bims-bac4me 2025-09-14 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2025–09–14
twenty papers selected by
Chun-Chi Chang, Lunds universitet

Divergent metabolic rewiring shapes altered innate immunity.
Aurora kinase A promotes trained immunity via regulation of endogenous S-adenosylmethionine metabolism.
TLR2 supports γδ T cell IL-17A response to ocular surface commensals by metabolic reprogramming.
Correction: BCG and beyond: unlocking new frontiers in TB vaccine development.
Candida albicans and Staphylococcus aureus reciprocally promote their virulence factor secretion and pro-inflammatory effects.
Nasal microbiome inhabitants with anti-Staphylococcus aureus activity.
Bacterial toxins rewire the trans-Golgi network to activate the inflammatory response.
Innovative engineering approaches to model host-microbiome interactions in vitro.
Lactate and Lactylation in Respiratory Diseases: from Molecular Mechanisms to Targeted Strategies.
Toll-like receptor 4 induces trained innate immune tolerance in the heart in a model of stress-induced cardiomyopathy.
Dissecting antimicrobial logic: species-specific strategies for intracellular pathogen defense.
Dendritic cells: understanding ontogeny, subsets, functions, and their clinical applications.
Probiotics as modulators of intestinal barrier integrity and immune homeostasis: a comprehensive review.
Streptococcus pyogenes EVs induce the alternative inflammasome via caspase-4/-5 in human monocytes.
Active screening and decolonization reduce the incidence of Staphylococcus aureus bacteremia and mortality in hemodialysis patients: An interrupted time series study in a hemodialysis unit.
Potential Impact of Extracorporeal Photopheresis on Trained Immunity and Organ Transplant Acceptance.
Metabolic-epigenetic interactions in heart failure: Current understanding and future directions.
Early events in dengue virus infection inducing cytokine storm: The dynamic interplay of pattern-recognition receptors, inflammasome activation, and biphasic NF-κB and STAT1-dependent inflammatory responses in human mononuclear phagocytes.
Gut microbe-derived metabolites drive psoriatic inflammation via modulation of skin Th17 cells.
Endotoxin tolerance inhibits NLRP3 inflammasome activation in macrophages of septic mice by restoring autophagic flux through TRIM26.

Cell Immunol. 2025 Sep 06. pii: S0008-8749(25)00111-X. [Epub ahead of print]417 105025

Divergent metabolic rewiring shapes altered innate immunity.

Mohua Liu, Xiao Wang, Xiaoya Qu, Yao Wang, Xihui Shen, Lei Xu.

  Both trained immunity (TRIM) and endotoxin tolerance (ET) initiate similar metabolic reprogramming characterized by enhanced glycolysis following an initial stimulus. However, TRIM exhibited heightened immune activation upon restimulation, whereas ET showed suppressed innate immune response. This divergence is attributed to distinct metabolic intermediates accumulated after the initial stimulation. In TRIM, metabolites like fumarate and glutamine derivatives accumulate, reinforcing pro-inflammatory epigenetic modifications. Conversely, ET is characterized by increased itaconate and lactate levels, promoting anti-inflammatory epigenetic changes and metabolic paralysis. This review highlights metabolic intermediates as key regulators of innate immune fate decisions, presenting avenues for targeted immune modulation.

Keywords:  Endotoxin tolerance (ET); Fumarate; Itaconate; Mevalonate pathway; Trained immunity (TRIM)

DOI:  https://doi.org/10.1016/j.cellimm.2025.105025
Elife. 2025 Sep 08. pii: RP104138. [Epub ahead of print]14

Aurora kinase A promotes trained immunity via regulation of endogenous S-adenosylmethionine metabolism.

Mengyun Li, Huan Jin, Yongxiang Liu, Zining Wang, Lin Li, Tiantian Wang, Xiaojuan Wang, Hongxia Zhang, Bitao Huo, Tiantian Yu, Shoujie Wang, Wei Zhao, Jinyun Liu, Peng Huang, Jun Cui, Xiaojun Xia.

  Innate immune cells can acquire a memory phenotype, termed trained immunity, but the mechanism underlying the regulation of trained immunity remains largely elusive. Here, we demonstrate that inhibition of Aurora kinase A (AurA) dampens trained immunity induced by β-glucan. ATAC-seq and RNA-seq analysis reveal that AurA inhibition restricts chromatin accessibility of genes associated with inflammatory pathways such as JAK-STAT, TNF, and NF-κB pathways. Specifically, AurA inhibition promotes nuclear localization of FOXO3 and the expression of glycine N-methyltransferase (GNMT), a key enzyme responsible for S-adenosylmethionine (SAM) consumption. Metabolomic analysis confirms a reduction in SAM level upon AurA inhibition. As a result of SAM deficiency, trained mouse macrophages exhibit decreased H3K4me3 and H3K36me3 enrichment on gene regions of Il6 and Tnf. Additionally, the tumor inhibition effect of β-glucan is notably abolished by AurA inhibition. Together, our findings identify an essential role of AurA in regulating trained immunity via a methylation-dependent manner by maintaining endogenous SAM levels through the mTOR-FOXO3-GNMT axis.

