bims-imicid 2025-05-25 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2025–05–25
fourteen papers selected by
Dylan Ryan, University of Cambridge

Macrophage immunometabolism dysregulation and inflammatory disorders.
S-adenosylmethionine metabolism shapes CD8+ T cell functions in colorectal cancer.
Meta-epigenetic shifts in T cell aging and aging-related dysfunction.
Regulation of immune cell metabolism by therapeutic normal IgG intravenous immunoglobulin.
Cimicifuga racemosa extract Ze 450 shifts macrophage immunometabolism and attenuates pro-inflammatory signaling.
Age-associated nicotinamide adenine dinucleotide decline drives CAR-T cell failure.
Caspase-11 drives macrophage hyperinflammation in models of Polg-related mitochondrial disease.
Powering immunity: mitochondrial dynamics in natural killer cells.
Sphingolipid synthesis in tumor-associated macrophages confers immunotherapy resistance in hepatocellular carcinoma.
Fatty acid desaturases link cell metabolism pathways to promote proliferation of Epstein-Barr virus-infected B cells.
Multi-omics analysis of glycolytic reprogramming and ROS dynamics in host-specific responses to Salmonella Typhi infection in mice.
Antibiotic-Induced Dysbiosis of the Gut Microbiota Shifts Host Tryptophan Metabolism and Increases the Susceptibility of Mice to Pulmonary Infection With Pseudomonas aeruginosa.
Kaposi's sarcoma-associated herpesvirus induces mitochondrial fission to evade host immune responses and promote viral production.
Low butyrate concentrations exert anti-inflammatory and high concentrations exert pro-inflammatory effects on macrophages.

Biomed Pharmacother. 2025 May 14. pii: S0753-3322(25)00336-1. [Epub ahead of print]188 118142

Macrophage immunometabolism dysregulation and inflammatory disorders.

Karen Pomeyie, Francis Abrokwah, Daniel Boison, Benjamin Amoani, Foster Kyei, Cynthia A Adinortey, Prince Amoah Barnie.

  Macrophages are innate immune cells which are involved in triggering inflammation. Growing evidence shows that, macrophages respond to intracellular and extracellular cues which makes them adopt either anti-inflammatory or pro-inflammatory functions and phenotypes. Immunometabolism has been identified as one of the prominent factors which contributes massively towards the cessation and the development of inflammation as an immune response to infections and autoimmune diseases. However, when inflammation is poorly regulated, it leads to dire consequences. This illustrates that, understanding the role of immunometabolism in the regulation of inflammation, is paramount. In view of this, the review investigated the role of metabolic pathways such as: glycolysis, tricarboxylic acid cycle, pentose phosphate pathway, fatty acid oxidation, amino acid metabolism in macrophage reprogramming. The role of the intermediates and enzymes associated with these metabolic pathways in the regulation of, macrophage reprogramming and polarisation or activation was also reviewed. It was unveiled that, manipulating metabolic intermediates and enzymes could impact cellular immunometabolism. This eventually influences macrophage reprogramming and thus influences the generation of either a pro-inflammatory or anti-inflammatory response.

Keywords:  Immunometabolism; Inflammatory disorders; Macrophage

DOI:  https://doi.org/10.1016/j.biopha.2025.118142
Cancer Metab. 2025 May 19. 13(1): 23

S-adenosylmethionine metabolism shapes CD8+ T cell functions in colorectal cancer.

Xiaohua Yang, Tianzhang Kou, Hongmiao Wang, Ji Zhu, Zheng-Jiang Zhu, Yuping Cai.

  Metabolite nutrients within the tumor microenvironment shape both tumor progression and immune cell functionality. It remains elusive how the metabolic interaction between T cells and tumor cells results in different anti-cancer immunotherapeutic responses. Here, we use untargeted metabolomics to investigate the metabolic heterogeneity in patients with colorectal cancer (CRC). Our analysis reveals enhanced S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) metabolism in microsatellite stable (MSS) CRC, a subtype known for its resistance to immunotherapy. Functional studies reveal that SAM and SAH enhance the initial activation and effector functions of CD8+ T cells. Instead, cancer cells outcompete CD8+ T cells for SAM and SAH availability to impair T cell survival. In vivo, SAM supplementation promotes T cell proliferation and reduces exhaustion of the tumor-infiltrating CD8+ T cells, thus suppressing tumor growth in tumor-bearing mice. This study uncovers the metabolic crosstalk between T cells and tumor cells, which drives the development of tumors resistant to immunotherapy.

