bims-bac4me 2025-02-23 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2025–02–23
37 papers selected by
Chun-Chi Chang, Universitäts Spital Zürich

Ablation of the deubiquitinating enzyme cylindromatosis (CYLD) augments STAT1-mediated M1 macrophage polarization and fosters Staphylococcus aureus control.
Metabolic reprogramming shapes post-translational modification in macrophages.
ADAM28 promotes epithelial mesenchymal transition and impairs tight junctions in non-eosinophilic chronic rhinosinusitis with nasal polyps by inducing M1 polarization of macrophages.
Microbial influencers: the airway microbiome's role in asthma.
Characterization of agr-like Loci in Lactiplantibacillus plantarum and L. paraplantarum and Their Role in Quorum Sensing and Virulence Inhibition of Staphylococcus aureus.
PBMC and fibroblast cocultures to mimic the in vivo effect of BCG on trained immunity.
Establishment and characterization of persistent Pseudomonas aeruginosa infections in air-liquid interface cultures of human airway epithelial cells.
Linking macrophage metabolism to function in the tumor microenvironment.
Health benefits, antimicrobial activities, and potential applications of probiotics: A review.
ILC3s regulate the gut microbiota via host intestinal galactosylation to limit pathogen infection in mice.
Role of the microbiome in regulation of the immune system.
CF airway epithelia display exaggerated host defense responses and prolonged cilia loss during RSV infection.
Crosstalk Between the Skin Environment and Microbial Community in Immune-Related Skin Diseases.
Planning and describing a microbiome data analysis.
Uncovering a gut microbiota-derived metabolite that triggers host cellular senescence.
The physiological role of macrophages in reproductive organs.
Non-Membrane Active Peptide Resensitizes MRSA to β-Lactam Antibiotics and Inhibits S. aureus Virulence.
Identification of signaling networks associated with lactate modulation of macrophages and dendritic cells.
Mastitis-related Staphylococcus aureus-derived extracellular vesicles induce a pro-inflammatory response in bovine monocyte-derived macrophages.
TREM2 promotes lung fibrosis via controlling alveolar macrophage survival and pro-fibrotic activity.
PGLYRP1-mediated intracellular peptidoglycan detection promotes intestinal mucosal protection.
Comparison of air-liquid interface transwell and airway organoid models for human respiratory virus infection studies.
Characterization of the Cellular Immune Response to Group B Streptococcal Vaginal Colonization.
Myeloid-Mesenchymal Crosstalk in Lung Fibrosis.
HNF4A mitigates sepsis-associated lung injury by upregulating NCOR2/GR/STAB1 axis and promoting macrophage polarization towards M2 phenotype.
Staphylococcus aureus-specific TIGIT+ Treg are present in the blood of healthy subjects - a hurdle for vaccination?
Pro-inflammatory macrophages produce mitochondria-derived superoxide by reverse electron transport at complex I that regulates IL-1β release during NLRP3 inflammasome activation.
Effect of hyperglycemia on lung microbiota and treatment outcome in pulmonary tuberculosis: A scoping review.
Innate Immune Sensors in Health and Disease.
Redefining Cell Culture Using a 3D Flipwell Co-culture System: A Mimetic for Gut Architecture and Dynamics In Vitro.
Beneficial effects of Lactiplantibacillus plantarum BGPKM22 manifest only in interaction with healthy, but not with diseased human bronchial epithelial cells.
Endogenous production of nitric oxide by iNOS in human cells restricts inflammatory activation and cholesterol/fatty acid biosynthesis.
Immunostimulatory effects of Streptococcus sanguinis extracellular membrane vesicles protect oral gingival epithelial cells from periodontal pathobiont damage.
The role of bacterial metabolism in antimicrobial resistance.
Helminths target macrophage epigenetics and metabolism to evade immunity.
Lactobacillus lysates protect oral epithelial cells from pathogen-associated damage, increase secretion of pro-inflammatory cytokines and enhance barrier integrity.
Macrophages hijack carbapenem-resistance hypervirulent Klebsiella pneumoniae by blocking SLC7A11/GSH-manipulated iron oxidative stress.

Front Immunol. 2025 ;16 1507989

Ablation of the deubiquitinating enzyme cylindromatosis (CYLD) augments STAT1-mediated M1 macrophage polarization and fosters Staphylococcus aureus control.

Christina Schmidt, Kunjan Harit, Stephan Traidl, Michael Naumann, Thomas Werfel, Lennart M Roesner, Gopala Nishanth, Dirk Schlüter.

  In atopic dermatitis (AD), lesional skin is frequently colonized by Staphylococcus aureus, which promotes clinical symptoms of the disease. The inflammatory milieu in the skin is characterized by a Th2 response, including M2 macrophages, which cannot eradicate S. aureus. Therefore, repolarization of macrophages toward the M1 phenotype may foster control of S. aureus. Our data show that the deubiquitinating enzyme cylindromatosis (CYLD) is strongly expressed in macrophages of AD patients and prevents the clearance of S. aureus. Mechanistically, CYLD impaired M1 macrophage polarization by K63-specific deubiquitination of STAT1 and activation of the NF-κB pathway via its interaction with TRAF6, NEMO, and RIPK2. Inhibition of STAT1 and NF-κB, independently, abolished the differences between S. aureus-infected CYLD-deficient and CYLD-competent M1 macrophages. Infection of Cyld-deficient and wild-type mice with S. aureus confirmed the protective CYLD function. Collectively, our study shows that CYLD impairs the control of S. aureus in macrophages of AD patients, identifying CYLD as a potential therapeutic target.

Keywords:  CYLD; NF-κB; STAT1; Staphylococcus aureus; atopic dermatitis; macrophage; ubiquitin

DOI:  https://doi.org/10.3389/fimmu.2025.1507989
Mol Aspects Med. 2025 Feb 19. pii: S0098-2997(25)00002-0. [Epub ahead of print]102 101338

Metabolic reprogramming shapes post-translational modification in macrophages.

Ziyi Han, Yinhao Shen, Yuqi Yan, Peng Bin, Meimei Zhang, Zhending Gan.

  Polarized macrophages undergo metabolic reprogramming, as well as extensive epigenetic and post-translational modifications (PTMs) switch. Metabolic remodeling and dynamic changes of PTMs lead to timely macrophage response to infection or antigenic stimulation, as well as its transition from a pro-inflammatory to a reparative phenotype. The transformation of metabolites in the microenvironment also determines the PTMs of macrophages. Here we reviewed the current understanding of the altered metabolites of glucose, lipids and amino acids in macrophages shape signaling and metabolism pathway during macrophage polarization via PTMs, and how these metabolites in some macrophage-associated diseases affect disease progression by shaping macrophage PTMs.

Keywords:  Innate immunity; Macrophage; Metabolic reprogramming; Post-translational modifications

DOI:  https://doi.org/10.1016/j.mam.2025.101338
Int Immunopharmacol. 2025 Feb 14. pii: S1567-5769(25)00266-8. [Epub ahead of print]150 114276

ADAM28 promotes epithelial mesenchymal transition and impairs tight junctions in non-eosinophilic chronic rhinosinusitis with nasal polyps by inducing M1 polarization of macrophages.

Jiajia Zi, Longgang Yu, Lin Wang, Danyang Li, Xiaoyun Du, Han Chen, Jisheng Zhang, Yan Jiang.

   BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by tight junction dysfunction associated with epithelial-mesenchymal transition (EMT) processing. ADAM28 participates in the pathogenic process of inflammatory airway diseases.
METHODS: The effects of ADAM28 knockdown on the expression levels of the M1-type macrophage markers were examined using M1-type macrophage polarization model established with the THP1 cells. An inflammation model was established by collecting cell supernatants from M1-polarized macrophages with stable ADAM28 knockdown to stimulate HNEPC and primary nasal mucosal epithelial cells (pHNECs).The expression levels of EMT markers and tight junction proteins were detected.
RESULTS: ADAM28 was highly expressed in non-eosinophilic CRSwNP (NE-CRSwNP) and correlated with NE-CRSwNP clinical scores. Immunofluorescence assay demonstrated that the number of ADAM28-positive macrophages significantly increased in the NE-CRSwNP group compared with the control group. In addition, ADAM28 levels were significantly elevated in M1-type macrophages. ADAM28 knockdown significantly reduced the expression levels of M1-type macrophage polarization markers in M1 macrophages. Furthermore, ADAM28 knockdown elevated the expression of EMT marker E-cadherin and decreased the expression of α-SMA in HNEPC and pHNECs. Additionally, ADAM28 knockdown increased the expression levels of tight junction proteins in pHNECs cultured at an air-liquid interface.
CONCLUSION: ADAM28 is markedly elevated in NE-CRSwNP and is correlated with the clinical scores of NE-CRSwNP. ADAM28 induces the M1-type polarization of macrophages. ADAM28 promotes EMT and impairs tight junctions of nasal epithelia by inducing M1-type polarization of macrophages.

Keywords:  ADAM28; Chronic rhinosinusitis with nasal polyps; Epithelial-mesenchymal transition; Macrophages; Tight junctions

DOI:  https://doi.org/10.1016/j.intimp.2025.114276
J Clin Invest. 2025 Feb 17. pii: e184316. [Epub ahead of print]135(4):

Microbial influencers: the airway microbiome's role in asthma.

Young Jin Kim, Supinda Bunyavanich.

Asthma is a common chronic respiratory disease affecting people of all ages globally. The airway hosts diverse microbial communities increasingly recognized as influential in the development and disease course of asthma. Here, we review recent findings on the airway microbiome in asthma. As relationships between the airway microbiome and respiratory health take root early in life, we first provide an overview of the early-life airway microbiome and asthma development, where multiple cohort studies have identified bacterial genera in the infant airway associated with risk of future wheeze and asthma. We then address current understandings of interactions between environmental factors, the airway microbiome, and asthma, including the effects of rural/urban environments, pet ownership, smoking, viral illness, and antibiotics. Next, we delve into what has been observed about the airway microbiome and asthma phenotypes and endotypes, as airway microbiota have been associated with asthma control, severity, obesity-related asthma, and treatment effects as well as with type 2 high, type 2 low, and more newly described multi-omic asthma endotypes. We then discuss emerging approaches to shape the microbiome for asthma therapy and conclude the Review with perspectives on future research directions.

DOI: https://doi.org/10.1172/JCI184316
Probiotics Antimicrob Proteins. 2025 Feb 19.

Characterization of agr-like Loci in Lactiplantibacillus plantarum and L. paraplantarum and Their Role in Quorum Sensing and Virulence Inhibition of Staphylococcus aureus.

Weizhe Wang, Ifigeneia Kyrkou, Martin S Bojer, Dina Kalloubi, Abdul Jabbar Kali, Miguel Alena-Rodriguez, Jørgen J Leisner, Stephanie Fulaz, Hanne Ingmer.

  The pathogenicity of Staphylococcus aureus is largely regulated by the agr quorum sensing (QS) system encoded by agrBDCA, which coordinates virulence factor production through secretion and sensing of auto-inducing peptides (AIPs). agr-like systems are also present in coagulase-negative staphylococci, and several of these encode AIPs that inhibit S. aureus QS. In lactic acid bacteria, a similar locus was previously identified in Lactiplantibacillus plantarum WCSF1 termed lamBDCA. Here, we characterized the lamBDCA locus in L. plantarum LMG 13556 and L. paraplantarum CIRM-BIA 1870, and explored the effects on S. aureus QS. Notably, we found that co-cultivation with L. paraplantarum significantly inhibits S. aureus QS and hemolysin production, while less so for L. plantarum. The inhibition by L. paraplantarum was lost upon disruption of its lamBDCA locus, suggesting that the L. paraplantarum AIP mediates cross-species interference with S. aureus agr activation. Transcriptomic analysis revealed that lamBDCA in L. paraplantarum controls the expression of genes belonging to various functional categories, including stress response and metabolism. The latter includes genes encoding riboflavin (B2 vitamin) biosynthesis, which enabled the growth of the L. paraplantarum lamB mutant in the presence of roseoflavin, a toxic riboflavin analogue. Collectively, our results show that L. paraplantarum CIRM-BIA 1870 interferes with S. aureus virulence gene expression through QS suppression, and they implicate QS in the probiotic properties of L. paraplantarum.

Keywords:   agr system; Anti-virulence therapy; Auto-inducing peptides (AIPs); Cross-species communication; Probiotics; Quorum sensing

DOI:  https://doi.org/10.1007/s12602-025-10476-8
MicroPubl Biol. 2025 ;2025

PBMC and fibroblast cocultures to mimic the in vivo effect of BCG on trained immunity.

David Merriam, Adriana Weinberg.

BCG greatly stimulates innate immune cells. Previous studies demonstrated that BCG-stimulated monocytes develop trained immunity whereby they respond to homologous and heterologous antigens. Previous studies used isolated monocytes or animal models to study BCG-induced trained immunity, which have benefits and limitations. To approximate in vivo conditions, we stimulated peripheral blood mononuclear cells (PBMCs) with BCG-treated human fibroblasts. We found that compared with BCG stimulation, the addition of fibroblasts increased the expression of IFN-γ in NK and γδ T cells and of TNF-α and IL-10 in monocytes. We conclude that BCG-treated fibroblasts offer advantages over BCG alone for studying trained immunity.

DOI: https://doi.org/10.17912/micropub.biology.001449
Infect Immun. 2025 Feb 18. e0060324

Establishment and characterization of persistent Pseudomonas aeruginosa infections in air-liquid interface cultures of human airway epithelial cells.

Safaa Bouheraoua, Sven Cleeves, Matthias Preusse, Mathias Müsken, Peter Braubach, Maximilian Fuchs, Christine Falk, Katherina Sewald, Susanne Häussler.

  Bacteria exhibit distinct behaviors in laboratory settings compared to infection environments. The presence of host cells induces changes in bacterial activity, while pathogens trigger immune responses that shape the microenvironment. Studying infection dynamics by microscopy, cytokine screening, and dual RNA sequencing in an air-liquid interface model, we found that prolonged Pseudomonas aeruginosa colonization of airway epithelium led to a pro-inflammatory response, consistent across P. aeruginosa strains, despite differences in the dynamics of this response. Concurrently, P. aeruginosa formed non-attached aggregates on the apical side of the cell layer and upregulated genes involved in biofilm formation and virulence. Notably, there was remarkable resemblance between the P. aeruginosa transcriptional profile in our model and that previously reported upon host cell contact. Developing a platform that replicates host microenvironments is vital not only for gaining deeper insights into the interplay between host and pathogen but also for evaluating therapeutic strategies in conditions that closely mirror clinical environments.

Keywords:  3D in vitro models; Pseudomonas aeruginosa; airway infection model; bacterial infection; host–pathogen interactions; lung infection; persistent infections

DOI:  https://doi.org/10.1128/iai.00603-24
Nat Cancer. 2025 Feb 17.

Linking macrophage metabolism to function in the tumor microenvironment.

Robbie Jin, Luke Neufeld, Tracy L McGaha.

Macrophages are present at high frequency in most solid tumor types, and their relative abundance negatively correlates with therapy responses and survival outcomes. Tissue-resident macrophages are highly tuned to integrate tissue niche signals, and multiple factors within the idiosyncratic tumor microenvironment (TME) drive macrophages to polarization states that favor immune suppression, tumor growth and metastasis. These diverse functional states are underpinned by extensive and complex rewiring of tumor-associated macrophage (TAM) metabolism. In this Review, we link distinct and specific macrophage functional states within the TME to major, phenotype-sustaining metabolic programs and discuss the metabolic impact of macrophage-modulating therapeutic interventions.

