bims-bac4me 2025-06-22 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2025–06–22
23 papers selected by
Chun-Chi Chang, Lunds universitet

The Role of Pattern Recognition Receptors in Epigenetic and Metabolic Reprogramming: Insights into Trained Immunity.
Staphylococci in high resolution: Capturing diversity within the human nasal microbiota.
Uncovering metabolic pathways in human alveolar macrophages in response to lipopolysaccharide.
Dendritic cells activate pyroptosis and effector-triggered apoptosis to restrict Legionella infection.
Trained immunity: A new player in cancer immunotherapy.
Pattern Recognition Receptors and Inflammasome: Now and Beyond.
Targeting alveolar macrophages: a promising intervention for pulmonary infection and acute lung injury.
Involvement of protein A and IL-16 in the hyperalgesia and allodynia evoked by Staphylococcus aureus in mice.
KLF feedback loops in innate immunity.
Respiratory tract antimicrobial peptides more effectively killed multiple methicillin-resistant Staphylococcus aureus and nontypeable Haemophilus influenzae isolates after disruption from biofilm residence.
The Beneficial Role of Probiotics and Gut Microbiota in Signaling Pathways, Immunity, Apoptosis, Autophagy, and intestinal barrier for Effective Wound Healing Post-Burn Injury.
TNF switches homeostatic efferocytosis to lytic caspase-8-dependent pyroptosis and IL-1β maturation.
Experimental evolution of a pathogen confronted with innate immune memory increases variation in virulence.
Itaconate promotes inflammatory responses in tissue-resident alveolar macrophages and exacerbates acute lung injury.
Role of Staphylococcus aureus Nasal Carriage in Uremic Pruritus and Infection in Hemodialysis Patients.
Being a better version of yourself: genetically engineered probiotic bacteria as host defense enhancers in the control of intestinal pathogens.
Cytokine-mediated inhibition of Staphylococcus aureus adherence and invasion into nonphagocytic cells.
Lactiplantibacillus Plantarum strengthens the intestinal barrier: involvement of the endocannabinoidome.
Innate immune responses to pathogens at the maternal-fetal interface.
Trained Innate Immunity in Extracorporeal Photopheresis.
Quorum sensing modulates microbial community structure through regulation of secondary metabolites.
Pro-inflammatory properties of M1 phenotypes of human macrophages: prolongation of myeloperoxidase-mediated oxidative stress.
Associations between total protein, globulin, and nasal Methicillin-Resistant Staphylococcus aureus (MRSA) colonization in US adults: results from the national health and nutrition examination survey 2001-2004.

J Inflamm Res. 2025 ;18 7795-7811

The Role of Pattern Recognition Receptors in Epigenetic and Metabolic Reprogramming: Insights into Trained Immunity.

Yanjie Li, Mingzhu Chen, Junxiong Li, Jiangtian Hu.

  Pattern recognition receptors (PRRs) function as pivotal components of the innate immune system by orchestrating trained immunity through dynamic epigenetic and metabolic reprogramming. Recent discoveries demonstrate that PRRs not only detect pathogens but also actively regulate immune cell metabolism and transcriptional landscapes, thereby potentiating the speed and magnitude of defensive responses upon secondary challenges. These functional adaptations are coordinated through evolutionarily conserved signaling cascades that establish persistent immunological modifications at cellular and systemic levels. Nevertheless, despite substantial advances in characterizing PRR-driven immune activation, the molecular mechanisms governing their role in innate immune memory formation remain incompletely elucidated. This review systematically explores emerging paradigms of PRR-mediated epigenetic remodeling and metabolic rewiring, with particular emphasis on their mechanistic integration into trained immunity. We critically assess current evidence, identify unresolved questions regarding signal transduction specificity and memory maintenance, and propose novel methodological approaches to decipher the multilayered regulatory networks of innate immune adaptation. By elucidating these processes, our analysis establishes a conceptual framework for developing immunomodulatory therapies and leveraging trained immunity in precision medicine applications.

Keywords:  epigenetic; immunocyte; metabolic reprogramming; pattern recognition receptors; trained immunity

DOI:  https://doi.org/10.2147/JIR.S513325
Cell Rep. 2025 Jun 14. pii: S2211-1247(25)00625-4. [Epub ahead of print]44(6): 115854

Staphylococci in high resolution: Capturing diversity within the human nasal microbiota.

Anna Cäcilia Ingham, Duncan Y K Ng, Søren Iversen, Cindy M Liu, Khoa Manh Dinh, Silva Holtfreter, Sofie Marie Edslev, Thor Bech Johannesen, Amalie Katrine Rendboe, Mette Theilgaard Christiansen, Kim Lee Ng, Robert Skov, Stefanie Samietz, Dörte Radke, Stefan Weiss, Uwe Völker, Barbara M Bröker, Lise Tornvig Erikstrup, Christian Erikstrup, Lance B Price, Paal Skytt Andersen, Marc Stegger.

  Staphylococci include both nasal commensals and opportunistic pathogens, globally responsible for a large proportion of infection-related deaths, especially in S. aureus carriers. To understand staphylococcal temporal dynamics within the nasal microbiota, we employed Staphylococcus-targeted sequencing in two cohorts from Denmark and Germany. We identified two major staphylococcal community state types (sCSTs)-one dominated by S. aureus and one dominated by S. epidermidis-and eight subgroups defined by co-colonizing coagulase-negative staphylococci. The distribution of sCSTs was similar between the two cohorts. Predominance of either S. aureus or S. epidermidis was highly persistent over time, whereas co-colonizing staphylococcal species were transient with varying stability among the sCST subgroups. Detection of S. aureus by culture was positively associated with absolute abundance by qPCR. S. aureus domination was diminished when Dolosigranulum and Corynebacterium co-occurred. Our findings could inform efforts to reduce S. aureus nasal colonization and infection.