Keywords:  CD8+ T cell function; Metabolite nutrients; Metabolomics; Microsatellite stable colorectal cancer; S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) metabolism

DOI:  https://doi.org/10.1186/s40170-025-00394-2
J Biomed Sci. 2025 May 23. 32(1): 51

Meta-epigenetic shifts in T cell aging and aging-related dysfunction.

Lorène Rousseau, Karina L Hajdu, Ping-Chih Ho.

  Epigenetic regulation, including DNA methylation and histone modifications, play a pivotal role in shaping T cell functionality throughout life. With aging, these epigenetic changes profoundly affect gene expression, altering T cell plasticity, activation, and differentiation. These modifications contribute significantly to immunosenescence, increasing susceptibility to infections, cancer, and autoimmune diseases. In CD8⁺ T cells, chromatin closure at key regulatory regions suppresses activation and migration, while chromatin opening in pro-inflammatory gene loci amplifies inflammation. These changes drive terminal differentiation, characterized by increased expression of senescence-associated markers, impaired migration and loss of epigenetic plasticity. CD4⁺ T cells experience fewer but critical epigenetic alterations, including disrupted pathways, a skewed Th1/Th2 balance, and reduced Treg functionality. These epigenetic changes, compounded by metabolic dysfunctions, such as mitochondrial deficiency and oxidative stress, impair T-cell adaptability and resilience in the aging organism. Therefore, understanding the interplay between epigenetic and metabolic factors in T cell aging offers promising therapeutic opportunities to mitigate immunosenescence and enhance immune function in aging populations. This review explores the interplay between DNA methylation, histone alterations, and metabolic changes underlying T cell aging.

Keywords:  DNA methylation; Immune aging; Immunosenescence; T cell aging; T cell dysfunction; T cell metabolism

DOI:  https://doi.org/10.1186/s12929-025-01146-6
J Allergy Clin Immunol. 2025 May 16. pii: S0091-6749(25)00552-4. [Epub ahead of print]

Regulation of immune cell metabolism by therapeutic normal IgG intravenous immunoglobulin.

Naresh Rambabu, Fawaz Alzaid, Boban D Anđelković, Sruthi Vijaya Retnakumar, Anupama Karnam, Srinivasa Reddy Bonam, Lucie Orliaguet, Tina Ejlalmanesh, Dorothy Tonui, Emeline Chu-Van, Ludovic Brunet, Nina Bozinovic, Ivan Nemazanyy, Fabian Käsermann, Nicolas Venteclef, Srini V Kaveri, Thibaut Léger, François Fenaille, Benoit Colsch, Jagadeesh Bayry.

   BACKGROUND: Immune cell metabolism and metabolic end-products influence the nature and magnitude of immune responses. Various autoimmune and inflammatory diseases are associated with dysregulated cellular metabolism. Intravenous immunoglobulin (IVIG), a therapeutic pooled normal IgG, is extensively used for the immunotherapy of a wide-range of autoimmune and inflammatory diseases. Although several cellular and molecular mechanisms of action of IVIG have been reported, the role of IVIG in modulating the immune cell metabolism remains unknown.
OBJECTIVES: To investigate the influence of IVIG on the metabolic events of human immune cells.
METHODS: We performed metabolic flux analyses on inflammatory mediators-stimulated human peripheral blood mononuclear cells (PBMCs). Further, intracellular metabolites were extracted from activated PBMCs and subjected to liquid chromatography coupled to high-resolution mass spectrometry. Untargeted global metabolic profiling of PBMCs was performed to determine the metabolic landscape of immune cells and metabolic reprogramming by IVIG. Targeted lipidomics was used for the mechanistic studies on IVIG-induced lipogenesis.
RESULTS: IVIG, and its Fc and F(ab')2 fragments regulate the Warburg effect in activated PBMCs depending on the glucose availability. Untargeted global metabolic profiling revealed that IVIG alters the overall metabolic landscape of inflammatory mediators-stimulated PBMCs, blocks prenylation of amino acid cysteine and promotes lipogenesis of well-known anti-inflammatory lipids like diacylglycerol and triacylglycerol by shuttling acetyl-CoA away from the mevalonate pathway. Mechanistically, IVIG-induced lipogenesis was mediated via F(ab')2 fragments and dependent on the sialylated glycans of IgG.
CONCLUSIONS: Our data indicate that IVIG targets immune cell metabolism and highlights a novel mechanism of action of IVIG in the context of immunotherapy of autoimmune and inflammatory diseases.