DOI: https://doi.org/10.1038/s43018-025-00909-2
Medicine (Baltimore). 2024 Dec 27. 103(52): e32412

Health benefits, antimicrobial activities, and potential applications of probiotics: A review.

Amin Sepehr, Seyedeh Tina Miri, Shadi Aghamohammad, Nazanin Rahimirad, Mahnaz Milani, Mohammad-Reza Pourshafie, Mahdi Rohani.

Gut microbiota and its metabolic activities can influence the physiology and pathology of the human body. It is well established that alterations in the balance of living microbiota can contribute to various health problems, such as inflammatory bowel disease and autoimmune disorders. Probiotics administered in sufficient quantities as functional food ingredients provide health benefits to hosts. They help to maintain the stability and composition of the gut microbiota and provide resistance to infection by pathogens. The most important probiotic bacteria are Lactobacillus spp. and Bifidobacteria spp., which protect the intestine through various mechanisms such as the production of organic acids and bacteriocins. Scientific and clinical research has demonstrated that probiotics play a role in modulating immune response and preventing cancer and chronic inflammatory diseases, especially in the gastrointestinal tract. This article summarizes the potential health benefits, antimicrobial activities, and purposes for which probiotics can be used as functional foods to improve human health.

DOI: https://doi.org/10.1097/MD.0000000000032412
Nat Microbiol. 2025 Feb 17.

ILC3s regulate the gut microbiota via host intestinal galactosylation to limit pathogen infection in mice.

Wenyan Wang, Na Li, Hongkai Xu, Siting Wei, Yiping Li, Jiayao Ou, Jiacheng Hao, Jing Zhang, Liyou Dong, Ying Qiu, Xiaoyu Hu, Yang-Xin Fu, Xiaohuan Guo.

Host immunity and commensal bacteria synergistically maintain intestinal homeostasis and mediate colonization resistance against pathogens. However, the molecular and cellular mechanisms remain unclear. Here, with a mouse infection model of Citrobacter rodentium, a natural mouse intestinal pathogen that mimics human enteropathogenic Escherichia coli and enterohaemorrhagic Escherichia coli, we find that group 3 innate lymphoid cells (ILC3s) can protect the host from infection by regulating gut microbiota. Mechanistically, ILC3s can control gut dysbiosis through IL-22-dependent regulation of intestinal galactosylation in mice. ILC3 deficiency led to an increase in intestinal galactosylation and the expansion of commensal Akkermansia muciniphila in colonic mucus. The increased A. muciniphila and A. muciniphila-derived metabolic product succinate further promoted the expression of pathogen virulence factors tir and ler, resulting in increased susceptibility to C. rodentium infection. Together, our data reveal a mechanism for ILC3s in protecting against pathogen infection through the regulation of intestinal glycosylation and gut microbiota metabolism.

DOI: https://doi.org/10.1038/s41564-025-01933-9
Allergol Int. 2025 Feb 14. pii: S1323-8930(24)00163-1. [Epub ahead of print]

Role of the microbiome in regulation of the immune system.

Songhui Kim, Cebile Ndwandwe, Hannah Devotta, Lamiah Kareem, Lu Yao, Liam O'Mahony.

  Immune health and metabolic functions are intimately connected via diet and the microbiota. Immune cells are continuously exposed to a wide range of microbes and microbial-derived compounds, with important mucosal and systemic ramifications. Microbial fermentation of dietary components in vivo generates thousands of molecules, some of which are integral components of the molecular circuitry that regulates immune and metabolic functions. These in turn protect against aberrant inflammatory or hyper-reactive processes and promote effector immune responses that quickly eliminate pathogens, such as SARS-CoV-2. Potent tolerance mechanisms should ensure that these immune cells do not over-react to non-pathogenic factors (e.g. food proteins), while maintaining the ability to respond to infectious challenges in a robust, effective and well controlled manner. In this review we examine the factors and mechanisms that shape microbiota composition and interactions with the host immune system, their associations with immune mediated disorders and strategies for intervention.

Keywords:  Allergic inflammation; Bifidobacterium; Commensals; Hygiene hypothesis; Intestinal microbiota

DOI:  https://doi.org/10.1016/j.alit.2024.12.006
J Cyst Fibros. 2025 Feb 15. pii: S1569-1993(25)00055-4. [Epub ahead of print]

CF airway epithelia display exaggerated host defense responses and prolonged cilia loss during RSV infection.

Jennifer A Bartlett, Eric D Huntemann, Sateesh Krishnamurthy, Stacey M Hartwig, Alvin Pewa, Andrew L Thurman, Michael S Chimenti, Eric B Taylor, Steven M Varga, Paul B McCray.

   BACKGROUND: In individuals with cystic fibrosis (CF), respiratory viral infections frequently result in hospitalization and have been linked to secondary bacterial infection and colonization, highlighting viral infections as possible contributors to CF lung disease progression. We hypothesized that expression of antiviral host defense genes is dysregulated in CF airway epithelia.
METHODS: We infected primary CF and Non-CF airway epithelia with respiratory syncytial virus (RSV) and characterized their responses at 12 hr, 24 hr, 48 hr, 72 hr, and 120 hr post infection (hpi) by RNA sequencing (RNAseq).
RESULTS: Our analysis revealed strikingly different gene expression profiles for the CF and Non-CF epithelia over the course of the infection. While both CF and Non-CF cells exhibited an early signature for interferon signaling and antiviral defense pathways, this response was relatively exaggerated and sustained in CF epithelia. We also observed, in both genotypes, a transient downregulation of cilia-associated genes and loss of ciliary activity by 72 hpi. Interestingly, recovery of cilia activity was delayed in the CF epithelia.
CONCLUSIONS: These findings further our understanding of innate immune dysfunction in the CF airway epithelium and suggest that virus-induced cilia injury may further compromise host defenses in CF airways.

Keywords:  Antiviral; Cilia; Cystic fibrosis; Interferon; RNAseq; Viral infection

DOI:  https://doi.org/10.1016/j.jcf.2025.02.003
Clin Rev Allergy Immunol. 2025 Feb 15. 68(1): 16

Crosstalk Between the Skin Environment and Microbial Community in Immune-Related Skin Diseases.

Kecheng Liu, Shuting Deng, Yuan Zhou, Beilei Xu, Yu Zhang, Wei Li, Xiaochun Liu, Xu Yao.

  The skin surface hosts diverse skin microbiota, including bacteria, fungi, and viruses. Intricate interactions between the skin microenvironment and microbial community are crucial for maintaining cutaneous homeostasis. This review explores the bidirectional relationship between the skin ecosystem and its microbiota. The skin microenvironment is shaped by a combination of intrinsic factors, dominated by sweat glands and pilosebaceous units, and external factors, such as UV radiation and personal care products, which create distinct niches that influence microbial colonization patterns across different skin regions. The skin microbiome, in turn, modulates the physical, chemical, immunological, and microbial barriers of the skin. We also discuss the alterations in this crosstalk in various immune-related skin conditions such as atopic dermatitis, psoriasis, rosacea, hidradenitis suppurativa, skin cancer, and aging. Understanding these interactions is vital for developing targeted microbiome-based therapies for various skin disorders. Further researches are needed to deepen insights into the microbial roles and their therapeutic potentials in skin health and disease.

Keywords:  Dysbiosis; Host microbial interactions; Skin diseases; Skin micro-environment; Skin microbiota; Symbiosis

DOI:  https://doi.org/10.1007/s12016-025-09029-2
Nat Microbiol. 2025 Feb 21.

Planning and describing a microbiome data analysis.