Keywords:  Aurora kinase A; FOXO3; GNMT; S-adenosylmethionine; epigenetics; immunology; inflammation; mouse; trained immunity

DOI:  https://doi.org/10.7554/eLife.104138
J Exp Med. 2025 Nov 03. pii: e20251046. [Epub ahead of print]222(11):

TLR2 supports γδ T cell IL-17A response to ocular surface commensals by metabolic reprogramming.

Wenjie Zhu, Xiaoyan Xu, Vijayaraj Nagarajan, Jing Guo, Akriti Gupta, Zixuan Peng, Amy Zhang, Jie Liu, Mary J Mattapallil, Yingyos Jittayasothorn, Reiko Horai, Yasmine Belkaid, Michael G Constantinides, Anthony J St Leger, Rachel R Caspi.

The ocular surface is a mucosal barrier tissue colonized by commensal microbes, which tune local immunity by eliciting IL-17 from conjunctival γδ T cells to prevent pathogenic infection. The commensal Corynebacterium mastitidis (C. mast) elicits protective IL-17 responses from conjunctival Vγ4 T cells through a combination of γδ TCR ligation and IL-1 signaling. Here, we identify Vγ6 T cells as a major C. mast-responsive subset in the conjunctiva and uncover its unique activation requirements. We demonstrate that Vγ6 cells require both extrinsic (via dendritic cells) and intrinsic TLR2 stimulation for optimal IL-17A response. Mechanistically, intrinsic TLR2 signaling was associated with epigenetic changes and enhanced expression of genes involved in fatty acid oxidation to support Il17a transcription. We identify a key transcription factor, IκBζ, which is upregulated by TLR2 stimulation and is essential for this program. Our study highlights the importance of intrinsic TLR2 signaling in driving metabolic reprogramming and production of IL-17A in microbiome-specific mucosal γδ T cells.

DOI: https://doi.org/10.1084/jem.20251046
Front Immunol. 2025 ;16 1677868

Correction: BCG and beyond: unlocking new frontiers in TB vaccine development.

Aishwarya Shaji, Akanksha Verma, Ashima Bhaskar, Ved Prakash Dwivedi.

  [This corrects the article DOI: 10.3389/fimmu.2025.1608104.].

Keywords:  BCG; host genetics; trained immunity; tuberculosis; vaccine

DOI:  https://doi.org/10.3389/fimmu.2025.1677868
Front Cell Infect Microbiol. 2025 ;15 1629373

Candida albicans and Staphylococcus aureus reciprocally promote their virulence factor secretion and pro-inflammatory effects.

Raymond Pasman, Bastiaan P Krom, Martijs J Jonker, Wim C de Leeuw, Gertjan Kramer, Stanley Brul, Sebastian A J Zaat, Jianbo Zhang.

   Background: Co-infections of Candida albicans and Staphylococcus aureus can significantly increase morbidity and mortality. However, the effect of C. albicans-S. aureus co-existence on virulence factor secretion and pro-inflammatory effects remain elusive.
Methods: We systematically investigated the virulence factors released by C. albicans and S. aureus under different culturing conditions using proteomics. We characterized their pro-inflammatory effects in macrophages with transcriptomics and gene set enrichment analysis.
Results and Discussion: We showed that co-culturing of C. albicans and S. aureus promoted the secretion of 7 cytolytic, 11 proteolytic, and 3 lipolytic extracellular virulence factors (ECVFs) and impacted non-ECVFs, owing to Als1/Als3-mediated interactions, the presence of C. albicans, or its pH maintenance. Co-culturing promotes C. albicans hypha formation and β-glucan masking, suggesting that co-culturing enhances both C. albicans invasion and immune evasion. Moreover, the secretome of C. albicans-S. aureus co-culture increased pro-inflammatory pathways including promoting TNF-, NFKB-, and Toll-like receptor signaling pathways, as well as cytokine-cytokine receptor interactions in macrophages. Our findings support that C. albicans and S. aureus reciprocally promote their virulence potential and pro-inflammatory effects, which may provide mechanistic insights into the increased morbidity and mortality during their co-infection in vivo.

Keywords:  Candida albicans (C. albicans); Staphylococcus aureus; extracellular virulence factors; inflammation; macrophages; nonextracellular virulence factors; virulence factors

DOI:  https://doi.org/10.3389/fcimb.2025.1629373
Microbiol Spectr. 2025 Sep 10. e0102425

Nasal microbiome inhabitants with anti-Staphylococcus aureus activity.