Keywords:  Acetyl-CoA; Diacylglycerol; Fatty acid synthesis; IVIG; Lipogenesis; Metabolic flux; Metabolism; PBMC; Triacylglycerol; Warburg effect

DOI:  https://doi.org/10.1016/j.jaci.2025.05.003
Biomed Pharmacother. 2025 May 17. pii: S0753-3322(25)00324-5. [Epub ahead of print]188 118130

Cimicifuga racemosa extract Ze 450 shifts macrophage immunometabolism and attenuates pro-inflammatory signaling.

Madeline Günther, Nicole Paczia, Susanne Michels, Bernd L Fiebich, Sebastian Vogt, Jürgen Drewe, Georg Boonen, Veronika Butterweck, Carsten Culmsee.

  Extracts from the rhizomes of Cimicifuga racemosa (CRE) are well-studied for treating climacteric symptoms and considered as a safe alternative to hormone replacement therapy (HRT). Chronic low-grade inflammation, or "inflammaging," resulting from the loss of oestrogen's regulatory effect on the immune system, is increasingly recognized as a significant factor in the health of postmenopausal women, contributing to a higher risk for cardiovascular disease, osteoporosis, metabolic syndrome, and cognitive decline. Recent studies have suggested that CRE may exert anti-inflammatory effects, though the underlying mechanisms remain unclear. In this study, we aimed to investigate the effects of Cimicifuga racemosa extract Ze 450 on lipopolysaccharide (LPS)-induced inflammation in macrophages, as macrophage inflammation is crucial in the pathogenesis of several metabolic diseases associated with menopause. Our results demonstrated that CRE Ze 450 reduced the production of NO, IL-1α/β, IL-6, and IL-10, as well as the expression of the pro-inflammatory proteins iNOS, HIF-1α, and mTOR in LPS-stimulated macrophages. Moreover, we observed that Ze 450 induced a shift in energy production from oxidative phosphorylation (OXPHOS) to glycolysis. Mechanistically this was mediated by the modulation of TCA cycle and electron transport chain activity at an early stage, which was further accompanied by the reduction of metabolic signaling molecules such as succinate and citrate. In conclusion, our study identifies a novel mode of action for the Cimicifuga racemosa extract Ze 450, demonstrating its ability to regulate mitochondrial function and macrophage metabolism, but also highlighting its potential to improve the climacteric symptoms by mitigating pro-inflammatory signaling.

Keywords:  Aging; Black cohosh; Cimicifuga racemosa; HIF-1α; Inflammation; MTOR; Macrophages; Metabolic reprogramming; Mitochondria; Mitochondrial metabolism; Ze 450

DOI:  https://doi.org/10.1016/j.biopha.2025.118130
Nat Cancer. 2025 May 20.

Age-associated nicotinamide adenine dinucleotide decline drives CAR-T cell failure.

Helen Carrasco Hope, Jana de Sostoa, Pierpaolo Ginefra, Massimo Andreatta, Yi-Hsuan Chiang, Catherine Ronet, Christine Pich-Bavastro, Jesús Corria Osorio, François Kuonen, Johan Auwerx, Patrizia D'Amelio, Ping-Chih Ho, Santiago J Carmona, George Coukos, Denis Migliorini, Nicola Vannini.