Amy D Willis, David S Clausen.

DOI: https://doi.org/10.1038/s41564-025-01944-6
Nat Aging. 2025 Feb 17.

Uncovering a gut microbiota-derived metabolite that triggers host cellular senescence.

DOI: https://doi.org/10.1038/s43587-025-00831-3
Reprod Med Biol. 2025 Jan-Dec;24(1):24(1): e12637

The physiological role of macrophages in reproductive organs.

Osamu Yoshino, Yosuke Ono.

   Background: Macrophages are essential immune cells critical to reproductive physiology. They regulate key processes such as follicular development, ovulation, and luteinization in the ovaries. Macrophages are also involved in endometrial remodeling, immune tolerance, and placentation in the uterus.
Methods: This review examined the biological characteristics of macrophages and their role in ovarian, uterine, and fallopian tube physiology. It focused on findings from both animal and human studies to provide a comprehensive understanding of macrophage functions.
Main Findings: In the ovaries, M1 macrophages play a role in folliculogenesis and ovulation through the inflammatory and angiogenic pathways. Macrophages also maintain the corpus luteum and vascular integrity. In the uterus, macrophages regulate tissue repair and remodeling during the menstrual cycle and play a critical role in implantation by maintaining immune tolerance and supporting decidualization. Dysregulation of the M1/M2 balance can cause implantation failure. In the fallopian tubes, macrophages mediate tissue repair and immune responses. Macrophage polarization dynamically adapts to physiological and pathological conditions in all reproductive organs highlighting the functional plasticity of these cells.
Conclusion: Macrophage polarization and functions are pivotal in maintaining reproductive health. Hence, understanding the role of macrophages in various reproductive organs provides a foundation for developing new therapies.

Keywords:  macrophages; ovaries; reproductive physiology; uterus

DOI:  https://doi.org/10.1002/rmb2.12637
Adv Sci (Weinh). 2025 Feb 20. e2416260

Non-Membrane Active Peptide Resensitizes MRSA to β-Lactam Antibiotics and Inhibits S. aureus Virulence.

Jingru Shi, Chen Chen, Pan Kong, Feiyu Yu, Qingyan Lv, Zhiqiang Wang, Yuan Liu.

  Methicillin-resistant Staphylococcus aureus (MRSA) is a serious global health threat due to its high morbidity and mortality rates, creating a dire need for novel therapeutic strategies. Antimicrobial peptides (AMPs), with broad-spectrum activity and low propensity for resistance development, show promise as effective antibiotic adjuvants to reverse multidrug-resistance in bacteria. Herein, it is uncovered that a potent and non-toxic AMP termed GN1 substantially resensitizes MRSA to multiple β-lactam antibiotics at low concentrations. Mechanistic studies indicate that GN1 functions by suppressing both the production and enzymatic activity of MRSA-associated resistance determinants, including penicillin-binding protein 2a (PBP2a) and β-lactamase. Additionally, GN1 exhibits a robust anti-virulence profile by inhibiting MRSA biofilm formation and staphyloxanthin production. Furthermore, GN1 induces bacterial metabolic perturbation, resulting in glutamate accumulation and oxidative damage. Importantly, the combination of GN1 with β-lactam antibiotics effectively mitigates MRSA-induced infections in the animal infection models. Collectively, these findings suggest that GN1 represents a potent β-lactam adjuvant and anti-virulence agent, offering a safe and versatile solution to combat MRSA infections.

Keywords:  MRSA; antibiotic adjuvant; antibiotic resistance; antimicrobial peptides; virulence

DOI:  https://doi.org/10.1002/advs.202416260
Heliyon. 2025 Feb 15. 11(3): e42098

Identification of signaling networks associated with lactate modulation of macrophages and dendritic cells.

Rapeepat Sangsuwan, Bhasirie Thuamsang, Noah Pacifici, Phum Tachachartvanich, Devan Murphy, Abhineet Ram, John Albeck, Jamal S Lewis.

  The advancement in the understanding of cancer immune evasion has manifested the development of cancer immunotherapeutic approaches such as checkpoint inhibitors and interleukin agonists. Although cancer immunotherapy breakthroughs have demonstrated improved potency for cancer treatment, only a fraction of patients effectively respond to these treatments. Moreover, there is compelling evidence indicating that cancer cells develop a unique microenvironment through adaptive metabolic reprogramming, which aberrantly modulates host immunity to evade immunosurveillance. As part of the tumor cell adaptive metabolic switch, lactate is produced and released into the tumor environment. Recent studies have shown that lactate significantly modulates immune functions, especially in innate immune cells. Dendritic cells (DCs) and macrophages (MΦs) are specialized antigen-presenting cells serving as key players in innate immunity and anticancer-associated immune responses. Although most studies have shown that lactate affects immune phenotypes (e.g., surface protein expression and cytokine production), the cell signaling network mediated by lactate is not fully understood. In the present study, we identified the key signaling pathways in bone marrow-derived DCs and MΦs that were changed by cancer-relevant concentrations of lactate. First, transcriptome analysis was used to guide notable signaling pathways mediated by lactate. Subsequently, biomolecular techniques, including immunoblotting, flow cytometry, and immunofluorescence imaging were performed to corroborate the changes in these key signaling pathways at the protein level. The results indicated that lactate differentially impacted the biochemical networks of DCs and MΦs. While lactate mainly altered STAT3, ERK, and p38 MAPK signaling cascades in DCs, the STAT1 and GSK-3β signaling in MΦs were the major pathways significantly impacted by lactate. This study identifies key biochemical pathways in innate immune cells that are impacted by lactate, which advances our understanding of the interplay between the tumor microenvironment and innate immunity.

Keywords:  Dendritic cells; Immunomodulatory; Lactate; Macrophages; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.heliyon.2025.e42098
Sci Rep. 2025 Feb 19. 15(1): 6059

Mastitis-related Staphylococcus aureus-derived extracellular vesicles induce a pro-inflammatory response in bovine monocyte-derived macrophages.

Mara D Saenz-de-Juano, Giulia Silvestrelli, Samuel Buri, Léa V Zinsli, Mathias Schmelcher, Susanne E Ulbrich.

Staphylococcus aureus (S. aureus) is one of the most common causative agents of mammary gland infection and mastitis, but the specific role of S. aureus-derived extracellular vesicles (SaEVs) in mastitis has been poorly studied to date. Here, we aimed to investigate the response of bovine monocyte-derived macrophages (boMdM) to SaEVs of the genotype B (GTB) mastitis-related strain M5512B. Specifically, we evaluated the effects on the actin cytoskeleton, gene expression, and the SaEV proteomic cargo. Furthermore, we assessed to what extent the cellular and molecular response of boMdM to SaEVs differed from peripheral mononuclear blood cells (PBMCs) used for in vitro derivation of the former. We observed that SaEVs induced morphological changes in boMdM, leading to a pro-inflammatory and pyroptosis-related increased gene expression. Additionally, our study revealed that boMdM and PBMCs exhibited stimulus-specific differing responses. The proteomic analysis of SaEVs identified clusters of proteins related to virulence and antibiotic resistance, supporting the theory that S. aureus might use EVs to evade host defences and colonize the mammary gland. Our results bring new insights into how SaEVs might impact the host during an S. aureus infection, which can be useful for future S. aureus vaccine development.

DOI: https://doi.org/10.1038/s41598-025-90466-6
Nat Commun. 2025 Feb 19. 16(1): 1761

TREM2 promotes lung fibrosis via controlling alveolar macrophage survival and pro-fibrotic activity.

Huachun Cui, Sami Banerjee, Na Xie, Musaddique Hussain, Ashish Jaiswal, Hongli Liu, Tejaswini Kulkarni, Veena B Antony, Rui-Ming Liu, Marco Colonna, Gang Liu.

