bims-bac4me 2025-04-20 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2025–04–20
39 papers selected by
Chun-Chi Chang, Universitäts Spital Zürich

How does Staphylococcus aureus successfully colonize the nasal cavity.
Hematopoietic stem and progenitor cells fine-tunning the "sweet" of trained immunity.
Staphylococcus saprophyticus prevents skin damage by inhibiting Staphylococcus aureus quorum sensing.
Hematopoietic stem cell state and fate in trained immunity.
Upper Respiratory Microbiome in Vasculitis.
Bacterial pneumonia induces senescence in resident alveolar macrophages that are outcompeted by monocytes.
Skin mycobiota-mediated antagonism against Staphylococcus aureus through a modified fatty acid.
SAAP-148 and halicin exhibit synergistic antimicrobial activity against antimicrobial-resistant bacteria in skin but not airway epithelial culture models.
Interaction Between Staphylococcus aureus and Microbiota: Invasion or Commensalism.
Lung surfactant reduces Staphylococcus aureus cytotoxicity and protects host immune cells from membrane damage.
Influence of cell bioenergetics on host-pathogen interaction in the lung.
Lung Microbiome in Autoimmune-Associated Interstitial Lung Disease.
Within-host competition causes pathogen molecular evolution and perpetual microbiota dysbiosis.
Role of endosomal toll-like receptors in immune sensing of Klebsiella pneumoniae.
The immunology of asthma and chronic rhinosinusitis.
SLAMF7 and SLAMF8 receptors shape human plasmacytoid dendritic cell responses to intracellular bacteria.
Beyond Adaptive Immunity: Trained Innate Immune Responses as a Novel Frontier in Hepatocellular Carcinoma Therapy.
Innate immune reprogramming in circulating neutrophils of COPD patients.
Development of a 3D bioengineered human lung submucosal gland ductal airway model to study mucociliary clearance in vitro.
Folate from probiotic bacteria and its therapeutic applications.
Microbiome Maturation Trajectory and Key Milestones in Early Life.
Serine protease Rv2569c inhibits inflammatory response and promotes intracellular survival of Mycobacterium tuberculosis by targeting the RhoG-NF-κB-NLRP3 pathway.
Microbiota-derived bile acids antagonize the host androgen receptor and drive anti-tumor immunity.
A mechanistic understanding of the effect of Staphylococcus aureus VraS histidine kinase single-point mutation on antibiotic resistance.
Itaconate modulates immune responses via inhibition of peroxiredoxin 5.
Fumarate integrates metabolism and immunity in diseases.
Glutathione Attenuates Diesel Exhaust-Induced Lung Epithelial Injury via NF-κB/Nrf2/GPX4-Mediated Ferroptosis.
The relationship between the skin microbiome and probiotics in the healing of burn injuries.
Development of a Polidocanol-based Human In Vitro Model to Explore Airway Epithelial Repair.
Exploring the Mucosal Immune Response in Axial Spondyloarthritis Through Immunoglobulin A-Coated Microbiota.
Mechanical Force Triggers Macrophage Pyroptosis and Sterile Inflammation by Disrupting Cellular Energy Metabolism.
Genome-scale metabolic modeling reveals specific vaginal Lactobacillus strains and their metabolites as key inhibitors of Candida albicans.
Innate immunity of the lungs in homeostasis and disease.
Intervention of Corynebacterium striatum in the sessile lifestyle of Staphylococcus aureus wild-type and mutants for ica genes in polymicrobial biofilms.
Ligilactobacillus salivarius Lac45 inhibits MRSA and suppresses inflammation in human keratinocyte.
Epidemiology and Mortality of Invasive Staphylococcus aureus Infections in Hospitalized Infants.
Natural and induced immune responses in oral cavity and saliva.
Dynamic coexistence driven by physiological transitions in microbial communities.
Alzheimer's disease as an auto-innate immune pathology with potential cell trans-differentiation and enhanced trained immunity in 3xTg-AD mouse model.

Crit Rev Microbiol. 2025 Apr 17. 1-20

How does Staphylococcus aureus successfully colonize the nasal cavity.

Pan Chen, Yingying Ma, Yonghong Xiao.

  Staphylococcus aureus (S. aureus) is a clinically significant opportunistic pathogen, and its colonization of the nasal cavity increases the risk of S. aureus infections in humans. Elucidating the mechanisms of nasal colonization by S. aureus would be beneficial in preventing infections, although this is intricate. The colonization of the nasal cavity by S. aureus depends firstly on the organism's ability to adhere to the nasal cavity, with surface components such as ClfB, IsdA, and wall teichoic acid playing an important role. Secondly, S. aureus must continuously adapt to the unfavorable environment in the nasal cavity, including epithelial cell shedding, weak acids, low nutrients, and mechanical forces, which is a prerequisite for maintaining reproduction. Furthermore, S. aureus evades the host immune system's clearance mechanisms by resisting antimicrobial substances and interfering with immune cells. Concurrently, there are interfering, competitive, or mutually beneficial relationships between the nasal microbiota and S. aureus that influence colonization.

Keywords:  Staphylococcus aureus; adhere; colonize; nasal cavity; nasal microbiota

DOI:  https://doi.org/10.1080/1040841X.2025.2486171
J Leukoc Biol. 2025 Apr 15. pii: qiaf043. [Epub ahead of print]

Hematopoietic stem and progenitor cells fine-tunning the "sweet" of trained immunity.

Jiawei Li, Hui Wang, Sheng Xia.

  Recent studies have challenged the traditional view of innate immunity as non-specific and transient by demonstrating that innate immune cells can develop immune memory in response to various activating factors, a phenomenon known as trained immunity. This process involves epigenetic modifications, such as changes in chromatin accessibility, and metabolic reprogramming, which can provide protection against unrelated pathogens but may also trigger immune-mediated damage. This review summarizes the current understanding of innate immune memory, with a particular focus on recent findings regarding the training of innate immune cells at the hematopoietic stem and progenitor cell stage. We present observations of trained immunity in innate immune cells, summarize key activating factors and underlying mechanisms, and propose potential host-directed immunotherapeutic strategies and preventive measures based on trained immunity. Our aim is to highlight the biological significance of trained immunity and its potential applications in enhancing long-term immunity, improving vaccine efficacy, and preventing immune-related diseases.

Keywords:  epigenetic changes; hematopoietic stem and progenitor cells; metabolic reprogramming; trained immunity

DOI:  https://doi.org/10.1093/jleuko/qiaf043
Sci Rep. 2025 Apr 16. 15(1): 13082

Staphylococcus saprophyticus prevents skin damage by inhibiting Staphylococcus aureus quorum sensing.

Liuying Song, Xiaobao Bai, Sushma Halekote Rudramurthy, Tauqeer Alam, Michael Otto, Masanori Matsumoto.

  Coagulase-negative staphylococci are prominent skin commensals that play a crucial role in maintaining skin homeostasis and eliminating pathogens. Coagulase-negative staphylococci, such as Staphylococcus caprae, S. hominis, S. simulans, and S. warneri, have been implicated in suppressing skin inflammation by inhibiting S. aureus virulence; however, it remains unclear whether other staphylococcal species, including S. saprophyticus, also prevent S. aureus-induced skin injury. The present study showed that coagulase-negative S. saprophyticus suppresses skin damage by interfering with S. aureus accessory gene regulator (Agr) quorum sensing. To identify novel coagulase-negative staphylococci that inhibit S. aureus virulence, S. aureus was cultured in the presence of culture supernatants from various coagulase-negative Staphylococcus strains. S. saprophyticus culture supernatant significantly inhibited the virulence of S. aureus regulated by the Agr type-I and -II quorum sensing systems. S. saprophyticus secretes cognate autoinducing peptide (AIP) consisting of a 3-amino acid tail and a 5-amino acid thiolactone ring structure similar to that of S. aureus Agr type-I. Synthetic S. saprophyticus AIP mainly inhibited S. aureus Agr type-I and type-II signaling, without affecting pathogen growth. S. aureus Agr type-I virulence was partially inhibited by chimeric peptides in which either the tail or the thiolactone ring of S. aureus AIP was replaced with that of S. saprophyticus AIP. Furthermore, synthetic S. saprophyticus AIP significantly suppressed skin damage, which was associated with reduced pathogen loads, in murine epicutaneous and intradermal S. aureus inoculation models. Our findings demonstrate that commensal S. saprophyticus-derived AIP protects against cutaneous injury by interfering with S. aureus Agr quorum sensing.

Keywords:   Staphylococcus aureus ; Staphylococcus saprophyticus ; Quorum sensing; Skin damage

DOI:  https://doi.org/10.1038/s41598-025-97044-w
Cell Commun Signal. 2025 Apr 14. 23(1): 182

Hematopoietic stem cell state and fate in trained immunity.

Weinian Liao, Xiaodong Zai, Jun Zhang, Junjie Xu.

