bims-bac4me 2025-06-15 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2025–06–15
twenty-six papers selected by
Chun-Chi Chang, Lunds universitet

No (innate immune) training without lactate.
C1q reprograms innate immune memory.
Colonizing Bacteria Aggravate Inflammation, Cytotoxicity and Immune Defense During Influenza A Virus Infection.
Setdb2 Regulates Inflammatory Trigger-Induced Trained Immunity of Macrophages Through Two Different Epigenetic Mechanisms.
Metabolic ecology of microbiomes: Nutrient competition, host benefits, and community engineering.
Tolerance to Lung Infection in TWIK2 K + Efflux Mediated Macrophage Trained Immunity.
Antigen-presenting cells and lung CD8⁺ resident memory T cells coordinate local immune protection and shape responses to respiratory virus infection.
Immunometabolism at the Crossroads of Infection: Mechanistic and Systems-Level Perspectives from Host and Pathogen.
Redox signaling in innate immunity and inflammation: focus on macrophages and neutrophils.
H3K27me3 modulates trained immunity of monocytes in HDM-allergic diseases.
Epigenetic changes and serotype-specific responses of alveolar type II epithelial cells to Streptococcus pneumoniae in resolving influenza A virus infection.
Epigenetic Modulation by Lactylation in Sepsis: Linking Metabolism to Immune Dysfunction.
Working together: gut microbe-microbe interactions shape host inflammation.
The microbiome: An actor or stage for the beneficial action of probiotics, prebiotics, synbiotics, and postbiotics?
Host-pathogen interaction profiling of nontypeable Haemophilus influenzae and Moraxella catarrhalis coinfection of bronchial epithelial cells.
Tissue signatures of human macrophages during homeostasis and activation.
The Regulatory Network of Transcription Factors in Macrophage Polarization.
Polybacterial intracellular macromolecules shape single-cell inflammatory profiles in upper airway epithelia.
Trimming the fat: a brief review of lipids at the host-pathogen interface.
Antigen-specific CD4+ T cells promote monocyte recruitment and differentiation into glycolytic lung macrophages to control Mycobacterium tuberculosis.
Interferon-epsilon, an estrogen-induced type I interferon, is uniquely exploited by Neisseria gonorrhoeae via effects on sialic acid metabolism
Staphylococcus aureus α-hemolysin induces DNA methylation changes in human Th1 cells.
Spatial Heterogeneity of Macrophages in the Human Lung.
Airway basal stem cells are necessary for the maintenance of functional intraepithelial airway macrophages.
Unlocking the power of human milk and infant feeding: Understanding how nutrition and early microbiota interaction shapes health programming.
Protective mechanism of Bifidobacterium on intestinal mucosal barrier in sepsis.

Mol Cell. 2025 Jun 05. pii: S1097-2765(25)00448-4. [Epub ahead of print]85(11): 2065-2067

No (innate immune) training without lactate.

Jan Van den Bossche.

A recent study in Cell unveils lactate production and downstream histone lactylation as a new player in the induction of trained immunity.1 It provides insight into the intricate metabolic-epigenetic interplay that governs innate immune memory and offers a potential target to reverse maladaptive trained immunity in chronic inflammatory diseases.

DOI: https://doi.org/10.1016/j.molcel.2025.05.014
Front Immunol. 2025 ;16 1515127

C1q reprograms innate immune memory.

Inge Jonkman, Maaike M E Jacobs, Yutaka Negishi, Julia I P van Heck, Vasiliki Matzaraki, Joost H A Martens, Marijke Baltissen, Michiel Vermeulen, Zahi A Fayad, Abraham J P Teunissen, Willem J M Mulder, Luuk B Hilbrands, Leo A B Joosten, Mihai G Netea, Musa M Mhlanga, Nils Rother, Raphaël Duivenvoorden.