Lung macrophages play a pivotal role in pulmonary fibrosis, with monocyte-derived alveolar macrophages driving disease progression. However, the mechanisms regulating their pro-fibrotic behavior and survival remain unclear, and effective therapeutic strategies are lacking. Here we show that triggering receptors expressed on myeloid cells 2 are predominantly expressed on monocyte-derived alveolar macrophages in fibrotic mouse lungs and are significantly elevated in lung macrophages from patients with idiopathic pulmonary fibrosis. Deletion or knockdown of this receptor disrupts intracellular survival signaling, promotes macrophage apoptosis, and attenuates their pro-fibrotic phenotype. We further demonstrate that a lipid mediator and a high-avidity ligand of this receptor, encountered by macrophages in the alveolar milieu, enhance macrophage survival and activity. Ablation of TREM2 or blocking this receptor with soluble receptors or specific antibodies effectively alleviates lung fibrosis in male mice. These findings identify this receptor as a critical regulator of macrophage-mediated fibrosis and a promising therapeutic target for intervention.

DOI: https://doi.org/10.1038/s41467-025-57024-0
Nat Commun. 2025 Feb 21. 16(1): 1864

PGLYRP1-mediated intracellular peptidoglycan detection promotes intestinal mucosal protection.

Shuyuan Chen, Rachel Putnik, Xi Li, Alka Diwaker, Marina Vasconcelos, Shuzhen Liu, Sudershan Gondi, Junhui Zhou, Lei Guo, Lin Xu, Sebastian Temme, Klare Bersch, Stephen Hyland, Jianyi Yin, Ezra Burstein, Brian J Bahnson, Jeffrey C Gildersleeve, Catherine Leimkuhler Grimes, Hans-Christian Reinecker.

Peptidoglycan recognition proteins (PGLYRPs) are implicated in the control of the intestinal microbiota; however, molecular requirements for peptidoglycan (PGN) binding and receptor signaling mechanisms remain poorly understood. Here we show that PGLYRP1 is a receptor for the disaccharide motif of lysine N-acetylglucosamine N-acetylmuramic tripeptide (GMTriP-K). PGLYRP1 is required for innate immune activation by GMTriP-K but not muramyl dipeptide (MDP). In macrophages, intracellular PGLYRP1 complexes with NOD2 and GEF-H1, both of which are required for GMTriP-K-regulated gene expression. PGLYRP1 localizes to the endoplasmic reticulum and interacts at the Golgi with NOD2 upon GMTriP-K stimulation. PGLYRP1 and dependent gene expression signatures are induced in both mouse intestinal inflammation and human ulcerative colitis. Importantly, PGLYRP1 activation by GMTriP-K can result in the protection of mice from TNBS-induced colitis. Mammalian PGLYRPs can function as intracellular pattern recognition receptors for the control of host defense responses in the intestine.

DOI: https://doi.org/10.1038/s41467-025-57126-9
Front Immunol. 2025 ;16 1532144

Comparison of air-liquid interface transwell and airway organoid models for human respiratory virus infection studies.

Camilla T Ekanger, Nilima Dinesh Kumar, Rosanne W Koutstaal, Fan Zhou, Martin Beukema, Joanna Waldock, Simon P Jochems, Noa Mulder, Cécile A C M van Els, Othmar G Engelhardt, Nathalie Mantel, Kevin P Buno, Karl Albert Brokstad, Agnete S T Engelsen, Rebecca J Cox, Barbro N Melgert, Anke L W Huckriede, Puck B van Kasteren.

   Introduction: Complex in vitro respiratory models, including air-liquid interface (ALI) transwell cultures and airway organoids, have emerged as promising tools for studying human respiratory virus infections. These models address several limitations of conventional two-dimensional cell line and animal models. However, the lack of standardized protocols for the application of these models in infection studies limits the possibilities for comparing results across different research groups. Therefore, we applied a collaborative approach to harmonize several aspects of experimental methodology between different research laboratories, aiming to assess the comparability of different models of human airway epithelium in the context of respiratory viral infections.
Methods: In this study, we compared three different models of human respiratory epithelium: a primary human bronchial epithelial cell-derived ALI transwell model, and two airway organoid models established from human airway- and lung-derived adult stem cells. We first assessed the presence of various differentiated cell types using immunofluorescence microscopy. Using a shared stock of influenza A virus, we then assessed viral growth kinetics, epithelial cytokine responses, and serum-mediated inhibition of infection.
Results: The presence of club, goblet, and ciliated cells was confirmed in all models. We observed similar viral replication kinetics with a >4-log increase in virus titre across all models using a TCID50 assay. Following infection, a reproducible antiviral cytokine response, including a consistent increase in CXCL10, IL-6, IFN-λ1, IFN-λ2/3, and IFN-β, was detected across all models. Finally, neutralization was assessed by pre-incubation of virus with human serum. Reduced viral replication was observed across all models, resulting in a 3- to 6-log decrease in virus titres as quantified by TCID50.
Discussion: In conclusion, all three models produced consistent results regardless of the varying cell sources, culturing approaches, and infection methods. Our collaborative efforts to harmonize infection experiments and compare ALI transwell and airway organoid models described here aid in advancing our understanding and improving the standardization of these complex in vitro respiratory models for future studies.

Keywords:  complex in vitro models; harmonization; influenza virus; mucosal models; respiratory tract

DOI:  https://doi.org/10.3389/fimmu.2025.1532144
bioRxiv. 2025 Feb 02. pii: 2025.01.29.635275. [Epub ahead of print]

Characterization of the Cellular Immune Response to Group B Streptococcal Vaginal Colonization.

Brady L Spencer, Dustin T Nguyen, Stephanie M Marroquin, Laurent Gapin, Rebecca L O'Brien, Kelly S Doran.

Introduction: Group B Streptococcus (GBS) asymptomatic colonizes the female genital tract (FGT) but can contribute to adverse pregnancy outcomes including pre-term birth, chorioamnionitis, and neonatal infection. We previously observed that GBS elicits FGT cytokine responses, including IL-17, during murine vaginal colonization; yet the anti-GBS cellular immune response during colonization remained unknown. We hypothesized that GBS may induce cellular immunity, resulting in FGT clearance.
Methods: Herein, we utilize depleting antibodies and knockout mice and performed flow cytometry to investigate cellular immunes responses during GBS colonization.
Results: We found that neutrophils (effectors of the IL-17 response) are important for GBS mucosal control as neutrophil depletion promoted increased GBS burdens in FGT tissues. Flow cytometric analysis of immune populations in the vagina, cervix, and uterus revealed, however, that GBS colonization did not induce a marked increase in FGT CD45+ immune cells. We also found that that Vγ6+ γδ T cells comprise a primary source of FGT IL-17. Finally, using knockout mice, we observed that IL-17-producing γδ T cells are important for the control of GBS in the FGT during murine colonization.
Conclusions: Taken together, this work characterizes FGT cellular immunity and suggests that GBS colonization does not elicit a significant immune response, which may be a bacterial directed adaptive outcome. However, certain FGT immune cells, such as neutrophils and ɣδ T cells, contribute to host defense and control of GBS colonization.

DOI: https://doi.org/10.1101/2025.01.29.635275
Compr Physiol. 2025 Feb;15(1): e70004

Myeloid-Mesenchymal Crosstalk in Lung Fibrosis.

Aritra Bhattacharyya, Preeti Yadav, Mallar Bhattacharya.

Idiopathic pulmonary fibrosis (IPF) is a chronic respiratory disease characterized by progressive scarring of the lung parenchyma. While two drugs have been approved by the US Food and Drug Administration (FDA) for IPF, median survival remains limited at 3 years, and the discovery of novel therapeutic targets is urgently needed. Recent studies indicate that immune cells play a critical role in regulating fibrosis. In this Mini Review, we discuss the recent literature focused on cells of the myeloid lineage that serve as key agents of pathologic interorgan communication in fibrosis. These cells are recruited from the bone marrow and have been found to be key drivers of the fibrotic process in the lung.

