bims-imicid 2025-03-02 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2025–03–02
eightteen papers selected by
Dylan Ryan, University of Cambridge

Glycolytic reprogramming shapes the histone acetylation profile of activated CD4+ T cells in juvenile idiopathic arthritis.
Mitochondrial superoxide regulates pro-inflammatory macrophages.
The Effects of Fisetin on Gene Expression Profile and Cellular Metabolism in IFN-γ-Stimulated Macrophage Inflammation.
Hexokinase 2-mediated metabolic stress and inflammation burden of liver macrophages via histone lactylation in MASLD.
Macrophages recycle phagocytosed bacteria to fuel immunometabolic responses.
In-depth proteomic profiling identifies potentiation of the LPS response by 7-ketocholesterol.
Feline Calicivirus Infection Manipulates Central Carbon Metabolism.
Comparative metabolomic analysis reveals shared and unique features of COVID-19 cytokine storm and surgical sepsis.
Autophagy repression by antigen and cytokines shapes mitochondrial, migration and effector machinery in CD8 T cells.
Fructose induces inflammatory activation in macrophages and microglia through the nutrient-sensing ghrelin receptor.
Histone lactylation-driven B7-H3 expression promotes tumor immune evasion.
Metabolomics Profiling Reveals Critical Roles of Indoxyl Sulfate in the Regulation of Innate Monocytes in COVID-19.
Endogenous nitric oxide promotes Staphylococcus aureus virulence by activating autophagy.
Glutamate decarboxylase confers acid tolerance and enhances survival of mycobacteria within macrophages.
Altered hepatic metabolism mediates sepsis preventive effects of reduced glucose supply in infected preterm newborns.
Functional reprogramming of neutrophils within the brain tumor microenvironment by hypoxia-driven histone lactylation.
Viperin expression leads to downregulation of mitochondrial genes through misincorporation of ddhCTP by mitochondrial RNA polymerase.
Dietary cysteine enhances intestinal stemness via CD8 + T cell-derived IL-22.

Cell Rep. 2025 Feb 18. pii: S2211-1247(25)00058-0. [Epub ahead of print]44(2): 115287

Glycolytic reprogramming shapes the histone acetylation profile of activated CD4+ T cells in juvenile idiopathic arthritis.

Enric Mocholi, Edward Corrigan, Theo Chalkiadakis, Can Gulersonmez, Edwin Stigter, Bas Vastert, Jorg van Loosdregt, Stefan Prekovic, Paul J Coffer.

  Juvenile idiopathic arthritis (JIA) is an autoimmune disease characterized by accumulation of activated CD4+ T cells in the synovial fluid (SF) of affected joints. JIA CD4+ T cells exhibit a unique inflammation-associated epigenomic signature, but the underlying mechanisms remain unclear. We demonstrate that CD4+ T cells from JIA SF display heightened glycolysis upon activation and JIA-specific H3K27 acetylation, driving transcriptional reprogramming. Pharmacological inhibition of glycolysis altered the expression of genes associated with these acetylated regions. Healthy CD4+ T cells exposed to JIA SF exhibited increased glycolytic activity and transcriptomic changes marked by heightened histone 3 lysine 27 acetylation (H3K27ac) at JIA-specific genes. Elevated H3K27ac was dependent on glycolytic flux, while inhibiting glycolysis or pyruvate dehydrogenase (PDH) impaired transcription of SF-driven genes. These findings demonstrate a key role of glycolysis in JIA-specific gene expression, offering potential therapeutic targets for modulating inflammation in JIA.

Keywords:  CP: Immunology; CP: Metabolism; T cells; autoimmune disease; glucose metabolism; histone acetylation; juvenile idiopathic arthritis; pyruvate dehydrogenase

DOI:  https://doi.org/10.1016/j.celrep.2025.115287
Nat Metab. 2025 Feb 24.

Mitochondrial superoxide regulates pro-inflammatory macrophages.

DOI: https://doi.org/10.1038/s42255-025-01223-y
Antioxidants (Basel). 2025 Feb 04. pii: 182. [Epub ahead of print]14(2):

The Effects of Fisetin on Gene Expression Profile and Cellular Metabolism in IFN-γ-Stimulated Macrophage Inflammation.

Ziyu He, Xuchi Pan, Kun Xie, Kozue Sakao, Jihua Chen, Masaharu Komatsu, De-Xing Hou.