  Trained immunity serves as a de facto memory for innate immune responses, resulting in long-term functional reprogramming of innate immune cells. It enhances resistance to pathogens and augments immunosurveillance under physiological conditions. Given that innate immune cells typically have a short lifespan and do not divide, persistent innate immune memory may be mediated by epigenetic and metabolic changes in long-lived hematopoietic stem cells (HSCs) in the bone marrow. HSCs fine-tune their state and fate in various training conditions, thereby generating functionally adapted progeny cells that orchestrate innate immune plasticity. Notably, both beneficial and maladaptive trained immunity processes can comprehensively influence HSC state and fate, leading to divergent hematopoiesis and immune outcomes. However, the underlying mechanisms are still not fully understood. In this review, we summarize recent advances regarding HSC state and fate in the context of trained immunity. By elucidating the stem cell-intrinsic and extrinsic regulatory network, we aim to refine current models of innate immune memory and provide actionable insights for developing targeted therapies against infectious diseases and chronic inflammation. Furthermore, we propose a conceptual framework for engineering precision-trained immunity through HSC-targeted interventions.

Keywords:  Cell fate decision; Hematopoietic stem cell; Innate immune cell; Stem cell state; Trained immunity

DOI:  https://doi.org/10.1186/s12964-025-02192-1
Rheum Dis Clin North Am. 2025 May;pii: S0889-857X(25)00001-8. [Epub ahead of print]51(2): 189-200

Upper Respiratory Microbiome in Vasculitis.

A Nikolai von Krusenstiern, Noam A Cohen, Rennie L Rhee.

  The pathogenesis of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), such as granulomatosis with polyangiitis, is not well understood. These diseases cause significant inflammation in the upper airway. The nares and upper airway are host to many commensal microbes as well as a frequent site of exposure to pathogenic microbes. This review explores the association between upper airway microbial dysregulation and AAV. The role of Staphylococcus aureus colonization as a possible driver of disease is discussed, as well as recent work exploring how fluctuations in the abundance and diversity of commensal microbes are related to vasculitis and risk of flare.

Keywords:  ANCA; GPA; Microbiome; Upper airway; Vasculitis

DOI:  https://doi.org/10.1016/j.rdc.2025.01.001
Cell Rep. 2025 Apr 16. pii: S2211-1247(25)00342-0. [Epub ahead of print]44(5): 115571

Bacterial pneumonia induces senescence in resident alveolar macrophages that are outcompeted by monocytes.

Jinjing Zhang, Tao Wang, Yanling Wang, Ying Li, Lu Wang, Jiepu Wang, Yuxuan Miao, Feng Xu, Yushi Yao.

  Alveolar macrophages (AMs) are lung-resident macrophages critical to lung homeostasis and immunity. Replacement of embryonic-derived tissue-resident AMs (TRAMs) by circulating monocyte-derived AMs (MoAMs) reshapes the functionality of AMs and host susceptibility to respiratory diseases. However, mechanisms underlying such an AM turnover remain unclear. Using a mouse model of Streptococcus pneumoniae (S.P.) infection, we show here that respiratory S.P. infection induces the recruitment and differentiation of MoAMs, which dominate the post-infectious AM population and are functionally hyperresponsive. This turnover of AMs is not due to S.P.-induced irreversible loss of TRAMs. Instead, TRAMs experience a quick recovery in cell number shortly after the resolution of S.P. infection. While S.P.-experienced TRAMs keep the potential of long-term self-maintenance in a non-competitive environment, they demonstrate cellular senescence and a reduced rate of homeostatic proliferation and are, therefore, outcompeted by MoAMs. These data provide new insights into the mechanisms and functional significance of AM turnover during pulmonary bacterial infection.

Keywords:  CP: Immunology; alveolar macrophages; bacterial pneumonia; monocytes; respiratory mucosal immunology; senescence

DOI:  https://doi.org/10.1016/j.celrep.2025.115571
Curr Biol. 2025 Apr 09. pii: S0960-9822(25)00371-9. [Epub ahead of print]

Skin mycobiota-mediated antagonism against Staphylococcus aureus through a modified fatty acid.

Caitlin H Kowalski, Uyen Thy Nguyen, Susannah Lawhorn, T Jarrod Smith, Rebecca M Corrigan, Won Se Suh, Lindsay Kalan, Matthew F Barber.

  Microbiota promote host health by inhibiting pathogen colonization, yet how host-resident fungi or mycobiota contribute to this process remains unclear. The human skin mycobiota is uniquely stable compared with other body sites and dominated by skin-adapted yeasts of the genus Malassezia. We observe that colonization of human skin by Malassezia sympodialis significantly reduces subsequent colonization by the prominent bacterial pathogen Staphylococcus aureus. In vitro, M. sympodialis generates a hydroxyl palmitic acid isomer from environmental sources that has potent bactericidal activity against S. aureus in the context of skin-relevant stressors and is sufficient to impair S. aureus skin colonization. Leveraging experimental evolution to pinpoint mechanisms of S. aureus adaptation in response to antagonism by Malassezia, we identified multiple mutations in the stringent response regulator Rel that promote survival against M. sympodialis and provide a competitive advantage on human skin when M. sympodialis is present. Similar Rel alleles have been reported in S. aureus clinical isolates, and natural Rel variants are sufficient for tolerance to M. sympodialis antagonism. Partial stringent response activation underlies tolerance to clinical antibiotics, with both laboratory-evolved and natural Rel variants conferring multidrug tolerance in a manner that is dependent on the alternative sigma factor SigB. These findings demonstrate the ability of the mycobiota to mediate pathogen colonization resistance through generation of a hydroxy palmitic acid isomer, identify new mechanisms of bacterial adaptation in response to microbiota antagonism, and reveal the potential for microbiota-driven evolution to shape pathogen antibiotic susceptibility.

Keywords:  10-hydroxy palmitic acid; Malassezia; Staphylococcus aureus; antibiotic tolerance; colonization resistance; mycobiota; skin microbiome; stringent response

DOI:  https://doi.org/10.1016/j.cub.2025.03.055
JAC Antimicrob Resist. 2025 Apr;7(2): dlaf050

SAAP-148 and halicin exhibit synergistic antimicrobial activity against antimicrobial-resistant bacteria in skin but not airway epithelial culture models.

Patrick R Lennard, Pieter S Hiemstra, Julia R Dorin, Peter H Nibbering.

Background: The escalating global threat of antimicrobial resistance (AMR) necessitates the development of novel antimicrobial agents, innovative strategies, and representative infection models to combat AMR bacterial infections. Host defence peptides (HDPs) and their derivatives have been proposed as complements to conventional antibiotics due to their antibacterial activity and modulation of the immune response.
Objectives: This study investigated the novel use of the HDP-derived synthetic antibacterial and anti-biofilm peptide (SAAP)-148 as a pretreatment in epithelial tissue models to prevent colonization by AMR bacteria. The combined activities of SAAP-148 pretreatment with post-infection halicin to treat infections were also explored.
Methods: Employing cultured human skin equivalents (HSEs) and primary bronchial epithelial cells (PBECs) as models of tissue infection, we examined the prophylactic and therapeutic effects of SAAP-148, both singularly and in combination with the repurposed antibiotic halicin, against AMR bacteria. We additionally interrogated the response of HSE and PBEC cultures to SAAP-148 treatment via confocal microscopy and quantitative PCR of native HDPs and inflammatory cytokine genes.
Results: Our findings demonstrated that pretreatment with SAAP-148 significantly reduces colonization of HSEs and PBECs by AMR Staphylococcus aureus and Pseudomonas aeruginosa. Confocal microscopy revealed differential uptake and localization of SAAP-148 in these tissues, correlating with its distinct activity in these tissues. SAAP-148 exposure temporarily increased expression of the HDPs cathelicidin (CAMP) and β-defensin 1 (DEFB1), and the cytokine IL-8 (CXCL8), which did not correlate with the transient antibacterial activity observed. Sequential treatment with SAAP-148 prior to infection with AMR S. aureus and post-infection halicin treatment demonstrated synergistic activity in HSEs, whereas this combined activity was indifferent in PBEC cultures.
Conclusions: These results support SAAP-148 as a candidate for pre-infection prophylaxis and synergistic antibiotic therapy with halicin in skin, broadening the potential of both agents to address AMR bacterial infection.

DOI: https://doi.org/10.1093/jacamr/dlaf050
Curr Pharm Biotechnol. 2025 Apr 14.

Interaction Between Staphylococcus aureus and Microbiota: Invasion or Commensalism.

Ahmad Nasser, Shiva Jahanbakhshi.

  The term "Microbiota" refers to the vast array of symbiotic microorganisms that coexist with their hosts in practically all organs. However, the microbiota must obtain nutrition and minerals from its host to survive; instead, they produce beneficial compounds to protect the host and regulate the immune system. Conversely, pathogenic bacteria utilize their enzymes to independently gain sustenance through an invasive process without almost any beneficial compound production. One of the fully equipped pathogens, Staphylococcus aureus, is present in nearly every organ and possesses a variety of defense and invasion systems including an enzyme, a mineral collection system, a system for detecting environmental conditions, and broad toxins. The microbiota properly can defend its kingdom against S. aureus; however, if necessary, the host immune system is alerted against the pathogen, so this system also acts against the pathogen, a game that can ultimately lead to the death of the pathogen. However, S. aureus can change the host's conditions in its favor by changing the host's conditions and causing inflammation, a condition that cannot be tolerated by the microbiota. In this review, we will explain how microbiota defend against S. aureus.

