Results: HK2-engineered T cells exhibited increased glycolytic capacity, leading to enhanced cytokine secretion, activation marker expression, and metabolic activity compared to controls. In vivo studies using a human tumor xenograft model demonstrated the superior therapeutic efficacy of HK2-engineered T cells, including delayed tumor growth and improved survival.
Conclusion: HK2 overexpression improves T-cell metabolic fitness and functionality in hostile TMEs, offering a promising foundation for the development of next-generation immunotherapies targeting T-cell metabolism.

Keywords:  T-cells; TCR; cellular immunotherapy; hexokinase 2; immunometabolism

DOI:  https://doi.org/10.3389/fimmu.2025.1477929
Metabolism. 2025 Mar 26. pii: S0026-0495(25)00108-8. [Epub ahead of print]168 156239

The serine protease KLK7 promotes immune cell infiltration in visceral adipose tissue in obesity.

Aleix Ribas-Latre, Anne Hoffmann, Claudia Gebhardt, Juliane Weiner, Lilli Arndt, Nora Raulien, Martin Gericke, Adhideb Ghosh, Kerstin Krause, Nora Klöting, Paul T Pfluger, Bilal N Sheikh, Thomas Ebert, Anke Tönjes, Michael Stumvoll, Christian Wolfrum, Matthias Blüher, Ulf Wagner, Joan Vendrell, Sonia Fernández-Veledo, John T Heiker.

  Obesity is a major health problem associated with global metabolic dysfunction and increased inflammation. It is thus critical to identify the mechanisms underlying the crosstalk between immune cells and adipose tissue that drive cardiovascular and metabolic dysfunction in obesity. Expression of the kallikrein-related serine protease 7 (KLK7) in adipose tissue is linked to inflammation and insulin resistance in high fat diet (HFD)-fed mice. Here, we engineered mice with a macrophage-specific KLK7 knockout (KLK7MKO) to investigate how KLK7 loss impacts immune cell function and obesity-related pathology. Compared to control mice, we observed lower levels of systemic inflammation, with less infiltration and activation of inflammatory macrophages in HFD-fed KLK7MKO mice, particularly in the epididymal adipose tissue. Mechanistically, we uncover that Klk7 deficiency reduces pro-inflammatory gene expression in macrophages and restricts their migration through higher cell adhesion, hallmark features of macrophages in obese conditions. Importantly, through analyses of 1143 human visceral adipose tissue samples, we uncover that KLK7 expression is associated with pathways controlling cellular migration and inflammatory gene expression. In addition, serum KLK7 levels were strongly correlated with circulating inflammatory markers in a second cohort of 60 patients with obesity and diabetes. Our work uncovers the pro-inflammatory role of KLK7 in controlling inflammatory macrophage polarization and infiltration in visceral obesity, thereby contributing to metabolic disease. Thus, targeting KLK7 to control immune cell activation may dissociate adipose dysfunction from obesity, thereby representing an alternative obesity therapy.

Keywords:  Adipose tissue; Inflammation; Metabolic disease; Obesity; Protease; Serpin

DOI:  https://doi.org/10.1016/j.metabol.2025.156239
Vet Res. 2025 Apr 01. 56(1): 71

Foot-and-mouth disease virus activates glycolysis and hijacks HK2 to inhibit innate immunity and promote viral replication.

Wenxian Chen, Xinyan Wang, Xiaowen Li, Weijun Wang, Yaoyao Huang, Yuwei Qin, Pengfei Liu, Keke Wu, Bingke Li, Yintao He, Sen Zeng, Lin Yi, Lianxiang Wang, Mingqiu Zhao, Hongxing Ding, Shuangqi Fan, Zhaoyao Li, Jinding Chen.

  Foot-and-mouth disease (FMD) severely restricts the healthy development of global animal husbandry, and the unclear pathogenic mechanism of FMD virus (FMDV) leads to difficulty in preventing and purifying FMD. Glycolytic remodelling is considered one of the hallmarks of viral infection, providing energy and precursors for viral assembly and replication. In this work, the interaction and mechanism between FMDV and glycolysis were explored from the perspective of immune metabolism. We found that FMDV infection increased the extracellular acidification rate, lactic acid accumulation, and HK2 level. In addition, during FMDV infection, HK2 enhances glycolytic activity and mediates autophagic degradation of IRF3/7 to antagonize the innate immune response, thereby promoting viral replication. Our findings provide evidence that FMDV is closely correlated with host metabolism, increasing the understanding that glycolysis and HK2 facilitate virus infection, and provide new ideas for further elucidating the pathogenic mechanism of FMDV.

Keywords:  Foot-and-mouth disease virus; glycolysis; hexokinase 2; interferon regulatory factor; replication

DOI:  https://doi.org/10.1186/s13567-025-01497-w
Discov Oncol. 2025 Apr 02. 16(1): 453

Role of metabolic transformation in cancer immunotherapy resistance: molecular mechanisms and therapeutic implications.

Sandesh Shende, Jaishriram Rathored, Tanushree Budhbaware.

   BACKGROUND: Immunotherapy in the treatment of cancer, with immune inhibitors helps in many cancer types. Many patients still encounter resistance to these treatments, though. This resistance is mediated by metabolic changes in the tumour microenvironment and cancer cells. The development of novel treatments to overcome resistance and boost immunotherapy's effectiveness depends on these metabolic changes.
OBJECTIVE: This review concentrates on the molecular mechanisms through which metabolic transformation contributes to cancer immunotherapy resistance. Additionally, research therapeutic approaches that target metabolic pathways to enhance immunotherapy for resistance.
METHODS: We used databases available on PubMed, Scopus, and Web of Science to perform a thorough review of peer-reviewed literature. focusing on the tumor microenvironment, immunotherapy resistance mechanisms, and cancer metabolism. The study of metabolic pathways covers oxidative phosphorylation, glycolysis, lipid metabolism, and amino acid metabolism.
RESULTS: An immunosuppressive tumour microenvironment is produced by metabolic changes in cancer cells, such as dysregulated lipid metabolism, enhanced glutaminolysis, and increased glycolysis (Warburg effect). Myeloid-derived suppressor cells and regulatory T cells are promoted, immune responses are suppressed, and T cell activity is impaired when lactate and other metabolites build up. changes in the metabolism of amino acids in the pathways for arginine and tryptophan, which are nutrients crucial for immune function. By enhancing their function in the tumour microenvironment, these metabolic alterations aid in resistance to immune checkpoint inhibitors.
CONCLUSION: Metabolic change plays a key role in cancer immunotherapy resistance. Gaining knowledge of metabolic processes can help develop efficient treatments that improve immunotherapy's effectiveness. In order to determine the best targets for therapeutic intervention, future studies should concentrate on patient-specific metabolic profiling.