Chimeric antigen receptor (CAR) T cell therapy is one of the most promising cancer treatments. However, different hurdles are limiting its application and efficacy. In this context, how aging influences CAR-T cell outcomes is largely unknown. Here we show that CAR-T cells generated from aged female mice present a mitochondrial dysfunction derived from nicotinamide adenine dinucleotide (NAD) depletion that leads to poor stem-like properties and limited functionality in vivo. Moreover, human data analysis revealed that both age and NAD metabolism determine the responsiveness to CAR-T cell therapy. Targeting NAD pathways, we were able to recover the mitochondrial fitness and functionality of CAR-T cells derived from older adults. Altogether, our study demonstrates that aging is a limiting factor to successful CAR-T cell responses. Repairing metabolic and functional obstacles derived from age, such as NAD decline, is a promising strategy to improve current and future CAR-T cell therapies.

DOI: https://doi.org/10.1038/s43018-025-00982-7
Nat Commun. 2025 May 20. 16(1): 4640

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

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

Mitochondrial diseases (MtD) represent a significant public health challenge due to their heterogenous clinical presentation, often severe and progressive symptoms, and lack of effective therapies. Environmental exposures, such bacterial and viral infection, can further compromise mitochondrial function and exacerbate the progression of MtD. However, the underlying immune alterations that enhance immunopathology in MtD remain unclear. Here we employ in vitro and in vivo approaches to clarify the molecular and cellular basis for innate immune hyperactivity in models of polymerase gamma (Polg)-related MtD. We reveal that type I interferon (IFN-I)-mediated upregulation of caspase-11 and guanylate-binding proteins (GBP) increase macrophage sensing of the opportunistic microbe Pseudomonas aeruginosa (PA) in Polg mutant mice. Furthermore, we show that excessive cytokine secretion and activation of pyroptotic cell death pathways contribute to lung inflammation and morbidity after infection with PA. Our work provides a mechanistic framework for understanding innate immune dysregulation in MtD and reveals potential targets for limiting infection- and inflammation-related complications in Polg-related MtD.

DOI: https://doi.org/10.1038/s41467-025-59907-8
Trends Mol Med. 2025 May 19. pii: S1471-4914(25)00106-6. [Epub ahead of print]

Powering immunity: mitochondrial dynamics in natural killer cells.

Tias Verhezen, An Wouters, Evelien Smits, Jorrit De Waele.

  Natural killer (NK) cells are innate lymphocytes that are crucial for eliminating malignant and infected cells, and have significant therapeutic potential against cancer and viral infections. However, their functionality is often impaired under pathological conditions. Emerging evidence identifies mitochondria as key regulators of NK cell metabolism, fitness, and fate. This review examines how mitochondrial dysfunction impacts on NK cell activity in cancer, viral infections, and inflammatory disorders. We discuss strategies to target mitochondrial architecture, dynamics, and function as potential therapies to restore NK cell fitness. Finally, we highlight unanswered questions and future directions to better understand mitochondrial regulation in NK cells and its implications for therapeutic development.

Keywords:  HIV; cellular therapies; immunometabolism; mitochondria; natural killer cells; oncology

DOI:  https://doi.org/10.1016/j.molmed.2025.04.004
Sci Adv. 2025 May 23. 11(21): eadv0558

Sphingolipid synthesis in tumor-associated macrophages confers immunotherapy resistance in hepatocellular carcinoma.

Xiaozhen Zhang, Mengyi Lao, Kang Sun, Hanshen Yang, Lihong He, Xinyuan Liu, Linyue Liu, Sirui Zhang, Chengxiang Guo, Sicheng Wang, Jiatao Shi, Xiaoyu Zhang, Daqian Xu, Xiongbin Lu, Xueli Bai, Tingbo Liang.