  Innate immune memory, also called trained immunity, is a metabolic and epigenetically regulated process that enables innate immune cells to recalibrate their inflammatory reactivity in response to pathogenic or endogenous stimuli. In addition to its function in host defense, trained immunity contributes to diverse immune-mediated diseases. We discovered that complement component 1q (C1q) is an effective modulator of innate immune memory, potently suppressing the responsiveness of myeloid cells. We found that C1q leads to profound reprogramming of myeloid cell metabolism, particularly glycolysis, and exerts control over the transcriptional regulation of important metabolic and inflammatory genes. We corroborate our findings by identifying single-nucleotide polymorphisms close to the C1q gene that are linked to induction of trained immunity by Bacillus Calmette-Guérin (BCG) or beta-glucan in healthy peripheral blood mononuclear cells. Our results reveal an immunomodulatory role for C1q and provide evidence of a molecular interaction between the complement system and innate immune memory. These findings expand our understanding of innate immune memory.

Keywords:  C1q; complement; immunometabolism; innate immune memory; tolerance; trained immunity

DOI:  https://doi.org/10.3389/fimmu.2025.1515127
Int J Mol Sci. 2025 Jun 03. pii: 5364. [Epub ahead of print]26(11):

Colonizing Bacteria Aggravate Inflammation, Cytotoxicity and Immune Defense During Influenza A Virus Infection.

Liane Giebeler, Christina Ehrhardt, Antje Häder, Thurid Lauf, Stefanie Deinhardt-Emmer, Bettina Löffler.

  A diverse bacterial community colonizes the respiratory system, including commensals such as Staphylococcus epidermidis (S. epidermidis) and Streptococcus salivarius (S. salivarius), as well as facultative pathogens like Staphylococcus aureus (S. aureus). This study aimed to establish a colonized cell culture model to investigate the impact of these bacteria on influenza A virus (IAV) infection. Respiratory epithelial cells were exposed to S. epidermidis, S. salivarius, or S. aureus, using either live or heat-inactivated bacteria, followed by IAV infection. Cell integrity was assessed microscopically, cytotoxicity was measured via LDH assay, and inflammatory responses were analyzed through cytokine expression. Additionally, macrophage function was examined in response to bacterial colonization and IAV infection. While commensals maintained epithelial integrity for 48 h, S. aureus induced severe cell damage and death. The most pronounced epithelial destruction was caused by coinfection with S. aureus and IAV. Notably, commensals did not confer protection against IAV but instead enhanced epithelial inflammation. These effects were dependent on live bacteria, as inactivated bacteria had no impact. However, prior exposure to S. epidermidis and S. salivarius improved macrophage-mediated immune responses against IAV. These findings suggest that while individual commensals do not directly protect epithelial cells, they may contribute to immune training and enhance lung defense mechanisms.

Keywords:  cell culture model; commensal bacteria; cytotoxicity; facultative pathogenic bacteria; influenza A virus; macrophages; respiratory microbiome

DOI:  https://doi.org/10.3390/ijms26115364
Res Sq. 2025 May 28. pii: rs.3.rs-6702384. [Epub ahead of print]

Setdb2 Regulates Inflammatory Trigger-Induced Trained Immunity of Macrophages Through Two Different Epigenetic Mechanisms.

Timothy Osborne, Anant Jaiswal, Laszlo Halasz, David Williams.

"Trained immunity" of innate immune cells occurs through a sequential two-step process where an initial pathogenic or sterile inflammatory trigger is followed by an amplified response to a later un-related secondary pathogen challenge. The memory effect is mediated at least in part through epigenetic modifications of the chromatin landscape. Here, we investigated the role of the epigenetic modifier Setdb2 in microbial (β-glucan) or sterile trigger (Western-diet-WD/oxidized-LDL-oxLDL)-induced trained immunity of macrophages. Using genetic mouse models and genomic analysis, we uncovered a critical role of Setdb2 in regulating proinflammatory and metabolic pathway reprogramming. We further show that Setdb2 regulates trained immunity through two different complementary mechanisms: one where it positively regulates glycolytic and inflammatory pathway genes via enhancer-promoter looping, and is independent of its enzymatic activity; while the second mechanism is associated with both increased promoter associated H3K9 methylation and repression of interferon response pathway genes. Interestingly, while both mechanisms occur in response to pathogenic training, only the chromatin-looping mechanism operates in response to the sterile inflammatory stimulus. These results reveal a previously unknown bifurcation in the downstream pathways that distinguishes between pathogenic and sterile inflammatory signaling responses associated with the innate immune memory response and may provide potential therapeutic opportunities to target cytokine vs. interferon pathways to limit complications of chronic inflammation.