Keywords:  Amino acid metabolism; Cancer metabolism; Glycolysis; Immune checkpoint inhibitors; Immunotherapy resistance; Tumour microenvironment

DOI:  https://doi.org/10.1007/s12672-025-02238-3
Cell Rep. 2025 Apr 01. pii: S2211-1247(25)00267-0. [Epub ahead of print]44(4): 115496

SOSTDC1 downregulation in CD4+ T cells confers protection against obesity-induced insulin resistance.

Dehai Li, Jing Zhu, Mingyue Zhang, Qiping Shi, Rong Guo, Daming Zhang, Pei Zheng, Hua Zhang, Guangqiang Li, Jie Wu, Guodong Sun, Qiong Wen, Jingyi Tan, Zonghua Liu, Xindong Liu, Hengwen Yang, Hongyun Lu, Guangchao Cao, Zhinan Yin, Qian Wang.

  Adipose-resident T cells play a crucial role in the development of obesity-induced insulin resistance. However, the specific mechanisms, particularly those involving non-immune cytokines, remain unclear. Here, we report significantly elevated levels of sclerostin domain-containing protein 1 (SOSTDC1) in individuals with type 2 diabetes (T2D), showing positive correlations with fasting glucose and HbA1c. T cell-specific Sostdc1-deficient mice exhibit resistance to age-induced adipose lipid accumulation and glucose dysregulation at 12 months and protect against obesity-induced insulin resistance without affecting proinflammatory macrophage infiltration or adipose inflammation. Mechanistically, SOSTDC1 disrupts the lipid balance in adipocytes by promoting lipogenesis and inhibiting lipolysis through the LRP5/6-β-catenin pathway. Furthermore, T cell receptor (TCR) signaling significantly amplifies SOSTDC1 secretion in CD4+ T cells. In summary, our study uncovers an additional mechanism by which T cells contribute to obesity and insulin resistance, suggesting that inhibiting SOSTDC1 could be a promising immunotherapeutic strategy for metabolic disorders.

Keywords:  CD4+ T cells; CP: Immunology; CP: Metabolism; SOSTDC1; adipocyte; adipose tissue; immune cells; immunometabolism; insulin resistance; obesity

DOI:  https://doi.org/10.1016/j.celrep.2025.115496
J Clin Invest. 2025 Apr 01. pii: e183559. [Epub ahead of print]135(7):

Spermidine restricts neonatal inflammation via metabolic shaping of polymorphonuclear myeloid-derived suppressor cells.

Jiale Chen, Lin Zhu, Zhaohai Cui, Yuxin Zhang, Ran Jia, Dongmei Zhou, Bo Hu, Wei Zhong, Jin Xu, Lijuan Zhang, Pan Zhou, Wenyi Mi, Haitao Wang, Zhi Yao, Ying Yu, Qiang Liu, Jie Zhou.

  Newborns exhibit a heightened vulnerability to inflammatory disorders due to their underdeveloped immune system, yet the underlying mechanisms remain poorly understood. Here we report that plasma spermidine is correlated with the maturity of human newborns and reduced risk of inflammation. Administration of spermidine led to the remission of neonatal inflammation in mice. Mechanistic studies revealed that spermidine enhanced the generation of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) via downstream eIF5A hypusination. Genetic deficiency or pharmacological inhibition of deoxyhypusine synthase (DHPS), a key enzyme of hypusinated eIF5A (eIF5AHyp), diminished the immunosuppressive activity of PMN-MDSCs, leading to aggravated neonatal inflammation. The eIF5AHyp pathway was found to enhance the immunosuppressive function via histone acetylation-mediated epigenetic transcription of immunosuppressive signatures in PMN-MDSCs. These findings demonstrate the spermidine-eIF5AHyp metabolic axis as a master switch to restrict neonatal inflammation.

Keywords:  Immunology; Innate immunity; Metabolism; Polyamines

DOI:  https://doi.org/10.1172/JCI183559
EBioMedicine. 2025 Mar 29. pii: S2352-3964(25)00116-1. [Epub ahead of print]114 105672

Impact of rosuvastatin on the memory potential and functionality of CD8+ T cells from people with HIV.

Federico Perdomo-Celis, Caroline Passaes, Valérie Monceaux, Olivier Lambotte, Dominique Costagliola, Mathieu F Chevalier, Laurence Weiss, Asier Sáez-Cirión.

   BACKGROUND: Virus-specific CD8+ T cells play a major role in the natural control of HIV infection, linked to memory-like features such as high survival capacity and polyfunctionality. However, virus-specific CD8+ T cells from HIV non-controllers exhibit an effector-like and exhausted profile, with limited antiviral potential. Metabolic reprogramming of cells from non-controllers could reinvigorate their functional capacities. Considering the implication of the cholesterol pathway in the induction of T cell exhaustion, here we evaluated the impact of rosuvastatin, an inhibitor of cholesterol synthesis, on the functionality and memory profile of HIV-specific CD8+ T cells from people on antiretroviral treatment.
METHODS: We analysed samples from 10 individuals with HIV-1 on ART who participated in the IMEA 043-CESAR trial and received rosuvastatin for 12 weeks. We explored whether rosuvastatin treatment was accompanied by changes in the memory potential of CD8+ T cells. We evaluated the phenotype and functionality of total and HIV-specific CD8+ T cells before, during, and after treatment with rosuvastatin. A mixed effects model was used for repeated measures and corrected for multiple comparisons.
FINDINGS: Total and HIV-specific CD8+ T cell survival and functionality were enhanced in individuals who received a 12-week course of rosuvastatin, with a consistent increase in polyfunctional IFN-γ+ TNF-α+ cells. The superior CD8+ T cell functionality after rosuvastatin treatment was associated with intrinsic metabolic changes, including the decrease of fatty acid uptake, as well as a reduction in effector/exhaustion markers. Changes in the characteristics of CD8+ T cells coincided with the duration of rosuvastatin administration, and most effects waned after the cessation of the treatment.
INTERPRETATION: CD8+ T cell metabolic reprogramming by targeting the cholesterol pathway, combined with other available immunotherapies, might represent a promising strategy in the search for the cure of HIV or other chronic viral infections.
FUNDING: The CESAR trial was sponsored by IMEA. This work was supported by the NIH (grants UM1AI164562 and R01DK131476).

Keywords:  CD8(+) T cells; HIV control; HIV remission; HIV-1; Statins; T cell reprogramming

DOI:  https://doi.org/10.1016/j.ebiom.2025.105672
Circ Res. 2025 Mar 31.

Srsf3-Dependent APA Drives Macrophage Maturation and Limits Atherosclerosis.