DOI: https://doi.org/10.1002/cph4.70004
Cell Death Dis. 2025 Feb 21. 16(1): 120

HNF4A mitigates sepsis-associated lung injury by upregulating NCOR2/GR/STAB1 axis and promoting macrophage polarization towards M2 phenotype.

Yu-Hang Yang, Ri Wen, Xin-Mei Huang, Tao Zhang, Ni Yang, Chun-Feng Liu, Tie-Ning Zhang.

Sepsis can trigger systemic inflammation and lead to detrimental effects on several organs, with particular emphasis on the lungs. In sepsis-associated lung injury, macrophages assume a pivotal role, as their overactivation could facilitate the secretion of inflammatory factors and the imbalance of polarization. Hepatocyte nuclear factor 4 alpha (HNF4A) has been reported its potential involvement in the regulation of inflammatory response and macrophage polarization. This study discusses the role and mechanism of HNF4A in sepsis-induced lung damage. HNF4A exhibits a decrease in expression by analyzing the differentially expressed genes in the lungs of septic mice from the Gene Expression Omnibus dataset GSE15379. Then, we established a mouse sepsis model through a cecal ligation and puncture method and observed that the expression of HNF4A was reduced in both lung tissues and alveolar macrophages. To evaluate the function of HNF4A, we overexpressed HNF4A mediated by adenovirus vectors, which were injected into mice. We found that HNF4A overexpression resulted in a higher survival rate in septic mice and an amelioration of pulmonary damage. Meanwhile, HNF4A overexpression mitigated the infiltration of inflammatory cells and impeded the M1 polarization but facilitated the M2 polarization of macrophages in the lung tissues or the alveolar lavage fluid. In vitro, we treated bone marrow-derived macrophages with interleukin-4. Consistent results were obtained that HNF4A overexpression promoted the M2 polarization of macrophages. Mechanistically, we found that HNF4A transcriptionally regulate the expression of nuclear receptor coactivator 2 (NCOA2) through binding to its promoter region. NCOA2 interacted with glucocorticoid receptor (GR). Stabilin 1 (STAB1) was selected as a possible target by transcriptome sequencing analysis. Functional experiments confirmed STAB1 as a downstream target of the HNF4A/NCOA2/GR axis. Overall, this research investigated the potential impact of HNF4A on pulmonary injury in sepsis. It is suggested that one of the regulatory mechanisms involved in this association may be the NCOR2/GR/STAB1 axis.

DOI: https://doi.org/10.1038/s41419-025-07452-z
Front Immunol. 2024 ;15 1500696

Staphylococcus aureus-specific TIGIT+ Treg are present in the blood of healthy subjects - a hurdle for vaccination?

Jonah Clegg, Malgorzata E Mnich, Alberto Carignano, Giovanni Cova, Simona Tavarini, Chiara Sammicheli, Bruna Clemente, Megan Smith, Emilio Siena, Monia Bardelli, Michela Brazzoli, Fabio Bagnoli, Rachel M McLoughlin, Elisabetta Soldaini.

  Staphylococcus aureus poses an enormous burden of morbidity and mortality worldwide. Making an efficacious vaccine has however proven extremely challenging. Due to colonizing interactions, pre-existing S. aureus-specific CD4+ T cells are often found in the human population and yet a detailed characterization of their phenotypes and how they might in turn impact vaccine efficacy are thus far unknown. Using an activation induced marker assay to sort for S. aureus-specific CD4+ T cells in an effector function-independent manner, single cell transcriptomic analysis was conducted. Remarkably, S. aureus-specific CD4+ T cells consisted not only of a broader spectrum of conventional T cells (Tcon) than previously described but also of regulatory T cells (Treg). As compared to polyclonally-activated CD4+ T cells, S. aureus-specific Tcon were enriched for the expression of the Th17-type cytokine genes IL17A, IL22 and IL26, while higher percentages of S. aureus-specific Treg expressed the T Cell Immunoreceptor with Ig and ITIM domains (TIGIT), a pleiotropic immune checkpoint. Notably, the antagonistic anti-TIGIT mAb Tiragolumab increased IL-1β production in response to S. aureus in vitro. Therefore, these results uncover the presence of S. aureus-specific TIGIT+ Treg in the blood of healthy subjects that could blunt responses to vaccination and indicate TIGIT as a potential targetable biomarker to overcome pre-exposure-induced immunosuppression.

Keywords:  Staphylococcus aureus; TIGIT; Th17; Treg; colonization; host-pathogen interactions; vaccines

DOI:  https://doi.org/10.3389/fimmu.2024.1500696
Nat Metab. 2025 Feb 19.

Pro-inflammatory macrophages produce mitochondria-derived superoxide by reverse electron transport at complex I that regulates IL-1β release during NLRP3 inflammasome activation.

Alva M Casey, Dylan G Ryan, Hiran A Prag, Suvagata Roy Chowdhury, Eloïse Marques, Keira Turner, Anja V Gruszczyk, Ming Yang, Dane M Wolf, Jan Lj Miljkovic, Joyce Valadares, Patrick F Chinnery, Richard C Hartley, Christian Frezza, Julien Prudent, Michael P Murphy.

Macrophages stimulated by lipopolysaccharide (LPS) generate mitochondria-derived reactive oxygen species (mtROS) that act as antimicrobial agents and redox signals; however, the mechanism of LPS-induced mitochondrial superoxide generation is unknown. Here we show that LPS-stimulated bone-marrow-derived macrophages produce superoxide by reverse electron transport (RET) at complex I of the electron transport chain. Using chemical biology and genetic approaches, we demonstrate that superoxide production is driven by LPS-induced metabolic reprogramming, which increases the proton motive force (∆p), primarily as elevated mitochondrial membrane potential (Δψm) and maintains a reduced CoQ pool. The key metabolic changes are repurposing of ATP production from oxidative phosphorylation to glycolysis, which reduces reliance on F1FO-ATP synthase activity resulting in a higher ∆p, while oxidation of succinate sustains a reduced CoQ pool. Furthermore, the production of mtROS by RET regulates IL-1β release during NLRP3 inflammasome activation. Thus, we demonstrate that ROS generated by RET is an important mitochondria-derived signal that regulates macrophage cytokine production.

DOI: https://doi.org/10.1038/s42255-025-01224-x
F1000Res. 2024 ;13 1543

Effect of hyperglycemia on lung microbiota and treatment outcome in pulmonary tuberculosis: A scoping review.

Victor Moses Musyoki, Marianne Mureithi, Annamari Heikinheimo, Elizabeth Maleche-Obimbo, Dennis Kithinji, Susan Musau, Kariuki Njaanake, Omu Anzala.

  The comorbidity due to pulmonary tuberculosis (TB) and diabetes mellitus (DM) is a global health problem, but its mechanism remains unclear. It is suspected that hyperglycemic alteration of the immune response to TB and the composition of the lung microbiota play an important role. This scoping review aimed to contribute to the understanding of the mechanisms by mapping evidence on the effect of hyperglycemia on physical health indicators, immune cell counts, cytokine levels, and the composition of lung microbiota in patients with the DM-TB comorbidity. A systematic search for research articles about the relationship between hyperglycemia and physical health, immune cells, and cytokine levels in humans was conducted in MEDLINE, Scopus, and CINAHL Plus. Then, articles on the interactions between the immune cells, cytokines, and lung microbiota were identified through Google Scholar and Google search engines. Characteristics of the studies focusing on effects of hyperglycemia, the findings of the articles relevant to the research objectives, and strengths and weaknesses of the selected articles were charted in a data extraction tool. Twenty-one articles on the effects of hyperglycemia on immune mediators and health outcomes of patients with DM-TB were included. The evidence showed hyperglycemia to be associated with unfavorable treatment outcomes; altered counts and functioning of dendritic cells, monocytes, and CD4+ T cells; and changes in cytokine levels (mainly INF-γ, IL-17, IL-1β, IL-2, IL-6, IL-10, and TNF-α) in patients with DM-TB. The composition of the lung microbiota changed in correlation with changes in physical health outcomes, counts of immune cells, and cytokine levels. Thus, hyperglycemia, immune responses, and dysbiosis of the lung microbiota are integral in the pathogenesis of DM-TB and TB treatment outcomes. A prospective cohort study, especially in individuals with newly diagnosed DM versus known DM and concomitant latent TB versus active TB, is recommended to define causal relationships.