Keywords:  Antimicrobial peptides; Bacteriocins; Host microbial interaction; Lactobacillus.; Microbiota; Staphylococcus aureus

DOI:  https://doi.org/10.2174/0113892010364717250404175242
Microbiol Spectr. 2025 Apr 16. e0138624

Lung surfactant reduces Staphylococcus aureus cytotoxicity and protects host immune cells from membrane damage.

Maria Predtechenskaya, Corbin J Arbizzani, Sofia R Shomento, Timothy R Borgogna, Jovanka M Voyich.

  In this study, we identify that lung surfactant significantly reduces the cytotoxicity of Staphylococcus aureus (S. aureus) membrane-damaging toxins. Data demonstrate that natural surfactants from mice and rats and commercially available surfactant, Infasurf, protect human primary cells (neutrophils and peripheral blood mononuclear cells) from cytolytic activity caused by S. aureus supernatants. Supernatants from S. aureus grown in surfactant showed a significant reduction in plasma membrane damage against primary human cells as compared to supernatants grown without surfactant. This reduction was not due to a direct bactericidal effect of the surfactants on S. aureus growth. Rat and mouse surfactants downregulated the gene expression of saeR, the response regulator of the S. aureus two-component system SaeR/S that is responsible for the production of virulence factors which are important during lung infection and cause membrane damage in host cells. Rat and lung surfactants also reduced transcript abundance of SaeR/S-regulated genes lukF-PV, hla, and hlgA. Interestingly, the commercially available surfactant Infasurf did not recapitulate the effect of natural surfactants and did not decrease gene transcription of the virulence genes tested. These data suggest that components of natural surfactants protect lungs from S. aureus by suppressing S. aureus virulence factors and have implications for the role of surfactants in host defense against S. aureus.IMPORTANCEThis study explored the influence of lung surfactants on membrane-damaging Staphylococcus aureus (S. aureus) toxins. We demonstrate that natural and commercially available lung surfactants minimize the cytolytic capacity of S. aureus supernatants against primary human cells. Data indicate that cytolytic reduction by mouse and rat surfactants was partially due to surfactants reducing transcript abundance of virulence factors. This work identifies a novel role for surfactants and suggests their importance in modulating the severity of S. aureus lung infections.

Keywords:  Staphylococcus aureus; gene expression; neutrophils; surfactant; toxin

DOI:  https://doi.org/10.1128/spectrum.01386-24
Front Immunol. 2025 ;16 1549293

Influence of cell bioenergetics on host-pathogen interaction in the lung.

Gaurav Kumar Lohia, Sebastián A Riquelme.

  Pulmonary diseases, arising from infections caused by bacteria, fungi, and viruses, or stemming from underlying genetic factors are one of the leading causes of mortality in humans, accounting for millions of deaths every year. At the onset of pulmonary diseases, crucial roles are played by phagocytic immune cells, particularly tissue-resident macrophages, in regulating the immune response at the mucosal barrier. Recent strides have illuminated the pivotal role of host bioenergetics modulated by metabolites derived from both pathogens and hosts in influencing the pathophysiology of major organs. Their influence extends to processes such as the infiltration of immune cells, activation of macrophages, and the polarization phenomenon. Furthermore, host-derived metabolites, such as itaconate, contribute to the promotion of anti-inflammatory responses, thereby preventing immunopathology and facilitating the preservation of mucosal niches to thrive for the long-term. This review explores recent advancements in the field of immunometabolism, with a particular emphasis on the intricacies of disease progression in pulmonary infections caused by bacteria such as P. aeruginosa, M. tuberculosis and S. aureus and fungi like C. albicans.

Keywords:  ESKAPE bacteria; MACROPHAGE METABOLISM; bioenergetics; fungal infection; host-pathogen interaction; immunometabolism; itaconate; pneumonia (infectious disease)

DOI:  https://doi.org/10.3389/fimmu.2025.1549293
Rheum Dis Clin North Am. 2025 May;pii: S0889-857X(25)00003-1. [Epub ahead of print]51(2): 201-212

Lung Microbiome in Autoimmune-Associated Interstitial Lung Disease.

Timothy M Wilson.

  The lung microbiome is a diverse mucosal environment that has been shown to be implicated in the pathogenesis of various chronic lung diseases including insterstitial lung diseases (ILD) such as idiopathic pulmonary fibrosis (IPF). ILD is a well-established manifestation of several types of autoimmune diseases. This review will highlight recent work exploring the role of the lung microbiome in the pathogenesis of autoimmune-related ILD.

Keywords:  Connective tissue disease; Interstitial lung disease; Lung microbiome

DOI:  https://doi.org/10.1016/j.rdc.2025.01.003
ISME J. 2025 Apr 17. pii: wraf071. [Epub ahead of print]

Within-host competition causes pathogen molecular evolution and perpetual microbiota dysbiosis.

Emily J Stevens, Jingdi D Li, Tobias E Hector, Georgia C Drew, Kim Hoang, Samuel T E Greenrod, Steve Paterson, Kayla C King.

  Pathogens newly invading a host must compete with resident microbiota. This. within-host microbial warfare could lead to more severe disease outcomes or constrain the evolution of virulence. By passaging a widespread pathogen (Staphylococcus aureus) and a native microbiota community across populations of nematode hosts, we show that the pathogen displaced microbiota and reduced species richness, but maintained its virulence across generations. Conversely, pathogen populations and microbiota passaged in isolation caused more host harm relative to their respective no-host controls. For the evolved pathogens, this increase in virulence was partly mediated by enhanced biofilm formation and expression of the global virulence regulator agr. Whole genome sequencing revealed shifts in the mode of selection from directional (on pathogens evolving in isolation) to fluctuating (on pathogens evolving in host microbiota). This approach also revealed that competitive interactions with the microbiota drove early pathogen genomic diversification. Metagenome sequencing of the passaged microbiota shows that evolution in pathogen-infected hosts caused a significant reduction in community stability (dysbiosis), along with restrictions on the co-existence of some species based on nutrient competition. Our study reveals how microbial competition during novel infection could determine the patterns and processes of evolution with major consequences for host health.

Keywords:  bacterial evolution; host-pathogen interactions; microbiota; molecular evolution; pathogenesis; virulence

DOI:  https://doi.org/10.1093/ismejo/wraf071
Front Immunol. 2025 ;16 1538425

Role of endosomal toll-like receptors in immune sensing of Klebsiella pneumoniae.

Giuseppe Valerio De Gaetano, Agata Famà, Germana Lentini, Francesco Coppolino, Mario Venza, Isabella Venza, Pasqualina Laganà, Alessia Berbiglia, Federica Grasso, Luigi Fiore, Giuseppe Teti, Concetta Beninati.

  Klebsiella pneumoniae is the causative agent of a wide range of antibiotic-resistant infections, including nosocomial pneumonia and neonatal sepsis. We investigate here the mechanisms underlying innate immune recognition of this pathogen by focusing on the role of endosomal Toll-like receptors (TLRs), which sense prokaryotic nucleic acids, in comparison with TLR4, which recognizes the cell-wall lipopolysaccharide component. Lack of functional endosomal TLRs made mice more susceptible to pulmonary infection by K. pneumoniae, in association with reduced production of proinflammatory and chemotactic cytokines and reduced neutrophil recruitment to the lung. This phenotype was as severe as that of TLR4-deficient mice and only moderately milder than that of mice lacking the TLR adaptor MyD88. Notably, macrophages lacking at the same time TLR7, 9 and 13 were more defective than those lacking only TLR9 in their ability to produce proinflammatory cytokines, suggesting a role for the RNA sensing TLR7 and 13 receptors in K. pneumoniae recognition. Collectively, our results unveil the presence of an integrated system of DNA and RNA sensing TLRs that cooperates with TLR4 in immune detection and clearance of K. pneumoniae. These data may be useful to devise alternative therapeutic approaches aimed at stimulating responses against antibiotic-resistant K. pneumoniae strains.

Keywords:  bacterial RNA; cytokines; gram negative bacteria; neutrophils; pattern recognition receptors; pneumonitis

DOI:  https://doi.org/10.3389/fimmu.2025.1538425
Nat Rev Immunol. 2025 Apr 16.

The immunology of asthma and chronic rhinosinusitis.

Atsushi Kato, Hirohito Kita.

Asthma and chronic rhinosinusitis (CRS) are common chronic inflammatory diseases of the respiratory tract that have increased in prevalence over the past five decades. The clinical relationship between asthma and CRS has been well recognized, suggesting a common pathogenesis between these diseases. Both diseases are driven by complex airway epithelial cell and immune cell interactions that occur in response to environmental triggers such as allergens, microorganisms and irritants. Advances, including a growing understanding of the biology of the cells involved in the disease, the application of multiomics technologies and the performance of large-scale clinical studies, have led to a better understanding of the pathophysiology and heterogeneity of asthma and CRS. This research has promoted the concept that these diseases consist of several endotypes, in which airway epithelial cells, innate lymphoid cells, T cells, B cells, granulocytes and their mediators are distinctly involved in the immunopathology. Identification of the disease heterogeneity and immunological markers has also greatly improved the protocols for biologic therapies and the clinical outcomes in certain subsets of patients. However, many clinical and research questions remain. In this Review, we discuss recent advances in characterizing the immunological mechanisms of asthma and CRS, with a focus on the main cell types and molecules involved in these diseases.