Amy L Cole, Melissa R Marzahn, Erika L Valdespino, Ruchi Patel, Alexander M Cole.

  Staphylococcus aureus (SA) colonizes most mammals but also represents a danger in clinical settings because it evolves resistance against antibiotics, and SA infections represent a leading cause of death worldwide. SA nasal carriage provides the bacterial reservoir for opportunistic infection because clinical strains often match the patient's own nasally carried strain. The global SA carriage rate is typically reported as 25%-30% after sampling subjects once or twice and defining carrier status using culture-based methods. Here, we collected nasal swabs from 31 healthy subjects twice weekly for an average of 5 months and determined that 23 of 31 subjects (74.9%) presented SA colonies at least once during longitudinal sampling. We explored the nasal microbiota of individuals who rarely or never tested SA-positive and evaluated 25 nasal isolates for anti-SA properties using culture conditions modeling the nasal mucosa. We determined that members of the Gammaproteobacteria class, including Klebsiella spp., Serratia marcescens, and Enterobacter hormaechei, inhibited SA survival. Firmicutes Dolosigranulum pigrum and Streptococcus mitis/oralis also inhibited SA recovery from nasal tissues. Klebsiella spp. (aerogenes, variicola, pneumoniae) activity was contact-independent and not mediated by sequestration of iron or other vital nutrients. K. aerogenes was the most potent SA inhibitor (>99% reduction), and its action was mediated by secreted cationic peptide(s) or protein(s). Collectively, this project determined that most people may be nasally colonized with SA throughout life. It also represents an important step toward explaining why some hosts don't exhibit detectable nasal SA and highlights a potential source of naturally occurring and novel antibiotics targeting SA.
IMPORTANCE: Staphylococcus aureus (SA) is a common member of the human microbiota, colonizing people transiently throughout life, and SA nasal carriage is an important reservoir for the spread of this bacterium. The global economic toll of SA infections is enormous, and antibiotic-resistant strains continue to emerge. Therefore, new approaches to decolonize carriers of SA are urgently needed. To better understand the dynamics of nasal SA carriage versus non-carriage, we monitored subjects longitudinally and isolated and identified species that associate with SA culture-negative noses. While several members of the Gammaproteobacteria class demonstrated anti-SA activity, the nasal Klebsiella spp. potently inhibited (>99%) SA survival in a contact-independent manner. For multiple nasal isolates of K. aerogenes from our donor cohort, this inhibition was attributed to a small, cationic, proteinaceous molecule(s). The secreted products of nasal Gammaproteobacteria (e.g., Klebsiella/Serratia spp.) warrant further investigation as potential sources of new SA decolonization agents.

Keywords:  Staphylococcus aureus; microbiome; nasal carriage; nasal microbiota

DOI:  https://doi.org/10.1128/spectrum.01024-25
Nat Immunol. 2025 Sep 09.

Bacterial toxins rewire the trans-Golgi network to activate the inflammatory response.

DOI: https://doi.org/10.1038/s41590-025-02278-5
Adv Drug Deliv Rev. 2025 Sep 05. pii: S0169-409X(25)00162-0. [Epub ahead of print] 115677

Innovative engineering approaches to model host-microbiome interactions in vitro.

Karen M Mancera Azamar, Samanvitha Deepthi Sudi, Zahra Mohammadalizadeh, Carleigh Coffin, Ivana K Parker, Ana Maria Porras.

  The human microbiome plays a critical role in health and disease. Disruptions in microbiota composition or function have been implicated not only as markers but also as drivers of diverse pathologies, creating opportunities for targeted microbiome interventions. Advancing these therapies requires experimental models that can unravel the complex, bidirectional interactions between human tissue and microbial communities. This scoping review examines emerging engineering approaches to design in vitro platforms that successfully integrate host and microbial components to model these interactions. Compared to traditional in vitro and in vivo approaches, these advanced microphysiological systems offer greater experimental control, human-specific biology, and reduced cost and ethical concerns. Here, we identify key challenges in the creation of these in vitro models and innovative solutions to address them by leveraging microfluidics, biomaterials, and organoid technologies, among others. These strategies have enabled the development of co-culture systems that replicate critical features of host-microbiome interfaces, including mucosal barriers, oxygen and pH gradients, mechanical stimuli, and host cell diversity. We also describe how these physiologically relevant models are uncovering new insights into epithelial-microbiota crosstalk, immune modulation by commensal microbes, and systemic effects of microbiota and their metabolites across multiple body sites. We conclude by discussing opportunities to expand these systems in scale, complexity, and clinical relevance. As these models continue to evolve, they hold the potential to transform our ability to mechanistically probe microbiome interactions, personalize therapeutic strategies, and accelerate the translation of microbiome science into clinical practice.