Keywords:  Comorbidity; Cytokines; Diabetes; Immune response; Lung microbiome; Pathogenesis; Scoping review; Tuberculosis

DOI:  https://doi.org/10.12688/f1000research.159555.1
Immunol Rev. 2025 Mar;330(1): e70008

Innate Immune Sensors in Health and Disease.

Prajwal Gurung.



Keywords:  cell lineages and subsets; cytokines; immune‐mediated diseases; infectious diseases; inflammation; molecules; monocytes/macrophages; processes; toll‐like receptors/pattern recognition receptors

DOI:  https://doi.org/10.1111/imr.70008
Curr Protoc. 2025 Feb;5(2): e70107

Redefining Cell Culture Using a 3D Flipwell Co-culture System: A Mimetic for Gut Architecture and Dynamics In Vitro.

Maria A Beamer, Saori Furuta.

  Gut mucosae are composed of stratified layers of microbes, a selectively permeable mucus, an epithelial lining, and connective tissue homing immune cells. Studying cellular and chemical interactions between the gut mucosal components has been limited without a good model system. We have engineered a three-dimensional (3D) multi-cellular co-culture system we coined "3D Flipwell system" using cell culture inserts stacked against each other. This system allows an assessment of the impact of a gut mucosal environmental change on interactions between gut bacteria, epithelia, and immune cells. As such, this system can be utilized in examining the effects of exogenous stimuli, such as dietary nutrients, bacterial infection, and drugs, on the gut mucosa that could predetermine how these stimuli might influence the rest of body. Here, we describe the methods of construction and application of the new 3D Flipwell system we utilized previously in assessing the crosstalk between the gut mucosa and macrophage polarization. We demonstrate the physiological responses of different components of the co-cultures to Sepiapterin (SEP), the precursor of the nitric oxide synthase cofactor tetrahydrobiopterin (BH4). We reported previously that SEP induces a pro-immunogenic shift of macrophages having acquired an immune suppressive phenotype. We also showed that SEP induces a defense mechanism of commensal gut bacteria. The protocol describing the assembly and use of the 3D Flipwell co-culture system herein would grant its utility in evaluating the concurrent effects of pharmacologic and microbiologic stimuli on gut mucosal components. © 2025 The Author(s). Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: 3D Flipwell construction, assembly, and collagen coating Basic Protocol 2: Flipwell cell seeding and cell culture Basic Protocol 3: Addition of bacterial culture to the Flipwell system Basic Protocol 4: Flipwell disassembly for scanning electron microscopy (SEM) studies Basic Protocol 5: Immunofluorescence antibody staining for confocal microscopy.

Keywords:  3D co‐culture; Caco‐2; gut; immune cells; macrophages; microbiome

DOI:  https://doi.org/10.1002/cpz1.70107
Benef Microbes. 2025 Feb 13. 1-17

Beneficial effects of Lactiplantibacillus plantarum BGPKM22 manifest only in interaction with healthy, but not with diseased human bronchial epithelial cells.

H Mitrovic, S Sokovic Bajic, K Veljovic, N Golic, M Stankovic.

It has already been recognised that lung microbiota differs in healthy and diseased lungs. In chronic obstructive pulmonary disease (COPD), a change in the structure, abundance and diversity of lung microbiota correlates with the severity of disease. But how the members of lung microbiota influence healthy and diseased lungs, as well as how they are affected by the lung health status is still largely unknown. In this study, we applied a dual RNA sequencing in order to scrutinise an early interspecies interaction between healthy and diseased human primary bronchial epithelial cells exposed to the beneficial bacteria Lactiplantibacillus plantarum BGPKM22. In healthy and diseased cells interaction with BGPKM22 led to a change in expression of 52 and 45 genes, respectively. The genes IQCN, LINC01554, KCNB1, and CDK7 indicated a specific response of human bronchial epithelial cells exposed to the BGPKM22 strain, regardless of the health status. Markedly more genes showed a change in expression in the BGPKM22 strain in interaction with healthy than with diseased cells, 486 and 101, respectively. Interaction with human bronchial epithelial cells caused a stress to bacteria, but the response of bacteria depended on the health status of the cells. The adhesion of the BGPKM22 strain was better to healthy, than to diseased cells. The fitness of the BGPKM22 strain increased only in interaction with healthy, but not with diseased cells. Remarkably, interaction with healthy, but not with diseased cells, stimulated the synthesis of exopolysaccharide layer of the strain BGPKM22. So, beneficial effects of bacteria can be diminished in interaction with diseased cells. Also, a lowered affinity of bacteria towards diseased environment can explain microbiota dysbiosis in the diseased lungs, such as lungs in patients with COPD.

DOI: https://doi.org/10.1163/18762891-bja00060
Free Radic Biol Med. 2025 Feb 18. pii: S0891-5849(25)00097-8. [Epub ahead of print]

Endogenous production of nitric oxide by iNOS in human cells restricts inflammatory activation and cholesterol/fatty acid biosynthesis.

Franklin F Tam, Jenice M Dumlao, Amy Hy Lee, Jonathan C Choy.

  Nitric oxide (NO) is a bioactive gas that is known to control many physiological processes. In human parenchymal cells, the function of iNOS-derived NO is incompletely understood. Here, we used RNA-seq to examine the role of iNOS-derived NO in the control of gene expression in a human lung epithelial cell line treated with inflammatory cytokines. iNOS-derived NO restricted the expression of genes involved in immune signaling, including the immune-related genes CXCL9 and E-selectin that were not previously known to be inhibited by iNOS. We also determined that iNOS-derived NO inhibits the expression of genes needed for cholesterol/fatty acid biosynthesis in response to cytokine stimulation, a process not previously known to be affected by NO. These findings establish the regulation of immune activation and cholesterol/fatty acid biosynthesis as main functions of iNOS in human parenchymal cells.

Keywords:  Nitric oxide; cell biology; cell signaling; cholesterol biosynthesis; cytokines; immune activation; inducible nitric oxide synthase

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.02.022
Infect Immun. 2025 Feb 19. e0053524

Immunostimulatory effects of Streptococcus sanguinis extracellular membrane vesicles protect oral gingival epithelial cells from periodontal pathobiont damage.

Emily Helliwell, Isabella Rauch, Tim Nice, Justin Merritt, Jens Kreth.

