bims-bac4me 2025-08-31 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2025–08–31
24 papers selected by
Chun-Chi Chang, Lunds universitet

Pathobiont immune tuning: the untold consequences of Staphylococcus aureus exposure on host immunity.
Trained Immunity and Its Potential Implications in the Etiopathogenesis of Hidradenitis Suppurativa: A New Paradigm in Chronic Inflammation?
Strategic antagonism: how Lactobacillus plantarum counters Staphylococcus aureus pathogenicity.
The Susceptibility Profiles of Human Peripheral Blood Cells to Staphylococcus aureus Cytotoxins.
Methicillin-resistant and susceptible Staphylococcus aureus: tolerance, immune evasion and treatment.
Innate Immunity Reimagined: Metabolic Reprogramming as a Gateway to Novel Therapeutics.
Lactate metabolic reprogramming and histone lactylation modification in sepsis.
CCL20/CCR6 signaling modulates disease severity during the establishment of Staphylococcus aureus osteomyelitis.
Considering local immunity for innovative immunomodulatory approaches: pulmonary sepsis as a use case.
Macrophages in the male genital tract.
From "Traditional" to "Trained" Immunity: Exploring the Novel Frontiers of Immunopathogenesis in the Progression of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD).
Respiratory viral coinfections: interactions, mechanisms and clinical implications.
Targeting macrophage phenotypes to prevent diseases caused by Leishmania and Trypanosoma cruzi infections.
Macrophage-derived IL-1β directs fibroblast progenitor cell fate via metabolic reprogramming in wound healing.
Glycolysis to lactylation: Unraveling the metabolic and epigenetic landscape in tissue fibrosis (Review).
Miconazole attenuates LPS-induced lung inflammation by modulating alveolar macrophage polarization via promoting lipid metabolic reprogramming.
Enrichment of Streptococcus oralis in respiratory microbiome enhance innate immunity and protects against influenza infection.
Interferons in health and disease.
Host-directed therapeutic targets in macrophages and their ligands against mycobacteria tuberculosis.
An epitope vaccine derived by analyzing clinical trial samples safeguards hosts with prior exposure to S. aureus against reinfection.
Paternal microbiota manipulation influences offspring microbial colonization and development in a sex role-reversed pipefish.
Host niche-specific challenges hindering the treatment of polymicrobial infections.
From mucus plugging to airway dilatation in chronic airway diseases: A perspective on the contribution of the airway microbiome and inflammation.
The Multifaceted Functions of Lactoferrin in Antimicrobial Defense and Inflammation.

Trends Microbiol. 2025 Aug 22. pii: S0966-842X(25)00219-7. [Epub ahead of print]

Pathobiont immune tuning: the untold consequences of Staphylococcus aureus exposure on host immunity.

Seán C Cahill, Elisabetta Soldaini, Rachel M McLoughlin.

  Staphylococcus aureus is a formidable pathogen and major challenge to human health. However, the bacterium is dichotomous and also acts as an asymptomatic coloniser. Given its ubiquity, every individual has been exposed to the bacterium, which may 'tune' the host immune system. This prior exposure potentially hampers the efficacy of anti-S. aureus vaccines, diminishing their protective effect. Conversely, by preserving its niche as a commensal coloniser, the bacterium simultaneously contributes to host defence through interbacterial competition and stimulation of host immune responses, potentially fending off pathogenic threats. This review examines how S. aureus shapes host immunity via infection and colonisation and explores how S. aureus-associated immune tuning can be both problematic and beneficial for the host.

Keywords:  Staphylococcus aureus; colonisation; innate immune training; prior exposure; vaccination

DOI:  https://doi.org/10.1016/j.tim.2025.07.008
Exp Dermatol. 2025 Aug;34(8): e70160

Trained Immunity and Its Potential Implications in the Etiopathogenesis of Hidradenitis Suppurativa: A New Paradigm in Chronic Inflammation?

Annalisa Marcuzzi, Erika Rimondi, Giada Lodi, Marta Manfredini, Paola Maura Tricarico, Chiara Moltrasio, Angelo Valerio Marzano, Muhammad Suleman, Paola Secchiero, Elisabetta Melloni, Sergio Crovella.

  Hidradenitis suppurativa (HS) is a chronic auto-inflammatory skin disorder characterised by recurrent, painful nodules, abscesses and tunnels, often leading to tissue destruction with a significant impairment in quality of life. Despite advancements in understanding, HS remains a complex disease, whose exact pathogenesis is yet to be revealed. Nevertheless, the role of a dysregulated innate immune response has been established, potentially contributing to the persistent and chronic inflammation. Recent advances in immunology have highlighted the concept of trained immunity, a form of innate immune memory that may provide new insights into HS pathophysiology. Trained immunity is mediated by epigenetic and metabolic reprogramming of innate immune cells, enabling them to mount a heightened and prolonged inflammatory response upon subsequent stimuli, even in the absence of the original trigger. We hypothesize that trained immunity could contribute to the persistent inflammatory state, influencing HS progression and severity. Environmental and microbial factors may act as persistent stimuli, leading to activation of innate immune pathways. From a mechanistic perspective, trained immunity in HS might involve increased cytokine production, altered myeloid cell differentiation and persistent epigenetic modifications favouring a pro-inflammatory phenotype. Identifying specific molecular markers associated with trained immunity in HS could provide new diagnostic and prognostic tools and may open novel therapeutic avenues. By exploring the potential role of trained immunity in HS, we provide a new perspective on chronic inflammation, thus hypothesizing another actor involved in the aetiology/pathogenesis of this complex disease.