Keywords:  Biomaterials; Human-microbiome interactions; In vitro models; Microbiome; Microphysiological systems; Organ-on-chip; Tissue engineering

DOI:  https://doi.org/10.1016/j.addr.2025.115677
Lung. 2025 Sep 10. 203(1): 94

Lactate and Lactylation in Respiratory Diseases: from Molecular Mechanisms to Targeted Strategies.

Qi Jia, Quan Yuan, Xiangdong Chen, Zhiqiang Hu.

   INTRODUCTION: Lactate has emerged as a multifunctional signaling molecule regulating various physiological and pathological processes. Furthermore, lactylation, a newly identified posttranslational modification triggered by lactate accumulation, plays significant roles in human health and diseases. This study aims to investigate the roles of lactate/lactylation in respiratory diseases.
METHODS: Comprehensive literature analysis was conducted using PubMed database, utilizing a range of keywords including "lactate", "lactylation", "lung", "pulmonary", and "disease".
RESULTS: Emerging evidence indicates that increased glycolytic flux, resultant lactate accumulation, and elevated lactylation levels play key roles in the pathogenesis of respiratory diseases, including lung cancer, idiopathic pulmonary fibrosis (IPF), acute lung injury/acute respiratory distress syndrome (ALI/ARDS), pulmonary hypertension (PH), and asthma. Under these conditions, the upregulation of glycolytic enzymes and increased lactate transport are observed. Elevated levels of lactate and lactylation profoundly influence multiple biological processes, such as inflammatory responses, immune cell activation, autophagy, ferroptosis, EMT, tumorigenesis, and fibrosis, and lactate/lactylation-targeted therapies have demonstrated therapeutic efficacy against diverse respiratory illnesses.
CONCLUSIONS: Elevated levels of lactate and lactylation play key roles in the pathogenesis of various respiratory diseases, and lactate/lactylation-targeted therapies appear to be potential therapeutic strategies for these respiratory diseases.

Keywords:  Fibrosis; Immune cell activation; Inflammatory response; Lactate; Lactylation; Respiratory diseases; Tumorigenesis

DOI:  https://doi.org/10.1007/s00408-025-00848-w
Cardiovasc Res. 2025 Sep 09. pii: cvaf158. [Epub ahead of print]

Toll-like receptor 4 induces trained innate immune tolerance in the heart in a model of stress-induced cardiomyopathy.

Kenji Rowel Q Lim, Junedh Amrute, Attila Kovacs, Abhinav Diwan, David L Williams, Douglas L Mann.

   AIMS: Although the ability of the heart to adapt to environmental stress has been studied extensively, the molecular and cellular mechanisms responsible for cardioprotection are not yet fully understood. In this study, we sought to elucidate these mechanisms for cytoprotection using a model of stress-induced cardiomyopathy.
METHODS AND RESULTS: We administered Toll-like receptor (TLR) agonists or diluent to wild-type mice and assessed for cardioprotection against injury from a high intraperitoneal dose of isoproterenol (ISO) administered 7 days later. Cardioprotective effects were analyzed through serum cardiac troponin I levels, immune profiling via flow cytometry, echocardiography, and multiomic single-nuclei RNA/ATAC sequencing. Pretreatment with the TLR4 agonist lipopolysaccharide (LPS), but not TLR1/2 or TLR3 agonists, conferred cardioprotection, as demonstrated by reduced cardiac troponin I leakage, decreased inflammation, preserved cardiac structure and function, and improved survival. Remarkably, LPS-induced tolerance was reversed by β-glucan treatment. Multiomic analysis showed that LPS-tolerized hearts had greater chromatin accessibility and upregulated gene expression versus hearts treated with LPS and β-glucan (reverse-tolerized). LPS tolerance was associated with upregulation of interferon response pathways across various cell types, including cardiac myocytes and stromal cells. Blocking both type 1 and 2 interferon signaling eliminated LPS-induced tolerance against ISO, while pretreatment with recombinant type 1 and 2 interferons conferred cardiac protection. Multiomic sequencing further revealed enhanced cytoprotective signaling in interferon-treated hearts. Analysis of cell-cell communication networks indicated increased autocrine signaling by cardiac myocytes, as well as greater paracrine signaling between stromal cells and myeloid cells, in LPS-tolerized versus reverse-tolerized hearts.
CONCLUSIONS: LPS pretreatment confers cardiac protection against ISO-induced injury through TLR4-mediated type 1 and 2 interferon signaling, consistent with trained innate immune tolerance. The observation that LPS-induced protection in cardiac myocytes involves both cell-autonomous and non-cell-autonomous mechanisms underscores the complexity of innate immune tolerance in the heart, warranting further investigation into this cardioprotective phenotype.

Keywords:  Toll-like receptor 4; interferon; tolerance; trained innate immunity

DOI:  https://doi.org/10.1093/cvr/cvaf158
mSphere. 2025 Sep 10. e0009125

Dissecting antimicrobial logic: species-specific strategies for intracellular pathogen defense.