  The commensal Streptococcus sanguinis is highly prevalent in the oral cavity and characterized for its ability to inhibit growth of oral pathogens. Like many other cell types, streptococci produce extracellular membrane vesicles (EMVs), which contain specific molecular cargo and facilitate interactions with host cells. We previously demonstrated that EMVs from S. sanguinis are internalized by gingival epithelial cells (GECs) without causing cell death. Our aim is to characterize the effects of vesicles on eukaryotic cells. Microscopy studies of gingival epithelial cells inoculated with EMVs from wild-type and specific deletion mutants show differential uptake, with decreased uptake of ΔSSA1099 EMVs and increased uptake of ΔSSA1882 EMVs relative to SK36 EMVs. However, EMVs from wild-type and deletion mutants showed similar patterns in cytokine and chemokine secretion. Transcriptomic analysis of gingival epithelial cells inoculated with SK36 EMVs showed a downregulation of genes implicated in apoptosis as well as interferon signaling, while showing an upregulation of genes involved in cytokine production. Gelatin zymography results show that SK36 EMVs have a contrasting result on production of MMP2/9; MMP2 production is decreased while MMP9 is increased by 48 hours post-inoculation (hpi). Dual-inoculation studies demonstrate that prior internalization of S. sanguinis EMVs protects gingival epithelial cells from exposure to pathobiont Porphyromonas gingivalis outer membrane vesicles (OMVs), preventing dissociation and cell death. Our overall findings suggest that S. sanguinis EMVs trigger an immune response on gingival epithelial cells; however, this response suggests inhibition of some immune signaling pathways. Our results highlight an important role in commensalism, in which a microbe induces an immune response but avoids damage to host cells, thus discouraging infection by pathobionts.

Keywords:  Streptococcus sanguinis; commensals; immune response; oral biofilm; vesicles

DOI:  https://doi.org/10.1128/iai.00535-24
Nat Rev Microbiol. 2025 Feb 20.

The role of bacterial metabolism in antimicrobial resistance.

Mehrose Ahmad, Sai Varun Aduru, Robert P Smith, Zirui Zhao, Allison J Lopatkin.

The relationship between bacterial metabolism and antibiotic treatment is complex. On the one hand, antibiotics leverage cell metabolism to function. On the other hand, increasing research has highlighted that the metabolic state of the cell also impacts all aspects of antibiotic biology, from drug efficacy to the evolution of antimicrobial resistance (AMR). Given that AMR is a growing threat to the current global antibiotic arsenal and ability to treat infectious diseases, understanding these relationships is key to improving both public and human health. However, quantifying the contribution of metabolism to antibiotic activity and subsequent bacterial evolution has often proven challenging. In this Review, we discuss the complex and often bidirectional relationships between metabolism and the various facets of antibiotic treatment and response. We first summarize how antibiotics leverage metabolism for their function. We then focus on the converse of this relationship by specifically delineating the unique contribution of metabolism to three distinct but related arms of antibiotic biology: antibiotic efficacy, AMR evolution and AMR mechanisms. Finally, we note the relevance of metabolism in clinical contexts and explore the future of metabolic-based strategies for personalized antimicrobial therapies. A deeper understanding of these connections is crucial for the broader scientific community to address the growing crisis of AMR and develop future effective therapeutics.

DOI: https://doi.org/10.1038/s41579-025-01155-0
Trends Parasitol. 2025 Feb 13. pii: S1471-4922(25)00034-0. [Epub ahead of print]

Helminths target macrophage epigenetics and metabolism to evade immunity.

Bart Everts.

  Parasitic helminths are well known master regulators of host immune responses. Yet, the underlying molecular principles remain largely enigmatic. Recent work from Bohnacker et al. reveals that glutamate dehydrogenase (GDH), a metabolic enzyme secreted by Heligmosomoides polygyrus, can suppress type 2 immunity by multimodal regulation of macrophage metabolism and epigenetics.

Keywords:  epigenetics; helminth; immunomodulation; macrophage; metabolism; prostaglandin E2

DOI:  https://doi.org/10.1016/j.pt.2025.01.012
Sci Rep. 2025 Feb 18. 15(1): 5894

Lactobacillus lysates protect oral epithelial cells from pathogen-associated damage, increase secretion of pro-inflammatory cytokines and enhance barrier integrity.

Steven D Mercer, Christopher Doherty, Gurdeep Singh, Thomas Willmott, Tanaporn Cheesapcharoen, Rawee Teanpaisan, Catherine O'Neill, Ruth G Ledder, Andrew J McBain.

  Periodontitis is a chronic gum disease characterised by inflammation and the loss of bone. We have explored the potential prophylactic effects of lysates from four Lactobacillus strains against the toxic effects of three periodontal pathogens (Porphyromonas gingivalis, Fusobacterium nucleatum, and Aggregatibacter actinomycetemcomitans). TR146 oral epithelial cells were pre-treated with Lactobacillus lysates (L. rhamnosus - GG, L. rhamnosus - SD11, L. reuteri and L. plantarum) and then challenged with pathogenic material (live cells, lysates, or supernatants). Cytokine analysis was performed on supernatants of cells treated with probiotic lysates from 1.5 h to 24 h. Effects of probiotic lysates on re-epithelialisation were determined using keratinocyte scratch assays, monitoring both migration and proliferation. Epithelial barrier function was observed after lysate addition by trans-epithelial electrical resistance (TEER) and by quantifying claudin-1 expression. Treatment of host cells with Lactobacillus lysates before pathogen exposure conferred significant protection against viability loss. Although extended pre-treatment did not generally increase protection, against live Aggregatibacter actinomycetemcomitans, significant increases in viability were seen after 24 h of pre-treatment for GG, SD11 and L. plantarum. Pro-inflammatory cytokines TNF-α, IP-10, IL-6, and IL-8 increased significantly with extended probiotic treatment, while IL-1β and IL-1α secretion significantly increased but remained constant over time. Secretion of the growth-promoting cytokine TGF-β increased after 3 h of treatment, however no increases in the regulatory cytokine IL-10 were recorded. Only exposure to SD11 significantly enhanced re-epithelialisation, TEER and claudin-1 expression while GG increased TEER but decreased claudin-1 expression. L. plantarum significantly inhibited re-epithelialisation but did not impact TEER or claudin-1 expression. All lysates significantly improved TEER in the presence of pathogenic material, demonstrating a protective effect on barrier function.

Keywords:  Oral-disease; Oral-health; Periodontitis; Postbiotics; Probiotics

DOI:  https://doi.org/10.1038/s41598-025-86914-y
Free Radic Biol Med. 2025 Feb 16. pii: S0891-5849(25)00094-2. [Epub ahead of print]

Macrophages hijack carbapenem-resistance hypervirulent Klebsiella pneumoniae by blocking SLC7A11/GSH-manipulated iron oxidative stress.

Qing Yu, Jie Yang, Heyu Chen, Ruishan Liu, Ruomeng Hu, Jiachang Cai, Shikuan Yang, Beiwen Zheng, Peng Guo, Zhijian Cai, Shufang Zhang, Gensheng Zhang.

  Infection with carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKP) is life-threatening because of its pronounced virulence and antibiotic resistance. Recent studies revealed that iron and ROS enhance the ability of macrophages to eliminate intracellular pathogenic bacteria. However, whether and how iron-related oxygen stress responses in macrophages elicit a protective role against CR-hvKP infection remains largely unknown. In a mouse model of CR-hvKP pulmonary infection, the production of the Solute Carrier Family 7 member 11 (SLC7A11) was increased. Treatment with the ferroptosis agonist Erastin or Sorafenib decreased the SLC7A11 expression and the bacterial load in infected lung tissues, alleviating CR-hvKP-induced acute lung injury, increasing the content of TLR4, ROS and LPO. In vitro experiments showed that CR-hvKP infection resulted in a remarkable time-dependent changes in the expression of SLC7A11, GSH, ferrous iron, ROS and LPO in MH-S cells. Mechanically, blocking the expression of SLC7A11 in CR-hvKP-infected MH-S cells increased iron and ROS, improving the ability of macrophages to clear CR-hvKP in an LPO-dependent manner. Taken together, our study reveals that improving iron-related oxygen stress via blocking the SLC7A11/GSH pathway promoting the macrophages to phagocytose and eliminate CR-hvKP, which provides a new promising strategy against CR-hvKP infection.

Keywords:  Carbapenem-resistance hypervirulent Klebsiella pneumoniae; Glutathione; Lipid peroxidation; Macrophage; Solute Carrier Family 7 Member 11

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.02.019