Keywords:  epigenetics; hidradenitis suppurativa; inflammation; metabolic reprogramming; trained immunity

DOI:  https://doi.org/10.1111/exd.70160
Front Microbiol. 2025 ;16 1635123

Strategic antagonism: how Lactobacillus plantarum counters Staphylococcus aureus pathogenicity.

Ly Tuan Kiet Bui, Fariha Alam Bushra, Pirachat Rattananon, Arifa Afrose Rimi, Carmen Lee, S M Tahmid, Sumaiya Akter Tisha, Irfan Fayaz Jisan, Rachita Das, Jahin Ibnat Sneha, Victoria Pitts, Olalekan Uchechukwu Owasanoye, Saphal Khadka, Shariful Islam.

  Staphylococcus aureus is a clinically significant pathogen known for its antibiotic resistance, immune evasion, and biofilm formation, making it a major contributor to persistent infections. Lactobacillus plantarum, a versatile probiotic bacterium, has emerged as a promising antagonist against S. aureus through multifaceted inhibitory mechanisms. This review synthesizes current evidence on the antagonistic interactions between L. plantarum and S. aureus, highlighting bacteriocin-mediated membrane disruption, quorum sensing interference, biofilm degradation, and metabolic competition. In addition, we explore how L. plantarum contributes to a less favorable inflammatory environment for S. aureus by modulating local immune responses at infection sites. Clinical relevance is explored across diverse anatomical sites such as the skin, vaginal tract, urinary system, and gastrointestinal tract, where L. plantarum demonstrates both direct and adjunctive therapeutic potential. We also consider environmental influences like pH and nutrient availability that modulate this antagonism. Together, the findings position L. plantarum as a compelling candidate for probiotic-based interventions against persistent and device-associated S. aureus infections.

Keywords:  Lactobacillus plantarum; Staphylococcus aureus; antagonism; antibiotic resistance; antimicrobial; metabolite; microbiota; probiotics

DOI:  https://doi.org/10.3389/fmicb.2025.1635123
Microorganisms. 2025 Aug 04. pii: 1817. [Epub ahead of print]13(8):

The Susceptibility Profiles of Human Peripheral Blood Cells to Staphylococcus aureus Cytotoxins.

Tyler K Nygaard, Jovanka M Voyich.

  Staphylococcus aureus is a Gram-positive bacterium that causes significant human morbidity and mortality. The capacity of S. aureus to cause disease is primarily attributed to an array of virulence factors produced by this pathogen that collectively overcome immune defenses and promote survival in a variety of host tissues. These include an arsenal of different cytotoxins that compromise plasma membrane integrity, with the specificity of each dependent upon the host organism and cell type. S. aureus encounters a variety of peripheral blood cell types during infection that play important roles in maintaining homeostasis and defending against microbial invasion, namely erythrocytes, thrombocytes, and leukocytes. S. aureus targets each of these cell types with specific cytotoxins to successfully establish disease. This review summarizes our current understanding of the susceptibility of different human peripheral blood cell types to each of these cytotoxins.

Keywords:  B cells; Staphylococcus aureus; T cells; bicomponent leukocidin; cytotoxin; erythrocytes; monocytes; neutrophils; peripheral blood cell; platelets

DOI:  https://doi.org/10.3390/microorganisms13081817
Nat Rev Microbiol. 2025 Aug 20.

Methicillin-resistant and susceptible Staphylococcus aureus: tolerance, immune evasion and treatment.

Joshua B Parsons, Ahmad Mourad, Brian P Conlon, Tammy Kielian, Vance G Fowler.

Staphylococcus aureus is capable of infecting every organ system in the body and developing resistance to every available antibiotic used to treat it, such as methicillin-resistant S. aureus (commonly referred to as MRSA). This pathogen is characterized by the sudden emergence of virulent new clones and an array of mechanisms to circumvent the immune system and antibiotics. Furthermore, despite the development of new antibiotics and a growing body of high-quality data to inform their use, S. aureus continues to be a leading bacterial cause of death worldwide. In this Review, we provide an overview of the basic research on the complex interplay between S. aureus, the host and antibiotics. We also provide an update on the contemporary clinical studies on the treatment and prevention of S. aureus.

DOI: https://doi.org/10.1038/s41579-025-01226-2
Int J Biol Sci. 2025 ;21(11): 5056-5078

Innate Immunity Reimagined: Metabolic Reprogramming as a Gateway to Novel Therapeutics.

Chuan-Han Deng, Chen-Tong Wang, Xin Zhou, Xin Chen, Ying Wang.

  The interplay between cellular metabolism and innate immunity critically shapes the body's ability to fight infections, repair tissue, and manage stress. Metabolic reprogramming not only drives innate immune activation but also regulates the resolution of inflammation. Phenotypes of immune cell are closely linked to metabolic shifts that adapt to varying energy demands. However, the precise relationship between perturbations in the cellular respiratory-metabolic axis and the inflammatory response remains a critical field of investigation. In depth understanding of key metabolic pathways, such as glycolysis, NADPH oxidase activity, mitochondrial ROS production, TCA cycle metabolites, and cGAS-STING/AIM2 inflammasome activation, is essential to unravel the complexities of innate immunity. This article highlights the central role of metabolic reprogramming mainly in innate immunity and explores its potential as a therapeutic target for modulating inflammatory response.