Keywords:  CP: Microbiology; Staphylococcus aureus; Staphylococcus epidermidis; antagonist; carriage; community state type; microbial abundance; microbiome; nasal microbiota; staphylococci

DOI:  https://doi.org/10.1016/j.celrep.2025.115854
Clin Exp Immunol. 2025 Jun 14. pii: uxaf028. [Epub ahead of print]

Uncovering metabolic pathways in human alveolar macrophages in response to lipopolysaccharide.

Christine C A van Linge, Erik H A Michels, Liza Pereverzeva, Regina de Beer, Augustijn M Klarenbeek, Bauke V Schomakers, Michel van Weeghel, Riekelt H Houtkooper, W Joost Wiersinga, Peter I Bonta, Jouke T Annema, Tom van der Poll, Alex F de Vos.

   INTRODUCTION: Alveolar macrophages (AMs) play an essential role in maintaining homeostasis in the lung and in innate immunity for host defense. To fuel inflammatory responses, AMs do not rely on glycolysis, but require oxidative phosphorylation. However, which nutrients AMs use to fuel their energy demand during inflammatory responses, is still unknown. The present study aimed to determine the contribution of three key metabolic pathways; fatty acid oxidation, glutaminolysis, and glycogenolysis, to the inflammatory response of AMs.
METHODS: Primary AMs were isolated from healthy human volunteers and stimulated with lipopolysaccharide (LPS). After 24 hours, cells were subjected to analyses of metabolic flux, expression of genes involved in these metabolic pathways, and inflammatory cytokine secretion in the presence of metabolic inhibitors.
RESULTS: The results of our study show that human AMs display expression of genes involved in fatty acid and glutamine metabolism and are capable of metabolizing oleic acid and glutamine during homeostasis, but do not use these metabolites to fuel the production of inflammatory cytokines. We demonstrate that AMs, while residing in a glucose-deprived environment, contain glycogen and use glycogenolysis to fuel inflammatory cytokine secretion, as reflected by reduced TNF, IL-1βand IL-6 levels in supernatant of LPS-stimulated AMs treated with the glycogenolysis inhibitor CP316819. Moreover, AMs display marked expression of genes involved in glycogenesis, including FBP1 and GYS.
CONCLUSION: Taken together, these results indicate that primary human AMs are equipped to use different nutrients to fuel their metabolic demands. Moreover, our findings suggest that glycogenolysis is critical for the inflammatory response of AMs.

Keywords:  Cellular Immunology; Lipopolysaccharide; Macrophage; Metabolism

DOI:  https://doi.org/10.1093/cei/uxaf028
mBio. 2025 Jun 18. e0125725

Dendritic cells activate pyroptosis and effector-triggered apoptosis to restrict Legionella infection.

Víctor R Vázquez Marrero, Jessica Doerner, Kimberly A Wodzanowski, Jenna Zhang, Allyson Lu, Frankie D Boyer, Isabel Vargas, Suzana Hossain, Karly B Kammann, Madison V Dresler, Sunny Shin.

  The innate immune system relies on pattern recognition receptors (PRRs) to detect pathogen-associated molecular patterns (PAMPs) and guard proteins to monitor pathogen disruption of host cell processes. How different immune cell types engage PRRs and guard proteins to respond to infection is poorly understood. Here, we show that macrophages and dendritic cells (DCs) distinctly respond to bacterial virulence activities. In macrophages, the bacterial pathogen Legionella pneumophila deploys its Dot/Icm type IV secretion system (T4SS) to deliver effector proteins that facilitate robust intracellular replication. In contrast, T4SS activity triggers rapid death of DCs, which potently restricts Legionella replication. Intriguingly, we found that infected DCs exhibit considerable heterogeneity at the single-cell level. Initially, some DCs activate caspase-11 and NLRP3 inflammasome-dependent pyroptosis early during infection. At later time points, other DCs undergo apoptosis driven by T4SS effectors that block host protein synthesis, thereby depleting the pro-survival proteins Mcl-1 and cFLIP. Together, pyroptosis and effector-triggered apoptosis robustly restrict Legionella replication in DCs. Collectively, our findings suggest a model where Mcl-1 and cFLIP guard host translation in DCs. Furthermore, our work shows that macrophages and DCs distinctly employ innate immune sensors and guard proteins to mount divergent responses to Legionella infection.IMPORTANCEThe innate immune system senses bacterial pathogens by employing pattern recognition receptors that detect pathogen-associated molecular patterns (PAMPs) and guard proteins that monitor pathogen disruption of host cell processes. How different immune cell types engage pattern recognition receptors (PRRs) and guard proteins to respond to infection is poorly understood. Here, we reveal how dendritic cells (DCs) detect and restrict the intracellular bacterial pathogen Legionella pneumophila. At the single-cell level, we find that early during infection, some DCs activate caspase-11 pyroptosis. At later time points, other DCs undergo apoptosis driven by type IV secretion system (T4SS) effectors that block host protein synthesis, which depletes levels of the pro-survival proteins Mcl-1 and cFLIP. Our findings suggest Mcl-1 and cFLIP safeguard mRNA translation in DCs and highlight differences in how macrophages and DCs employ PRRs and guard proteins to respond to bacterial infection.