Xian Yang, Xin Zhang, Yaru Tian, Jiaxuan Yang, Yunhui Jia, Yuhuai Xie, Lianping Cheng, Shenglai Chen, Linfeng Wu, Yihong Qin, Zhen Zhao, Dejian Zhao, Yuanyuan Wei.

   BACKGROUND: Circulating monocytes largely contribute to macrophage buildup in atheromata, which is crucial for clearing subendothelial LDLs (low-density lipoproteins) and dead cells; however, the transitional trajectory from monocytes to macrophages in atherosclerotic plaques and the underlying regulatory mechanism remain unclear. Moreover, the role of alternative polyadenylation, a posttranscriptional regulator of cell fate, in monocyte/macrophage fate decisions during atherogenesis is not entirely understood.
METHODS: To identify monocyte/macrophage subtypes in atherosclerotic lesions and the effect of alternative polyadenylation on these subtypes and atherogenesis, single-cell RNA sequencing, 3'-end sequencing, flow cytometric, and histopathologic analyses were performed on plaques obtained from Apoe-/- mouse arteries with or without myeloid deletion of Srsf3 (serine/arginine-rich splicing factor 3). Cell fractionation, polysome profiling, L-azidohomoalanine metabolic labeling assay, and metabolomic profiling were conducted to disclose the underlying mechanisms. Reprogramming of widespread alternative polyadenylation patterns was estimated in human plaques via bulk RNA sequencing.
RESULTS: We identified a subset of lesional cells in a monocyte-to-macrophage transitional state, which exhibited high expression of chemokines in mice. Srsf3 deletion caused a maturation delay of these transitional cells and phagocytic impairment of lesional macrophages, aggravating atherosclerosis. Mechanistically, Srsf3 deficiency shortened 3' untranslated regions of mitochondria-associated Aars2 (alanyl-tRNA synthetase 2), disrupting its translation. The resultant impairment of protein synthesis in mitochondria led to mitochondrial dysfunction with declined NAD+ levels, activation of the integrated stress response, and metabolic reprogramming in macrophages. Administering an NAD+ precursor nicotinamide mononucleotide or the integrated stress response inhibitor partially restored Srsf3-deficient macrophage maturation, and nicotinamide mononucleotide treatment mitigated the proatherosclerotic effects of Srsf3 deficiency. Consistently, Srsf3 downregulation, global 3' untranslated region shortening, and accumulation of these transitional macrophages were associated with atherosclerosis progression in humans.
CONCLUSIONS: Our study reveals that Srsf3-dependent generation of long 3' untranslated region is required for efficient mitochondrial translation, which promotes mature phagocytic macrophage formation, thereby playing a protective role in atherosclerosis.

Keywords:  atherosclerosis; cardiovascular diseases; macrophage activation; monocytes; phagocytosis

DOI:  https://doi.org/10.1161/CIRCRESAHA.124.326111
Eur J Immunol. 2025 Apr;55(4): e202451586

IgA2 ACPA Drives a Hyper-Inflammatory Phenotype in Macrophages via ATP Synthase and COX2.

Luís Almeida, Alice Bacon, Mohan Ghorasaini, Alwin J van der Ham, René E M Toes, Martin Giera, Bart Everts.

  IgA can form immune complexes (ICs) and activate myeloid cells via Fc alpha receptor-mediated signalling to secrete pro-inflammatory cytokines. It was previously described that of the two IgA subclasses (IgA1 and IgA2), IgA2 is more inflammatory than IgA1. However, the mechanisms underlying this differential pro-inflammatory potential remain poorly defined. Using anti-citrullinated protein IgA1 and IgA2 antibodies (ACPA) that are commonly found in rheumatoid arthritis (RA) patients and linked to chronic inflammation, we show here that, in macrophages, IgA2-ICs boost TLR-induced TNF and IL6 secretion, COX2 expression, and production of COX2-dependent lipid mediators to a higher level than IgA1-ICs. Metabolically, we found the amplification of TLR-induced cytokine production and COX2 induction by IgA2-ICs to be dependent on mitochondrial ATP synthesis, but not glycolysis. Finally, we found the potentiation of TLR-induced cytokine production by IgA-ICs to be COX2-dependent. Together this work points towards a key role for mitochondrial ATP synthesis in driving COX2 expression and subsequent IgA2-IC-dependent potentiation of TLR-induced cytokine production by macrophages. As such, our work provides new insights into the mechanisms underlying IgA2-induced inflammation in the context of RA. Thus, this may hold novel clues to be explored as therapeutic possibilities to target antibody-driven inflammation in chronic inflammatory diseases.

Keywords:  COX2; IgA ACPA; lipid mediators; macrophages; rheumatoid arthritis

DOI:  https://doi.org/10.1002/eji.202451586
Curr Opin Microbiol. 2025 Apr 02. pii: S1369-5274(25)00030-X. [Epub ahead of print]85 102608

Pathogen adaptation to lung metabolites.

Gaurav Kumar Lohia, Sebastián A Riquelme.

Opportunistic pathogens like Pseudomonas aeruginosa and Staphylococcus aureus rapidly adapt to the dynamic metabolic landscape of the respiratory mucosa during infection. Host phagocytes recognize these pathogens and trigger metabolic reprogramming, releasing immunometabolites such as succinate and itaconate. P. aeruginosa preferentially consumes succinate as a carbon source to enhance planktonic growth. In response to itaconate-induced membrane stress, it forms protective biofilms, allowing bacterial survival despite host defenses. Additionally, host ketone bodies support microbial communities that are less immunostimulatory and better tolerated by the lung. Similarly, S. aureus responds to itaconate by forming biofilms, aiding colonization in glucose-limited airways. In this milieu, S. aureus consumes proline, linking its survival with the metabolic activity of proline-producing fibroblasts. Here, we will review the competence of both P. aeruginosa and S. aureus to hijack host metabolic pathways, underscoring pathogen metabolic plasticity as an essential strategy to thrive in the human lung.

DOI: https://doi.org/10.1016/j.mib.2025.102608
Mol Psychiatry. 2025 Apr 02.

RVG engineered extracellular vesicles-transmitted miR-137 improves autism by modulating glucose metabolism and neuroinflammation.

Qian Qin, Mengyue Li, Linlin Fan, Xin Zeng, Danyang Zheng, Han Wang, Yutong Jiang, Xinrui Ma, Lei Xing, Lijie Wu, Shuang Liang.

Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder. The microglia activation is a hallmark of ASD, which involves increased glycolysis. Elevated glycolysis regardless of oxygen availability, known as "Warburg effect", is crucial to pathogenesis in neuropsychiatric disorders. Psychiatric risk gene MIR137 plays an important role in neurogenesis and neuronal maturation, but the impact on neuroinflammation and glucose metabolism remains obscure. Extracellular vesicles (EVs) can delivery miR-137 crossing the blood-brain barrier. Meanwhile, EVs can help miR-137 avoid being rapidly degraded by endogenous nucleases. Here, after first detecting miR-137 decreased both in the peripheral blood of individuals with ASD and the serum and cerebellum of BTBR mice, we demonstrated that microglia activation, the level of lactate and key enzymes (HK2, PKM2 and LDHA) involved in glycolysis were increased significantly in BTBR mice. Of particular note, EVs engineered by rabies virus glycoprotein (RVG) could promote the miR-137 (RVG-miR137-EVs) targeted to the brain accurately, and alleviated autism-like behaviors. Pro-inflammatory activation of BTBR mice was considerably inhibited by RVG-miR137-EVs via tail vein administration, accompanied by decreased lactate production. Mechanically, these effects were attributed to TLR4, the key target gene, which was regulated by miR-137. The TLR4/NF-κB pathway was inhibited, subsequently reducing HIF-1α and repressing the transcription of HK2, PKM2 and LDHA involved in glycolysis. Pharmacological inhibition of glycolysis and TLR4 attenuated microglial activation and lactate production, ultimately improved autism-like behaviors of BTBR mice. In conclusion, our results indicated that miR-137 could alleviate autism-like behaviors by HIF-1α-mediated adaptive metabolic changes in glycolysis and neuroinflammation.

DOI: https://doi.org/10.1038/s41380-025-02988-0
Chembiochem. 2025 Mar 31. e202400980

Lipid Metabolism and Immune Function: Chemical Tools for Insights into T-Cell Biology.

L Reinalda, M van der Stelt, Sander Izaak van Kasteren.

  Lipids are essential biomolecules playing critical roles in cellular processes, including energy storage, membrane structure, and signaling. This review highlights the chemical tools that have been developed to study the role of lipid metabolism in immune function, focusing on T-cell biology. Fatty acids (FAs), as core lipid components, influence immune responses through structural, signaling, and metabolic roles. Recent studies reveal how specific FAs modulate T-cell activation, proliferation, and function, with implications for regulatory and effector subsets. Emerging tools, such as fluorescence-based lipids and click chemistry, enable precise tracking of lipid uptake and metabolism at single-cell levels, addressing limitations of traditional bulk methods. Advances in metabolomics and proteomics offer further insights into lipid-mediated immune regulation. Understanding these mechanisms provides opportunities for targeting lipid metabolism in therapeutic strategies for cancer and other immune-related diseases. The integration of lipidomic technologies into immunology uncovers novel perspectives on how lipids shape immune responses at cellular and molecular scales.

Keywords:  Fatty acids, T-cells, bioorthogonal chemistry, immunometabolism

DOI:  https://doi.org/10.1002/cbic.202400980
Front Immunol. 2025 ;16 1565133

Restoring immune tolerance in pre-RA: immunometabolic dialogue between gut microbiota and regulatory T cells.

Anqi Gao, Ruihe Wu, Yanfei Mu, Ruqing Jin, Saixin Jiang, Chong Gao, Xiaofeng Li, Caihong Wang.

  Rheumatoid arthritis (RA) is a complex chronic autoimmune disease that remains incurable for most patients. With advances in our understanding of the disease's natural history, the concept of pre-RA has emerged as a window of opportunity to intervene before irreversible joint damage occurs. Numerous studies have indicated that the key step driving autoimmunity in early pre-RA lies at an extra-articular site, which is closely related to the regulatory T (Treg) cell-established immune tolerance to the gut microbiota. The intricate immunometabolic crosstalk between Treg cells and the gut microbiota is beginning to be understood, with the re-recognition of Treg cells as metabolic sensors in recent years. In the future, deciphering their immunometabolic dialogue may help to elucidate the underlying mechanisms of pre-RA. Identifying novel biological pathways in the pre-RA stage will bring insights into restoring immune tolerance, thereby potentially curing or preventing the onset of RA.

Keywords:  gut microbiota; immunometabolism; pre-RA; regulatory T cell; rheumatoid arthritis

DOI:  https://doi.org/10.3389/fimmu.2025.1565133
J Clin Invest. 2025 Apr 03. pii: e181243. [Epub ahead of print]

Gut microbial metabolite 4-hydroxybenzeneacetic acid drives colorectal cancer progression via accumulation of immunosuppressive PMN-MDSCs.

Qing Liao, Ximing Zhou, Ling Wu, Yuyi Yang, Xiaohui Zhu, Hangyu Liao, Yujie Zhang, Weidong Lian, Feifei Zhang, Hui Wang, Yanqing Ding, Liang Zhao.

  Colorectal cancer (CRC) is characterized by an immune-suppressive microenvironment that contributes to tumor progression and immunotherapy resistance. The gut microbiome produces diverse metabolites that feature unique mechanisms of interaction with host targets, yet the role of many metabolites in CRC remains poorly understood. In this study, the microbial metabolite 4-hydroxybenzeneacetic acid (4-HPA) promoted the infiltration of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in the tumor microenvironment, consequently inhibiting the anti-tumor response of CD8+ T cells and promoting CRC progression in vivo. Mechanistically, 4-HPA activates the JAK2/STAT3 pathway, which upregulates CXCL3 transcription, thereby recruiting PMN-MDSCs to the CRC microenvironment. Selective knockdown of CXCL3 re-sensitized tumors to anti-PD1 immunotherapy in vivo. Chlorogenic acid (CGA) reduces the production of 4-HPA by microbiota, likewise abolishing 4-HPA-mediated immunosuppression. The 4-HPA content in CRC tissues was notably increased in patients with advanced CRC. Overall, the gut microbiome uses 4-HPA as a messenger to control chemokine-dependent accumulation of PMN-MDSC cells and regulate anti-tumor immunity in CRC. Our findings provide a scientific basis for establishing clinical intervention strategies to reverse the tumor immune microenvironment and improve the efficacy of immunotherapy by reducing the interaction between intestinal microbiota, tumor cells and tumor immune cells.

Keywords:  Cancer immunotherapy; Colorectal cancer; Gastroenterology; Immunology; Oncology

DOI:  https://doi.org/10.1172/JCI181243
Front Immunol. 2025 ;16 1545790

Immunometabolic analysis of primary murine group 2 innate lymphoid cells: a robust step-by-step approach.

Sai Sakktee Krisna, Rebecca C Deagle, Nailya Ismailova, Ademola Esomojumi, Audrey Roy-Dorval, Frederik Roth, Gabriel Berberi, Sonia V Del Rincon, Jörg H Fritz.