DOI: https://doi.org/10.21203/rs.3.rs-6702384/v1
Cell Host Microbe. 2025 Jun 11. pii: S1931-3128(25)00196-9. [Epub ahead of print]33(6): 790-807

Metabolic ecology of microbiomes: Nutrient competition, host benefits, and community engineering.

Erik Bakkeren, Vit Piskovsky, Kevin R Foster.

  Many plants and animals, including humans, host diverse communities of microbes that provide many benefits. A key challenge in understanding microbiomes is that the species composition often differs among individuals, which can thwart generalization. Here, we argue that the key to identifying general principles for microbiome science lies in microbial metabolism. In the human microbiome and in other systems, every microbial species must find ways to harvest nutrients to thrive. The available nutrients in a microbiome interact with microbial metabolism to define which species have the potential to persist in a host. The resulting nutrient competition shapes other mechanisms, including bacterial warfare and cross-feeding, to define microbiome composition and properties. We discuss impacts on ecological stability, colonization resistance, nutrient provision for the host, and evolution. A focus on the metabolic ecology of microbiomes offers a powerful way to understand and engineer microbiomes in health, agriculture, and the environment.

Keywords:  bacterial warfare; colonization resistance; community assembly; community engineering; community stability; cross-feeding; gut; microbiome; nutrient competition; pathogens

DOI:  https://doi.org/10.1016/j.chom.2025.05.013
bioRxiv. 2025 May 28. pii: 2025.05.25.655979. [Epub ahead of print]

Tolerance to Lung Infection in TWIK2 K + Efflux Mediated Macrophage Trained Immunity.

Josh Thompson, Yufan Li, Yuanling Song, Ki-Wook Kim, Asrar B Malik, Jingsong Xu.

Alveolar macrophages (AMφ) are essential for innate immune function in the lungs. It is now apparent that macrophages can be trained to become better at attacking infections. Although trained immunity is thought to result from metabolic and epigenetic reprogramming, the underlying mechanisms remain unclear. Here, we report that AMφ can be trained by extracellular ATP, which is ubiquitously released during inflammation. ATP ligates the canonical Purinergic Receptor 2 subtype X7 receptor (P2X7) to mediate endosomal Two-pore domain Weak Inwardly rectifying K + channel 2 (TWIK2) translocation into the plasma membrane (PM). This endows the cells to transit to a 'ready' state for microbial killing in two directions: first, K + efflux via PM-TWIK2 induces NLRP3 inflammasome activation, which further activates metabolic pathways; second, upon bacterial phagocytosis, PM-TWIK2 internalizes into phagosome membrane with proper topological orientation, where TWIK2 mediates K + influx into phagosomes to control pH and ionic strength favoring bacterial killing. Therefore, the enhanced association of TWIK2 in phagosomal and plasma membranes signaled by danger-associated molecular patterns (DAMPs), such as ATP, mediates trained immunity in AMφ and enhances the microbiocidal activity.

DOI: https://doi.org/10.1101/2025.05.25.655979
Int Immunol. 2025 Jun 10. pii: dxaf033. [Epub ahead of print]

Antigen-presenting cells and lung CD8⁺ resident memory T cells coordinate local immune protection and shape responses to respiratory virus infection.

Takumi Kawasaki, Moe Ikegawa, Taro Kawai.