Keywords:  Legionella pneumophila; apoptosis; caspase-11; dendritic cells; guard immunity; innate immunity; pyroptosis

DOI:  https://doi.org/10.1128/mbio.01257-25
Elife. 2025 Jun 18. pii: e104920. [Epub ahead of print]14

Trained immunity: A new player in cancer immunotherapy.

Shu Li, Yi Zou, Austin McMasters, Fuxiang Chen, Jun Yan.

  In the past, immune memory was considered an exclusive feature of the adaptive immune system. However, accumulating evidence suggests that the innate immune system, the most primitive and fundamental component of immunity, can mount more robust responses to non-specific stimuli following prior exposure to different types of initial stimuli, a phenomenon known as trained immunity. Trained immunity has been extensively studied in diverse disease contexts, including infectious diseases, autoimmune disorders, and chronic inflammatory conditions. Notably, significant advancements have been made in recent years in understanding the roles and therapeutic potential of trained immunity in oncology. This review aims to explore the multifaceted roles of trained immunity across different cancer types, providing a comprehensive summary of the pertinent stimuli and associated molecular mechanisms. Additionally, we evaluate the clinical applications of various trained immunity stimuli in cancer therapy and offer perspectives on future directions for integrating trained immunity into cancer treatment strategies.

Keywords:  cancer immunotherapy; immunology; inflammation; innate immune cells; trained immunity

DOI:  https://doi.org/10.7554/eLife.104920
Mol Cells. 2025 Jun 15. pii: S1016-8478(25)00063-9. [Epub ahead of print] 100239

Pattern Recognition Receptors and Inflammasome: Now and Beyond.

SuHyeon Oh, Young Ki Choi, SangJoon Lee.

  Pattern recognition receptors (PRRs) are fundamental to the innate immune system, functioning to detect and eliminate invading pathogens by inhibiting their replication and limiting host tissue damage. Through direct recognition of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), PRRs initiate inflammatory responses, including cytokine production, and modulate the adaptive immune response. Ligand binding activates downstream signaling pathways that promote pathogen clearance and drive inflammasome assembly. Accumulating evidence underscores the critical role of PRRs in sensing cellular damage and preserving homeostasis. Importantly, interactions within PRR networks facilitate the formation of multiple PRR-containing inflammasomes (PANoptosome), enabling coordinated inflammatory cell death under combined PAMP and DAMP stimulation. A comprehensive understanding of these interconnected signaling networks is essential for elucidating the regulation of innate immunity and its implications for disease pathogenesis, particularly in the context of infection and inflammation. This review provides a detailed overview of PRR-ligand recognition, downstream signaling mechanisms, and inflammasome activation, and discusses emerging insights into PRR regulation that hold promise for novel immunotherapeutic interventions.

Keywords:  Immune response; Inflammasome; Inflammatory cell death; Innate immunity; Pattern recognition receptor

DOI:  https://doi.org/10.1016/j.mocell.2025.100239
Cell Mol Biol Lett. 2025 Jun 14. 30(1): 69

Targeting alveolar macrophages: a promising intervention for pulmonary infection and acute lung injury.

Fei Hou, Nan Shi, Haoran Yuan, Bingyi Li, Junjie Xiao, Kun Xiao, Lixin Xie.

  Pulmonary infections are common respiratory diseases caused by a variety of pathogens, some of which can lead to epidemics. When they progress to acute lung injury or acute respiratory distress syndrome, the mortality rate is high and effective treatment options are lacking. Macrophages play a crucial role in the development and progression of lung injury, and serve as core components of immune regulation in the lungs. Therefore, regulation of macrophages to intervene in the progression of infection-induced lung injury is a promising research direction. However, the existence of different macrophage subsets and their inherent heterogeneity has led to the failure of many studies to achieve effective results, thereby limiting their clinical applications. We believe that interventions targeting macrophages must consider factors, such as macrophage subsets, timing of interventions, patients' varying immune states, and clinical stages, rather than simply focusing on regulating their phenotypes. This distinction is the key to the success of macrophage-targeted therapies. In this review, we summarize the characteristics of two distinct macrophage subpopulations, lung-tissue-resident alveolar macrophages and monocyte-derived macrophages, along with intervention strategies and research progress at various time points, with the aim of providing insights and directions for future research.

Keywords:  Acute lung injury; Alveolar macrophage; Pulmonary infection; Targeted therapy

DOI:  https://doi.org/10.1186/s11658-025-00750-6
Eur J Pharmacol. 2025 Jun 18. pii: S0014-2999(25)00615-6. [Epub ahead of print] 177861

Involvement of protein A and IL-16 in the hyperalgesia and allodynia evoked by Staphylococcus aureus in mice.

Luis Menéndez, Alejandro Álvarez-Artime, Sara González-Rodríguez, Gemma Fernández-García, María González-Amor, Ángel Manteca, Ana Baamonde.

  Staphylococcus aureus is a Gram-positive bacteria that induces painful infections. Since S. aureus releases a protein called staphylococcal protein A (SpA) that can stimulate the release of interleukin IL-16 and the involvement of this interleukin in inflammatory pain has been recently demonstrated in mice, we explored whether SpA and IL-16 participate in S. aureus-evoked hypernociception. The intraplantar (i.pl.) administration of SpA (0.3-3 μg) produced thermal hyperalgesia and mechanical allodynia prevented by an anti-IL-16 antibody (0.3-1 μg/kg). Moreover, the i.pl. inoculation of S. aureus (103-106 CFU, 6 h before) induced hyperalgesia and allodynia together with an increase of local concentrations of IL-16 and the up-regulation of caspase-3 mRNA. Immunofluorescence assays indicated that neutrophils are the main cells expressing IL-16 after S. aureus i.pl. injection. Supporting the involvement of IL-16, antibodies against IL-16 (1-30 μg/kg) or CD4 receptors (1-30 μg/kg) inhibited hyperalgesia and allodynia evoked by this microorganism. In contrast, the anti-IL-16 antibody did not alter hypernociception produced by Streptococcus pyogenes, another Gram-positive bacteria unrelated to SpA. Since septic arthritis is one of the main clinical entities related to S. aureus-induced pain, we inoculated S. aureus (2 x 105 CFU, 5 days before) into the knee. Hyperalgesia, allodynia and local IL-16 up-regulation were observed, being the presence of IL-16 mainly related to macrophage-like synovial cells and fibroblasts. Accordingly, the anti-IL-16 antibody also completely prevented hypernociceptive reactions in these mice. Overall, the present results support the possible relevance of IL-16 as an innovative target for the control of pain during S. aureus infections.