Keywords:  cellular respiration; inflammation; innate immune response; metabolism programming; mitochondria

DOI:  https://doi.org/10.7150/ijbs.114010
Int J Biol Sci. 2025 ;21(11): 5034-5055

Lactate metabolic reprogramming and histone lactylation modification in sepsis.

Ji Zhang, Dan Wu, Fu Zeng, Haiyun Gu, Chengbao Li, Juan P Cata, Kefang Guo, Changhong Miao, Hao Zhang.

  Sepsis, a serious condition characterized by life-threatening organ dysfunction owing to infection, lacks specific therapeutic interventions. Lactate serves as a crucial biomarker in sepsis, reflecting both the patient's metabolic state and the severity of the condition. Lactylation, the process whereby lactate is conjugated to lysine residues in proteins, profoundly alters protein structure and function. This review delves into the crucial roles of lactate and lactylation within the septic environment, illuminating the intricate feedback loop between metabolic reprogramming and lactylation in sepsis. Herein, fluctuations in lactate levels influence patterns of lactylation, which subsequently regulate energy metabolism. Lactylation is essential for modulating immune responses, adjusting gene expression profiles in immune cells, and shifting the balance between pro-inflammatory and anti-inflammatory pathways. The discovery of these pathways has significant implications for development of targeted therapies against sepsis. Furthermore, this review addresses the advancements and current limitations associated with lactylation research methodologies, and proposes new directions for future research. Overall, this narrative underscores the transformative potential of lactylation in understanding and managing sepsis, advocating for a multidisciplinary approach to unravel the complex interplay between metabolic processes and epigenetic regulation in critical illnesses.

Keywords:  inflammation; lactylation; sepsis; therapeutic targets

DOI:  https://doi.org/10.7150/ijbs.116088
mBio. 2025 Aug 25. e0141325

CCL20/CCR6 signaling modulates disease severity during the establishment of Staphylococcus aureus osteomyelitis.

Himanshu Meghwani, Javier Rangel-Moreno, Kyra M Sandercock, Motoo Saito, Katya A McDonald, Chloe M Kraft, Robert Constantine, Sophia Lenigk, Adryiana Rodriguez, Stephen L Kates, Jennifer H Jonason, Edward M Schwarz, Gowrishankar Muthukrishnan.

  Chemokines are essential mediators of immune responses, and the CCL20/CCR6 chemokine signaling axis is known to be involved in inflammation, infectious diseases, and cancer progression. However, the role of the CCL20/CCR6 axis in host defense against Staphylococcus aureus osteomyelitis remains unknown. We hypothesized that the CCL20/CCR6 axis is critical for the recruitment and activation of immune cells against S. aureus, and the lack of CCL20 or its monogamous receptor CCR6 leads to exacerbation of S. aureus osteomyelitis. In vitro studies confirmed that osteoblasts and macrophages (M0 and M2 subtypes) secrete CCL20 following S. aureus exposure. Implant-associated osteomyelitis in C57BL/6, CCL20-/-, and CCR6-/- mice revealed an early increase in planktonic bacterial growth on day 1 and increased bacterial loads in soft tissue and bone on day 14 post-infection in both CCL20-/- and CCR6-/- mice. Immunohistochemistry and flow cytometry revealed that CCL20-/- and CCR6-/- mice have impaired recruitment of T cells, especially CCR6+ T cells, to the site of infection. Interestingly, CCR6-/- mice exhibited increases in osteoclast numbers, reactive bone formation, and reduced bone mineral density. In a clinical pilot study, we observed a fivefold increase in serum CCL20 levels (P < 0.05) in S. aureus osteomyelitis patients (n = 23) vs uninfected controls (n = 10). Remarkably, serum CCL20 levels immediately following septic death were 100-fold higher vs uninfected patients (P < 0.05). Collectively, these results highlight the critical role of CCL20/CCR6-mediated host immunity during the establishment of S. aureus osteomyelitis and the potential of CCL20 as a biomarker of osteomyelitis-induced sepsis.
IMPORTANCE: Staphylococcus aureus is the most common pathogen in orthopedic infections, and hard-to-treat strains (methicillin-resistant S. aureus) cause >50% of these infections. Thus, there is an urgent need to develop immunotherapies to treat these life-threatening infections. The role of the CCL20/CCR6 chemokine signaling axis on S. aureus osteomyelitis is unknown. In our efforts to uncover its role, we reveal that osteoblasts and macrophages secrete CCL20 in response to infection, and mice lacking CCL20 or its monogamous receptor CCR6 are more susceptible to S. aureus osteomyelitis. Mechanistically, we observed that increased infection severity in the knockout mice is associated with decreased T cell recruitment and increased osteoclastogenesis at the bone infection site. Importantly, in a clinical pilot study, we observed that CCL20 can be a useful biomarker of osteomyelitis-induced septic death. Overall, our study highlights the crucial immunomodulatory role that the CCL20/CCR6 axis plays during osteomyelitis.

Keywords:  CCL20; CCR6; Staphylococcus aureus; T cells; host immunity; osteomyelitis

DOI:  https://doi.org/10.1128/mbio.01413-25
Front Immunol. 2025 ;16 1627313

Considering local immunity for innovative immunomodulatory approaches: pulmonary sepsis as a use case.