  The respiratory mucosa, encompassing the lungs and nasal tissues, serves as the primary barrier against respiratory viruses. While neutralizing antibodies are effective at preventing viral entry, virus-specific CD8⁺ T cells play a vital role in eliminating infected cells and inducing an antiviral state, which curbs disease progression. Among these, CD8⁺ tissue-resident memory T (TRM) cells persist long term in the lungs, where they serve as first responders and rapidly expand upon secondary respiratory virus infection to provide local protection. The establishment and maintenance of lung CD8⁺ TRM cells require not only local cytokine signals but also antigen presentation. Specific subsets of antigen-presenting cells, such as dendritic cells, alveolar macrophages, monocytes, and endothelial cells also influence the quality and durability of CD8⁺ TRM cell responses. This review summarizes key findings on CD8⁺ T cell dynamics during respiratory viral infections, with a particular focus on CD8⁺ TRM cell formation and function. We also highlight the importance of local antigen presentation in driving TRM development and discuss how this knowledge can inform vaccine strategies aimed at eliciting robust, long-lasting mucosal immunity.

Keywords:  CD8+ T cell; SARS-CoV-2; TRM cells; antigen presentation; influenza virus

DOI:  https://doi.org/10.1093/intimm/dxaf033
ArXiv. 2025 Jun 02. pii: arXiv:2506.02236v1. [Epub ahead of print]

Immunometabolism at the Crossroads of Infection: Mechanistic and Systems-Level Perspectives from Host and Pathogen.

Sunayana Malla, Nabia Shahreen, Rajib Saha.

The emerging field of immunometabolism has underscored the central role of metabolic pathways in orchestrating immune cell function. Far from being passive background processes, metabolic activities actively regulate key immune responses. Fundamental pathways such as glycolysis, the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation critically shape the behavior of immune cells, influencing macrophage polarization, T cell activation, and dendritic cell function. In this review, we synthesize recent advances in immunometabolism, with a focus on the metabolic mechanisms that govern the responses of both innate and adaptive immune cells to bacterial, viral, and fungal pathogens. Drawing on experimental, computational, and integrative methodologies, we highlight how metabolic reprogramming contributes to host defense in response to infection. These findings reveal new opportunities for therapeutic intervention, suggesting that modulation of metabolic pathways could enhance immune function and improve pathogen clearance.
Free Radic Biol Med. 2025 Jun 06. pii: S0891-5849(25)00755-5. [Epub ahead of print]

Redox signaling in innate immunity and inflammation: focus on macrophages and neutrophils.

Ilana Braunstein, Hozumi Motohashi, Tobias Dallenga, Ulrich E Schaible, Moran Benhar.

  Redox signaling plays a central role in regulating macrophage and neutrophil function, integrating reactive oxygen species (ROS), reactive nitrogen species (RNS), and reactive sulfur species (RSS) to modulate innate immune responses. Reactive species modulate diverse cellular processes in phagocytes, including differentiation, metabolic adaptation, cytokine production, and cell death. Antioxidant systems, including the glutathione and thioredoxin systems, play essential roles in maintaining redox balance, counteracting excessive oxidants, and preserving immune cell function. Oxidative post-translational modifications of proteins, mainly on cysteine and methionine residues, act as redox switches that regulate innate immune cell function. Dynamic redox modifications critically influence phagocyte metabolism, migration, phagocytosis, survival and communication with neighboring immune and non-immune cells, thereby controlling the response to infection as well as initiation and resolution of inflammation. Additionally, other oxidized mediators, such as oxidized mitochondrial DNA and oxidized lipids, contribute to immune regulation and its dysregulation in inflammatory diseases. Thus, redox signaling is tightly linked to both immune homeostasis and pathological inflammation. This review explores the mechanistic basis of redox regulation in macrophages and neutrophils, emphasizing the interplay between ROS, RNS, RSS and antioxidant defenses. We also discuss recent insights into the role of redox regulation in the context of pulmonary infection and inflammation. Overall, a deeper understanding of these redox-regulated pathways may reveal novel strategies for selectively modulating inflammation while preserving essential immune functions.

Keywords:  Redox regulation; infection; inflammation; macrophages; neutrophils; pulmonary disease

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.06.006
Front Immunol. 2025 ;16 1572796

H3K27me3 modulates trained immunity of monocytes in HDM-allergic diseases.

Lingli Han, Lin Li, Liangjiao Yao, Huaqin Bu, Yajie Tian, Qifan Li, Ke Zhu, Haili Yao, Xiaochuan Wang, Maoxiang Qian, Wei Lu, Jinqiao Sun.