Keywords:  Interleukin-16; Staphylococcus aureus; allodynia; hyperalgesia; pain; protein A

DOI:  https://doi.org/10.1016/j.ejphar.2025.177861
Front Immunol. 2025 ;16 1606277

KLF feedback loops in innate immunity.

Jessica M Salmon, Holly Adams, Graham W Magor, Andrew C Perkins.

  The Krüppel-like factor (KLF) family of zinc finger transcription factors regulate the expression of genes involved in a wide range of cellular processes, including cell proliferation and differentiation. In haematopoiesis, KLFs have essential roles in myeloid cell differentiation and function. KLF4 is a critical regulator of macrophage development and initiates pro- and anti-inflammatory signalling pathways in response to various stimuli. KLF2, KLF3 and KLF6 also play important roles in regulating these pathways. Here we review how KLFs cooperate and compete to either activate or repress target genes to influence initiation and resolution of inflammatory responses in macrophages. We also discuss how KLFs may be involved in the development of chronic inflammatory conditions.

Keywords:  KLF3; KLF4; chronic inflammatory disease; feedback loops; inflammation; innate immunity; macrophage; transcriptional regulation

DOI:  https://doi.org/10.3389/fimmu.2025.1606277
Microbiol Spectr. 2025 Jun 18. e0306624

Respiratory tract antimicrobial peptides more effectively killed multiple methicillin-resistant Staphylococcus aureus and nontypeable Haemophilus influenzae isolates after disruption from biofilm residence.

Nikola Kurbatfinski, Joseph A Jurscisek, Kathryn Q Wilbanks, Steven D Goodman, Lauren O Bakaletz.

  Bacteria newly released (NRel) from biofilm residence via multiple methodologies are commonly significantly more sensitive to antibiotics. We've induced NRel with this phenotype after incubation of biofilms formed by diverse human pathogens with an epitope-targeted monoclonal antibody directed at protective domains within bacterial DNABII proteins that provide structural support to the eDNA-dependent biofilm matrix. The observed heightened sensitivity was due, in part, to increased NRel membrane permeability. In three animal models of human biofilm-mediated infections, this monoclonal induced biofilm disruption with rapid concomitant bacterial clearance and disease resolution in the absence of any co-delivered antibiotic, which suggested a key role of innate immune effectors. Recently, we showed that NRel of the respiratory pathogen nontypeable Haemophilus influenzae (NTHI), as mediated by the DNABII-directed monoclonal, are also highly vulnerable to killing by human polymorphonuclear neutrophils (PMNs). Here, we extended these observations to show that the transient, yet highly vulnerable anti-DNABII NRel phenotype of three isolates of both NTHI and methicillin-resistant Staphylococcus aureus (MRSA) included significant sensitivity to killing by three antimicrobial peptides commonly expressed within the respiratory tract or by PMNs (e.g., human β-defensins 1 and 3 as well as the cathelicidin, LL-37). We envision induction of the NRel phenotype by delivery of this monoclonal antibody to patients with recalcitrant biofilm-mediated diseases to provide greatly improved medical management. Ideally, clearance of NRel will be mediated by innate immune effectors of an immunocompetent host or, if needed, by co-delivered traditional antibiotics, which are canonically ineffective against biofilm-resident bacteria but would be highly effective against NRel.
IMPORTANCE: Pathogenesis of most common chronic and/or recurrent bacterial diseases (e.g., middle ear infections, urinary tract infections, rhinosinusitis, among others) can be attributed to biofilms that are canonically highly resistant to both immune effectors and antibiotics. If we treat biofilms formed by diverse human pathogens with a targeted monoclonal antibody directed at protective domains of bacterial DNA-binding proteins integral to the structural stability of the eDNA-rich biofilm matrix, they are rapidly disrupted with concomitant release of the resident bacteria. These newly released (NRel) bacteria are transiently significantly more sensitive to killing by both traditional antibiotics and human PMNs, and herein, we showed that they are also more readily killed by antimicrobial peptides. Clinically, we hope to leverage this understanding of the NRel phenotype for better medical management of these challenging infections, as well as perhaps even limit or eliminate further contribution to the global antimicrobial resistance 'pandemic'.

Keywords:  DNABII; LL-37; MRSA; NRel; beta defensins; cathelicidin; nontypeable Haemophilus influenzae

DOI:  https://doi.org/10.1128/spectrum.03066-24
Microb Pathog. 2025 Jun 18. pii: S0882-4010(25)00541-8. [Epub ahead of print] 107816

The Beneficial Role of Probiotics and Gut Microbiota in Signaling Pathways, Immunity, Apoptosis, Autophagy, and intestinal barrier for Effective Wound Healing Post-Burn Injury.