  Although interferon-gamma (IFN-γ) is known as a critical factor in polarizing macrophages into the pro-inflammatory state for immune response, how dietary flavonoids regulate IFN-γ response for anti-inflammation is incompletely elucidated. This study aims to investigate the effect of fisetin, a typical flavonol, on the inhibition of IFN-γ-induced inflammation by RNA sequencing (RNA-Seq) and cellular metabolism analysis. RAW264 macrophages pretreated with fisetin following IFN-γ stimulation were subjected to RNA-Seq to analyze alterations in gene expression. Cellular signaling and transcription were investigated using enrichment analysis, motif analysis, and transcription factor prediction. Cellular metabolic state was assessed by measuring the oxygen consumption rate (OCR) and lactate level to reflect mitochondrial respiration and glycolysis. Alterations in signaling proteins were confirmed by Western blot. The results revealed that fisetin downregulated the IFN-γ-induced expression of pro-inflammatory genes and M1 marker genes such as Cxcl9, Il6, Cd80, Cd86, and Nos2. In cellular metabolism, fisetin upregulated the oxidative phosphorylation (OXPHOS) pathway, restored impaired OCR, and reduced lactate production induced by IFN-γ. Motif analysis suggested that fisetin suppressed the activation of IFN-regulatory factor 1 (IRF1). Western blot data further confirmed that fisetin inhibited the phosphorylation of Jak1, Jak2, and STAT1, and decreased the nuclear accumulation of phosphorylated STAT1 and IRF1 induced by IFN-γ. Taken together, our data revealed that fisetin is a potent flavonoid that attenuates IFN-γ-stimulated murine macrophage inflammation and ameliorates disrupted cellular metabolism with a possible Jak1/2-STAT1-IRF1 pathway.

Keywords:  IFN-γ; IRF1; RNA-Seq; cellular metabolism; fisetin; inflammation; macrophages

DOI:  https://doi.org/10.3390/antiox14020182
Cell Rep. 2025 Feb 25. pii: S2211-1247(25)00121-4. [Epub ahead of print]44(3): 115350

Hexokinase 2-mediated metabolic stress and inflammation burden of liver macrophages via histone lactylation in MASLD.

Jinyang Li, Xiancheng Chen, Shiyu Song, Wangjie Jiang, Tianjiao Geng, Tiantian Wang, Yan Xu, Yongqiang Zhu, Jun Lu, Yongxiang Xia, Rong Wang.

  Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by metabolic dysfunction and inflammation burden, involving a significant enhancement of cellular glycolytic activity. Here, we elucidate how a positive feedback loop in liver macrophages drives MASLD pathogenesis and demonstrate that disrupting this cycle mitigates metabolic stress and macrophage M1 activation during MASLD. We detect elevated expression of hexokinase 2 (HK2) and H3K18la in liver macrophages from patients with MASLD and MASLD mice. This lactate-dependent histone lactylation promotes glycolysis and liver macrophage M1 polarization by enriching the promoters of glycolytic genes and activating transcription. Ultimately, the HK2/glycolysis/H3K18la positive feedback loop exacerbates the vicious cycle of enhancing metabolic dysregulation and histone lactylation and the inflammatory phenotype of liver macrophages. Myeloid-specific deletion of Hk2 or pharmacological inhibition of the transcription factor HIF-1α significantly disrupts this deleterious cycle. Therefore, our study illustrates that targeting this amplified pathogenic loop may offer a promising therapeutic strategy for MASLD.

Keywords:  CP: Immunology; CP: Metabolism; MASLD; hexokinase 2; histone lactylation; liver macrophages; positive feedback loop

DOI:  https://doi.org/10.1016/j.celrep.2025.115350
Nature. 2025 Feb 26.

Macrophages recycle phagocytosed bacteria to fuel immunometabolic responses.

Juliette Lesbats, Aurélia Brillac, Julie A Reisz, Parnika Mukherjee, Charlène Lhuissier, Mónica Fernández-Monreal, Jean-William Dupuy, Angèle Sequeira, Gaia Tioli, Celia De La Calle Arregui, Benoît Pinson, Daniel Wendisch, Benoît Rousseau, Alejo Efeyan, Leif Erik Sander, Angelo D'Alessandro, Johan Garaude.