Bryan D Bryson.

  Control of intracellular pathogens is a critical element of host defense. Defining the molecular mechanisms by which the host restricts or eliminates these pathogens may inform the development of novel immunotherapeutics and antimicrobial strategies, particularly in the face of rising antibiotic resistance. In parallel, understanding how pathogens subvert these immune responses may yield new approaches to disrupt virulence rather than viability. Yet, the precise mechanisms by which primates-and especially humans-achieve intracellular pathogen control remain poorly understood. Five years ago, I reflected on the complexity of interferon-induced control of Legionella pneumophila in a murine infection model. In this review, I revisit those questions considering emerging evidence, highlighting how cross-species comparisons and context-specific immune programs are reshaping our understanding of host-pathogen interactions and the logic of antimicrobial defense.

Keywords:  host-pathogen interactions; innate immunity; phagosome

DOI:  https://doi.org/10.1128/msphere.00091-25
Mol Biomed. 2025 Sep 08. 6(1): 62

Dendritic cells: understanding ontogeny, subsets, functions, and their clinical applications.

Wenhao Li, Chenyu Yu, Xujian Zhang, Yunshen Gu, Xiaobo He, Rongrong Xu, Jia Xu, Ganjun Yu, Yanfeng Wu.

  Dendritic cells (DCs) play a central role in coordinating immune responses by linking innate and adaptive immunity through their exceptional antigen-presenting capabilities. Recent studies reveal that metabolic reprogramming-especially pathways involving acetyl-coenzyme A (acetyl-CoA)-critically influences DC function in both physiological and pathological contexts. This review consolidates current knowledge on how environmental factors, tumor-derived signals, and intrinsic metabolic pathways collectively regulate DC development, subset differentiation, and functional adaptability. Acetyl-CoA emerges as a dual-function metabolite, serving not only as an energy carrier but also as an epigenetic regulator that controls DC fate via lipid biosynthesis, mitochondrial metabolism, and chromatin modification. In the tumor microenvironment (TME), DCs may experience immune suppression polarization and insufficient T cell activation due to disrupted acetyl-CoA related metabolic pathways. While existing DC-based therapies remain constrained by TME-induced metabolic limitations, emerging approaches that restore acetyl-CoA related metabolic pathways balance show enhanced antitumor efficacy. The review further examines distinct metabolic adaptations among DC subsets and their relevance to autoimmune diseases, infectious immunity, and transplant outcomes. By integrating current research on targeting DC metabolic targets, we outline strategies for developing immunotherapies that target DC metabolic flexibility. Remaining hurdles include tailoring interventions to specific subsets, refining metabolic manipulation techniques, and addressing TME heterogeneity through combination therapies. These findings position acetyl-CoA as a key therapeutic target for recalibrating immunometabolism circuits, with significant implications for DC-focused cancer treatment.

Keywords:  Acetyl-CoA; Cancer therapy; Dendritic cells; Immunotherapy; Metabolic reprogramming; Tumor microenvironment

DOI:  https://doi.org/10.1186/s43556-025-00300-8
J Sci Food Agric. 2025 Sep 12.

Probiotics as modulators of intestinal barrier integrity and immune homeostasis: a comprehensive review.

José Mercado-Monroy, Reyna Nallely Falfán-Cortés, Victor Manuel Muñóz-Pérez, Carlos Alberto Gómez-Aldapa, Javier Castro-Rosas.

  The gastrointestinal tract is the largest interface between the human body and external agents and hosts a vast community of microorganisms that confer diverse health benefits. Among these microorganisms are probiotics, which, when consumed in adequate amounts, provide benefits beyond basic nutrition. Through membrane-associated glycoproteins and the secretion of metabolites, probiotics can: (1) enhance intestinal epithelial barrier integrity by reinforcing tight junction expression; (2) stimulate mucin production, strengthening the mucus layer and promoting mucosal adhesion; (3) prevent pathogen and toxin adhesion to the intestinal epithelium; (4) inhibit pathogenic microorganisms by competing directly for environmental nutrients and producing antimicrobial metabolites (e.g., bacteriocins and organic acids); and (5) stimulate the intestinal immune system through membrane components that activate immune cells such as macrophages, neutrophils, and epithelial cells, thereby eliciting an effective immune response. This review describes the intestinal barrier and its function, the role of probiotics, and the most extensively studied mechanisms by which they benefit the intestinal immune system. © 2025 Society of Chemical Industry.

Keywords:  immune cells; immune system; intestinal barrier; microbiota; probiotics

DOI:  https://doi.org/10.1002/jsfa.70168
EMBO Rep. 2025 Sep 08.

Streptococcus pyogenes EVs induce the alternative inflammasome via caspase-4/-5 in human monocytes.