Roya Hajialibabaei, Fatemeh Ghaffarian Sayeli, Esmat Aghadavod, Mohsen Poudineh, Azad Khaledi, Khadijeh Bamneshin.

  Severe burn injuries are associated with complex systemic disturbances, including profound immune dysregulation, compromised intestinal barrier function, and alterations in gut microbiota composition-factors that collectively contribute to impair wound healing and increased mortality. While broad-spectrum antibiotics are routinely employed to combat infection, their use may inadvertently aggravate mucosal barrier dysfunction and facilitate bacterial translocation. Emerging evidence underscores the potential of probiotics in restoring intestinal homeostasis and enhancing immune responses in critically ill populations; however, their application within the context of burn care remains insufficiently studied. This review seeks to address this knowledge gap by evaluating the therapeutic utility of probiotic supplementation in supporting gastrointestinal barrier integrity, attenuating inflammatory responses, and facilitating post-burn recovery. A comprehensive narrative review of relevant literature was performed via PubMed and Google Scholar, targeting studies involving microbiota, probiotics, and burn trauma. Probiotic strains, particularly Lactobacillus and Bifidobacterium, have been shown to modulate cytokine profiles, boost secretory IgA production, enhance epithelial regeneration, and influence key signaling pathways such as PI3K/Akt/mTOR, which are integral to regulating apoptosis and autophagy. Experimental models indicate that probiotics can decrease bacterial translocation and systemic inflammation, reinforce tight junction architecture, and elevate short-chain fatty acid concentrations. Notably, probiotic administration in burn models has resulted in up to a 75% reduction in infection-related mortality and enhanced anti-inflammatory responses via IL-10 and Th1 pathway activation. Moreover, adjunctive use of probiotics in topical formulations has shown efficacy in promoting wound healing in both diabetic and surgical settings. Collectively, these findings highlight the promise of probiotics as a complementary therapeutic approach in burn management, offering multifaceted benefits in reducing infection, supporting tissue regeneration, and improving clinical outcomes.

Keywords:  Burn injuries; Cutaneous injuries; Immune system; Infection; probiotics

DOI:  https://doi.org/10.1016/j.micpath.2025.107816
Sci Immunol. 2025 Jun 20. 10(108): eadq0043

TNF switches homeostatic efferocytosis to lytic caspase-8-dependent pyroptosis and IL-1β maturation.

Hayley I Muendlein, Wilson M Connolly, Jamie Leiriao, Mei-An Nolan, Jennifer Judge, Irina Smirnova, Rebecca Batorsky, Alexander Poltorak.

Efferocytosis, wherein phagocytes engulf dead or dying cells, is a critical function of macrophages that supports cellular turnover, tissue repair, and resolution of inflammation. Despite its well-established anti-inflammatory mechanism in homeostasis, whether efferocytosis remains immunologically silent in the context of dysregulated immune responses such as sepsis or systemic inflammatory response syndrome (SIRS) has not been investigated. Here, we used mouse models of tumor necrosis factor (TNF)-induced SIRS and Escherichia coli-induced septic peritonitis to uncover a potential negative consequence of efferocytosis. We found that when activated with TNF, phagocytes efferocytosing neutrophils initiated a caspase-8-dependent, but NLRP3 inflammasome-independent, form of pyroptosis, which we termed "efferoptosis." The maturation of IL-1β, a hallmark of pyroptotic cell death, also occurred independently of canonical inflammasome activation, supporting direct cleavage by caspase-8. Inhibition of efferocytosis protected mice against TNF-induced SIRS, suggesting that efferoptosis contributes to the pathology of sepsis and other TNF-mediated inflammatory conditions.

DOI: https://doi.org/10.1126/sciimmunol.adq0043
PLoS Pathog. 2025 Jun;21(6): e1012839

Experimental evolution of a pathogen confronted with innate immune memory increases variation in virulence.

Ana Korša, Moritz Baur, Nora K E Schulz, Jaime M Anaya-Rojas, Alexander Mellmann, Joachim Kurtz.

Understanding the drivers and mechanisms of virulence evolution is still a major goal of evolutionary biologists and epidemiologists. Theory predicts that the way virulence evolves depends on the balance between the benefits and costs it provides to pathogen fitness. Additionally, host responses to infections, such as resistance or tolerance, play a critical role in shaping virulence evolution. But, while the evolution of pathogens has been traditionally studied under the selection pressure of host adaptive immunity, less is known about their evolution when confronted to simpler and less effective forms of immunity such as immune priming. In this study, we used a well-established insect model for immune priming - red flour beetles and their bacterial pathogen Bacillus thuringiensis tenebrionis - to test how this form of innate immune memory drives the pathogen evolution. Through controlled experimental evolution of the pathogen in primed versus non-primed hosts, we found no change in average virulence after eight selection cycles in primed host. Nonetheless, we observed a notable rise in the variability of virulence, defined as the ability to kill hosts, among independent pathogen lines that evolved in primed hosts, and the bacteria were unable to develop resistance to host priming. Whole genome sequencing revealed increased activity in the bacterial mobilome (prophages and plasmids). Expression of the Cry toxin - a well-known virulence factor - was linked to evolved differences in copy number variation of the cry-carrying plasmid, though this did not correlate directly with virulence. These findings highlight that innate immune memory can drive variability in pathogen traits, which may favor adaptation to variable environments. This underscores the need to consider pathogen evolution in response to innate immune memory when applying these mechanisms in medicine, aquaculture, pest control, and insect mass production.

DOI: https://doi.org/10.1371/journal.ppat.1012839
Cell Metab. 2025 Jun 14. pii: S1550-4131(25)00268-2. [Epub ahead of print]

Itaconate promotes inflammatory responses in tissue-resident alveolar macrophages and exacerbates acute lung injury.