Macrophages specialize in phagocytosis, a cellular process that eliminates extracellular matter, including microorganisms, through internalization and degradation1,2. Despite the critical role of phagocytosis during bacterial infection, the fate of phagocytosed microbial cargo and its impact on the host cell are poorly understood. In this study, we show that ingested bacteria constitute an alternative nutrient source that skews immunometabolic host responses. By tracing stable isotope-labelled bacteria, we found that phagolysosomal degradation of bacteria provides carbon atoms and amino acids that are recycled into various metabolic pathways, including glutathione and itaconate biosynthesis, and satisfies the bioenergetic needs of macrophages. Metabolic recycling of microbially derived nutrients is regulated by the nutrient-sensing mechanistic target of rapamycin complex C1 and is intricately tied to microbial viability. Dead bacteria, as opposed to live bacteria, are enriched in cyclic adenosine monophosphate, sustain the cellular adenosine monophosphate pool and subsequently activate adenosine monophosphate protein kinase to inhibit the mechanistic target of rapamycin complex C1. Consequently, killed bacteria strongly fuel metabolic recycling and support macrophage survival but elicit decreased reactive oxygen species production and reduced interleukin-1β secretion compared to viable bacteria. These results provide a new insight into the fate of engulfed microorganisms and highlight a microbial viability-associated metabolite that triggers host metabolic and immune responses. Our findings hold promise for shaping immunometabolic intervention for various immune-related pathologies.

DOI: https://doi.org/10.1038/s41586-025-08629-4
J Mol Cell Cardiol Plus. 2025 Mar;11 100285

In-depth proteomic profiling identifies potentiation of the LPS response by 7-ketocholesterol.

Iain R Phair, Magdalena Sovakova, Noor Alqurashi, Raid B Nisr, Alison D McNeilly, Douglas Lamont, Graham Rena.

  In patients with stable coronary artery disease, plasma levels of 7-ketocholesterol (7-KC), found at high levels in atherosclerotic lesions, predict risk of incident heart failure dose dependently, potentially contributing to disease aetiology. Previous studies demonstrated that 7-KC can elicit effects on macrophage function; however, effects of 7-KC on the macrophage proteome have not been studied systematically. Here we used quantitative mass spectrometry to establish the effect of 7-KC on the mouse macrophage proteome. 7-KC independently mediated dynamic changes, including on atherogenic/M1 markers, cholesterol metabolism, biosynthesis and transport, as well as nutrient transport more broadly. These changes were however insufficient alone to drive changes in cytokine and chemokine secretion. Rather, they prime the macrophage, potentiating LPS-stimulated TNF alpha secretion and key pro-inflammatory enzymes. Our results indicate that 7-KC has independent metabolic effects on the macrophage; however, effects on the immune system are primarily due to the changes in metabolism priming the response to an inflammatory stimulus. Earlier findings from CANTOS and the recent FDA approval of colchicine highlight that inflammation is a viable target for cardiovascular disease; however, it is currrently unclear which will be the best anti-inflammatory targets to pursue in the future. In this context, our findings suggest that drugs targeting atherogenic markers induced by 7-KC might be well tolerated, as they will not necessarily be expected to be immunosuppressive.

Keywords:  Cholesterol; Inflammation; Ketocholesterol; Macrophages; Oxysterol

DOI:  https://doi.org/10.1016/j.jmccpl.2025.100285
Vet Sci. 2025 Feb 07. pii: 138. [Epub ahead of print]12(2):

Feline Calicivirus Infection Manipulates Central Carbon Metabolism.

Guangrong Zhao, Hongwei Zhu, Xiu Xue, Chenpei Zhao, Xin Yu, Linlin Jiang, Jingxian Cong, Yang Liu, Yuanlong He, Jianlong Zhang, Xingxiao Zhang.

  Viruses can manipulate the host metabolism to achieve optimal replication conditions, and central carbon metabolism (CCM) pathways are often crucial in determining viral infections. Feline calicivirus (FCV), a diminutive RNA viral agent, induces upper respiratory tract infections in feline hosts, with highly pathogenic strains capable of precipitating systemic infections and subsequent host cell necrosis, thereby presenting a formidable challenge to feline survival and protection. However, the relationship between FCV and host cell central carbon metabolism (CCM) remains unclear, and the precise pathogenic mechanisms of FCV are yet to be elucidated. Upon FCV infection of Crandell-Rees Feline Kidney (CRFK) cells, an enhanced cellular uptake of glucose and glutamine was observed. Metabolomics analyses disclosed pronounced alterations in the central carbon metabolism of the infected cells. FCV infection was found to augment glycolytic activity while sustaining the tricarboxylic acid (TCA) cycle flux, with cellular ATP levels remaining invariant. Concurrently, both glutamine metabolism and the flux of the pentose phosphate pathway (PPP) were noted to be intensified. The application of various inhibitory agents targeting glycolysis, glutamine metabolism, and the PPP resulted in a significant suppression of FCV proliferation. Experiments involving glucose and glutamine deprivation demonstrated that the absence of either nutrient markedly curtailed FCV replication. Collectively, these findings suggest a critical interplay between central carbon metabolism and FCV proliferation. FCV infection stimulates CRFK cells to augment glucose and glutamine uptake, thereby supplying the necessary metabolic substrates and energy for viral replication. During the infection, glutamine emerges as the primary energy substrate, ensuring ATP production and energy homeostasis, while glucose is predominantly channeled into the pentose phosphate pathway to facilitate nucleotide synthesis.