   Background: Monocytes have been confirmed to increase in persistently food-allergic children. A phenomenon of innate immune memory, called trained immunity, has also been observed in monocytes from allergic children. However, the underlying mechanism remains poorly understood.
Methods: We enrolled a cohort of HDM-allergic children alongside age-matched healthy controls and established an HDM-sensitized allergic mouse model. Flow cytometric analyses were conducted to quantify monocyte frequencies in clinical cohorts and experimental animals. We performed integrated transcriptomic profiling via RNA-seq combined with chromatin occupancy analysis using CUT&Tag technology in parallel human and murine samples to elucidate the molecular mechanisms.
Results: In our study, we demonstrated a reduced H3K27me3 methylation level accompanied by an increased proportion and a proinflammatory transcriptional memory in monocytes from house dust mite (HDM)-allergic human subjects. The same transcriptional and epigenetic phenotype was also confirmed in HDM-sensitized mice. Finally, the administration of GSK-J4, which upregulates H3K27me3 level in murine monocytes, attenuated the inflammatory response in vitro and in vivo.
Conclusions: Our study confirms that H3K27me3 methylation modulates the trained immunity in monocytes and regulates HDM-allergic diseases through an inflammatory-dependent mechanism.

Keywords:  H3K27me3; HDM; KDM6B; inflammation; monocytes

DOI:  https://doi.org/10.3389/fimmu.2025.1572796
Cell Commun Signal. 2025 Jun 12. 23(1): 278

Epigenetic changes and serotype-specific responses of alveolar type II epithelial cells to Streptococcus pneumoniae in resolving influenza A virus infection.

Julia D Boehme, Andreas Jeron, Kristin Schultz, Lars Melcher, Katharina Schott, Elif Gelmez, Andrea Kröger, Sabine Stegemann-Koniszewski, Dunja Bruder.

   BACKGROUND: Pneumococcal pneumonia following influenza A virus (IAV) infection is a synergistic complication with high mortality in which IAV infection modulates host antibacterial responses and affects bacterial invasiveness of Streptococcus pneumoniae (S. pn.). IAV-mediated effects can last beyond viral clearance. In acute IAV pneumonia, alveolar type II epithelial cells (AECII) are primary targets for viral replication and contribute to the immune response. Our study addresses sustained effects of IAV infection on AECII and consequences for their response towards different serotypes of S. pn.
METHODS: We analyzed bacterial loads, respiratory inflammation and AECII gene transcription profiling in mice infected with IAV and/or one of three S. pn. serotypes of varying invasiveness (4 > 7F > 19F). We inferred a scale-free-like ARACNE gene co-expression network on AECII transcriptional regulation under these conditions. We performed Western blotting for protein expression of interferon signaling components in AECII. We additionally performed ATAC-seq analysis of AECII isolated 14 days following IAV infection.
RESULTS: Previous IAV infection rendered the lung susceptible to invasive S. pn. infection with serotype 4 and the mildly invasive 7F but not 19F. Particularly secondary infection with 7F induced exacerbated inflammatory responses as compared to bacterial infection alone, marked by increased protein expression of type I and II interferons. AECII gene co-expression network revealed interferon-response network modules. Network-mapping unfolded S. pn. serotype-specific transcriptional network responses/usage and secondary S. pn. infection was found to abrogate an IAV-induced AECII proliferative configuration. Enhanced expression of several ARACNE network genes were found to be associated with increased chromatin accessibility at their promoter regions.
CONCLUSIONS: Our study demonstrates AECII to retain a sustained IAV-associated configuration with epigenetic involvement, affecting their proliferation and serotype-specifically intensifying their transcriptional response, mainly to interferons, in secondary S. pn.
INFECTION: In a broader context, our results suggest the concepts of peripheral inflammatory imprinting and trained innate immunity to apply to cells of the respiratory epithelium in the context of subsequent viral/bacterial challenges.