Dysregulated metabolism of immune cells in the tumor microenvironment leads to immune evasion and tumor progression. As a major cell component in the tumor, the metabolic reprogramming of tumor-associated macrophages (TAMs) creates an immunosuppressive microenvironment in hepatocellular carcinoma (HCC). Our study found that sphingolipid (particularly, sphingosine-1-phosphate or S1P) levels are a clinical indicator for prognosis and immunotherapy response in patients with HCC. S1P primarily derived from TAMs, where NIMA-related kinase 2 (NEK2) plays a key role in controlling the activity of serine palmitoyl-CoA transferase, a rate-limiting enzyme in S1P biosynthesis. The S1P produced by NEK2hi TAMs promotes hepatic tumor progression and confers immunotherapy resistance. Targeting S1P synthesis with a NEK2 inhibitor or S1P antagonist disrupted the immunosuppressive function of macrophages, shifted regulatory T cells (Tregs) to TH17 cells, and increased the number and activity of tumor-infiltrating T effectors, thereby enhancing antitumor efficacy in synergy with immune checkpoint blockade therapy.

DOI: https://doi.org/10.1126/sciadv.adv0558
PLoS Pathog. 2025 May 22. 21(5): e1012685

Fatty acid desaturases link cell metabolism pathways to promote proliferation of Epstein-Barr virus-infected B cells.

Emmanuela N Bonglack, Kaeden K Hill, Ashley P Barry, Alexandria Bartlett, Pol Castellano-Escuder, Matthew D Hirschey, Micah A Luftig.

Epstein-Barr virus (EBV) is a gamma herpesvirus that infects up to 95% of the human population by adulthood, typically remaining latent in the host memory B cell pool. In immunocompromised individuals, EBV can drive the transformation and rapid proliferation of infected B cells, ultimately resulting in neoplasia. The same transformation process can be induced in vitro, with EBV-infected peripheral blood B cells forming immortalized lymphoblastoid cell lines (LCLs) within weeks. In this study, we found that the fatty acid desaturases stearoyl-CoA desaturase 1 (SCD1) and fatty acid desaturase 2 (FADS2) are upregulated by EBV and crucial for EBV-induced B cell proliferation. We show that pharmacological and genetic inhibition of both SCD1 and FADS2 results in a significantly greater reduction in proliferation and cell cycle arrest, compared to perturbing either enzyme individually. Additionally, we found that inhibiting either SCD1 or FADS2 alone hypersensitizes LCLs to palmitate-induced apoptosis. Further free fatty acid profiling and metabolic analysis of dual SCD1/FADS2-inhibited LCLs revealed an increase in free unsaturated fatty acids, a reduction of oxidative phosphorylation, and a reduction of glycolysis, thereby linking the activity of SCD1 and FADS2 to overall growth-promoting metabolism. Lastly, we show that SCD1 and FADS2 are important in the growth of clinically derived EBV+ immunoblastic lymphoma cells. Collectively, these data demonstrate a previously uncharacterized role of lipid desaturation in EBV+ transformed B cell proliferation, revealing a metabolic pathway that can be targeted in future anti-lymphoma therapies.

DOI: https://doi.org/10.1371/journal.ppat.1012685
J Adv Res. 2025 May 18. pii: S2090-1232(25)00345-5. [Epub ahead of print]

Multi-omics analysis of glycolytic reprogramming and ROS dynamics in host-specific responses to Salmonella Typhi infection in mice.

Yanrui Bai, Wenxiu Liu, Zhiyuan Liu, Dandan Ding, Huiya Jin, Shangyu Xiao, Jiayin Guo, Xiaoe He, Qian Wang, Han Xiao, Yan Wang, Tiansheng Zhang, Yana Li, Jing Yang, Hui Sun.