Kathrin Krause, Sandra Franch Arroyo, Matteo Ugolini, Tonya Kueck, Timothy J Sullivan, Eric J C Gálvez, Matthias Muenzner, Christian Goosmann, Volker Brinkmann, Christian K Frese, Kathirvel Alagesan, Tim Vierbuchen, Holger Heine, Ulrike Resch, Leif E Sander, Emmanuelle Charpentier.

  The sensing of Gram-negative Extracellular Vesicles (EVs) by the innate immune system has been extensively studied in the past decade. In contrast, recognition of Gram-positive EVs by innate immune cells remains poorly understood. Comparative genome-wide transcriptional analysis in human monocytes uncovered that S. pyogenes EVs induce proinflammatory signatures that are markedly distinct from those of their parental cells. Among the 209 genes exclusively upregulated by EVs, caspase-5 prompted us to study inflammasome signaling pathways in depth. We show that lipoteichoic acid (LTA), a structural component of Gram-positive bacterial membranes present on EVs from S. pyogenes and other Gram-positive species, is sensed by TLR2 which triggers the alternative inflammasome composed of NLRP3 and the inflammatory caspases-4/-5 to mount an IL-1β response without inducing cell death. For S. pyogenes, we identify TLR8 as a sensor to mediate caspase-4/-5-dependent IL-1β secretion. Notably, inflammasome activation by intact bacteria is independent of the global virulence regulator CovS in monocytes. Overall, our study highlights a new role for TLR2 and caspase-4/-5 in the recognition of Gram-positive EVs in human monocytes.

Keywords:   Streptococcus pyogenes ; Caspases; Extracellular Vesicles; Inflammasome; Monocytes

DOI:  https://doi.org/10.1038/s44319-025-00558-7
J Microbiol Immunol Infect. 2025 Sep 06. pii: S1684-1182(25)00173-2. [Epub ahead of print]

Active screening and decolonization reduce the incidence of Staphylococcus aureus bacteremia and mortality in hemodialysis patients: An interrupted time series study in a hemodialysis unit.

Han-Chuan Chuang, Tzu-Wen Huang, Jen-Zon Chen, Hsin-Yi Liu, Chin-Ting Wu, Shih-Feng Tsai, Hsi-Hsien Chen, Te-Chao Fang, Hsiao-Wen Huang, Chi-Tai Fang, Po-Ren Hsueh, Yuarn-Jang Lee.

   BACKGROUND: Hemodialysis (HD) patients with nasal Staphylococcus aureus carriage are at an increased risk of S. aureus infection.
PURPOSE: This study investigated the incidence of S. aureus bacteremia and associated mortality in HD patients receiving active screening and decolonization (ASD) program for nasal S. aureus carrier in a teaching hospital HD unit.
METHODS: The ASD program was divided into five stages: 1: preintervention, 2: preparation, 3: intervention, 4: interruption, and 5: reintervention. Nasal screening was conducted every 3 months in stages 3 and 5. Patients colonized with S. aureus received decolonization with mupirocin to the nares and 4 % chlorhexidine gluconate body wash. S. aureus bacteremia and mortality were assessed. Whole-genome sequencing was conducted on S. aureus isolate in stage 3.
RESULTS: In preintervention stage, the bacteremia incidence and mortality rate were 7.8 and 3.1 cases per 100 patient-years(PY). In the intervention stage, the incidence rate decreased to 1 case per 100 PY without mortality. In the reintervention stage, the incidence and mortality rates were 2.1 and 0.6 cases per 100 PY. The rates in stages 3, 4, and 5 were significantly lower than those in preintervention stage (p < 0.05). Genomic analysis of S. aureus isolates from stage 3 revealed genetically diversity. High-level mupirocin-resistant S. aureus isolates carrying mupA-bearing plasmids were identified.
CONCLUSIONS: ASD programs for S. aureus carrier may improve clinical outcomes in HD units. However, mupirocin resistance may emerge after decolonization, indicating a need for ongoing monitoring and alternative decolonization strategies.

Keywords:  Active screening; Chlorhexidine; Decolonization; Hemodialysis; Mupirocin; Staphylococcus aureus

DOI:  https://doi.org/10.1016/j.jmii.2025.08.015
Transplant Direct. 2025 Sep;11(9): e1835

Potential Impact of Extracorporeal Photopheresis on Trained Immunity and Organ Transplant Acceptance.

Clémentine Tocco, Jordi Ochando.