Keywords:   Streptococcus pneumoniae ; ARACNE; ATAC sequencing; Alveolar type II epithelial cells; Gene co-expression network; Influenza A virus; Interferon response; Secondary infection; Trained innate immunity

DOI:  https://doi.org/10.1186/s12964-025-02284-y
J Inflamm Res. 2025 ;18 7357-7367

Epigenetic Modulation by Lactylation in Sepsis: Linking Metabolism to Immune Dysfunction.

Yinghong Chen, Hanrong Hu, Congwei Wang, Junxuan Wu, Jie Zan, Yuntao Liu.

  Lactate, traditionally viewed as a metabolic byproduct, is now recognized as a key regulator of immune and epigenetic processes in sepsis. A recently discovered post-translational modification, lactylation, utilizes lactate as a substrate and plays a crucial role in cellular regulation. Accumulating evidence suggests that elevated lactate levels contribute to immune dysfunction in sepsis by modulating the activity of various immune cells. This modification links metabolic changes to immune regulation, making it a crucial factor in sepsis progression. Understanding how lactylation is altered in sepsis unveils critical links between immunometabolism, epigenetic regulation, and disease pathophysiology. These insights also highlight the interplay between metabolic and epigenetic reprogramming during septic progression. As a result, lactylation has emerged as a promising biomarker and potential therapeutic target in sepsis. This review aims to summarize the latest findings on lactate metabolism, lactylation modifications, and their immunometabolic implications in sepsis.

Keywords:  histone; lactate; lactylation; sepsis

DOI:  https://doi.org/10.2147/JIR.S522081
Infect Immun. 2025 Jun 13. e0051224

Working together: gut microbe-microbe interactions shape host inflammation.

Ally Lawing, Rachel Bleich.

  Inflammatory bowel disease (IBD) is a debilitating disorder characterized by chronic intestinal inflammation that currently has no cure. Alterations to the composition of the gut microbiota, including reduced microbial diversity and expansion of pathobionts like Enterobacteriaceae, are implicated in IBD. While this dysbiosis has been well-documented, our understanding of the function of these microbes in the development and progression of IBD is more limited. As part of the gut microbiota, these microbes undergo complex interactions with many other microorganisms that impact the structure and function of the microbial community and the health of the host. These include competitive interactions for nutrients and space and cooperative interactions that help optimize resource utilization and microbial fitness. In this minireview, we discuss the microbe-microbe interactions that can impact host inflammation and IBD progression and treatment. Due to their association with IBD, we put special emphasis on interactions between Enterobacteriaceae and other members of the microbiota that are competitive, commensal, and mutualistic. To better understand these interactions, the signals that mediate microbial interactions are highlighted, including contact-dependent and contact-independent mechanisms. Finally, mucosal biofilms involving pathobionts are examined due to their proximity to the host and ability to influence inflammation.

Keywords:  inflammation; microbe-microbe interactions; polymicrobial interactions

DOI:  https://doi.org/10.1128/iai.00512-24
Cell Host Microbe. 2025 Jun 11. pii: S1931-3128(25)00150-7. [Epub ahead of print]33(6): 777-789

The microbiome: An actor or stage for the beneficial action of probiotics, prebiotics, synbiotics, and postbiotics?

Mary Ellen Sanders, Colin Hill.

  Probiotics, prebiotics, synbiotics, and postbiotics are required, by definition, to confer a health benefit on the host. It is often presumed the host microbiome plays a central role in the mechanism of action of these substances, collectively referred to here as "biotics." However, the definitions of both probiotics and postbiotics do not include an associated mechanism nor the involvement of the microbiome. The definitions of prebiotics and synbiotics require evidence of selective utilization by the host microbiome, but do not state that confirmatory evidence must be provided that this utilization causes the associated health benefit. In this perspective, we discuss evidence supporting a role for the microbiome in delivering these health benefits and whether or not measuring microbiome alterations can serve as important readouts of efficacy. We also discuss the possibility of expanding the biotics family with substances such as bacteriophage, fermented foods, and live dietary microbes.