DOI: https://doi.org/10.1038/s41577-025-01159-0
J Clin Invest. 2025 Apr 15. pii: e182467. [Epub ahead of print]135(8):

SLAMF7 and SLAMF8 receptors shape human plasmacytoid dendritic cell responses to intracellular bacteria.

Joaquín Miguel Pellegrini, Anne Keriel, Laurent Gorvel, Sean Hanniffy, Vilma Arce-Gorvel, Mile Bosilkovski, Javier Solera, Stéphane Méresse, Sylvie Mémet, Jean-Pierre Gorvel.

  Plasmacytoid dendritic cells (pDCs), professional type I IFN-producing cells, have been implicated in host responses against bacterial infections. However, their role in host defense is debated, and the operating molecular mechanisms are unknown. Certain signaling lymphocyte activation molecule family (SLAMF) members act as microbial sensors and modulate immune functions in response to infection. Here, human blood transcriptomic analyses reveal the involvement of SLAMF7 and SLAMF8 in many infectious diseases, with elevated levels associated with type I IFN responses in salmonellosis and brucellosis patients. We further identify SLAMF7 and SLAMF8 as key regulators of human pDC function. They activate pDC maturation and cytokine production during infection with bacteria that induce acute (Salmonella) or chronic (Brucella) inflammation. SLAMF7 and SLAMF8 signal through NF-κB, IRF7, and STAT-1, and limit mitochondrial ROS accumulation upon Salmonella infection. Remarkably, this SLAMF7/8-dependent control of mitochondrial ROS levels favors bacterial persistence and NF-κB activation. Overall, our results unravel essential shared multifaceted roles of SLAMF7 and SLAMF8 in finely tuning human pDC responses to intracellular bacterial infections with potential for future diagnostic and therapeutic applications.

Keywords:  Bacterial infections; Dendritic cells; Immunology; Infectious disease; Microbiology

DOI:  https://doi.org/10.1172/JCI182467
Cancers (Basel). 2025 Apr 07. pii: 1250. [Epub ahead of print]17(7):

Beyond Adaptive Immunity: Trained Innate Immune Responses as a Novel Frontier in Hepatocellular Carcinoma Therapy.

Ching-Hua Hsieh, Pei-Chin Chuang, Yueh-Wei Liu.

  Hepatocellular carcinoma (HCC) is a leading cause of cancer death globally, with the majority of cases detected at advanced stages when curative options are limited. Current systemic therapies, including immune checkpoint inhibitors, demonstrate limited efficacy with durable responses in only 15-20% of patients. This poor response is largely attributed to HCC's immunosuppressive microenvironment, which blunts effective T-cell responses. By illustrating that innate immune cells can acquire memory-like characteristics through a process known as trained immunity, recent evidence has challenged the conventional belief that innate immunity is devoid of memory. This review investigates the potential of trained immunity, which is defined by the long-term functional reprogramming of innate immune cells through epigenetic, transcriptomic, and metabolic changes, to provide new therapeutic opportunities for HCC. We discuss mechanisms by which trained immunity can transform the HCC microenvironment, including enhanced inflammatory cytokine production, repolarization of tumor-associated macrophages toward anti-tumor phenotypes, increased immune cell infiltration, and improved bridging to adaptive immunity. We further evaluate emerging therapeutic strategies leveraging trained immunity principles, including BCG vaccination, β-glucan administration, cytokine-trained NK cell therapy, and innovative combination approaches. Finally, we address potential resistance mechanisms and future directions for clinical application. By integrating trained immunity into conventional immunotherapeutic regimens, we may significantly improve outcomes for HCC patients, potentially transforming advanced disease into a more manageable condition.

Keywords:  hepatocellular carcinoma (HCC); immune checkpoint inhibitors (ICIs); innate immune reprogramming; trained immunity; tumor microenvironment (TME)

DOI:  https://doi.org/10.3390/cancers17071250
J Allergy Clin Immunol. 2025 Apr 14. pii: S0091-6749(25)00418-X. [Epub ahead of print]

Innate immune reprogramming in circulating neutrophils of COPD patients.

Barbara Mariotti, Chiara Bracaglia, Sara Gasperini, Giulia Sartori, Ernesto Crisafulli, Flavia Bazzoni.

   BACKGROUND: Chronic obstructive pulmonary disease (COPD) involves both local and systemic neutrophilic inflammation, with dysregulation in blood neutrophil numbers, frequencies, and functions.
OBJECTIVE: To characterize the transcriptional and epigenetic profiles of circulating neutrophils in COPD patients and explore correlations with neutrophil dysfunction and clinical disease parameters.
METHODS: Circulating neutrophils of COPD patients and control donors were subjected to RNA-sequencing (RNA-seq) and genome-wide analysis of histone 3 lysine 4 trimethylation (H3K4me3) by Chromatin Immunoprecipitation coupled with sequencing (ChIP-seq). Neutrophils' activation was assessed by cytofluorimetric analysis, O2- release and C. albicans phagocytosis assays.
RESULTS: RNA-seq and ChIP-seq analysis of H3K4me3 revealed a poised state in genes involved in innate immune activation, resembling the phenotype observed in neutrophils from BCG-vaccinated individuals, referred to as "trained", that is marked by weak or no expression under resting conditions but ready to be expressed at higher levels upon stimulation. The epigenetic signature identified in neutrophils from BCG-vaccinated subjects was enriched in COPD neutrophils. In particular, and consistent with what has been described in "trained" neutrophils, COPD neutrophils exhibited transcriptional reprogramming of metabolically relevant genes. Functionally, COPD neutrophils produced higher CXCL8 and IL-1β levels, released more O2-, and displayed greater phagocytic activity upon in vitro stimulation.
CONCLUSION: These findings suggest that COPD neutrophils undergo epigenetic, transcriptomic, and metabolic reprogramming, which enhances their responsiveness and aligns with the phenotype of neutrophils previously identified as "trained", offering mechanistic insight into the functional dysregulation observed in COPD.

Keywords:  COPD; epigenetic; neutrophils; trained-immunity

DOI:  https://doi.org/10.1016/j.jaci.2025.04.011
Cell Biomater. 2025 Mar 25. pii: 100013. [Epub ahead of print]1(2):

Development of a 3D bioengineered human lung submucosal gland ductal airway model to study mucociliary clearance in vitro.

Hoyeol Kim, Sujung Yi, Pramodha Liyanage, Shuyang Zhao, Kathryn A Wikenheiser-Brokamp, Lisa McMillin, Yan Xu, Joseph A Kitzmiller, Jeffrey A Whitsett, Anjaparavanda P Naren, Kyu Shik Mun.

Mucociliary clearance (MCC) is critical in maintaining lung health and preventing respiratory infections. MCC is impaired in people with cystic fibrosis, due to accumulation of thick, sticky mucus resulting from defective cystic fibrosis transmembrane conductance regulator channel function. In this study, we developed a unique 3D lung submucosal gland ductal airway model utilizing primary human submucosal gland epithelial cells, which enables the formation of physiologically relevant architecture of the ductal epithelium including ciliary cells within a 3D bioprinted scaffold. Our observation demonstrates that this model not only enables the fabrication of human lung submucosal gland ductal airway-like structure mimicking in vivo physiology, also facilitates quantitative measurement of patient-specific MCC and determines pharmacological effects. Our results suggest that this model could be a valuable tool for understanding mechanisms underlying impaired MCC and testing the efficacy of novel therapeutic strategies for the treatment of respiratory diseases such as cystic fibrosis.

DOI: https://doi.org/10.1016/j.celbio.2025.100013
Arch Microbiol. 2025 Apr 18. 207(6): 124

Folate from probiotic bacteria and its therapeutic applications.

G Megala, M Kavitha.

  Folate, an essential water soluble vitamin B9 that cannot be synthesized naturally by the bodily function. Dietary sources or probiotic-folates are the two biological modes for acquiring the target vitamin which aids DNA synthesis and repair. Probiotics are known for their divergent health benefits and have garnered significant interest. Particularly in microbial strains that produce folate offers a promising way to enhance the level of folate. Notably, folate-producing probiotic strain includes Lactiplantibacillus, Lactococcus, Bifidobacterium, and Streptococcus. As an emerging source of health benefits, folate producing probiotics helps in improving the gut microbiota for overall well-being of human body. On the other side, chemically synthesized folic acid were not highly advantageous as they lacks absorption, conversion and excretion. Hence, usage of microbial-folate are safer as it can easily undergo absorption and reduces severe side effects. The present review mainly focus on folate one-carbon metabolism, its significance in human health, folate deficiency and malabsorption, adverse effects and folate synthesis from probiotic bacterial strains, and also toxicological impacts. In particular, the beneficiary role of these probiotic strains were found to be associated with therapeutic applications in several diseases such as autoimmune disorder, metabolic disorders, and cardiovascular diseases (CVDs), wound healing, drug delivery and cancer.

Keywords:  Folate; One carbon metabolism; Probiotics; Therapeutic applications

DOI:  https://doi.org/10.1007/s00203-025-04327-x
Ann Nutr Metab. 2025 Apr 14. 1-8

Microbiome Maturation Trajectory and Key Milestones in Early Life.

Marie-Claire Arrieta.