Extracorporeal photopheresis (ECP) is a well-established, safe, and effective immunomodulatory therapy currently used in clinics to decrease T cell-mediated immunity in various disorders, including autoimmune diseases and chronic rejection in organ transplantation. Although the ECP procedure has been shown to induce apoptotic cells that are reintroduced into the patient at the end of the treatment, the precise tolerogenic mechanisms mediated by ECP are not fully understood. Previous in vitro studies have demonstrated that early apoptotic cells express annexins on their cell surface, which suppress myeloid cell activation on stimulation with bacterial lipopolysaccharide through Toll-like receptors. Mechanistically, annexins prevent the upregulation of costimulatory molecules (CD40 and CD86) and decrease the secretion of proinflammatory cytokines (tumor necrosis factor and interferon-γ) through nuclear factor kappa B signaling pathways, altogether inhibiting antigen-specific T-cell responses in vivo. In human and mouse bone marrow-derived macrophages, binding of annexin to Dectin-1, a c-type lectin receptor, promotes peripheral tolerance through the spleen tyrosine kinase signaling pathway and NADPH oxidase 2 downstream activation. In animal models, the synergistic activation of Dectin-1 and Toll-like receptor 4 by damage-associated molecular patterns in graft-infiltrating monocytes leads to the induction of trained immunity. Because trained immunity prevents long-term allograft survival in organ transplant recipients, we hypothesize pretreatment with ECP represents a potential unexplored therapeutic option to favor transplantation tolerance. Specifically, ECP may serve as a prophylactic therapy to prevent trained immunity in contexts involving the activation of the Dectin-1 pathway.

DOI: https://doi.org/10.1097/TXD.0000000000001835
Biochem Biophys Res Commun. 2025 Sep 06. pii: S0006-291X(25)01324-5. [Epub ahead of print]783 152608

Metabolic-epigenetic interactions in heart failure: Current understanding and future directions.

Benjamin Flowers, Bea Duric.

  Heart failure remains a major global health concern characterized by complex pathophysiological processes and significant clinical challenges. While the distinct roles of metabolic and epigenetic dysregulation in heart failure are increasingly recognized, their intricate interplay remains a critical, yet underexplored, aspect of its pathophysiology. This review provides a comprehensive examination of this metabolic-epigenetic crosstalk, exploring how metabolic changes, such as impaired fatty acid oxidation, increased glycolysis, and mitochondrial dysfunction, alter epigenetic landscapes through shifts in intermediary metabolites including acetyl-CoA, NAD+, and α-ketoglutarate. Conversely, epigenetic dysregulation in the forms of DNA methylation and histone acetylation, for example, contribute to metabolic maladaptation through suppression of critical genes for oxidative phosphorylation and mitochondrial biogenesis. By providing an integrative framework linking metabolic and epigenetic circuits, this review aims to enhance our understanding of this pervasive condition and highlight emerging therapeutic targets within these networks.

Keywords:  Epigenetic changes; Glycolysis; Heart failure; Histone modifications; Metabolism; Warburg effect

DOI:  https://doi.org/10.1016/j.bbrc.2025.152608
PLoS Negl Trop Dis. 2025 Sep;19(9): e0013366

Early events in dengue virus infection inducing cytokine storm: The dynamic interplay of pattern-recognition receptors, inflammasome activation, and biphasic NF-κB and STAT1-dependent inflammatory responses in human mononuclear phagocytes.

Juan Felipe Valdés-López, Yordi Sebastián Tamayo-Molina, Geysson J Fernandez, Lady Johana Hernández-Sarmiento, Paula A Velilla, Silvio Urcuqui-Inchima.

A Cytokine storm is critical in severe dengue, significantly contributing to disrupted endothelial integrity, plasma leakage, and haemorrhage manifestations in affected patients. Various reports have demonstrated that mononuclear phagocytes, including monocytes, dendritic cells, and macrophages, are target cells of DENV infection. They contribute to viral spread into tissues and promote robust inflammatory responses and immunopathology. However, it remains unclear whether the early events of DENV infection play a role in triggering cytokine storms in infected mononuclear phagocytes. To address this knowledge gap, we conducted a comprehensive analysis of the transcriptomic profile of in vitro DENV-2-infected human monocyte-derived macrophages (MDMs) based on the kinetics of viral replication through a standard growth curve. To verify the accuracy of our approach, we used RT-qPCR, ELISA, and transcriptomic data from in vitro DENV-2-infected monocyte-derived dendritic cells (MDDCs) and monocytes obtained from acute dengue patients. RNA-Seq analysis revealed dynamic changes in the transcriptional profile of DENV-2-infected MDMs throughout the viral growth curve. Two waves of differentially expressed genes were observed: the first occurred during the eclipse period of viral replication (3 to 5.5 h.p.i) and was associated with the induction of NF-kB-dependent pro-inflammatory factors, while the second wave at 24 h.p.i coincided with peaks of DENV-2 replication and induction of both NF-kB- and STAT1-dependent pro-inflammatory responses. Additionally, DENV-2 infection promoted the dynamic activation of Toll-like receptors, RIG-like receptors, inflammasomes, and inflammatory pathways, triggering innate pro-inflammatory and antiviral responses. A robust multi-type IFN-dependent antiviral response was also observed at the late stage of infection. A similar transcriptomic profile was found in DENV-2-infected MDDCs and monocyte subsets from acute dengue patients, further confirming the reliability of our in vitro model of DENV-infected MDMs. Together, results suggest that recognizing viral PAMPs during the eclipse period of DENV-2 infection promotes a robust NF-kB-dependent pro-inflammatory response in MDMs. In addition, at later stages of infection, recognizing structural DENV-PAMPs and/or viral replication intermediates induces both NF-kB- and STAT1-dependent pro-inflammatory responses, leading to a cytokine storm. These findings highlight the critical role of monocytes, macrophages, and dendritic cells in detecting DENV infection and triggering a cytokine storm in vitro and in vivo. This suggests that these cell populations could be potential targets for future immunotherapies to modulate the inflammatory response to DENV infection.