Keywords:  glutamine metabolism; glycolysis; metabolomics; pentose phosphate pathway

DOI:  https://doi.org/10.3390/vetsci12020138
Sci Rep. 2025 Feb 24. 15(1): 6622

Comparative metabolomic analysis reveals shared and unique features of COVID-19 cytokine storm and surgical sepsis.

Iana V Russkikh, Oleg S Popov, Tatiana G Klochkova, Natalia N Sushentseva, Svetlana V Apalko, Anna Yu Asinovskaya, Sergey V Mosenko, Andrey M Sarana, Sergey G Shcherbak.

  The clinical manifestations of the cytokine storm (CS) associated with COVID-19 resemble the acute phase of sepsis. Metabolomics may contribute to understanding the specific pathobiology of these two syndromes. The aim of this study was to compare serum metabolomic profiles in CS associated with COVID-19 vs. septic surgery patients. In a retrospective cross-sectional study, serum samples from patients with CS associated with COVID-19, with and without comorbidity, as well as serum samples from patients with surgical sepsis were investigated. Targeted metabolomic analysis was performed on all samples using LC-MS/MS. Analysis revealed that similar alterations in the serum metabolome of patients with COVID-19 and surgical septic patients were associated with amino acid metabolism, nitrogen metabolism, inflammatory status, methionine cycle and glycolysis. The most significant difference was found for serum levels of metabolites of kynurenine synthesis, tricarboxylic acid cycle, gamma-aminobutyric acid and niacinamide. The metabolic pathway of cysteine and methionine metabolism was significantly disturbed in COVID-19 and surgical septic patients. For the first time, the similarities and differences between the serum metabolomic profiles of patients with CS associated with COVID-19 and patients with surgical sepsis were investigated for patients from the Northwest of the Russian Federation.

Keywords:  COVID-19; Cytokine storm; LC–MS/MS; Metabolic pathways; Sepsis; Targeted metabolomic analysis

DOI:  https://doi.org/10.1038/s41598-025-90426-0
Nat Immunol. 2025 Feb 27.

Autophagy repression by antigen and cytokines shapes mitochondrial, migration and effector machinery in CD8 T cells.

Linda V Sinclair, Tom Youdale, Laura Spinelli, Milica Gakovic, Alistair J Langlands, Shalini Pathak, Andrew J M Howden, Ian G Ganley, Doreen A Cantrell.

Autophagy shapes CD8 T cell fate; yet the timing, triggers and targets of this process are poorly defined. Herein, we show that naive CD8 T cells have high autophagic flux, and we identify an autophagy checkpoint whereby antigen receptor engagement and inflammatory cytokines acutely repress autophagy by regulating amino acid transporter expression and intracellular amino acid delivery. Activated T cells with high levels of amino acid transporters have low autophagic flux in amino-acid-replete conditions but rapidly reinduce autophagy when amino acids are restricted. A census of proteins degraded and fueled by autophagy shows how autophagy shapes CD8 T cell proteomes. In cytotoxic T cells, dominant autophagy substrates include cytolytic effector molecules, and amino acid and glucose transporters. In naive T cells, mitophagy dominates and selective mitochondrial pruning supports the expression of molecules that coordinate T cell migration and survival. Autophagy thus differentially prunes naive and effector T cell proteomes and is dynamically repressed by antigen receptors and inflammatory cytokines to shape T cell differentiation.

DOI: https://doi.org/10.1038/s41590-025-02090-1
FASEB J. 2025 Feb 28. 39(4): e70412

Fructose induces inflammatory activation in macrophages and microglia through the nutrient-sensing ghrelin receptor.

Zheng Shen, Zeyu Liu, Hongying Wang, Danilo Landrock, Ji Yeon Noh, Qun Sophia Zang, Chih-Hao Lee, Yuhua Z Farnell, Zheng Chen, Yuxiang Sun.