  Group 2 Innate Lymphoid Cells (ILC2s) have recently been shown to exert key regulatory functions in both innate and adaptive immune response networks that drive the establishment and progression of type 2 immunity. Although mainly tissue resident, ILC2s and their crosstalk within tissue microenvironments influence metabolism at both the local and systemic levels. In turn, the energetic demand and metabolic status within these systems shape the diverse phenotypes and effector functions of ILC2s. Deciphering these metabolic networks in ILC2s is therefore essential in understanding their various roles in health as well as their associated pathophysiologies. Here we detail a framework of experimental approaches to study key immunometabolic states of primary murine ILC2s and link them to unique phenotypes and their corresponding functionality. Utilizing flow cytometry, Single Cell ENergetic metabolism by profilIng Translation inHibition (SCENITH), and the Seahorse platform we provide a framework that allows in-depth analysis of cellular bioenergetic states to determine the immunometabolic wiring of ILC2s. Connecting immunometabolic states and networks to ILC2 phenotypes and effector functions with this method will allow future in-depth studies to assess the potential of novel pharmaceutics in altering ILC2 functionality in clinical settings.

Keywords:  SCENITH (Single Cell ENergetic metabolism by profilIng Translation inhibition); group 2 innate lymphoid cells (ILC2); immunometabolism; mitochondria; seahorse analysis

DOI:  https://doi.org/10.3389/fimmu.2025.1545790
FEBS J. 2025 Apr 02.

Protein succinylome analysis identifies citrate synthase as a central regulator of osteoclast metabolic activity.

Dayoung Yu, Yue Gao, Marcin Luzarowski, Elisabeth Seebach, Thomas Heitkamp, Michael Börsch, Thomas Ruppert, Katharina F Kubatzky.

  Tumour necrosis factor ligand superfamily member 11 (TNFSF11; RANKL) and macrophage colony-stimulating factor 1 receptor (M-CSF) differentiate macrophages into osteoclasts. This process is characterised by changes in metabolic activity that support energy-consuming processes. Treatment with RANKL triggers a phenotype of accelerated metabolism with enhanced glycolysis and an initial disruption of the tricarboxylic acid cycle (TCA) through increased expression of the enzyme aconitate decarboxylase (ACOD1), which results in an upregulation of intracellular succinate levels. Succinate then causes post-translational succinylation of lysine residues. ACOD1 as an inducer of protein succinylation and the desuccinylase NAD-dependent protein deacylase sirtuin-5, mitochondrial (SIRT5) are regulated differentially, and the initially high expression of ACOD1 decreases towards the end of differentiation, whereas SIRT5 levels increase. To mimic the effect of protein succinylation, diethyl succinate or a SIRT5 inhibitor was added during differentiation, which reduced the formation of large osteoclasts, showing its relevance for osteoclastogenesis. To identify succinylated proteins, we used an immunoaffinity-based liquid chromatography-tandem mass spectrometry (LC-MS/MS) approach. Most lysine succinylated proteins were mitochondrial metabolic enzymes. Citrate synthase (CS), the enzyme catalysing the first reaction of the TCA cycle, showed a notable difference in succinylation levels before and after RANKL stimulation, with succinylation detected exclusively in stimulated cells. Immunoprecipitation assays confirmed CS succinylation. Using whole cell extracts, we observed that RANKL treatment decreased CS activity in a concentration-dependent manner. This suggests that CS could be critical in the context of energy production during osteoclastogenesis and that protein succinylation modulates the differentiation program of osteoclasts.

Keywords:  PTM scan; RANKL; citrate synthase; metabolism; mitochondria; osteoclast; post‐translational modification; succinylation

DOI:  https://doi.org/10.1111/febs.70090
ACS Infect Dis. 2025 Apr 01.

SIRT1 and SIRT3 Impact Host Mitochondrial Function and Host Salmonella pH Balance during Infection.

Dipasree Hajra, Vikas Yadav, Amit Singh, Dipshikha Chakravortty.

  Mitochondria are important organelles that regulate energy homeostasis. Mitochondrial health and dynamics are crucial determinants of the outcome of several bacterial infections. SIRT3, a major mitochondrial sirtuin, along with SIRT1 regulates key mitochondrial functions. This led to considerable interest in understanding the role of SIRT1 and SIRT3 in governing mitochondrial functions during Salmonella infection. Here, we show that loss of SIRT1 and SIRT3 function either by shRNA-mediated knockdown or by inhibitor treatment led to increased mitochondrial dysfunction with alteration in mitochondrial bioenergetics alongside increased mitochondrial superoxide generation in Salmonella-infected macrophages. Consistent with dysfunctional mitochondria, mitophagy was induced along with altered mitochondrial fusion-fission dynamics in S. typhimurium-infected macrophages. Additionally, the mitochondrial bioenergetic alteration promotes acidification of the infected macrophage cytosolic pH. This host cytosolic pH imbalance skewed the intraphagosomal and intrabacterial pH in the absence of SIRT1 and SIRT3, resulting in decreased SPI-2 gene expression. Our results suggest a novel role for SIRT1 and SIRT3 in maintaining the intracellular Salmonella niche by modulating the mitochondrial bioenergetics and dynamics in the infected macrophages.

Keywords:  SPI-2 secretion; Salmonella; fusion-fission dynamics; macrophage-bacterial pH regulation; mitochondrial bioenergetics; mitophagy

DOI:  https://doi.org/10.1021/acsinfecdis.4c00751
Neuroimmunomodulation. 2025 Apr 03. 1-15

The Metabolomic Mind: Microbial Metabolite Programming of Microglia.

Branden G Verosky, Michael T Bailey, Tamar L Gur.

The gut microbiota is increasingly recognized as a critical regulator of brain function, influencing neurodevelopment, adult brain physiology, and disease vulnerability in part through its interactions with microglia, the resident immune cells of the central nervous system. Emerging evidence demonstrates that microbial metabolites, beginning prenatally and persisting throughout the lifespan, regulate fundamental aspects of microglial biology including maturation, metabolic function, and activation. Microglia from germ-free mice exhibit persistent immaturity, altered energy metabolism, and blunted inflammatory responses, which are partially reversible by restoring microbial communities or supplementing key microbial metabolites. Short-chain fatty acids, tryptophan-derived indoles, and other bacterial metabolites derived from the gut microbiota shape microglial function to modulate neurons and synaptic architecture, and influence neuroinflammatory processes. These findings reveal distinct metabolite-driven pathways linking microbial composition to microglial phenotypes, positioning the microbiome as a potential key influencer of neurodevelopmental trajectories and the pathophysiology of psychiatric and neurological disorders. Despite recent advances, major knowledge gaps persist in understanding the precise molecular intermediaries and mechanisms through which metabolite signaling to microglia shape neural function to influence susceptibility or resilience to brain-based disorders. Understanding both the bacterial metabolomic landscape and its collective impact on microglial programming holds substantial therapeutic promise, offering avenues to target microbial metabolite production or administer them directly to modulate brain health.