Keywords:  bacteriophage; biotic; fermented food; mechanisms of action; microbiome; microbiota; postbiotic; prebiotic; probiotic; synbiotic

DOI:  https://doi.org/10.1016/j.chom.2025.04.017
mSphere. 2025 Jun 10. e0024225

Host-pathogen interaction profiling of nontypeable Haemophilus influenzae and Moraxella catarrhalis coinfection of bronchial epithelial cells.

Adonis D'Mello, Timothy F Murphy, Martina Wade, Charmaine Kirkham, Yong Kong, Hervé Tettelin, Melinda M Pettigrew.

  Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory lung disease and the third leading cause of death globally. Nontypeable Haemophilus influenzae (NTHi) and Moraxella catarrhalis (Mcat) are common pathogens in individuals with COPD. Acquisition of NTHi or Mcat can cause acute exacerbations of COPD. NTHi and/or Mcat also persist for months in the lower airways and lead to chronic inflammation. We hypothesized that infection by NTHi or Mcat, singly or during coinfection, requires regulation of specific bacterial and host cell pathways. We investigated this phenomenon using an in vitro cell culture model consisting of lung carcinoma H292 cell lines, infected with NTHi, Mcat, or both species. Samples were fractionated into "apical fluid," containing free-floating bacteria, and adhered/invaded bacteria on or within H292 cells. We used transcriptomic profiling with RNA-seq and various bioinformatic analyses to disentangle host-pathogen interactions in epithelial cell infection from the perspective of each species. Several biological pathways were differentially regulated across all conditions (31, NTHi; 22, Mcat; and 169, human). NTHi transcriptomic profiles differed during mono-infection and coinfection; examples included downregulation of iron-sulfur metabolism (IscR regulon) and differential regulation of quorum sensing in coinfection compared to mono-infection. Mcat was comparatively less affected by the presence of NTHi during coinfection. H292 epithelial cells responded broadly to all infections with distinct responses to mono-infection and coinfection. Enriched host pathways included influenza/interferon/Wnt and proinflammatory responses. These findings suggest common and distinct processes involved in NTHi and/or Mcat-induced COPD pathogenesis and have implications for therapeutic intervention.IMPORTANCEChronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide. Bacteria such as nontypeable Haemophilus influenzae (NTHi) and Moraxella catarrhalis (Mcat) can cause exacerbations of COPD, and they can persist in the lungs for months, which increases inflammation. We studied how these bacteria interact with lung cells by infecting a cell culture model with NTHi, Mcat, or both. We used RNA sequencing and bioinformatic analysis to examine how the bacteria and host cells respond. When NTHi and Mcat were present together, they behaved differently than when each was alone. We found that different host biological pathways were activated during infection, including those related to inflammation and immune responses. These results provide insights into how NTHi and Mcat contribute to COPD progression and suggest potential targets for new treatments.

Keywords:  Haemophilus influenzae; Moraxella catarrhalis; RNA sequencing; chronic obstructive pulmonary disease; coinfection

DOI:  https://doi.org/10.1128/msphere.00242-25
bioRxiv. 2025 May 28. pii: 2025.05.23.655632. [Epub ahead of print]

Tissue signatures of human macrophages during homeostasis and activation.

Daniel P Caron, William L Specht, David Chen, Steven B Wells, Peter A Szabo, Peter A Sims, Donna L Farber.

Human macrophages (MΦs) reside in tissues and develop tissue-specific identities. While studies in mice have identified molecular signatures for site-specific MΦ differentiation, we know less about the transcriptional profiles of human MΦs in distinct sites, including mucosal tissues and lymphoid organs during homeostasis and activation. Here, we use multimodal single-cell sequencing and ex vivo stimulation assays to define tissue signatures for populations of human MΦs isolated from lungs, small intestine, spleen, bone marrow, and lymph nodes obtained from individual organ donors. Our results reveal distinct tissue-adapted gene and protein profiles of metabolic, adhesion, and immune interaction pathways, which are specific to MΦs and not monocytes isolated from the same sites. These signatures exhibit homology to murine MΦs from the same sites. Tissue-adapted MΦs remained responsive to polarizing cytokine stimuli ex vivo , with upregulation of expected transcripts and secreted proteins, while retaining tissue-specific profiles. Together, our findings show how human MΦ identity is coupled to their site of residence for mucosal and lymphoid organs and is intrinsically maintained during activation and polarization.