  High fructose corn syrup (HFCS) is a commonly used sweetener in soft drinks and processed foods, and HFCS exacerbates inflammation when consumed in excess. Fructose, a primary component of HFCS; however, it is unclear whether fructose directly activates inflammatory signaling. Growth hormone secretagogue receptor (GHSR) is a receptor of the nutrient-sensing hormone ghrelin. We previously reported that GHSR ablation mitigates HFCS-induced inflammation in adipose tissue and liver, shifting macrophages toward an anti-inflammatory spectrum. Since inflammation is primarily governed by innate immune cells, such as macrophages in the peripheral tissues and microglia in the brain, this study aims to investigate whether GHSR autonomously regulates pro-inflammatory activation in macrophages and microglia upon fructose exposure. GHSR deletion mutants of RAW 264.7 macrophages and the immortalized microglial cell line (IMG) were generated using CRISPR-Cas9 gene editing. After treating the cells with equimolar concentrations of fructose or glucose for 24 h, fructose increased mRNA and protein expression of GHSR and pro-inflammatory cytokines (Il1β, Il6, and Tnfα) in both macrophages and microglia, suggesting that fructose activates Ghsr and induces inflammation directly in macrophages and microglia. Remarkably, GHSR deletion mutants (Ghsrmutant) of macrophages and microglia exhibited reduced inflammatory responses to fructose, indicating that GHSR mediates fructose-induced inflammation. Furthermore, we found that GHSR regulates fructose transport and fructose metabolism and mediates fructose-induced inflammatory activation through CREB-AKT-NF-κB and p38 MAPK signaling pathways. Our results underscore that fructose triggers inflammation, and reducing HFCS consumption would reduce disease risk. Moreover, these findings reveal for the first time that the nutrient-sensing receptor GHSR plays a crucial role in fructose-mediated inflammatory activation, suggesting that targeting GHSR may be a promising therapeutic approach to combat the immunotoxicity of foods that contain fructose.

Keywords:  fructose; growth hormone secretagogue receptor (GHSR); inflammation; macrophage; microglia

DOI:  https://doi.org/10.1096/fj.202402531R
Theranostics. 2025 ;15(6): 2338-2359

Histone lactylation-driven B7-H3 expression promotes tumor immune evasion.

Zhibo Ma, Jincui Yang, Wenlong Jia, Le Li, Yixin Li, Junjie Hu, Wei Luo, Ronghui Li, Dawei Ye, Peixiang Lan.

  Rationale: Tumor cells possess sophisticated strategies to circumvent immune detection, including the modulation of endogenous immune checkpoints, particularly those within the B7 family. Elucidating the mechanisms that govern the induction of B7 family molecules is crucial for the advancement of immunotherapy. Lysine lactylation (Kla), a newly identified epigenetic modification, is suggested may play a role in reshaping the tumor microenvironment and facilitating immune evasion. Methods: We analyzed the glycolysis pathway's enrichment in patients with immune-evading tumors and assessed the impact of lactate treatment on the antitumor immunity of CD8+ T cells in the tumor microenvironment. We interrupted glycolysis using lactate dehydrogenase A (LDHA) knockdown and sodium oxamate, and evaluated its effects on CD8+ T cell cytotoxicity. Additionally, we investigated the correlation between B7-H3 expression and the glycolysis pathway, and explored the molecular mechanisms underlying lactate-induced B7-H3 expression. Results: Our findings revealed that the glycolysis pathway was highly enriched in immune-evading tumors. Lactate treatment inhibited the antitumor immunity of CD8+ T cells, whereas interruption of glycolysis via LDHA knockdown or treatment with sodium oxamate augmented the cytotoxicity of CD8+ T cells, effectively counteracting tumor immune evasion. B7-H3 expression was found to be closely linked with the glycolysis pathway. Mechanistically, lactate-upregulated H3K18la directly bound to the B7-H3 promoter in conjunction with the transcription factor Creb1 and its co-activator Ep300, leading to increased B7-H3 expression and contributing to tumor progression by compromising the proportion and cytotoxicity of tumor-infiltrating CD8+ T cells. In mouse tumor bearing models, inhibiting glycolysis and B7-H3 expression suppressed tumor cell growth, activated tumor-infiltrating CD8+ T cells, and demonstrated potent anti-tumor efficacy. Furthermore, this approach enhanced the efficacy of anti-PD-1 treatment. Conclusions: This study uncovers a novel mechanism by which lactate modulates the immune microenvironment through the glycolysis pathway and B7-H3 expression, providing new avenues for lactate metabolism-targeted tumor immunotherapy.

Keywords:  B7-H3; Glycolysis; H3K18la; Histone lactylation; Immune evasion

DOI:  https://doi.org/10.7150/thno.105947
Cells. 2025 Feb 11. pii: 256. [Epub ahead of print]14(4):

Metabolomics Profiling Reveals Critical Roles of Indoxyl Sulfate in the Regulation of Innate Monocytes in COVID-19.

Liqing He, Yunke Wang, Fang Yuan, Samantha Morrissey, Anne E Geller, Xiaoling Hu, Raobo Xu, Xipeng Ma, Huang-Ge Zhang, Kenneth McLeish, Jiapeng Huang, Xiang Zhang, Jun Yan.