   BACKGROUND: The development of the gut microbiome during early life plays a critical role in shaping long-term health. The first 1,000 days represent a crucial period in which the microbiome is particularly malleable, influenced by various factors such as birth mode, diet, antibiotic exposure, and environmental interactions.
SUMMARY: This review outlines the key stages of microbiome maturation, beginning with initial colonization at birth and progressing through the diversification and stabilization phases during the first 5 years of life. Factors like breastfeeding, the introduction of solid foods, and early-life antibiotic have a critical impact on microbial diversity and immune system development. Disruptions to the microbiome during this critical window, particularly through antibiotic use, are associated with an increased risk of immune, metabolic, and neurodevelopmental disorders. Recent research emphasizes the need for a better understanding of these early-life trajectories to inform interventions that promote a healthy microbiome.

Keywords:  Colonization patterns; Diversity; Early life; Gut microbiome; Host-microbe interactions; Microbiome maturation

DOI:  https://doi.org/10.1159/000543754
Int J Biol Macromol. 2025 Apr 12. pii: S0141-8130(25)03574-3. [Epub ahead of print]309(Pt 4): 143022

Serine protease Rv2569c inhibits inflammatory response and promotes intracellular survival of Mycobacterium tuberculosis by targeting the RhoG-NF-κB-NLRP3 pathway.

Xinxin Zang, Jiajun Zhang, Tingting Feng, Hui Wang, Yingying Cui, Yanyan Jiang, Chunwen Chen, Siguo Liu, Guanghui Dang.

  Innate immunity is dominant in protecting the host's defense against intracellular bacterial infections. The secretion of IL-1β and activation of NLRP3 inflammasome in macrophages play a critical role in combating Mycobacterium tuberculosis (M.tb) infections. M.tb is an extremely successful intracellular pathogen that evades host innate immunity by interfering with a wide range of macrophage functions. However, the precise infection mechanism remains unclear. This study demonstrates that the mycobacterial serine protease Rv2569c interacts with RhoG in macrophages, effectively blocking the NF-κB signaling pathway's initiation and suppressing NLRP3 inflammasome activation, ultimately leading to a decrease in IL-1β secretion and promoting mycobacterial survival within macrophages. To investigate the role of Rv2569c in M.tb infection, an Rv2569c-deficient strain (H37RvΔRv2569c) was used to demonstrate a weakened suppression of the inflammatory response and lower intracellular survival compared to the wild-type (H37Rv) and complemented strain (H37RvΔRv2569c + Rv2569c) through in vitro and in vivo experiments. The findings provide the first proof that RhoG serves as an endogenous host sensor for pathogens and that Rv2569c-RhoG-mediated inflammatory response plays a crucial role in mycobacterial immune evasion.

Keywords:  Mycobacterium tuberculosis Rv2569c; NF-κB signaling pathway; NLRP3 inflammasome

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.143022
Cell. 2025 Apr 14. pii: S0092-8674(25)00256-9. [Epub ahead of print]

Microbiota-derived bile acids antagonize the host androgen receptor and drive anti-tumor immunity.

JRI IBD Live Cell Bank Consortium

  Microbiota-derived bile acids (BAs) are associated with host biology/disease, yet their causal effects remain largely undefined. Herein, we speculate that characterizing previously undefined microbiota-derived BAs would uncover previously unknown BA-sensing receptors and their biological functions. We integrated BA metabolomics and microbial genetics to functionally profile >200 putative microbiota BA metabolic genes. We identified 56 less-characterized BAs, many of which are detected in humans/mammals. Notably, a subset of these BAs are potent antagonists of the human androgen receptor (hAR). They inhibit AR-related gene expression and are human-relevant. As a proof-of-principle, we demonstrate that one of these BAs suppresses tumor progression and potentiates the efficacy of anti-PD-1 treatment in an AR-dependent manner. Our findings show that an approach combining bioinformatics, BA metabolomics, and microbial genetics can expand our knowledge of the microbiota metabolic potential and reveal an unexpected microbiota BA-AR interaction and its role in regulating host biology.

Keywords:  androgen receptor; anti-tumor immunity; bile acid HSDHs; bile acid metabolism; gut microbiota; host-microbe interactions; microbiota bile acids

DOI:  https://doi.org/10.1016/j.cell.2025.02.029
Microbiol Spectr. 2025 Apr 15. e0009525

A mechanistic understanding of the effect of Staphylococcus aureus VraS histidine kinase single-point mutation on antibiotic resistance.

Liaqat Ali, Salima Karki, Gunavanthi D Boorgula, Amir Mekakda, Brittnee Cagle-White, Shrijan Bhattarai, Robert Beaudoin, Aryanna Blakeney, Sanjay Singh, Shashikant Srivastava, May H Abdel Aziz.

  Bacterial genomic mutations in Staphylococcus aureus have been detected in isolated resistant clinical strains, yet their mechanistic effect on the development of antimicrobial resistance remains unclear. Resistance-associated regulatory systems acquire adaptive mutations under stress conditions that may lead to a gain-of-function effect and contribute to the resistance phenotype. Here, we investigate the effect of a single-point mutation (T331I) in VraS histidine kinase, part of the VraSR two-component system in S. aureus. VraSR senses and responds to environmental stress signals by upregulating gene expression for cell wall synthesis. A combination of enzyme kinetics, microbiological, and transcriptomic analyses revealed the mechanistic effect of the mutation on VraS and S. aureus. Michaelis-Menten kinetics show that the VraS mutation caused an increase in the autophosphorylation rate of VraS and enhanced its catalytic efficiency. The introduction of the mutation through recombineering coupled with CRISPR-Cas9 counterselection to the Newman strain wild-type (WT) genome doubled the minimum inhibitory concentration of three cell wall-targeting antibiotics. The mutation caused an enhanced S. aureus growth rate at sub-lethal doses of the antibiotics, confirming the causative effect of the mutation on bacterial persistence. Transcriptomic analysis showed a genome-wide alteration in gene expression levels and protein-protein interaction network of the mutant compared to the WT strain after exposure to vancomycin. The results suggest that the vraS mutation causes several mechanistic changes at the protein and cellular levels that favor bacterial survival under antibiotic stress and cause the mutation-harboring strains to become the dominant population during infection.IMPORTANCERising antimicrobial resistance (AMR) is a global health problem. Mutations in the two-component system have been linked to drug resistance in Staphylococcus aureus, yet the exact mechanism through which these mutations work is understudied. We investigated the T331I mutation in the vraS gene linked to sensing and responding to cell wall stress. The mutation caused changes at the protein level by increasing the catalytic efficiency of VraS kinase activity. Introducing the mutation to the genome of an S. aureus strain resulted in changes in phenotypic antibiotic susceptibility, growth kinetics, and genome-wide transcriptomic alterations. By a combination of enzyme kinetics, microbiological, and transcriptomic approaches, we highlight how small genetic changes can significantly impact bacterial physiology and survival under antibiotic stress. Understanding the mechanistic basis of antibiotic resistance is crucial to guide the development of novel therapeutic agents to combat AMR.

Keywords:  Staphylococcus aureus; VraS; antibiotic resistance; kinase; mutation

DOI:  https://doi.org/10.1128/spectrum.00095-25
Nat Metab. 2025 Apr 18.

Itaconate modulates immune responses via inhibition of peroxiredoxin 5.

Tomas Paulenda, Barbora Echalar, Lucie Potuckova, Veronika Vachova, Denis A Kleverov, Johannes Mehringer, Ekaterina Potekhina, Alex Jacoby, Devashish Sen, Chris Nelson, Rick Stegeman, Vladimir Sukhov, Danielle Kemper, Cheryl F Lichti, Nicholas J Day, Tong Zhang, Kamila Husarcikova, Monika Bambouskova, Daved H Fremont, Wei-Jun Qian, Sergej Djuranovic, Slavica Pavlovic-Djuranovic, Vsevolod V Belousov, Andrzej M Krezel, Maxim N Artyomov.

The immunoregulatory metabolite itaconate accumulates in innate immune cells upon Toll-like receptor stimulation. In response to macrophage activation by lipopolysaccharide, itaconate inhibits inflammasome activation and boosts type I interferon signalling; however, the molecular mechanism of this immunoregulation remains unclear. Here, we show that the enhancement of type I interferon secretion by itaconate depends on the inhibition of peroxiredoxin 5 and on mitochondrial reactive oxygen species. We find that itaconate non-covalently inhibits peroxiredoxin 5, leading to the modulation of mitochondrial peroxide in activating macrophages. Through genetic manipulation, we confirm that peroxiredoxin 5 modulates type I interferon secretion in macrophages. The non-electrophilic itaconate mimetic 2-methylsuccinate inhibits peroxiredoxin 5 and phenocopies immunoregulatory action of itaconate on type I interferon and inflammasome activation, providing further support for a non-covalent inhibition of peroxiredoxin 5 by itaconate. Our work provides insight into the molecular mechanism of actions and biological rationale for the predominantly immune specification of itaconate.

DOI: https://doi.org/10.1038/s42255-025-01275-0
Trends Endocrinol Metab. 2025 Apr 16. pii: S1043-2760(25)00051-7. [Epub ahead of print]

Fumarate integrates metabolism and immunity in diseases.

Jie Cheng, Yifeng Xiao, Peng Jiang.