Emilie Vernay, Elisabeth Cerrato, François Santinon, Céline Monard, Pauline Perez, Florence Allantaz, Anne-Claire Lukaszewicz, Jean-François Llitjos.

  Owing to faster identification of sepsis and improvement of patient management, most septic patients now survive the early phase of sepsis. Therefore, one of the major challenges in sepsis management today is to identify those patients at risk and propose effective personalized therapy. The complexity of the mechanisms involved in the septic immune response and its dysregulation is reflected in the diversity of immune profiles among sepsis patients. It is now well recognized that this heterogeneity is a major obstacle to stratifying patients based on their susceptibility to secondary infections. Since sepsis can originate from different anatomical sites, some studies have investigated their impact to decipher the heterogeneity. They concluded that the site of infection affects patient outcomes and leads to different immune alterations. This narrative review focuses on pulmonary sepsis to highlight the importance of studying organ response directly with local immune cells. Understanding the persistent dysregulation within the lung, whether it involves pulmonary immune cells or other lung components, is critical. Some studies have already examined the remodeling and loss of functionality of alveolar macrophages after the initial insult. Ongoing research is also investigating the impact of imbalances in other lung players, such as epithelial cells or the microbiota, on susceptibility to pulmonary reinfection.

Keywords:  alveolar macrophages (AMs); compartmentalisation; lung infection; pulmonary microbiota; sepsis

DOI:  https://doi.org/10.3389/fimmu.2025.1627313
Biomed J. 2025 Aug 25. pii: S2319-4170(25)00084-8. [Epub ahead of print] 100910

Macrophages in the male genital tract.

María Sol Martinez, Rubén Darío Motrich.

  Macrophages play essential roles in maintaining immune defence and tissue homeostasis within the male genital tract, which is essential for reproductive health. Since their initial discovery in the testes, macrophages have been established as highly adaptable immune cells that perform diverse functions ranging from immune surveillance to tissue repair. In the testes, macrophages play a crucial role in maintaining immune privilege and tissue homeostasis by regulating inflammatory responses and supporting steroidogenesis and spermatogenesis via intricate crosstalk with Leydig and Sertoli cells. In the epididymis, macrophages maintain a balance between immune tolerance and pathogen defence, ensuring the integrity of maturing sperm. Moreover, recent evidence has begun to reveal the complex and unique characteristics of prostate tissue-resident macrophages and their roles in homeostasis and disease. Notably, these cells exhibit dual functions in pathological conditions, contributing both to chronic inflammation in prostatitis and to the modulation of tumour dynamics in prostate cancer. Remarkably, dysregulation of macrophage function has been implicated in several prevalent male urological diseases and male infertility. This review integrates historical perspectives with recent advances in the immunobiology of macrophages in the male genital tract, highlighting their role as pivotal regulators of reproductive tract homeostasis.

Keywords:  homeostasis; immune regulation; inflammation; macrophage; male genital tract; reproduction

DOI:  https://doi.org/10.1016/j.bj.2025.100910
Biomedicines. 2025 Aug 18. pii: 2004. [Epub ahead of print]13(8):

From "Traditional" to "Trained" Immunity: Exploring the Novel Frontiers of Immunopathogenesis in the Progression of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD).

Mario Romeo, Alessia Silvestrin, Giusy Senese, Fiammetta Di Nardo, Carmine Napolitano, Paolo Vaia, Annachiara Coppola, Pierluigi Federico, Marcello Dallio, Alessandro Federico.

  Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most prevalent chronic hepatopathy and a leading precursor of hepatocellular carcinoma (HCC) worldwide. Initially attributed to insulin resistance (IR)-driven metabolic imbalance, recent insights highlight a multifactorial pathogenesis involving oxidative stress (OS), chronic inflammation, and immune dysregulation. The hepatic accumulation of free fatty acids (FFAs) initiates mitochondrial dysfunction and excessive reactive oxygen species (ROS) production, culminating in lipotoxic intermediates and mitochondrial DNA damage. These damage-associated molecular patterns (DAMPs), together with gut-derived pathogen-associated molecular patterns (PAMPs), activate innate immune cells and amplify cytokine-mediated inflammation. Kupffer cell activation further exacerbates OS, while ROS-induced transcriptional pathways perpetuate inflammatory gene expression. Traditional immunity refers to the well-established dichotomy of innate and adaptive immune responses, where innate immunity provides immediate but non-specific defense, and adaptive immunity offers long-lasting, antigen-specific protection. However, a paradigm shift has occurred with the recognition of trained immunity (TI)-an adaptive-like memory response within innate immune cells that enables enhanced responses upon re-exposure to stimuli. Following non-specific antigenic stimulation, TI induces durable epigenetic and metabolic reprogramming, leading to heightened inflammatory responses and altered functional phenotypes. These rewired cells acquire the capacity to produce lipid mediators, cytokines, and matrix-modifying enzymes, reinforcing hepatic inflammation and fibrogenesis. In this context, the concept of immunometabolism has gained prominence, linking metabolic rewiring with immune dysfunction. This literature review provides an up-to-date synthesis of emerging evidence on immunometabolism and trained immunity as pathogenic drivers in MASLD. We discuss their roles in the transition from hepatic steatosis to steatohepatitis, fibrosis, and cirrhosis, and explore their contribution to the initiation and progression of MASLD-related HCC. Understanding these processes may reveal novel immunometabolic targets for therapeutic intervention.