  The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is intricately related to the reprogramming of host metabolism. However, existing studies have mainly focused on peripheral blood samples and barely identified specific metabolites that are critically involved in the pathology of coronavirus disease 2019 (COVID-19). In the current small-scale study, we performed metabolic profiling in plasma (n = 61) and paired bronchoalveolar lavage fluid (BALF) samples (n = 20) using parallel two-dimensional liquid chromatography-mass spectrometry (2DLC-MS). In addition, we studied how an identified metabolite regulates the immunopathogenesis of COVID-19. The results unveiled distinct metabolome changes between healthy donors, and moderate and severe patients in both plasma and BALF, indicating that locations and disease severity play critical roles in COVID-19 metabolic alteration. Notably, a vital metabolite, indoxyl sulfate, was found to be elevated in both the plasma and BALF of severe COVID-19 patients. Indoxyl sulfate selectively induced TNF-α production, reduced co-stimulatory signals, and enhanced apoptosis in human monocytes. Moreover, its levels negatively correlated with the strength of co-stimulatory signals and antigen presentation capability in monocytes of COVID-19 patients. Collectively, our findings suggest that the levels of indoxyl sulfate could potentially serve as a functional biomarker to monitor COVID-19 disease progression and guide more individualized treatment for COVID-19 patients.

Keywords:  COVID-19; immune regulation; indoxyl sulfate; metabolism; monocytes

DOI:  https://doi.org/10.3390/cells14040256
mBio. 2025 Feb 25. e0400624

Endogenous nitric oxide promotes Staphylococcus aureus virulence by activating autophagy.

Nadira Nurxat, Qichen Wang, Na Zhao, Yanan Guo, Xilong Zhang, Yanan Wang, Ying Jian, Hua Wang, Shengbing Yang, Min Li, Qian Liu.

  Endogenous nitric oxide (NO) is a small molecule that has been demonstrated to affect the physiology and survival of bacteria. The role of endogenous NO for Staphylococcus aureus survival inside host cells remains unclear. Here, we show that the production of endogenous NO by bacterial nitrate reductase (NR) is affected by molybdopterin biosynthesis protein A (MoeA), which is essential for molybdenum cofactor synthesis in S. aureus. During the infection, the production of endogenous NO promotes S. aureus survival inside macrophages by initiating cellular autophagy. Mechanistically, bacterial endogenous NO can modify the host regulatory protein thioredoxin vis S-nitrosylation, subsequently triggering the phosphorylation of the JNK-Bcl-2 pathway and promoting the initiation of autophagy through the release of Beclin1. Moreover, we confirmed the critical role of MoeA in bacterial survival in vivo by using bloodstream infection, pneumonia, and skin abscess model on both wild-type and autophagy-deficient mice. Interestingly, we observed the significantly increased production of NO and activation of cellular autophagy of sequence type (ST)5 compared with ST239, suggesting that the initiation of autophagy is involved in the clone shift of S. aureus. Our data offered new insights on the role of bacterial endogenous NO in regulating the host signal pathway during infection inside host cells.IMPORTANCEUnderstanding the mechanism underlying Staphylococcus aureus pathogenesis is essential for developing innovative strategies for the prevention and treatment of infection. In this study, we underscore the critical role of molybdopterin biosynthesis protein A and nitric oxide (NO) in inducing autophagy during S. aureus survival within macrophage and in vivo infection. We demonstrate that host regulatory protein can be modified by bacterial metabolites, which may influence cellular processes. Furthermore, our findings indicated that increased endogenous NO production may contribute to the stable prevalence of S. aureus ST5 in the healthcare-associated environment. These findings highlight the significance of bacterial metabolism in modulating the host immune system, thereby facilitating S. aureus survival and persistence.

Keywords:  Staphylococcus aureus; autophagy; metabolism; nitric oxide; virulence

DOI:  https://doi.org/10.1128/mbio.04006-24
J Biol Chem. 2025 Feb 21. pii: S0021-9258(25)00187-5. [Epub ahead of print] 108338

Glutamate decarboxylase confers acid tolerance and enhances survival of mycobacteria within macrophages.

Rupal Rai, Bijina J Mathew, Rashmi Chourasia, Anirudh K Singh, Shivendra K Chaurasiya.