   INTRODUCTION: Salmonella Typhi (S. Typhi), a Gram-negative, serves as the etiological agent of typhoid fever. In contrast to other Salmonella serovars, S. Typhi exclusively infects humans. However, the molecular interactions it engages in with the host immune system remain inadequately characterized. This study adopts a multi-omics strategy to elucidate the immune and metabolic dynamics within the murine spleen during S. Typhi infection.
OBJECTIVES: To identify and analyze transcriptomic, proteomic, and metabolomic alterations in the spleens of mice infected with S. Typhi. By comparing these host responses with those elicited by Salmonella Typhimurium (S. Typhimurium), a closely related serovar possessing a broad host range, the study seeks to uncover the unique metabolic reprogramming and immune-modulatory mechanisms specific to S. Typhi infection.
METHODS: A multi-omics strategy was adopted, integrating transcriptomic, proteomic, and metabolomic data obtained from the spleen tissues of S. Typhi-infected mice. S. Typhimurium was utilized as a comparative control to distinguish host-specific responses. Additionally, the dynamics of reactive oxygen species (ROS), which play pivotal roles in mediating immune responses during infection, were examined.
RESULTS: Integration of multi-omics datasets demonstrated distinct metabolic and immunological responses orchestrated by S. Typhi infection. Host metabolism was reprogrammed by S. Typhi through the upregulation of glycolysis and the facilitation of glucose-to-pyruvate conversion, while concurrently suppressing the tricarboxylic acid cycle (TCA cycle). These changes culminated in increased lactate accumulation, and augmented ROS production, all of which were associated with intensified immune activation.
CONCLUSION: S. Typhi infection induces metabolic reprogramming in the host, characterized by a redirected glycolytic flux and altered pyruvate metabolism. This metabolic shift enhances ROS production and modulates the immune response. These findings yield novel insights into host-specific strategies employed by S. Typhi and highlight the significance of metabolic remodeling in immune defense, thereby presenting potential therapeutic targets for combating typhoid fever.

Keywords:  Glucose metabolism reprogramming; Host responses; Multi-Omics; ROS; Salmonella Typhi

DOI:  https://doi.org/10.1016/j.jare.2025.05.027
Immunology. 2025 May 19.

Antibiotic-Induced Dysbiosis of the Gut Microbiota Shifts Host Tryptophan Metabolism and Increases the Susceptibility of Mice to Pulmonary Infection With Pseudomonas aeruginosa.

Camila Bernardo de Brito, Raquel Duque do Nascimento Arifa, Rafael de Oliveira Bezerra, Carlos Eduardo Dias Igídio, Bárbara Maria de Amorim-Santos, Anna Clara Paiva de Menezes Santos, Larissa Mendes Barbosa, João Paulo Pezzini Barbosa, Larissa Marcely Gomes Cassiano, Markus Kohlhoff, Micheli Fagundes, Rafaela Ribeiro Álvares Batista, Celso Martins Queiroz-Junior, Alessandra M Saliba, Juliana Divina Almeida Raposo, Fernão Castro Braga, Roney Santos Coimbra, Mauro Martins Teixeira, Caio Tavares Fagundes, Danielle G Souza.

  Pseudomonas aeruginosa is an opportunistic bacterium that mainly infects those who have previously been treated with antibiotics. We hypothesised that antibiotic treatment disrupts tryptophan metabolism, leading to increased susceptibility to P. aeruginosa infection. Our results showed that mice receiving antibiotics exhibited intestinal dysbiosis with alterations in host tryptophan metabolism, a higher mortality rate and a higher bacterial load compared to eubiotic mice. In the lungs of the dysbiotic mice, there was an increase in IDO1 (Indoleamine 2,3-dioxygenase 1) activity and an accumulation of kynurenine after infection, and IDO1-/- mice were resistant to infection after induction of dysbiosis. Importantly, dysbiosis led to increased expression and activation of AHR (Aryl Hydrocarbon Receptor) in an IDO1-dependent manner. Blocking AHR activation in dysbiotic mice resulted in a lower bacterial load. Our data showed that increased AHR activation by kynurenine was associated with decreased phagocytosis of P. aeruginosa by macrophages and neutrophils. In conclusion, our results indicate that dysbiosis resulting from prolonged antimicrobial treatment alters tryptophan metabolism, leading to activation of the IDO1-AHR axis and increasing susceptibility to P. aeruginosa infection. Furthermore, these data suggest that IDO1 or AHR are potential host targets for the prevention of opportunistic infections in patients undergoing antimicrobial therapy.