Keywords:  immunometabolism; inflammation; oxidative stress; trained immunity

DOI:  https://doi.org/10.3390/biomedicines13082004
Nat Rev Microbiol. 2025 Aug 20.

Respiratory viral coinfections: interactions, mechanisms and clinical implications.

Pallavi Deol, Tanya A Miura.

Many heterologous viruses that infect the respiratory tract co-circulate within human populations. With the advent of multiplex diagnostic tests for respiratory viruses, there is increased appreciation of viral coinfection within an individual host. Thus, it is important to understand the interactions between heterologous respiratory viruses at the levels of populations, hosts and cells, as well as the impact of these interactions on pathogen prevalence and disease severity. In this Review, we summarize studies that demonstrate antagonistic or synergistic interactions between respiratory viruses, resulting in altered viral prevalence in populations, replication in hosts and cells, and disease severity in clinical cases and animal models. Understanding these interactions at a mechanistic level will affect future strategies to prevent and treat respiratory viral infections.

DOI: https://doi.org/10.1038/s41579-025-01225-3
Front Immunol. 2025 ;16 1595954

Targeting macrophage phenotypes to prevent diseases caused by Leishmania and Trypanosoma cruzi infections.

Natália S Vellozo, Thayane C Matos-Silva, Marcela F Lopes.

  Macrophage plasticity is remarkable, and recent studies have opened new prophylactic and therapeutic avenues for immunomodulation of macrophage phenotypes in inflammatory and infectious diseases. During infections caused by the pathogenic protozoans Leishmania spp. and Trypanosoma cruzi, susceptibility to disseminated or chronic infections and/or the development of inflammatory diseases depend on the balance between protective immunity mediated by macrophages and anti-inflammatory responses. Here, we will discuss strategies that exploit macrophage plasticity towards the extreme proinflammatory M1 or pro-infection M2 phenotypes to prevent the establishment of disseminated and chronic infection or to temper parasite-driven inflammatory responses. Immunomodulation of macrophage phenotypes has been tested in experimental models of protozoan infections through pharmacological approaches, synergy between pro-M1 cytokines, and targeting of pro-M2 macrophage functions, such as efferocytosis. We will address the cellular and molecular mechanisms underlying strategies designed to redirect macrophage activation towards M1 and M2 phenotypes, as well as the challenges and open questions.

Keywords:  ATRA; Axl; Chagas disease; Leishmaniasis; M1 and M2 macrophages; RANKL; Th1 and Th2 cytokines; efferocytosis

DOI:  https://doi.org/10.3389/fimmu.2025.1595954
Commun Biol. 2025 Aug 27. 8(1): 1291

Macrophage-derived IL-1β directs fibroblast progenitor cell fate via metabolic reprogramming in wound healing.

Huanyu Luo, Xiaoyi Yu, Tianmeng Sun, Zewen Sun, Tianyuan Zhao, Chen Li, Ana Angelova Volponi, Fabian Flores-Borja, Hongchen Sun, Zhengwen An.

The oral mucosa exhibits unique regenerative properties and distinct wound healing dynamics compared to facial skin, providing a valuable model for studying tissue-specific repair mechanisms. Using a rigorously controlled mouse model combined with single-cell transcriptomics, we identified a novel mechanism underlying this tissue-specific difference. Our study revealed a population of fibroblast progenitors in the oral buccal mucosa that rapidly activate and differentiate into mature fibroblasts, contributing to effective wound resolution. Mechanistically, IL-1β derived from tissue-resident macrophages activates NFκB signals in these progenitors, inducing a metabolic shift from glycolysis to oxidative phosphorylation in a proteasome-dependent manner. This metabolic reprogramming supports stem cell differentiation and contributes to the unique regenerative pattern of the oral buccal mucosa. Our findings highlight the specialized healing mechanisms of the oral tissue and suggest that modulating proteasome activation and the IL-1β/NFκB axis may offer new therapeutic avenues for enhancing wound repair in tissue requiring extensive connective remodeling, such as skin or gingiva.

DOI: https://doi.org/10.1038/s42003-025-08754-w
Mol Med Rep. 2025 11;pii: 290. [Epub ahead of print]32(5):

Glycolysis to lactylation: Unraveling the metabolic and epigenetic landscape in tissue fibrosis (Review).

Luna Zhang, Qianqian Li, Yuxin Deng, Yuanxia Zou, Li Wang, Jianchun Li.

  Tissue fibrosis represents a pathological condition characterized by excessive accumulation of extracellular matrix (ECM) components. Although historically considered a byproduct of glycolysis, lactate has emerged as a key signaling molecule influencing diverse physiological and pathological processes, including fibrosis. Roles have emerged for lactate metabolism and lactylation, a novel post‑translational modification, in regulating fibroblast activation, ECM deposition and fibrotic progression. The present review provides a comprehensive analysis of the current understanding of glycolysis, lactate and lactylation in tissue fibrosis, with emphasis on cardiac, liver, renal and pulmonary fibrosis. The present review examines how enhanced glycolysis supports the energetic and biosynthetic requirements of activated fibroblasts, how lactate functions as a signaling molecule promoting fibrogenesis and how lactylation connects metabolic changes to epigenetic regulation of gene expression. Furthermore, the present review explores potential therapeutic approaches targeting metabolic pathways and lactylation to mitigate fibrosis, while highlighting future directions in this rapidly evolving field.