Mengtian Shan, Song Zhang, Zhibing Luo, Shengjie Deng, Linyu Ran, Quan Zhou, Huimin Wan, Jihui Ye, Chenchen Qian, Ximin Fan, Yun Feng, David W Morse, Joerg Herrmann, Qiang Li, Zhongliang Guo, Feilong Wang.

  Itaconate is an anti-inflammatory metabolite with therapeutic potential in multiple inflammatory diseases. However, its immunomodulatory function has been mainly based on ex vivo-generated macrophages or cell lines, whereas its role in tissue-resident macrophages is still poorly understood. Here, we report that, in contrast to its effects on bone-marrow-derived macrophages (BMDMs), itaconate promotes the production of proinflammatory cytokines and augments the activation of the NACHT-, leucine-rich-repeat- (LRR), and pyrin domain-containing protein 3 (NLRP3) inflammasome in resident alveolar macrophages (AMs). Unlike native itaconate, the itaconate derivatives dimethyl itaconate (DI) and 4-octyl itaconate (4OI) suppress the inflammatory response in AMs. Notably, the intratracheal transfer of BMDMs reversed their responsiveness to itaconate, indicating an essential role of the alveolar microenvironment in shaping macrophage immunometabolism. We also demonstrate that itaconate promotes AM-mediated inflammatory responses in vivo and aggravates lung injury. Taken together, our study unexpectedly demonstrates a proinflammatory role of itaconate in tissue-resident AMs, suggesting that further investigations are needed before its clinical application.

Keywords:  inflammatory responses; itaconate; macrophages; succinate dehydrogenase; the NLRP3 inflammasome

DOI:  https://doi.org/10.1016/j.cmet.2025.05.012
Int J Dermatol. 2025 Jun 17.

Role of Staphylococcus aureus Nasal Carriage in Uremic Pruritus and Infection in Hemodialysis Patients.

Mei-Ju Ko, Jenny Chiang, Chun-Hsing Liao, Wan-Chuan Tsai, Ping-Hsiu Tsai, Le-Yin Hsu, Fang-Yeh Chu, Yen-Ling Chiu, Hon-Yen Wu.

   BACKGROUND: While Staphylococcus aureus (S. aureus) is a well-recognized concern in hemodialysis (HD) patients, its role in uremic pruritus remains unknown. This study investigated the impact of S. aureus nasal carriage on the prevalence and severity of uremic pruritus and its association with subsequent infection in HD patients.
METHODS: We conducted a prospective cohort study from April 2019 to January 2020, enrolling 100 HD patients in Taiwan. Nasal swab cultures determined S. aureus colonization status. Odds ratios (ORs) for uremic pruritus, effect estimates for pruritus intensity, and hazard ratios (HRs) for subsequent S. aureus infections were assessed.
RESULTS: S. aureus nasal carriage was detected in 24% of HD patients and was more prevalent among those with uremic pruritus (32.7% vs. 13.3%, p = 0.02). S. aureus nasal carriage was associated with a significantly increased risk of uremic pruritus (OR: 4.21; 95% confidence interval [CI], 1.34-13.24, p < 0.01) and correlated with higher pruritus intensity (effect estimate: 1.18; 95% CI, 0.05-2.30; p = 0.04). During a median follow-up of 8.97 months, five patients developed S. aureus infections. While S. aureus nasal carriage showed a trend toward an increased risk of subsequent infection, the finding did not reach statistical significance (HR: 50.93; 95% CI, 0.62-4181.02; p = 0.08).
CONCLUSIONS: S. aureus nasal carriage is significantly associated with the prevalence and severity of uremic pruritus in HD patients. Larger studies are needed to confirm its role in infection risk and to explore decolonization as a potential therapeutic strategy.

Keywords:   Staphylococcus aureus ; hemodialysis; infection risk; nasal carriage; uremic pruritus

DOI:  https://doi.org/10.1111/ijd.17904
Gut Microbes. 2025 Dec;17(1): 2519696

Being a better version of yourself: genetically engineered probiotic bacteria as host defense enhancers in the control of intestinal pathogens.

Ewa Carolak, Joanna Czajkowska, Adrianna Stypułkowska, Wiktoria Waszczuk, Agata Dutkiewicz, Krzysztof Grzymajlo.

  Intestinal pathogens pose a significant global health burden, and traditional antibiotic treatments often disrupt the beneficial gut microbiota that plays a crucial role in maintaining host health through pathogen prevention and immune regulation. Although probiotics have emerged as promising therapeutic agents, their efficacy is limited by strain-dependent variations, survival challenges in the gastrointestinal tract, and inconsistent immune responses. Recent advances in genetic engineering, particularly CRISPR-Cas systems and their combinations with complementary technologies, such as Cre-lox and RecE/T, have enabled the precise modification of probiotic strains to enhance their therapeutic potential. These enhanced probiotics demonstrate improved functionality through multiple mechanisms, including increased adhesion via the expression of specific proteins (InlA, FnBPA, and LAP), targeted antimicrobial activity through engineered sensing systems (Lactococcus lactis detecting Vibrio cholerae CAI-1), and enhanced immunomodulation through cytokine production. Results have demonstrated the potential of genetically modified probiotics in preventing and treating gastrointestinal infections through mechanisms that include competitive exclusion, bacteriocin production, intestinal barrier reinforcement, and immune modulation. However, challenges remain in ensuring genetic stability and preventing horizontal gene transfer. Future research should focus on optimizing probiotic strains for targeted applications while addressing biosafety concerns. By understanding the complex interplay between probiotics, pathogens, and host immunity, innovative strategies can be developed to harness the full therapeutic potential of probiotic interventions in maintaining gut health.