  Host-induced metabolic adaptations are crucial for Mycobacterium tuberculosis (Mtb) survival and drug resistance. Mtb's persistence in the acidic environments of phagosomes and phagolysosomes suggests its initial metabolic adjustments respond to acidic stress. Glutamate decarboxylase (Gad) enzyme, converts glutamate to GABA while consuming a proton, helping regulate intracellular pH in bacteria. However, the role of Gad in mycobacteria has been unexplored. In this study, we investigated the function of Gad in Mtb and Mycobacterium smegmatis (MS), which are encoded by Rv3432c (gadB) and MSMEG_1574 (gadA), an orthologue of gadB, respectively. We observed upregulation of gad in both Mtb and MS under acidic stress and during infection within macrophages. Additionally, the expression of genes involved in glutamate metabolism and the GABA shunt, such as glutamine synthetase (glnA1), glutamate dehydrogenase (gdh), glutamate synthase (gltD/B), GABA-aminotransferase (gab-T), succinic semialdehyde dehydrogenase (gabD1/gabD2), α-ketoglutarate dehydrogenase (kdh), and 2-oxoglutarate dehydrogenase (sucA), were responsive to acidic conditions, reflecting a metabolic shift. Similar gene expression patterns were observed during macrophage infection. These findings suggest that Gad plays a role in mycobacterial acid stress response. To further elucidate this, we generated an MS gadA knockout strain (MSΔgadA) using allelic exchange. MSΔgadA exhibited reduced survival at pH 3.0, a phenotype rescued by gene complementation. MSΔgadA also showed decreased survival within macrophages. Additionally, Mycobacterium bovis BCG, which lacks native Gad expression, demonstrated enhanced intracellular survival when overexpressing Mtb gadB. These results suggest that Gad confers acid tolerance and promotes intracellular survival in mycobacteria, highlighting its potential role in host adaptation.

Keywords:  Mycobacterium smegmatis; Mycobacterium tuberculosis; acid resistance; acid tolerance; bacterial metabolism; bacterial pathogenesis; glutamate decarboxylase; host‐pathogen interaction; phagocytosis; tuberculosis

DOI:  https://doi.org/10.1016/j.jbc.2025.108338
Elife. 2025 Feb 24. pii: RP97830. [Epub ahead of print]13

Altered hepatic metabolism mediates sepsis preventive effects of reduced glucose supply in infected preterm newborns.

Ole Bæk, Tik Muk, Ziyuan Wu, Yongxin Ye, Bekzod Khakimov, Alessandra Maria Casano, Bagirath Gangadharan, Ivan Bilic, Anders Brunse, Per Torp Sangild, Duc Ninh Nguyen.

  Preterm infants are susceptible to neonatal sepsis, a syndrome of pro-inflammatory activity, organ damage, and altered metabolism following infection. Given the unique metabolic challenges and poor glucose regulatory capacity of preterm infants, their glucose intake during infection may have a high impact on the degree of metabolism dysregulation and organ damage. Using a preterm pig model of neonatal sepsis, we previously showed that a drastic restriction in glucose supply during infection protects against sepsis via suppression of glycolysis-induced inflammation, but results in severe hypoglycemia. Now we explored clinically relevant options for reducing glucose intake to decrease sepsis risk, without causing hypoglycemia and further explore the involvement of the liver in these protective effects. We found that a reduced glucose regime during infection increased survival via reduced pro-inflammatory response, while maintaining normoglycemia. Mechanistically, this intervention enhanced hepatic oxidative phosphorylation and possibly gluconeogenesis, and dampened both circulating and hepatic inflammation. However, switching from a high to a reduced glucose supply after the debut of clinical symptoms did not prevent sepsis, suggesting metabolic conditions at the start of infection are key in driving the outcome. Finally, an early therapy with purified human inter-alpha inhibitor protein, a liver-derived anti-inflammatory protein, partially reversed the effects of low parenteral glucose provision, likely by inhibiting neutrophil functions that mediate pathogen clearance. Our findings suggest a clinically relevant regime of reduced glucose supply for infected preterm infants could prevent or delay the development of sepsis in vulnerable neonates.

Keywords:  glucose; immunology; immunometabolism; inflammation; medicine; neonatal sepsis; parenteral nutrition; pig; preterm infant

DOI:  https://doi.org/10.7554/eLife.97830
Cancer Discov. 2025 Feb 28.

Functional reprogramming of neutrophils within the brain tumor microenvironment by hypoxia-driven histone lactylation.

Alessio Ugolini, Alessandra De Leo, Xiaoqing Yu, Fabio Scirocchi, Xiaoxian Liu, Barbara Peixoto, Delia Scocozza, Angelica Pace, Michela Perego, Alessandro Gardini, Luca D'Angelo, James K C Liu, Arnold B Etame, Aurelia Rughetti, Marianna Nuti, Antonio Santoro, Michael A Vogelbaum, Jose R Conejo-Garcia, Paulo C Rodriguez, Filippo Veglia.