Keywords:  epigenetic regulation; fibrosis; glycolysis; lactate; lactylation; metabolic reprogramming

DOI:  https://doi.org/10.3892/mmr.2025.13655
Inflamm Res. 2025 Aug 25. 74(1): 113

Miconazole attenuates LPS-induced lung inflammation by modulating alveolar macrophage polarization via promoting lipid metabolic reprogramming.

Huanwen Wu, Qijiang Zhao, Liangliang Dong, Yuxin Wu, Chengzhi Zheng, Tongquan Wu, Daqing Ma, Yicheng Xie, Yingshuo Wang.

   OBJECTIVE: Pulmonary inflammation is closely associated with macrophage polarization and lipid metabolic reprogramming. Miconazole (MCZ), traditionally used as an antifungal agent, exhibits emerging anti-inflammatory potential, yet its underlying mechanisms remain unclear.
METHODS: A mouse model of lipopolysaccharide (LPS)-induced lung inflammation was employed to evaluate MCZ's anti-inflammatory efficacy. In vivo inflammatory cell infiltration, cytokine expression (IL-6, IL-1β, TNF-α), and lung histopathology were assessed. Single-cell RNA sequencing (scRNA-seq) characterized alveolar macrophage subpopulations and associated lipid metabolism pathways. In vitro experiments with bone marrow-derived macrophages (BMDM) validated the changes of macrophage polarization.
RESULTS: MCZ treatment significantly alleviated lung inflammation by decreasing inflammatory cell infiltration and suppressing pro-inflammatory cytokines. ScRNA-seq analysis revealed subcluster of Itgam (Cd11b) negative, Mrc1, Marco, and Lgals3 high AMs, MCZ decreased the proportions of pro-inflammatory neutrophils and macrophages, and promoted the phenotypic shift of alveolar macrophages from a pro-inflammatory subtype (AM1) to an anti-inflammatory subtype (AM2). Further cell-cell communication analysis showed that MCZ suppressed interactions between AM1 alveolar macrophages and neutrophils via TNF-TNFR, CCL3/5-CCR1, and CXCL1-CXCR2 signaling pathways. Mechanistically, MCZ inhibited lipid synthesis in AM1 alveolar macrophages while enhancing lipid catabolism in AM2 alveolar macrophages. In vitro studies using BMDM further confirmed that MCZ inhibited LPS-induced macrophage M1 polarization and lipid droplet accumulation marked by perilipin 3 (PLIN3), while promoting IL-4/IL-13-induced M2 polarization.
CONCLUSION: MCZ exerts therapeutic effects against pulmonary inflammation primarily by modulating macrophage polarization through lipid metabolic reprogramming, highlighting its promise as a novel therapeutic approach for inflammatory lung diseases.

Keywords:  Alveolar macrophage polarization; Lipid metabolic reprogramming; Miconazole; Pulmonary inflammatory; scRNA-seq

DOI:  https://doi.org/10.1007/s00011-025-02082-9
Signal Transduct Target Ther. 2025 Aug 27. 10(1): 272

Enrichment of Streptococcus oralis in respiratory microbiome enhance innate immunity and protects against influenza infection.

Xiaohui Zou, Hongyun Cao, Lizhe Hong, Lijun Suo, Chun Wang, Kang Chang, Yawen Ni, Bo Liu, Bin Cao.

Respiratory microbial dysbiosis has been implicated in the occurrence and progression of community-acquired pneumonia (CAP). However, the dynamic variation in the respiratory microbiota and its interaction with the host response remain poorly understood. Here, we performed metagenomic analysis of respiratory and gut microbiota, along with blood transcriptomics, using longitudinally collected samples from 38 CAP patients. CAP patients presented disrupted sputum microbiota at the early, middle, and late stages of hospitalization. Microbial pathways involved in peptidoglycan biosynthesis and immune evasion, particularly contributed by the Streptococcus genus, were enriched in CAP patients. Additionally, several Streptococcus strains demonstrated correlation between respiratory and gut microbiota in CAP patients. By incorporating host response data, we revealed that Streptococcus oralis (SOR) was associated with host pathways involved in the innate immune response to infection, and this microbe‒host interaction was reproduced in a newly enrolled CAP cohort consisting of 22 patients with influenza infection. The host-SOR interaction was validated in a mouse model, where SOR demonstrated protective efficacy against influenza virus infection comparable to that of the well-established respiratory probiotic Lactobacillus rhamnosus GG. Preaspiration of SOR in mice significantly mitigated body weight loss, reduced lung inflammation, and lowered viral loads following influenza virus challenge. Host response profiling indicated that SOR priming activated a greater innate immune response at the early stage of infection and that this response resolved timely as the host began to recover. These findings suggest that respiratory commensals play an immune-protective role by inducing a timely innate immune response to prevent CAP progression.

DOI: https://doi.org/10.1038/s41392-025-02365-x
Cell. 2025 Aug 21. pii: S0092-8674(25)00746-9. [Epub ahead of print]188(17): 4480-4504

Interferons in health and disease.

Daniel Boehmer, Ivan Zanoni.