DOI: https://doi.org/10.1371/journal.pntd.0013366
Immunity. 2025 Sep 09. pii: S1074-7613(25)00369-3. [Epub ahead of print]58(9): 2241-2255.e7

Gut microbe-derived metabolites drive psoriatic inflammation via modulation of skin Th17 cells.

Chenliang Wang, Shangzhi Dai, Shanshan Zhang, Zheyu Zheng, Zhixiao Zhou, Zhuojing Chen, Mingchao Wang, Yumei Gao, Yan Xin, Weihang Xiong, Sihan Xiong, Xiaowen Wang, Aiping Wang, Xueqiang Zhao, Hang Li, Xin Lin.

  The persistence of tissue-specific chronic inflammation results from an interplay of genetic and environmental factors. How these factors coordinate to sustain pathology in chronic conditions like psoriasis is not well resolved. Using a Card14E138A/+ murine model of psoriasis, we found that spontaneous skin inflammation reshaped not only the immune architecture in the skin but also systemic metabolites. We identified indole-producing microbiota in the gut-but not the skin-as drivers of psoriatic inflammation. Mechanistically, indole-producing intestinal microbes promoted host indoxyl sulfate (I3S) biosynthesis via a metabolic relay. I3S signaled through the aryl hydrocarbon receptor (AHR) in skin T helper (Th) 17 cells to modulate chromatin accessibility, which potentiated skin inflammation. In human psoriasis cohorts, serum I3S levels correlated with disease severity. In summary, our study uncovers a mechanistic link between gut microbial factors and skin inflammation, highlighting microbiota and metabolites as potential therapeutic targets for psoriasis.

Keywords:  AHR; CARD14; Th17 cell; gut microbiota; gut-skin axis; indole pathway; indoxyl sulfate; metabolite; psoriasis; skin inflammation

DOI:  https://doi.org/10.1016/j.immuni.2025.08.006
Open Med (Wars). 2025 ;20(1): 20251231

Endotoxin tolerance inhibits NLRP3 inflammasome activation in macrophages of septic mice by restoring autophagic flux through TRIM26.

Yanyan Yang, Shiwen Wu, Minghao Lin, Xueting Xie, Huifang Shi, Youran Chen, Shanshan Li, Yuchun Jiang, Sijie Zheng, Chibin Shen, Naibin Yang, Mingqin Lu.

   Objective: Endotoxin tolerance (ET) has been demonstrated to attenuate the inflammatory response in murine models of sepsis. This study seeks to elucidate the underlying mechanisms by which ET modulates inflammation in sepsis, with a particular focus on macrophage autophagy.
Methods: An in vivo sepsis model was generated using cecal ligation and perforation, while an in vitro model of inflammatory injury was induced via lipopolysaccharide (LPS) administration. ET was established through pretreatment with low-dose LPS. Subsequent analyses were conducted to assess the presence of the NLRP3 inflammasome, autophagic flux, and the expression levels of TRIM26.
Results: Heightened inflammation was observed in the TNF-α levels and various organs of the sepsis group; conversely, inflammation was reduced in the group receiving ET treatment. Upon stimulation with LPS, primary mouse peritoneal macrophages exhibited activation of the NLRP3 inflammasome and autophagy, accumulation of mitochondrial reactive oxygen species, compromised membrane potential, resulting in cell apoptosis, and decreased expression of TRIM26. ET was found to enhance autophagy, suppress the activation of NLRP3 inflammasomes, and upregulate the expression of TRIM26. Interestingly, modulation of autophagy levels either reversed or intensified the protective effects of ET on macrophages in vitro. Knockdown of TRIM26 using small interfering RNA (siRNA) resulted in increased NLRP3 inflammasome activation and accumulation of P62.
Conclusion: We reveal that ET restores the autophagic flux in macrophages, inhibit NLRP3 inflammasome activation, and mitigate inflammatory damage in septic mice, potentially through the regulation of TRIM26.

Keywords:  NLRP3; TRIM26; autophagic flux; endotoxin tolerance; sepsis

DOI:  https://doi.org/10.1515/med-2025-1231