DOI: https://doi.org/10.1159/000545484
Semin Cancer Biol. 2025 Mar 27. pii: S1044-579X(25)00049-5. [Epub ahead of print]112 58-70

Metabolic reprogramming of tumor microenviroment by engineered bacteria.

Heng Wang, Fang Xu, Chao Wang.

  The tumor microenvironment (TME) is a complex ecosystem that plays a crucial role in tumor progression and response to therapy. The metabolic characteristics of the TME are fundamental to its function, influencing not only cancer cell proliferation and survival but also the behavior of immune cells within the tumor. Metabolic reprogramming-where cancer cells adapt their metabolic pathways to support rapid growth and immune evasion-has emerged as a key factor in cancer immunotherapy. Recently, the potential of engineered bacteria in cancer immunotherapy has gained increasing recognition, offering a novel strategy to modulate TME metabolism and enhance antitumor immunity. This review summarizes the metabolic properties and adaptations of tumor and immune cells within the TME and summarizes the strategies by which engineered bacteria regulate tumor metabolism. We discuss how engineered bacteria can overcome the immunosuppressive TME by reprogramming its metabolism to improve antitumor therapy. Furthermore, we examine the advantages, potential challenges, and future clinical translation of engineered bacteria in reshaping TME metabolism.

Keywords:  Engineered bacteria; Immunotherapy; Metabolic reprogramming; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.semcancer.2025.03.003
bioRxiv. 2025 Mar 18. pii: 2025.03.17.643820. [Epub ahead of print]

Commensal-derived Trehalose Monocorynomycolate Triggers γδ T Cell-driven Protective Ocular Barrier Immunity.

Xiaoyan Xu, Yannis E Rigas, Mary J Mattapallil, Jing Guo, Vijayaraj Nagarajan, Eric Bohrnsen, Crystal Richards, Akriti Gupta, Guillaume Gaud, Paul E Love, Timothy Jiang, Amy Zhang, Biying Xu, Zixuan Peng, Yingyos Jittayasothorn, Mary Carr, M Teresa Magone, Nathan T Brandes, Jackie Shane, Benjamin Schwarz, Anthony J St Leger, Rachel R Caspi.

Commensals shape host physiology through molecular crosstalk with host receptors. Identifying specific microbial factors that causally influence host immunity is key to understanding homeostasis at the host-microbe interface and advancing microbial-based therapeutics. Here, we identify trehalose monocorynomycolate (TMCM) from Corynebacterium mastitidis ( C. mast ) as a potent stimulator of IL-17 production by γδ T cells at the ocular surface. Mechanistically, TMCM-driven IL-17 responses require both IL-1 signals and γδ TCR signaling, which also supports endogenous γδ T cell IL-1R1 expression. Notably, synthetic TMCM alone is sufficient to mimic the effect of C. mast in inducing γδ T cell immunity and protect against pathogenic corneal infection. Our findings establish TMCM as a key mediator of commensal-driven immune defense, highlighting its potential as a γδ T cell adjuvant and a microbiome-informed therapeutic to enhance IL-17-driven protection at barrier sites such as the ocular surface.
HIGHLIGHTS: Corynomycolates enable ocular C. mast colonization and protective IL-17 immunity TMCM drives IL-17 from γδ T cells through TCR and IL-1R signalingγδ TCR signaling maintains the expression of endogenous IL-1R1 Synthetic TMCM mimics the ability of C. mast to induce γδ T cell immunity in the eye TMCM protects against P. aeruginosa keratitis, highlighting its therapeutic potential.

DOI: https://doi.org/10.1101/2025.03.17.643820
Chem Biol Interact. 2025 Mar 31. pii: S0009-2797(25)00125-5. [Epub ahead of print] 111495

Fusobacterium nucleatum Derived 3-Indolepropionic acid Promotes Colorectal Cancer Progression via Aryl Hydrocarbon Receptor Activation in Macrophages.

Qi Song, Zhiliang Jin, Han Zhang, Kunqiao Hong, Beibei Zhu, Haisen Yin, Baoping Yu.

  An increasing body of research indicates that Fusobacterium nucleatum (F. nucleatum) significantly influences the onset and progression of colorectal cancer (CRC). Our previous study has shown that F. nucleatum exerts pro-tumorigenic effects through aryl hydrocarbon receptor (AhR) activation. However, the role of its microbial metabolites in regulating immune responses remains unclear. Here, we report for the first time that F. nucleatum-derived 3-Indolepropionic acid (IPA) activates AhR in macrophages, driving M2 polarization and tumor-promoting immunosuppression. We discovered that culture supernatant of F. nucleatum (CSF) robustly activates AhR in macrophages. In co-culture systems, CSF upregulated the expression of the M2 marker CD206 and elevated mRNA levels of CD163, TGF-β, IL-10, and VEGF. In a subcutaneous allograft model, CSF induced an elevated number of CD206+ macrophages and decreased presence of CD8+ T cells within the tumor microenvironment, thereby promoting tumor growth. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) revealed IPA as a novel major AhR-activating metabolite in CSF. Strikingly, IPA recapitulated CSF's effects in promoting tumor cell migration and immunosuppression, both in vitro and in vivo. Critically, the AhR inhibitor CH223191 abolished both IPA-mediated M2 polarization and tumor growth. Our study revealed a novel mechanism by which F. nucleatum-derived IPA reprograms macrophages through AhR activation to fuel CRC progression, providing potential therapeutic targets for CRC treatment and prognosis improvement.

Keywords:  3-Indolepropionic acid; Aryl Hydrocarbon Receptor; Colorectal Cancer; Fusobacterium nucle-atum; M2 Macrophage

DOI:  https://doi.org/10.1016/j.cbi.2025.111495
Cell Rep. 2025 Apr 02. pii: S2211-1247(25)00281-5. [Epub ahead of print]44(4): 115510

Cancer-cell-derived cGAMP limits the activity of tumor-associated CD8+ T cells.

Michael Herbst, Hakan Köksal, Silvan Brunn, Dominik Zanetti, Ioana Domocos, Viola De Stefani, Marco Gatti, Francesca Vivalda, Paulo Pereira, Marc Nater, Virginia Cecconi, Alessandro A Sartori, Maries van den Broek.