Keywords:  AHR and Pseudomonas aeruginosa; IDO1; antibiotics; host‐targeted therapy; inflammation; neutrophils

DOI:  https://doi.org/10.1111/imm.13932
Nat Microbiol. 2025 May 22.

Kaposi's sarcoma-associated herpesvirus induces mitochondrial fission to evade host immune responses and promote viral production.

Qing Zhu, Robert McElroy, Janvhi Suresh Machhar, Joel Cassel, Zihan Zheng, Behzad Mansoori, Hongrui Guo, Sen Guo, Christian Pangilinan, Jinghui Liang, Dongliang Shen, Lu Zhang, Qin Liu, Andrew V Kossenkov, Dario C Altieri, Paul M Lieberman, Shou-Jiang Gao, Pinghui Feng, Maureen E Murphy, Jikui Song, Joseph M Salvino, Qiming Liang, Jae U Jung, Chengyu Liang.

Mitochondrial dynamics are pivotal for host immune responses upon infection, yet how viruses manipulate these processes to impair host defence and enhance viral fitness remains unclear. Here we show that Kaposi's sarcoma-associated herpesvirus (KSHV), an oncogenic virus also known as human herpesvirus 8, encodes Bcl-2 (vBcl-2), which reprogrammes mitochondrial architecture. It binds with NM23-H2, a host nucleoside diphosphate (NDP) kinase, to stimulate GTP loading of the dynamin-related protein (DRP1) GTPase, which triggers mitochondrial fission, inhibits mitochondrial antiviral signalling protein (MAVS) aggregation and impairs interferon responses in cell lines. An NM23-H2-binding-defective vBcl-2 mutant fails to evoke fission, leading to defective virion assembly due to activated MAVS-IFN signalling. Notably, we identify two key interferon-stimulated genes restricting vBcl-2-dependent virion morphogenesis. Using a high-throughput drug screening, we discover an inhibitor targeting vBcl-2-NM23-H2 interaction that blocks virion production in vitro. Our study identifies a mechanism in which KSHV manipulates mitochondrial dynamics to allow for virus assembly and shows that targeting the virus-mitochondria interface represents a potential therapeutic strategy.

DOI: https://doi.org/10.1038/s41564-025-02018-3
J Nutr Biochem. 2025 May 15. pii: S0955-2863(25)00125-1. [Epub ahead of print] 109962

Low butyrate concentrations exert anti-inflammatory and high concentrations exert pro-inflammatory effects on macrophages.

Muwei Jiang, Danny Incarnato, Rutger Modderman, Aina Altimira Lazaro, Iris H Jonkers, Frans Bianchi, Geert van den Bogaart.

  Butyrate is a four-carbon short-chain fatty acid produced from microbial fermentation of dietary fibers present at high millimolar concentrations in the colonic lumen. However, in an intact epithelium, macrophages residing in the lamina propria are exposed to only micromolar butyrate concentrations. Current studies show anti-inflammatory properties of butyrate and suggest that it might have therapeutic applications in inflammatory bowel disease and colonic cancer. We now show that the effect of butyrate on human macrophages is strongly concentration dependent: 0.1 mM butyrate suppresses LPS-induced production of the pro-inflammatory cytokine tumor necrosis factor (TNF)-α. Experiments with siRNA knockdown and small molecule inhibitors suggest that this is mediated by a mechanism involving PPAR-γ signaling, whereas we observed no or only a minor effect of histone acetylation. In contrast, 10 mM butyrate promotes macrophage cell death, does not inhibit LPS-induced production of TNF-α, and promotes production of IL-1β, while production of anti-inflammatory IL-10 is reduced in a mechanism involving G protein-coupled receptors, the lipid transporter CD36, and the kinase SRC. We propose that butyrate is a signaling molecule for intestinal integrity, since intestinal disruption exposes macrophages to high butyrate concentrations.

Keywords:  Butyrate; cytokines; inflammation; macrophage; short-chain fatty acid

DOI:  https://doi.org/10.1016/j.jnutbio.2025.109962