Interferons (IFNs) are signaling proteins that play fundamental roles during health and disease. Although types I, II, and III IFNs are structurally and functionally different, all IFNs signal via an intricate network of Janus kinases, named after the Roman god of time and duality. IFNs are characterized by activities that vary over time and can lead to opposing outcomes. IFNs have protective roles during bacterial, viral, and fungal infections but can also drive numerous inflammatory and autoimmune diseases. In this review, we provide an overview of the cellular and molecular mechanisms governing IFN induction and responses, emphasizing their roles in infections, tumorigenesis, and inflammatory, autoimmune, and genetic diseases, with particular attention to mucosal tissues. Overall, we spotlight how the balanced production of distinct members of the IFN families over time is necessary to exert their protective functions and the detrimental consequences for the host when this balance is lost.

DOI: https://doi.org/10.1016/j.cell.2025.06.044
Infect Immun. 2025 Aug 25. e0006325

Host-directed therapeutic targets in macrophages and their ligands against mycobacteria tuberculosis.

Jin Li, Yanmei Wang, Lei He, Luchuan Yang, Tao Tao, Lang Bai, Youfu Luo.

  Although current combination regimens of antibiotics have significantly improved tuberculosis (TB) cure rates, substantial challenges persist in the global effort to end TB. These include poor patient compliance, the emergence of drug-resistant strains due to prolonged treatments, and the persistence of latent TB infections. Host-directed therapies (HDTs) have emerged as a promising complementary strategy, leveraging the modulation of host immune responses to combat Mycobacterium tuberculosis (Mtb). Unlike conventional antibiotics, HDTs can enhance therapeutic outcomes by boosting host defense mechanisms, reducing treatment duration and dosage, and minimizing the risk of resistance development. Notably, several HDTs have shown significant efficacy against multidrug-resistant (MDR) Mtb strains, while also mitigating excessive inflammation and lowering relapse rates-achievements that remain elusive with antibiotic regimens alone. This review provides a comprehensive overview of recent advancements in HDTs, focusing on druggable targets and the mechanisms by which these therapies restore or enhance immune functions disrupted by Mtb. By integrating insights into macrophage polarization, metabolic modulation, autophagy promotion, and cell death regulation, HDTs offer innovative and multifaceted approaches to TB treatment. Furthermore, the potential for HDTs to synergize with existing antibiotics underscores their relevance in overcoming current therapeutic limitations. This synthesis aims to inspire further research and development, with the ultimate goal of advancing HDTs as a transformative solution for TB management.

Keywords:  Mycobacterium tuberculosis; drug resistance; host-directed therapies; macrophage polarization; metabolism reprogramming

DOI:  https://doi.org/10.1128/iai.00063-25
Sci Transl Med. 2025 Aug 20. 17(812): eadr7464

An epitope vaccine derived by analyzing clinical trial samples safeguards hosts with prior exposure to S. aureus against reinfection.

Xiaokai Zhang, Shuang Ge, Yu Wang, Miao Wang, Yanyan Xu, Yulu Chen, Zhen Song, Liqun Zhao, Jinyong Zhang, Jianxun Qi, Yeping Sun, Jiang Gu, Zhuo Zhao, Xieyuan Jiang, Maoqi Gong, Yejun Zha, Yun Yang, Haiming Jing, Feng Yang, Ni Zeng, Xin Xia, Yanhao Zhang, Ping Luo, Weijun Zhang, Ping Cheng, Hao Zeng, Quanming Zou.

Humans, as natural carriers of Staphylococcus aureus (SA), have developed nonprotective immune imprints that can be reactivated by SA antigen vaccination and that contribute to the failure of SA vaccine trials. To test whether an epitope-focused vaccine strategy can overcome this issue, we explored the protective epitope of the notable SA antigen MntC. A surface loop of MntC (Loop101) was found to be essential for SA to absorb manganese(II) ion and survive oxidative stress. Our Loop101-deficient versus -competent MntC-based differential screening identified a Loop101-specific human monoclonal antibody (Hm0686). Hm0686 blocked SA from absorbing manganese(II) ion and exhibited a strong opsonophagocytic activity, suggesting that Hm0686-targeted Loop101 may be a protective epitope. A Loop101 epitope vaccine but not the whole MntC antigen protected against SA infection in mice with prior exposure-induced nonprotective imprints. Thus, this effective protective epitope-based vaccine strategy may be explored to overcome nonprotective immune imprints in humans.

DOI: https://doi.org/10.1126/scitranslmed.adr7464
Sci Rep. 2025 Aug 22. 15(1): 30911

Paternal microbiota manipulation influences offspring microbial colonization and development in a sex role-reversed pipefish.

Kim-Sara Wagner, Frédéric Salasc, Silke-Mareike Marten, Olivia Roth.

Microbes are acquired through vertical and environmental horizontal transmission. Vertical transmission is directly linked to reproductive success and entails early transmission, facilitating coexistence of host and microbes over generations. The multiple potentially interacting routes of vertical transmission are challenging to be disentangled in conventional sex-role species, as they are mostly intermingled on the maternal side, i.e., through egg production, pregnancy, birth and postnatal care. The evolution of male pregnancy in syngnathids (pipefishes and seahorses) offers an opportunity to separate vertical microbial provisioning through the egg (maternal) from provisioning through pregnancy (paternal). We experimentally evaluated the existence and role of paternal vertical microbiota provisioning through male pregnancy on offspring development and microbial colonization. Male pipefish were exposed to antibiotics, and subsequently recolonized with bacteria of paternal, maternal, and environmental origin (spike treatment). After pregnancy, the microbiota of developing offspring was characterized using 16 S rRNA sequencing of the V3-V4 region. Paternal antibiotic and spike treatments influenced the microbial composition of the brood pouch and offspring microbiome development. Paternal spike treatment shortened pregnancy duration and enhanced offspring survival, underlining its beneficial effect for early life stages. Expanding on how distinct vertical microbial transmission routes shape the offspring microbiome will foster our understanding of holobiont function in health and disease.