  Fumarate is a key metabolite produced primarily by the tricarboxylic acid (TCA) and urea cycles. In addition to having a metabolic role, its electrophilicity enables it to covalently modify cysteines; moreover, because of its α-ketoglutarate (α-KG)-like structure, it can also act as a competitive inhibitor of α-KG-dependent dioxygenases for epigenetic remodeling. Recent advances have broadened the role of fumarate as a bridge between metabolism and both innate and adaptive immunity, suggesting potentially important functions in anticancer immunity and autoimmune diseases. Here we review the connections between fumarate metabolism and immunity; we describe the mechanisms of fumarate regulation in cancer, autoimmunity, and other diseases; and we explore the clinical implications of fumarate and its esters for immunotherapy.

Keywords:  diseases; fumarate metabolism; immunity; succination

DOI:  https://doi.org/10.1016/j.tem.2025.03.008
Toxicology. 2025 Apr 14. pii: S0300-483X(25)00111-8. [Epub ahead of print] 154154

Glutathione Attenuates Diesel Exhaust-Induced Lung Epithelial Injury via NF-κB/Nrf2/GPX4-Mediated Ferroptosis.

Ekta Nagar, Naresh Singh, Neeru Saini, Naveen Arora.

  Diesel exhaust (DE) emissions pose a significant threat to public health. This study linked DE-mediated reactive oxygen species (ROS) and ferroptosis with lung epithelial disruption, also the protective potential of exogenous glutathione (GSH) administration was investigated. C57BL/6 mice were divided into three groups: filtered air (control), DE exposed, and DE+GSH (administered intranasally on alternate days). Airway hyperresponsiveness (AHR), lung tissues, and bronchoalveolar lavage fluid (BALF) were used for analysis. DE exposure significantly impaired lung function parameters as shown by AHR. Elevated ROS depleted the GSH/GSSG ratio and suppressed Nrf2 activity, disrupting antioxidant defense mechanisms, which were restored by GSH administration. DE-induced ROS acted as a key driver of ferroptosis, characterized by suppressed SLC7411 expression thereby decreased GSH synthesis and GPX-4 activity, inducing lipid peroxidation. Ferroptosis was significantly mitigated by increased GSH pool, which restored GPX-4 levels and reduced lipid peroxidation. Concurrently, DE induced ROS promoted DNA damage and apoptosis in lung epithelial cells wherein GSH treatment preserved cell survival in DE exposed mice. The heightened DE-associated ROS further amplified inflammation, as shown by increased cytokines (TNF-α, IL-6, TSLP, IL-33) and P-NF-κB activation. Activated inflammatory cascade disrupted tight junction proteins (claudins, occludin), resulted in weakened epithelial barrier and increased permeability. Lung barrier disruption was evidenced by transmission electron microscopy and immunohistochemistry, corroborated with elevated albumin levels. GSH effectively restored tight junction integrity and preserved barrier function in DE+GSH mice lungs. In conclusion, DE-induced oxidative stress and ferroptosis-triggered inflammation compromised epithelial barrier promoting lung injury. Exogenous GSH administration showed potential in restoring DE-associated lung damage.

Keywords:  Diesel Exhaust; Ferroptosis; Glutathione; Inflammation; Lung Epithelial Disruption; Reactive Oxygen Species

DOI:  https://doi.org/10.1016/j.tox.2025.154154
Folia Microbiol (Praha). 2025 Apr 14.

The relationship between the skin microbiome and probiotics in the healing of burn injuries.

Samane Teymouri, Maryam Pourhajibagher, Abbas Bahador.

  The relationship between the skin microbiome and probiotics in the healing of burn injuries has garnered significant attention in recent years. Burn injuries disrupt the delicate balance of the skin microbiome, leading to complications in the healing process. Probiotic therapies have emerged as promising interventions to restore microbial balance, inhibit biofilm formation, and accelerate tissue repair. Probiotics may also mitigate the risk of antibiotic-resistant infections, which is a major concern in burn units. By enhancing immune responses and stimulating the production of antimicrobial peptides, probiotics can effectively combat bacterial colonization and prevent the emergence of drug-resistant strains. A combination of probiotics with other therapies, such as phages or nanoparticles, holds significant promise for enhancing burn healing. This approach can effectively treat burn wounds by promoting wound healing synergy, preventing infection, modulating the immune response, and disrupting biofilms. Overall, the relationship between the skin microbiome and probiotics in burn wound healing has substantial potential to advance the field of burn wound management.

Keywords:  Burns; Microbiome; Probiotics; Therapeutics; Wounds and injuries

DOI:  https://doi.org/10.1007/s12223-025-01262-8
Am J Respir Cell Mol Biol. 2025 Apr 16.

Development of a Polidocanol-based Human In Vitro Model to Explore Airway Epithelial Repair.

Ashesh Chakraborty, Marie Zöller, Aydan Sardogan, Markus Klotz, Michal Mastalerz, Hannah Marchi, Raphael Meixner, Rudolf A Hatz, Jürgen Behr, Anne Hilgendorff, Misako Nakayama, Claudia A Staab-Weijnitz.

  The human airway epithelium is a primary site of toxicant exposure and crucial in the pathogenesis of acute and chronic lung disease (CLD). In CLD, the airway epithelium is frequently altered and distorted, and its restoration is desirable. The mechanisms underlying human aberrant epithelial regeneration, however, are poorly understood. Importantly, our knowledge about airway epithelial injury and regeneration largely stems from mouse models, yet airways differ considerably between mice and humans. We hypothesized that treatment of differentiated primary human bronchial epithelial cells (phBECs, or HBEC) with polidocanol or naphthalene would allow for studying mechanisms of human airway epithelial injury and regeneration. Injury of differentiated phBECs with 0.04%, but not 0.1% PDOC, resulted in full restoration of a functional epithelium and epithelial barrier integrity as monitored by qRT-PCR analysis, immunofluorescence stainings, and transepithelial electrical resistance measurements. Regeneration was associated with a transient but not parallel increase of p21+ and KRT17+ cells. Providing proof-of-concept, DAPT, an inhibitor of Notch signaling, blunted the restoration of secretory cell types post 0.04% PDOC injury. Differentiation of phBECs in presence of cigarette smoke extract (CSE) or ethanol as first hit significantly impaired the regeneration capacity of phBECs. While naphthalene is known to specifically induce club cell depletion in mouse airways, it failed to do so in phBECs. In conclusion, using fully differentiated phBECs treated with PDOC, we successfully established and thoroughly characterized a human in vitro system that will facilitate studies of mechanisms involved in susceptibility to injury as well as human airway repair and regeneration.

Keywords:  Airway injury; Airway regeneration; Bronchial epithelium; HBEC; Polidocanol

DOI:  https://doi.org/10.1165/rcmb.2024-0117OC
Rheum Dis Clin North Am. 2025 May;pii: S0889-857X(25)00006-7. [Epub ahead of print]51(2): 283-293

Exploring the Mucosal Immune Response in Axial Spondyloarthritis Through Immunoglobulin A-Coated Microbiota.

Tejpal Gill.

  In this review, we focus on the mucosal immune response through Immunoglobulin A (IgA)-coated microbes and their role in gut dysbiosis in axial spondyloarthritis (axSpA) and associated inflammatory bowel disease. IgA-coated microbes contribute significantly to the microbial dysbiosis observed in axSpA, potentially driving gut inflammation and translocating outside of the gut and initiating systemic immune activation, thus contributing to disease pathogenesis. These insights will provide new avenues for understanding and treating axSpA and other immune-mediated inflammatory disorders by targeting specific host immune-microbe interactions.

Keywords:  Axial spondyloarthritis; IgA-coated microbe sequencing; Immunoglobulin A; Inflammatory bowel disease; Mucosal immune response

DOI:  https://doi.org/10.1016/j.rdc.2025.01.006
Int J Mol Sci. 2025 Apr 02. pii: 3321. [Epub ahead of print]26(7):

Mechanical Force Triggers Macrophage Pyroptosis and Sterile Inflammation by Disrupting Cellular Energy Metabolism.

Hao Tan, Guoyin Yang, Ye Zhu, Xinyi He, Lan Yang, Yun Hu, Leilei Zheng.

  Mechanical force regulates tissue remodeling during orthodontic tooth movement (OTM) by inducing macrophage-mediated sterile inflammatory responses. Pyroptosis, as an inflammatory form of programmed cell death, triggers a robust inflammatory cascade by activating the inflammasome. Although recent reports have demonstrated that pyroptosis can be activated by mechanical force, it remains unclear whether and how orthodontic force induces macrophage pyroptosis and sterile inflammation. In this study, by establishing a rat OTM model and a force-loaded macrophage model, we found that force induces Caspase1-dependent pyroptosis in macrophages and activates sterile inflammation both in vivo and in vitro. Mechanistically, we uncovered that mechanical force disrupts macrophage energy metabolism, characterized by an imbalance between lactate dehydrogenase A (LDHA) and pyruvate dehydrogenase (PDH), as well as mitochondrial dysfunction. Notably, inhibiting pyruvate dehydrogenase kinase 1 (PDK1) effectively restored this metabolic balance, thereby alleviating pyroptosis and sterile inflammation in force-stimulated macrophages. Overall, this study elucidates that force induces macrophage pyroptosis and sterile inflammation, and further identifies imbalances in the LDHA/PDH ratio and mitochondrial dysfunction as pivotal mechanistic features. These insights offer novel perspectives and potential therapeutic targets for the precise and effective modulation of OTM.