  Using a mouse tumor model with inducible cancer-cell-intrinsic cyclic GMP-AMP (cGAMP) synthase (cGAS) expression, we show that cancer-cell-derived cGAMP is essential and sufficient to trigger a sustained type I interferon response within the tumor microenvironment. This leads to improved CD8+ T cell-dependent tumor restriction. However, cGAMP limits the proliferation, survival, and function of stimulator of IFN genes (STING)-expressing, but not of STING-deficient, CD8+ T cells. In vivo, STING deficiency in CD8+ T cells enhances tumor restriction. Consequently, cancer-cell-derived cGAMP both drives and limits the anti-tumor potential of CD8+ T cells. Mechanistically, T cell-intrinsic STING is associated with pro-apoptotic and antiproliferative gene signatures. Our findings suggest that STING signaling acts as a checkpoint in CD8+ T cells that balances tumor immunity.

Keywords:  CD8(+); CP: Cancer; CP: Immunology; STING; T cells; cGAMP; cGAS; cancer; immunity; tumor microenvironment

DOI:  https://doi.org/10.1016/j.celrep.2025.115510
J Exp Biol. 2025 Apr 04. pii: jeb.249705. [Epub ahead of print]

Mycoplasma gallisepticum (MG) infection inhibits mitochondrial respiratory function in a wild songbird.

Chidambaram Ramanathan, Elina Thomas, Amberleigh E Henschen, James S Adelman, Yufeng Zhang.

  An animal's immune function is vital for survival and potentially metabolically expensive, but some pathogens could manipulate their hosts' immune and metabolic responses. One example is Mycoplasma gallisepticum (MG), which infects both the respiratory system and conjunctiva of the eye in house finches (Haemorhous mexicanus). MG has been shown to exhibit immune- and metabolic-suppressive properties, but the physiological mechanisms are still unknown. Recent studies demonstrated that mitochondria could serve as powerhouses for both ATP production and immunity, notably inflammatory processes, through regulating complex II and its metabolites. Consequently, in this study, we investigate the short-term (3d post-inoculation) and long-term (34d post-inoculation) effects of MG infection on the hepatic mitochondrial respiration of house finches from two populations infected with two different MG isolates. After short-term infection, MG-infected birds had significantly lower state 2 and state 4 respiration, but only when using complex II substrates. After long-term infection, MG-infected birds exhibited lower state 3 respiration with both complex I and II substrates, resulting in lower respiratory control ratio compared to uninfected controls, which aligned with the hypothesized metabolic-suppressive properties of MG. Interestingly, there were limited differences in mitochondrial respiration regardless of house finch population of origin, MG isolate, and whether birds recovered from infection or not. We propose that MG may target mitochondrial complex II for its immune-suppressive properties during the early stages of infection and inhibit mitochondrial respiration for its metabolic-suppressive properties at later stage of infection, both of which should delay recovery of the host and extend infectious periods.

Keywords:  House Finch; Immunosuppression; Metabolic suppression; Mitochondrial respiration; Mycoplasma gallisepticum

DOI:  https://doi.org/10.1242/jeb.249705
Exp Mol Med. 2025 Apr 01.

PGC-1α mediates migrasome secretion accelerating macrophage-myofibroblast transition and contributing to sepsis-associated pulmonary fibrosis.

Yawen Peng, Shuya Mei, Xiaohui Qi, Ri Tang, Wenyu Yang, Jinhua Feng, Yang Zhou, Xi Huang, Guojun Qian, Shunpeng Xing, Yuan Gao, Qiaoyi Xu, Zhengyu He.

Sepsis-associated pulmonary fibrosis (SAPF) is a critical pathological stage in the progression of sepsis-induced acute respiratory distress syndrome. While the aggregation and activation of lung fibroblasts are central to the initiation of pulmonary fibrosis, the macrophage-myofibroblast transition (MMT) has recently been identified as a novel source of fibroblasts in this context. However, the mechanisms driving MMT remain inadequately understood. Given the emerging role of migrasomes (novel extracellular vesicles mediating intercellular communication), we investigated their involvement in pulmonary fibrosis. Here we utilized a lipopolysaccharide-induced SAPF mouse model and an in vitro co-culture system of fibroblasts and macrophages to observe the MMT process during SAPF. We found that lipopolysaccharide exposure suppresses PGC-1α expression in lung fibroblasts, resulting in mitochondrial dysfunction and the accumulation of cytosolic mitochondrial DNA (mtDNA). This dysfunction promotes the secretion of mtDNA-containing migrasomes, which, in turn, initiate the MMT process and contribute to fibrosis progression. Notably, the activation of PGC-1α mitigates mitochondrial dysfunction, reduces mtDNA-migrasome release, inhibits MMT and alleviates SAPF. In conclusion, our study identifies the suppression of PGC-1α in lung fibroblasts and the subsequent release of mtDNA migrasomes as a novel mechanism driving MMT in SAPF. These findings suggest that targeting the crosstalk between fibroblasts and immune cells mediated by migrasomes could represent a promising therapeutic strategy for SAPF.

DOI: https://doi.org/10.1038/s12276-025-01426-z
J Nutr Metab. 2025 ;2025 7075883

Polyunsaturated Fatty Acid Imbalance-A Contributor to SARS CoV-2 Disease Severity.

James P Chambers, Luke T Daum, Bernard P Arulanandam, James J Valdes.

  Overview: SARS CoV-2 infection is accompanied by the development of acute inflammation, resolution of which determines the course of infection and its outcome. If not resolved (brought back to preinjury status), the inflamed state progresses to a severe clinical presentation characterized by uncontrolled cytokine release, systemic inflammation, and in some death. In severe CoV-2 disease, the required balance between protective inflammation and its resolution appears missing, suggesting that the ω-3-derived specialized proresolving mediators (SPMs) needed for resolution are either not present or present at ineffective levels compared to competing ω-6 polyunsaturated fatty acid (PUFA) metabolic derivatives. Aim: To determine whether ω-6 PUFA linoleic acid (LA) metabolites increased in those infected with severe disease compared to uninfected controls. Findings: Increased levels of ω-6 LA metabolites, e.g., arachidonic acid (AA), epoxyeicosatrienoic (EET) acid derivatives of AA (8,9-, 11,12-, and 14,15-EETs), AA-derived hydroxyeicosatetraenoic (HETE) acid, dihydroxylated diols (leukotoxin and isoleukotoxin), and prostaglandin E2 with decreased levels of ω-3-derived inflammation resolving SPMs. Therapeutic treatment of SARS CoV-2 patients with ω-3 PUFA significantly increased 18-HEPE (SPM precursor) and EPA-derived diols (11,12- and 14,15-diHETE), while toxic 9,10- and 12,13-diHOMEs (leukotoxin and iosleukotoxin, respectively) decreased. Conclusion: Unbalanced dietary intake of ω-6/ω-3 PUFAs contributed to SARS CoV-2 disease severity by decreasing ω-3-dependent SPM resolution of inflammation and increasing membrane-associated ferroptotic AA peroxidation.