Keywords:  CRISPR-Cas; Probiotics; biosafety; gastrointestinal pathogens; genetic modification; gut health; microbiome

DOI:  https://doi.org/10.1080/19490976.2025.2519696
Med Microbiol Immunol. 2025 Jun 20. 214(1): 31

Cytokine-mediated inhibition of Staphylococcus aureus adherence and invasion into nonphagocytic cells.

Arif Luqman, Knut Ohlsen.



Keywords:  Bacterial adherence; Bacterial invasion; Cytokines; Receptors for adhesin and invasin; Staphylococcus aureus

DOI:  https://doi.org/10.1007/s00430-025-00840-4
Am J Physiol Gastrointest Liver Physiol. 2025 Jun 16.

Lactiplantibacillus Plantarum strengthens the intestinal barrier: involvement of the endocannabinoidome.

Bénédicte Allam-Ndoul, Elena Cristina Pulido Mateos, Frédéric Bégin, Gabrielle St-Arnaud, Briscia Anaid Tinoco Mar, Thomas Mayer, Elizabeth Dumais, Nicolas Flamand, Frederic Raymond, Denis Roy, Yves Desjardins, Vincenzo Di Marzo, Alain Veilleux.

  Probiotics have been suggested to ameliorate intestinal epithelial homeostasis and barrier function. They also modulate several mediators and receptors of the expanded endocannabinoid system, or endocannabinoidome (eCBome), potentially explaining their beneficial effects on intestinal function. Objective: We aimed to study the effects of probiotic strains on gut barrier functions and the possible involvement of the eCBome in these effects. Methods: We cocultured three strains of Lactiplantibacillus plantarum with murine small intestine epithelial organoids and explored the involvement of eCBome signaling and inflammation in mediating the beneficial effects of the probiotics on the epithelial barrier function. Results: All three L. plantarum strains reduced the trans-epithelial permeability of organoids and increased mRNA expression of several tight junction proteins (Clnd1, Clnd2, Ocln, Tjp1 and Cdh1) and intestinal barrier proteins (Muc2, Lyz1, Reg3a and Defa20). Concomitantly, the three strains increased the expression of genes encoding eCBome receptors, while decreasing the expression of two catabolic enzymes (Faah and Naaa), and increasing one anabolic enzyme (Daglb). Altogether, these changes led to an overall increase in levels of eCBome mediators, namely N-acyl-ethanolamines (NAEs) and, particularly, 2-monoacylglycerols (2-MAGs), as measured by LC-MS/MS. URB597 and JZL184, two selective inhibitors of NAE and 2-MAG catabolism, reduced the trans-epithelial permeability of organoids, as observed with L. plantarum strains. Interestingly, both inhibitors also reversed inflammation-induced trans-epithelial permeability in organoids. Conclusions: Elevated endogenous levels of NAEs or 2-MAGs promote improvement in small intestine trans-epithelial permeability, and L. plantarum strains may exploit this mechanism to exert this same beneficial effect.

Keywords:  Endocannabinoids; Inflammatory Response; Permeability; Probiotic Bacteria; Small Intestine

DOI:  https://doi.org/10.1152/ajpgi.00142.2024
Nat Rev Immunol. 2025 Jun 18.

Innate immune responses to pathogens at the maternal-fetal interface.

Yael Alippe, Joshua Hatterschide, Carolyn B Coyne, Michael S Diamond.

During pregnancy, the maternal immune system must navigate a balance between fetal tolerance and a response to acquired microbial infections. Cells at the maternal-fetal interface coordinate this response throughout gestational stages in a dynamic manner, integrating endocrine, developmental, inflammatory and metabolic cues. Although many maternal and fetal cell types activate innate immune signalling pathways in response to infections, excessive inflammation can disrupt tolerance, affect placental function and impair fetal development, leading to congenital disease and other pregnancy complications. In this Review, we discuss the mechanisms of pathogen recognition in the maternal and fetal compartments of the placenta and the consequences of these responses to pregnancy outcomes.

DOI: https://doi.org/10.1038/s41577-025-01191-0
Ther Apher Dial. 2025 Jun 17.

Trained Innate Immunity in Extracorporeal Photopheresis.

Yandy Marx Castillo-Aleman.

DOI: https://doi.org/10.1111/1744-9987.70057
mSphere. 2025 Jun 20. e0105024

Quorum sensing modulates microbial community structure through regulation of secondary metabolites.

April C Armes, Amy L Schaefer, Leah H Hochanadel, Dawn M Klingeman, Dana L Carper, Paul E Abraham, Larry M York, Alyssa A Carrell, Mitchel J Doktycz, Dale A Pelletier.