Keywords:  energy metabolism; macrophage; mechanical force; orthodontic tooth movement; pyroptosis; sterile inflammation

DOI:  https://doi.org/10.3390/ijms26073321
Microbiol Spectr. 2025 Apr 16. e0298424

Genome-scale metabolic modeling reveals specific vaginal Lactobacillus strains and their metabolites as key inhibitors of Candida albicans.

Tianqi Hu, Ya Meng, Changying Zhao, Dashuang Sheng, Sijie Yang, Junhui Dai, Tiantian Wei, Yiming Zhang, Guoping Zhao, Yanan Liu, Qinghua Wang, Lei Zhang.

  As the predominant constituents of the vaginal microbiome in healthy women, Lactobacillus species are considered essential in maintaining a homeostatic vaginal microbiome. Specific Lactobacillus species can produce beneficial metabolites to support their persistence within the host environment and inhibit Candida albicans colonization. Due to the extensive diversity of Lactobacillus species and their metabolites, comprehensively investigating all possible interactions remains challenging. This study employed an integrative approach combining genome-scale metabolic modeling, metagenomic sequencing, and in vitro validation to explore Lactobacillus and C. albicans interactions. Pairwise simulations of 159 Lactobacillus strains with C. albicans revealed that most strains exhibit inhibitory effects, altering fungal amino acid and carbohydrate metabolism. Key inhibitory metabolites identified included formate, L-lactate, and L-malate. Metagenomic analysis of vaginal swabs from 20 vulvovaginal candidiasis (VVC) patients and 20 healthy women showed a correlation between Lactobacillus species abundance and reduced C. albicans colonization. In vitro experiments confirmed the inhibitory effects of these metabolites and the selected Lactobacillus strains on C. albicans growth, thereby validating our computational predictions. These findings provide insights into the metabolic interactions within the vaginal microbiome and pave the way for targeted microbial or metabolite-based therapeutic strategies to manage VVC.IMPORTANCEVulvovaginal candidiasis is a prevalent fungal infection with significant implications for women's health, caused primarily by Candida albicans. Although the protective role of a Lactobacillus-dominated vaginal microbiome is well established, the metabolic mechanisms underlying the interactions between Lactobacillus species and C. albicans remain inadequately understood. Specifically, the Lactobacillus species that effectively inhibit C. albicans and the metabolic pathways involved warrant further investigation. This study offers novel insights into the metabolic mechanisms underlying Lactobacillus antagonism against C. albicans. By identifying critical metabolic pathways and inhibitory metabolites, this study enhances our understanding of vaginal microbiome dynamics and host-microbe interactions. The findings suggest that key Lactobacillus strains and their metabolites could significantly reduce harmful levels of C. albicans, paving the way for future therapeutic strategies that leverage these microbial characteristics to promote vaginal health.

Keywords:  Candida albicans; Lactobacillus; genome-scale metabolic models (GEMs); metabolic interactions; vulvovaginal candidiasis

DOI:  https://doi.org/10.1128/spectrum.02984-24
Mucosal Immunol. 2025 Apr 10. pii: S1933-0219(25)00039-X. [Epub ahead of print]

Innate immunity of the lungs in homeostasis and disease.

Peter A A Norris, Paul Kubes.

Humans breathe thousands of litres of non-sterile air each day containing bacteria, viruses, and fungi, as well as pollutants, allergens, and other particles. The continual exposure to foreign particles is juxtaposed with the vast surface area of the blood-air-barrier which becomes extremely thin to allow for efficient gas exchange. To prevent infection and injury, the healthy lung relies on a robust innate immune system to protect itself. Critically, this innate immune system must clear insults while maintaining immune tolerance and minimizing inflammation to avoid disrupting the lung's vital gas exchange function. In this review, we discuss how the innate immune system protects the lung from its environment.

DOI: https://doi.org/10.1016/j.mucimm.2025.04.001
Microb Pathog. 2025 Apr 11. pii: S0882-4010(25)00302-X. [Epub ahead of print]204 107577

Intervention of Corynebacterium striatum in the sessile lifestyle of Staphylococcus aureus wild-type and mutants for ica genes in polymicrobial biofilms.

Giorgio Silva-Santana, Eustáquio Souza Baêta Júnior, Greice Maria Silva Conceição, Fabio Aguiar-Alves, Marcelo Luiz Lima Brandão, Eduardo José Lopes-Torres, Ana Luiza Mattos-Guaraldi.

  This study investigated the interactions between Corynebacterium striatum and Staphylococcus aureus, two bacterial species commonly found in the human microbiota, particularly colonizing the skin and mucous membranes. Both organisms, however, are also capable of causing acute and chronic infections. While S. aureus is widely recognized as a clinically significant pathogen, C. striatum is frequently underestimated and often regarded as a contaminant-even when isolated in pure culture from nosocomial infections. The ability of these microorganisms to develop multidrug resistance and form biofilms complicates the management of the infections they cause. This study focused on the interaction between C. striatum and S. aureus, particularly the influence of the former on the pathogenic potential of the latter, emphasizing biofilm formation in S. aureus mutants deficient in the icaR and icaC genes. Antimicrobial susceptibility testing revealed that 85.7 % of the S. aureus strains were multidrug-resistant, with all strains resistant to β-lactam antibiotics. Additionally, 55.6 % of the strains produced strong slime on Congo Red agar, indicating a high potential for biofilm formation. In monomicrobial assays, both C. striatum and S. aureus exhibited enhanced adhesion to hydrophilic surfaces. In polymicrobial settings, C. striatum predominated in most cases: on glass surfaces, 70 % of biofilms were dominated by C. striatum, 20 % by S. aureus, and 10 % showed an even distribution. On polystyrene, 80 % of the biofilms were dominated by C. striatum, while 20 % were dominated by S. aureus. Analysis of extracellular polymeric substances (EPS) revealed distinct compositional profiles: C. striatum primarily produced proteinaceous matrices, whereas S. aureus biofilms were rich in polysaccharides. Ultrastructural examination showed that S. aureus formed dense clusters embedded in large amounts of EPS, while C. striatum biofilms exhibited lower EPS production overall. Furthermore, the effect of C. striatum-derived compounds on S. aureus biofilms was assessed. In 90 % of co-cultured strains, a progressive decrease in sessile cell populations was observed, accompanied by an increase in planktonic cells. This finding suggests that C. striatum can disrupt the biofilm integrity of S. aureus, potentially modulating its pathogenic phenotype. In conclusion, the results demonstrate that C. striatum competes effectively with S. aureus for surface colonization and, under certain conditions, may induce a transition of S. aureus from a sessile to a planktonic state. These findings highlight the complexity of interspecies interactions in polymicrobial communities and suggest that C. striatum may play a modulatory role in S. aureus virulence. Such insights have important implications for the understanding and treatment of polymicrobial infections.

Keywords:  Corynebacterium striatum; Staphylococcus aureus; bacterial infection; biofilm; locus ica

DOI:  https://doi.org/10.1016/j.micpath.2025.107577
Arch Dermatol Res. 2025 Apr 17. 317(1): 713

Ligilactobacillus salivarius Lac45 inhibits MRSA and suppresses inflammation in human keratinocyte.

Punploy Klawkla, Hung Gia Tran, Poorichaya Somparn, Somying Tumwasorn, Tanittha Chatsuwan, Jongkonnee Wongpiyabovorn.

  Dysbiosis, an imbalance in skin microflora, is a key contributor to inflammatory skin conditions, including atopic dermatitis (AD), seborrheic dermatitis (SD), and psoriasis. In AD, Staphylococcus aureus colonization of skin lesions is prevalent approximately 70% of cases, with disease severity positively correlating with bacterial presence. Moreover, methicillin-resistant Staphylococcus aureus (MRSA) is found in 10-30% of AD skin lesions, highlighting the need for novel therapeutic strategies that target both microbial imbalance and inflammation. This study evaluates Ligilactobacillus salivarius Lac45 (LS-Lac45), a breast milk-derived bacterial strain, for its antimicrobial and anti-inflammatory potential in dermatology. We assessed its antimicrobial activity against MRSA using an agar disk-diffusion assay and its anti-inflammatory effects in a peptidoglycan (PGN)-induced inflammation model in HaCaT keratinocytes. To elucidate its mechanisms of action, mass spectrometry was used to analyze protein expression changes in LS-Lac45-treated keratinocytes. Our results demonstrate that live LS-Lac45 effectively inhibits MRSA growth. Additionally, heat-killed LS-Lac45 significantly reduces PGN-induced production of pro-inflammatory cytokines IL-6, IL-8, and TNF-α. Proteomic analysis further identifies LS-Lac45-mediated modulation of immune-related proteins, including heat shock protein 60, metallothionein 2A, and antioxidant-1, suggesting a role in inflammatory regulation. These findings highlight LS-Lac45 as a candidate for managing MRSA-associated inflammatory skin conditions, particularly AD. While this study provides key insights into its antimicrobial and immunomodulatory properties, further research is needed to evaluate its probiotic characteristics and clinical applicability in dermatology.