DOI: https://doi.org/10.1038/s41598-025-16222-y
J Bacteriol. 2025 Aug 20. e0014225

Host niche-specific challenges hindering the treatment of polymicrobial infections.

Caroline Black, Catherine A Wakeman.

  Antimicrobial recalcitrance is a growing problem in today's world. Not only are bacteria developing resistance at an alarming pace but the antibiotic discovery pipeline has gone dry, making antimicrobial stewardship essential for preserving the activity of the antibiotics still currently available for use. In addition to resistance, bacteria also display tolerance to certain treatments as they adapt to their body site-specific niche and cooperate with other organisms in polymicrobial communities. Thus, new and existing antibiotics must contend with altered bacterial metabolism, polymicrobial synergy, increased biofilm production, and nutrient-related adaptations present within specific infectious sites. Finally, these treatments must face the challenging process of moving to the infection site and doing their job without causing harm to the patient. This minireview explores the difficulties antimicrobials face when challenging organisms at different body sites, focusing on the niche-specific dynamics present at sites of infection.

Keywords:  antimicrobial recalcitrance; host infection sites; polymicrobial communities

DOI:  https://doi.org/10.1128/jb.00142-25
Allergol Int. 2025 Aug 22. pii: S1323-8930(25)00083-8. [Epub ahead of print]

From mucus plugging to airway dilatation in chronic airway diseases: A perspective on the contribution of the airway microbiome and inflammation.

Naoya Tanabe, Hisako Matsumoto.

  Airway mucus plugs are the main pathological and computed tomography (CT) findings that affect clinical outcomes in patients with asthma, chronic obstructive pulmonary disease (COPD), and asthma-COPD overlap. Despite the introduction of biologics targeting type 2 inflammation, mucus plug removal remains challenging and understanding its pathogenesis is critical for improved management. In eosinophilic airways, elevated MUC5AC and eosinophil-derived molecules (galectin-10 and extracellular traps) cause highly viscoelastic plugs detectable as high-density regions on ultra-high-resolution CT. In neutrophilic airways, where phylum Proteobacteria and genus Haemophilus are predominant, excessive neutrophil elastase impairs mucociliary clearance, induces neutrophil extracellular traps (NETs), and promotes mucus overproduction. Since mucus plugs could be reservoirs for bacterial colonization, an altered airway microbiome and airway inflammation may be associated with mucus plugging. Phylum Firmicutes and genus Streptococcus are positively and genus Fusobacterium is negatively associated with mucus plugging in severe eosinophilic inflammation. Anaerobic commensals produce short-chain fatty acids, which suppress eosinophilic inflammation. In moderate eosinophilic inflammation, anaerobic commensals may be replaced by pathogenic bacteria of the phylum Proteobacteria and genus Haemophilus, which triggers severe neutrophilic inflammation and exacerbates mucus plugging. Finally, in eosinophilic inflammation, mucus plugs containing aggregated eosinophils may induce mechanical dilation of the airways. In contrast, the presence of mucus plugs in a neutrophilic milieu may reflect severe inflammation characterized by excessive neutrophil extracellular traps and degenerative tissue remodeling, which is consistent with the pathological features of bronchiectasis. This review provides clues regarding how inflammation and microbiome alterations interact with mucus plugging in chronic airway disease.

Keywords:  Asthma; COPD; Computed tomography; Microbiome; Mucus

DOI:  https://doi.org/10.1016/j.alit.2025.07.003
Biomolecules. 2025 Aug 16. pii: 1174. [Epub ahead of print]15(8):

The Multifaceted Functions of Lactoferrin in Antimicrobial Defense and Inflammation.

Jung Won Kim, Ji Seok Lee, Yu Jung Choi, Chaekyun Kim.

  Lactoferrin (Lf) is a multifunctional iron-binding glycoprotein of the transferrin family that plays a central role in host defense, particularly in protection against infection and tissue injury. Abundantly present in colostrum, secretory fluids, and neutrophil granules, Lf exerts broad-spectrum antimicrobial activity against bacteria, viruses, fungi, and parasites. These effects are mediated by iron sequestration, disruption of microbial membranes, inhibition of microbial adhesion, and interference with host-pathogen interactions. Beyond its antimicrobial functions, Lf regulates pro- and anti-inflammatory mediators and mitigates excessive inflammation. Additionally, Lf alleviates oxidative stress by scavenging reactive oxygen species and enhancing antioxidant enzyme activity. This review summarizes the current understanding of Lf's biological functions, with a particular focus on its roles in microbial infections, immune modulation, oxidative stress regulation, and inflammation. These insights underscore the therapeutic promise of Lf as a natural, multifunctional agent for managing infectious and inflammatory diseases and lay the groundwork for its clinical application in immune-related disorders.

Keywords:  antimicrobial defense; cytokine; infection; inflammation; lactoferrin; oxidative stress

DOI:  https://doi.org/10.3390/biom15081174