Keywords:  SARS CoV-2; dietary imbalance; disease severity; essential polyunsaturated acids; specialized proresolving mediators

DOI:  https://doi.org/10.1155/jnme/7075883
Eur J Immunol. 2025 Apr;55(4): e202451594

Modulation of Host Immunity by Microbiome-Derived Indole-3-Propionic Acid and Other Bacterial Metabolites.

Burkhard Schütz, Felix F Krause, R Verena Taudte, Mario M Zaiss, Maik Luu, Alexander Visekruna.

  In recent years, we have witnessed a rapidly growing interest in the intricate communications between intestinal microorganisms and the host immune system. Research on the human microbiome is evolving from merely descriptive and correlative studies to a deeper mechanistic understanding of the bidirectional interactions between gut microbiota and the mucosal immune system. Despite numerous challenges, it has become increasingly evident that an imbalance in gut microbiota composition, known as dysbiosis, is associated with the development and progression of various metabolic, immune, cancer, and neurodegenerative disorders. A growing body of evidence highlights the importance of small molecules produced by intestinal commensal bacteria, collectively referred to as gut microbial metabolites. These metabolites serve as crucial diffusible messengers, translating the microbial language to host cells. This review aims to explore the complex and not yet fully understood molecular mechanisms through which microbiota-derived metabolites influence the activity of the immune cells and shape immune reactions in the gut and other organs. Specifically, we will discuss recent research that reveals the close relationship between microbial indole-3-propionic acid (IPA) and mucosal immunity. Furthermore, we will emphasize the beneficial effects of IPA on intestinal inflammation and discuss its potential clinical implications.

Keywords:  Intestinal microbiota; gut microbial metabolites; indole‐3‐propionic acid; mucosal immune system

DOI:  https://doi.org/10.1002/eji.202451594
Cell Commun Signal. 2025 Mar 29. 23(1): 156

Retinoic acid enhances γδ T cell cytotoxicity in nasopharyngeal carcinoma by reversing immune exhaustion.

Guichao Liu, Qiang Quan, Lanhong Pan, Haibo Duan, Guojun Zhang, Ke Li, Xinhai Zhu, Dongdong Zhang, Peng Li, Jianfu Zhao.

  Recent studies have shown that the antitumor immunity of adaptive immune cells is regulated by Vitamin A (retinoic acid, RA). However, it remains unclear whether RA and retinoic acid receptor (RAR) signaling can modulate antitumor immunity by reversing immune exhaustion of innate-like γδ T cells in human nasopharyngeal carcinoma (NPC). Periphery blood samples from patients with NPC were prospectively collected, and phenotypic and functional analyses of γδ T cells were performed using flow cytometry. Tumor-bearing models and RAR inhibitor approaches were utilized to investigate RA/RAR-mediated regulation of T cell immunoglobulin domain and mucin domain 3 (Tim-3) and the antitumor activity of γδ T cells. Here, our findings indicate that immune exhaustion markers are highly expressed on peripheral αβ and γδ T cells in NPC patients. Serum RA levels are negatively correlated with the abundance of Tim-3 on circulating Vδ2 T cells. Mechanistic studies have demonstrated that RA/RAR signaling directly targets Vδ2 T cells, repressing Tim-3 expression, promoting NF-κB activation, and enhancing the production of antitumor-related cytokines. Notably, RA supplementation improved the efficacy of Vδ2 T cell-mediated immunotherapy in human NPC by suppressing Tim-3 expression. Collectively, these findings suggest that RA/RAR signaling plays a crucial role in reversing immune exhaustion and represents a promising target for γδ T cell antitumor immunotherapy.

Keywords:  Retinoic acid; Retinoic acid receptor; Tim-3; Tumor immunity; γδ T cells

DOI:  https://doi.org/10.1186/s12964-025-02161-8
mSphere. 2025 Apr 02. e0101124

Metabolic adaptability and nutrient scavenging in Toxoplasma gondii: insights from ingestion pathway-deficient mutants.

Patrick A Rimple, Einar B Olafsson, Benedikt M Markus, Fengrong Wang, Leonardo Augusto, Sebastian Lourido, Vern B Carruthers.

  The obligate intracellular parasite Toxoplasma gondii replicates within a specialized compartment called the parasitophorous vacuole (PV). Recent work showed that despite living within a PV, Toxoplasma endocytoses proteins from the cytosol of infected host cells via a so-called ingestion pathway. The ingestion pathway is initiated by dense granule protein GRA14, which binds host endosomal sorting complex required for transport (ESCRT) machinery to bud vesicles into the lumen of the PV. The protein-containing vesicles are internalized by the parasite and trafficked to the plant vacuole-like compartment (PLVAC), where cathepsin protease L (CPL) degrades the cargo, and the chloroquine resistance transporter (CRT) exports the resulting peptides and amino acids to the parasite cytosol. However, although the ingestion pathway was proposed to be a conduit for nutrients, there is limited evidence for this hypothesis. We reasoned that if Toxoplasma uses the ingestion pathway to acquire nutrients, then parasites lacking GRA14, CPL, or CRT should rely more on biosynthetic pathways or alternative scavenging pathways. To explore this, we conducted a genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screen in wild-type (WT) parasites and Δgra14, Δcpl, and Δcrt mutants to identify genes that become more fitness conferring in ingestion-deficient parasites. Our screen revealed a significant overlap of genes that potentially become more fitness conferring in the ingestion mutants compared to WT. Pathway analysis indicated that Δcpl and Δcrt mutants relied more on pyrimidine biosynthesis, fatty acid biosynthesis, tricarboxylic acid (TCA) cycle, and lysine degradation. Bulk metabolomic analysis showed reduced levels of glycolytic intermediates and amino acids in the ingestion mutants compared to WT, highlighting the pathway's potential role in host resource scavenging. Interestingly, Δcpl and Δcrt showed an exacerbated growth defect when cultured in amino acid-depleted media, suggesting that disrupting proteolysis or the export of proteolytic products from the PLVAC affects parasite survival during nutrient scarcity.
IMPORTANCE: Toxoplasma gondii is an obligate intracellular pathogen that infects virtually any nucleated cell in most warm-blooded animals. Infections are asymptomatic in most cases, but people with weakened immunity can experience severe disease. For the parasite to replicate within the host, it must efficiently acquire essential nutrients, especially as it is unable to make several key metabolites. Understanding the mechanisms by which Toxoplasma scavenges nutrients from the host is crucial for identifying potential therapeutic targets. Our study suggests that the ingestion pathway contributes to sustaining parasite metabolites and parasite replication under amino acid-limiting conditions. This work advances our understanding of the metabolic adaptability of Toxoplasma.

Keywords:  CRISPR; Toxoplasma gondii; amino acids; metabolism

DOI:  https://doi.org/10.1128/msphere.01011-24