Keywords:   Ligilactobacillus salivarius Lac45; MRSA; Probiotics; Skin inflammation

DOI:  https://doi.org/10.1007/s00403-025-04227-6
JAMA Pediatr. 2025 Apr 14.

Epidemiology and Mortality of Invasive Staphylococcus aureus Infections in Hospitalized Infants.

Maria Rain Jennings, Nora Elhaissouni, Elizabeth Colantuoni, Erica C Prochaska, Julia Johnson, Shaoming Xiao, Reese H Clark, Rachel G Greenberg, Daniel K Benjamin, Aaron M Milstone.

Importance: Historically, Staphylococcus aureus has been a leading cause of morbidity and mortality in the neonatal intensive care unit (NICU). The current incidence and attributable mortality of late-onset invasive S aureus infection in hospitalized infants is unknown.
Objective: To estimate the incidence and attributable mortality of late-onset S aureus infection among hospitalized infants in the US.
Design, Setting, and Participants: This retrospective cohort study included an emulated trial among a national convenience sample of 315 NICUs within the US between 2016 and 2021. Participants were infants aged at least 4 postnatal days who were hospitalized in a participating NICU. Data were analyzed from May to August 2024.
Exposures: The primary exposures were birth weight and postnatal age.
Main Outcomes and Measures: The outcomes were the incidence and attributable mortality of late-onset invasive S aureus infection. Methicillin-resistant and methicillin-sensitive S aureus classification was not universally available; thus, all invasive S aureus infections were pooled.
Results: From 468 201 infants (260 491 [55.6%] male; median [IQR] gestational age, 36 [33-38] weeks) eligible for analysis, 1724 infants experienced 1762 infections for an overall incidence of 37.6 (95% CI, 35.9-39.4) invasive S aureus infections per 10 000 infants. Most infants with invasive infections were 32 weeks' gestational age or younger (1394 infants [80.9%]), very low birth weight (VLBW; ie, <1500 g) (1318 infants [76.5%]), and/or had a central line during their hospital stay (1509 infants [87.5%]). Invasive infections mostly included bloodstream infections (1505 infections [85.4%]), and 1160 infections (65.8%) occurred within 4 to 28 postnatal days. Birth weight inversely correlated with incidence: infants with VLBW experienced a more than 20-fold higher incidence relative to infants born weighing at least 1500 g (227.1 [95% CI, 215.3-239.4] vs 10.1 [95% CI, 9.1-11.1] infections per 10 000 infants). Most deaths following invasive infection occurred among VLBW infants (189 of 209 deaths [90.4%]). Compared with matched infants without a late-onset invasive S aureus infection, infected infants had an absolute difference in mortality rate of 5.3% (95% CI, 3.8%-6.8%).
Conclusions and Relevance: This cohort study found late-onset invasive S aureus infection and subsequent attributable mortality disproportionally affected infants with VLBW. Targeted infection prevention and control measures are necessary to reduce morbidity and mortality from invasive S aureus infections in this vulnerable population.

DOI: https://doi.org/10.1001/jamapediatrics.2025.0429
BMC Immunol. 2025 Apr 18. 26(1): 34

Natural and induced immune responses in oral cavity and saliva.

Michele Matsuoka, Salim Abraham Soria, Julien Rodrigues Pires, Adriana Campos Passanezi Sant'Ana, Marcelo Freire.

  This review comprehensively explores the intricate immune responses within the oral cavity, emphasizing the pivotal role of saliva in maintaining both oral and systemic health. Saliva, a complex biofluid, functions as a dynamic barrier against pathogens, housing diverse cellular components including epithelial cells, neutrophils, monocytes, dendritic cells, and lymphocytes, which collectively contribute to robust innate and adaptive immune responses. It acts as a physical and immunological barrier, providing the first line of defense against pathogens. The multifaceted protective mechanisms of salivary proteins, cytokines, and immunoglobulins, particularly secretory IgA (SIgA), are elucidated. We explore the natural and induced immune responses in saliva, focusing on its cellular and molecular composition. In addition to saliva, we highlight the significance of a serum-like fluid, the gingival crevicular fluid (GCF), in periodontal health and disease, and its potential as a diagnostic tool. Additionally, the review delves into the impact of diseases such as periodontitis, oral cancer, type 2 diabetes, and lupus on salivary immune responses, highlighting the potential of saliva as a non-invasive diagnostic tool for both oral and systemic conditions. We describe how oral tissue and the biofluid responds to diseases, including considerations to periodontal tissue health and in disease periodontitis. By examining the interplay between oral and systemic health through the oral-systemic axis, this review underscores the significance of salivary immune mechanisms in overall well-being and disease pathogenesis, emphasizing the importance of salivary mechanisms across the body.

Keywords:  Barriers; Host response; Host-microbial interactions; Immunity; Microbiome; Saliva

DOI:  https://doi.org/10.1186/s12865-025-00713-8
Proc Natl Acad Sci U S A. 2025 Apr 22. 122(16): e2405527122

Dynamic coexistence driven by physiological transitions in microbial communities.

Avaneesh V Narla, Terence Hwa, Arvind Murugan.

  Microbial ecosystems are commonly modeled by fixed interactions between species in steady exponential growth states. However, microbes in exponential growth often modify their environments so strongly that they are forced out of the growth state into stressed, nongrowing states. Such dynamics are typical of ecological succession in nature and serial-dilution cycles in the laboratory. Here, we introduce a phenomenological model, the Community State Model, to gain insight into the dynamic coexistence of microbes due to changes in their physiological states during cyclic succession. Our model specifies the growth preference of each species along a global ecological coordinate, taken to be the biomass density of the community, but is otherwise agnostic to specific interactions (e.g., nutrient starvation, stress, aggregation), in order to focus on self-consistency conditions on combinations of physiological states, "community states," in a stable ecosystem. We identify three key features of such dynamical communities that contrast starkly with steady-state communities: enhanced community stability through staggered dominance of different species in different community states, increased tolerance of community diversity to fast growing species dominating distinct community states, and increased requirement of growth dominance by late-growing species. These features, derived explicitly for simplified models, are proposed here as principles aiding the understanding of complex dynamical communities. Our model shifts the focus of ecosystem dynamics from bottom-up studies based on fixed, idealized interspecies interaction to top-down studies based on accessible macroscopic observables such as growth rates and total biomass density, enabling quantitative examination of community-wide characteristics.

Keywords:  bacterial physiology; community assembly; ecological succession; microbial ecology

DOI:  https://doi.org/10.1073/pnas.2405527122
J Alzheimers Dis. 2025 Apr 15. 13872877251329583

Alzheimer's disease as an auto-innate immune pathology with potential cell trans-differentiation and enhanced trained immunity in 3xTg-AD mouse model.

Fatma Saaoud, Lu Liu, Keman Xu, Yifan Lu, Ying Shao, Mohammed Ben Issa, Xiaohua Jiang, Xianwei Wang, Xiaolei Liu, Michael Autieri, Sheng Wu, Juncheng Wei, Jun Yu, Rihab Bouchareb, Avrum Gillespie, Jin Jun Luo, Laisel Martinez, Roberto Vazquez-Padron, Jianxin Sun, Huaqing Zhao, Hong Wang, Domenico Pratico, Xiaofeng Yang.

  BackgroundAlzheimer's disease (AD) is a neurodegenerative disorder characterized by memory impairment. Neuroinflammatory processes, mediated by glial and immune cells, contribute to neuronal damage. Emerging evidence implicates innate immune mechanisms, including trained immunity and cell trans-differentiation, in AD pathogenesis, though their roles remain unclear.ObjectiveTo investigate transcriptomic changes in the 3xTg-AD mouse model, focusing on trained immunity and cell trans-differentiation in disease mechanisms.MethodsRNA-sequencing was performed on brain tissue (cortex plus hippocampus) from 11-month-old female 3xTg-AD and wild-type mice (n = 3/group). Differentially expressed genes (fold change > 1.5, p < 0.05) were identified and followed by bioinformatics and knowledge-based transcriptomic profiling. Public AD datasets were also analyzed.Results3xTg-AD mice exhibited 316 upregulated and 412 downregulated genes. Downregulated genes included those for blood-brain barrier protein, while upregulated genes related to cerebrospinal fluid. Increased expression of proinflammatory markers, as well as genes related to cell differentiation, proliferation, activation, and adhesion. Upregulation of genes associated with cell migration and trans-differentiation suggests a potential role for inflammation and cellular plasticity. Additionally, genes involved in inflammasome pathways, immunometabolism, and trained immunity were upregulated. Mechanistically, these genes were modulated by knockdown of trained immunity promoter SET-7, overexpression of trained immunity inhibitor IL-37, and knockout of inflammasome genes IL-1 receptor, caspase-1, and pattern recognition receptor CD36.ConclusionsThe finding underscore the potential role of trained immunity and cell trans-differentiation in AD, revealing a mechanistic framework in which danger-associated molecular patterns drive innate immune responses, inflammasome activation, and cell plasticity contribute to AD, offering therapeutic targets for neuroinflammation and cellular reprograming.

Keywords:  Alzheimer's disease; amyloid-β; blood-brain barrier; cell trans-differentiation; trained immunity

DOI:  https://doi.org/10.1177/13872877251329583