  Bacteria are recognized for their diverse metabolic capabilities, yet the impact of microbe-microbe interactions on multispecies community structure and dynamics is poorly understood. Cell-to-cell signaling in the form of quorum sensing (QS) often regulates secondary metabolite production and microbial interactions. Here, we examine how acylhomoserine lactone (AHL)-mediated QS impacts microbial community structure in a 10-member synthetic community of isolates from Populus deltoides. To explore the role of QS in microbial community structure and dynamics, we disrupted AHL signaling by exogenous addition of AiiA-lactonase, an enzyme that cleaves the lactone ring. Microbial community structure resulting from signal inactivation, as measured by 16S rRNA amplicon sequencing and secondary metabolite production, was assessed after successive passaging of the community. Further, we investigated the impact of quorum quenching on specific microbe-microbe interactions using pairwise inhibition assays. Our results indicate that AHL inactivation alters the relative abundance of dominant community members at later passages but does not impact the overall membership in the community. Quorum quenching significantly alters the metabolic profile in lactonase-treated communities. This metabolic alteration impacts microbe-microbe interactions through decreased inhibition of other community members. Together, these results indicate that QS impacts microbial community structure through the regulation of secondary metabolites in dominant members and that the membership of microbial communities can be relatively stable despite changes in metabolic profiles.IMPORTANCEIn terrestrial ecosystems, bacteria exist as multispecies consortia and provide diverse ecosystem services. Interactions among microbes contribute to determining their abundance and population structure and are often mediated by cell-to-cell communication. However, the role of microbial communication in community assembly is poorly understood. In this study, we investigated the disruption of AHL-based quorum sensing on bacterial community structure using a synthetic microbial community derived from a plant host. We found that disrupting AHL signaling did not change the membership but shifted the relative abundance of the dominant community members. Metabolic profiles of disrupted communities reveal alterations in key secondary metabolites that likely reduce antagonistic behavior. Investigating the driving mechanisms underlying microbial community assembly is fundamental to understanding microbial ecosystem ecology and can be broadly applied toward understanding sustainable systems and facilitating agricultural applications where plant-associated microbes are of growing importance.

Keywords:  AHLs; RAMs; SynComs; lactonase; microbial communities; phenazine; polymicrobial; quorum quenching; quorum sensing

DOI:  https://doi.org/10.1128/msphere.01050-24
Free Radic Res. 2025 Jun 18. 1-10

Pro-inflammatory properties of M1 phenotypes of human macrophages: prolongation of myeloperoxidase-mediated oxidative stress.

Maria D Yurkanova, Nastasia V Kosheleva, Arina A Teplova, Peter S Timashev, Irina I Vlasova.

  Macrophages and neutrophils are the main immune cells of the acute stage of inflammation. Upon their activation, membrane-bound NADPH oxidase produces superoxide anion radical, which is converted to H2O2 by superoxide dismutase (SOD). In this study, we compared the production of hydrogen peroxide by two phenotypes of pro-inflammatory human M1 macrophages and neutrophils activated with phorbol-12-myristate 13-acetate. Macrophages were obtained from blood monocytes (monocyte-derived macrophages (MDM)) differentiated into MDM using GM- or M-CSF growth factors and polarized into the M1 state, receiving GM_M1, M_M1, respectively. The total level of H2O2 production measured in the presence of horseradish peroxidase differed significantly between two types of macrophages. Only GM_M1 macrophages had a level of H2O2 production comparable to neutrophils. GM_M1 appear at the site of inflammation after neutrophils, they continue the work of neutrophils in creating a pro-inflammatory environment: they produce several times more H2O2 and pro-inflammatory cytokines than M_M1, which arrive at inflammatory site later. Upon activation, MDM_M1 formed big blot-like and smaller dense spheroid-like aggregates. Activated neutrophils secrete the enzyme myeloperoxidase (MPO), which synthesizes the very potent oxidant hypochlorous acid (HOCl) only in the presence of H2O2. Neutrophils are short lived cells, MPO can use H2O2 produced by activated cultured MDM to synthesize HOCl at physiologically relevant concentrations to prolong oxidative stress.

Keywords:  Macrophages; hydrogen peroxide; hypochlorous acid; myeloperoxidase; neutrophils

DOI:  https://doi.org/10.1080/10715762.2025.2519528
Front Immunol. 2025 ;16 1585718

Associations between total protein, globulin, and nasal Methicillin-Resistant Staphylococcus aureus (MRSA) colonization in US adults: results from the national health and nutrition examination survey 2001-2004.

Kanchao Chen, Xiaomeng Feng, Futong Liu, Yuping Fan, Tingting Zhang, Hui Wang, Sizhou Feng.

   Objective: There is limited evidence on the association between total serum protein (TP), serum globulin (GLB), and Methicillin-Resistant Staphylococcus aureus (MRSA) nasal colonization. The purpose of this study was to investigate the association between TP, GLB, and MRSA nasal colonization in US adults with data derived from the National Health and Nutrition Examination Survey (NHANES).
Methods: Using NHANES 2001-2004 data, we employed propensity score matching (PSM) to control confounders, weighted logistic regression to evaluate associations of TP and GLB with MRSA colonization, restricted cubic splines (RCS) for non-linear analysis, and subgroup and sensitivity analyses for validation.
Results: Among 7,585 adults, 1.31% (n = 99) had MRSA nasal colonization. Adjusted multivariable regression identified TP and GLB as independent protective factors (TP: OR=0.92, 95%CI 0.88-0.96; GLB: OR=0.91, 95%CI 0.86-0.97; p< 0.05 for all). Categorizing TP and GLB into quartiles (Q4 vs. Q1) reinforced this association (TP: OR=0.21, 95%CI 0.07-0.59; GLB: OR=0.28, 95%CI 0.12-0.67; p< 0.05 for all) with consistent results post-PSM. Restricted cubic splines confirmed dose-dependent negative correlations. Subgroup analyses and sensitivity analyses supported the robustness of these findings.
Conclusion: There was a negative correlation between TP, GLB, and MRSA nasal colonization in participants aged 18 years or older. Our data support the protective role of TP and GLB in MRSA colonization, and the specific mechanisms of these biomarkers in MRSA colonization and their clinical implications require further investigation.

Keywords:  MRSA colonization; NHANES; PSM; globulin; total protein

DOI:  https://doi.org/10.3389/fimmu.2025.1585718