Despite functional heterogeneity, high frequency of intratumoral neutrophils predicts poor clinical outcomes. The tumor microenvironment reprograms neutrophils into immunosuppressive subsets that hinder anti-cancer immunity, thereby contributing to tumor growth and resistance to immunotherapies. However, the mechanisms underlying neutrophil reprogramming remain elusive. Here, we report that the immunosuppressive ability of brain tumor-infiltrating neutrophils was restricted to a highly glycolytic and long-lived subset expressing CD71, which acquired immunosuppressive properties in response to hypoxia. Mechanistically, hypoxia boosted glucose metabolism in CD71+neutrophils, leading to high lactate production. Lactate caused histone lactylation, which subsequently regulated arginase-1 expression, required for T cell suppression. Targeting histone lactylation with the anti-epileptic drug isosafrole blocked CD71+neutrophil immunosuppressive ability, delayed tumor progression and sensitized brain tumors to immunotherapy. A distinctive gene signature characterizing immunosuppressive CD71+neutrophils correlated with adverse clinical outcomes across diverse human malignancies. This study identifies histone lactylation as a potential therapeutic target to counteract neutrophil-induced immunosuppression within tumors.

DOI: https://doi.org/10.1158/2159-8290.CD-24-1056
J Biol Chem. 2025 Feb 25. pii: S0021-9258(25)00208-X. [Epub ahead of print] 108359

Viperin expression leads to downregulation of mitochondrial genes through misincorporation of ddhCTP by mitochondrial RNA polymerase.

Srijoni Majhi, Pronay Roy, Minshik Jo, Jiying Liu, Rebecca Hurto, Lydia Freddolino, E Neil G Marsh.

Increasing lines of evidence link the expression of the interferon-stimulated gene RSAD2, encoding the antiviral enzyme, viperin, to autoimmune disease. Autoimmune diseases are characterized by chronic over-production of cytokines such as interferons that upregulate the inflammatory response. Immune cells exposed to interferon selectively downregulate transcription of the mitochondrially-encoded components of the oxidative phosphorylation system, which leads to mitochondria becoming dysfunctional and impairing their ability to produce ATP. But the mechanism by which downregulation occurs has remained unknown. Here we show that 3'-deoxy-3',4'-didehydrocytidine triphosphate (ddhCTP) which is synthesized by viperin suppresses mitochondrial transcription by causing premature chain termination when misincorporated by the mitochondrial RNA polymerase (POLRMT). We show that expression of viperin in human cell lines downregulates mitochondrially encoded gene expression. A similar effect is observed across multiple cell lines when cells are exposed to ddhC, the precursor to ddhCTP. The pattern of gene downregulation fits well with a simple, quantitative model describing chain-termination. In vitro measurements with purified POLRMT demonstrate that ddhCTP competes effectively with CTP, leading to its misincorporation into RNA. These findings reveal a new molecular mechanism for mitochondrial transcriptional regulation that explains the reduction in mitochondrially-encoded transcript levels in response to chronic interferon stimulation, characteristic of inflammatory diseases.

DOI: https://doi.org/10.1016/j.jbc.2025.108359
bioRxiv. 2025 Feb 16. pii: 2025.02.15.638423. [Epub ahead of print]

Dietary cysteine enhances intestinal stemness via CD8 + T cell-derived IL-22.

Fangtao Chi, Qiming Zhang, Jessica E S Shay, Johanna Ten Hoeve, Yin Yuan, Zhenning Yang, Heaji Shin, Sumeet Solanki, Yatrik M Shah, Judith Agudo, Ömer H Yilmaz.

A critical question in physiology is understanding how tissues adapt and alter their cellular composition in response to dietary cues. The mammalian small intestine, a vital digestive organ that absorbs nutrients, is maintained by rapidly renewing Lgr5 + intestinal stem cells (ISCs) at the intestinal crypt base. While Lgr5 + ISCs drive intestinal adaptation by altering self-renewal and differentiation divisions in response to diverse diets such as high-fat diets and fasting regimens, little is known about how micronutrients, particularly amino acids, instruct Lgr5 + ISC fate decisions to control intestinal homeostasis and repair after injury. Here, we demonstrate that cysteine, an essential amino acid, enhances the ability of Lgr5 + ISCs to repair intestinal injury. Mechanistically, the effects of cysteine on ISC-driven repair are mediated by elevated IL-22 from intraepithelial CD8αβ + T cells. These findings highlight how coupled cysteine metabolism between ISCs and CD8 + T cells augments intestinal stemness, providing a dietary approach that exploits ISC and immune cell crosstalk for ameliorating intestinal damage.

DOI: https://doi.org/10.1101/2025.02.15.638423