DOI: https://doi.org/10.1101/2025.05.23.655632
Immunotargets Ther. 2025 ;14 555-575

The Regulatory Network of Transcription Factors in Macrophage Polarization.

Jie Liu, Mengran Wang, Yong Zhao.

  Macrophage polarization, a dynamic process crucial for immune responses and tissue homeostasis, is tightly regulated by transcription factors. Understanding the transcriptional regulation of macrophage polarization holds significant therapeutic implications for various diseases, including cancer, autoimmune disorders, and metabolic syndromes. Studies have shown that transcription factors, including signal transducer and activator of transcription (STAT), nuclear transcription factor-κB (NF-κB), peroxisome proliferator-activated receptors (PPARs), interferon regulatory factors (IRFs), BTB and CNC homology (BACH), CCAAT-enhancer binding proteins (C/EBPs), kruppel-like factors (KLFs), Cellular Myc (c-Myc), the SNAIL family, v-Maf Musculoaponeurotic Fibrosarcoma Oncogene Homolog (Maf), and hypoxia-inducible factor alpha (HIFα), are highly involved in shaping macrophage polarization. Targeting transcription factors involved in macrophage polarization may provide promising avenues for immunomodulatory therapies aimed at restoring immune homeostasis and combating pathological conditions characterized by dysregulated macrophage activation. Here, we review the intricate transcriptional networks that govern macrophage polarization, highlighting the pivotal role of transcription factors in orchestrating these processes.

Keywords:  inflammation; macrophage polarization; macrophages; transcription factor

DOI:  https://doi.org/10.2147/ITT.S494550
NPJ Biofilms Microbiomes. 2025 Jun 10. 11(1): 100

Polybacterial intracellular macromolecules shape single-cell inflammatory profiles in upper airway epithelia.

Quinn T Easter, Zabdiel Alvarado-Martinez, Meik Kunz, Bruno F Matuck, Brittany T Rupp, Theresa Weaver, Zhi Ren, Aleksandra Tata, Juan Caballero-Perez, Nick Oscarson, Akira Hasuike, Ameer N Ghodke, Adam J Kimple, Purushothama R Tata, Scott H Randell, Hyun Koo, Kang I Ko, Kevin M Byrd.

Mucosal epithelial cells of the upper airways are continuously exposed to microbes throughout life. Specialized niches such as the anterior nares and the tooth are especially susceptible to dysbiosis and chronic inflammatory diseases. Here, we reanalyzed our v1-Human Periodontal Atlas, identifying polybacterial signatures (20% Gram-positive; 80% Gram-negative) and distinct responses of bacterial-associated epithelia. Fluorescence microscopy detected numerous persistent polybacterial intracellular macromolecules (PIMs) within human oral keratinocytes (HOKs), including bacterial rRNA, mRNA, and glycolipids. PIM levels directly correlated with enhanced receptor-ligand signaling in vivo. Inflammatory "keratokines" targeting immune cells were synergistically upregulated in lipopolysaccharide-challenged HOKs, while endogenous lipoteichoic acid (LTA) correlated with CXCL1/8 expression in vitro and in vivo. Application of Drug2Cell suggested altered drug efficacy predictions based on PIM detection-agnostic of disease state. CXCL1/8 expression again correlated with LTA in epithelial cells of the nasal cavity, oropharynx, and trachea. Thus, PIMs shape epithelial single-cell profiles across upper airway mucosae.

DOI: https://doi.org/10.1038/s41522-025-00735-5
Infect Immun. 2025 Jun 13. e0050624

Trimming the fat: a brief review of lipids at the host-pathogen interface.

Filiz T Korkmaz.

  Microbial-derived lipids and the host receptors that bind them are collectively critical for immune regulation on the host side and for a multitude of biological functions on the microbial side, including membrane structure, energy generation, resistance to stress, and, importantly, virulence. Bacteria, viruses, fungi, and eukaryotic microorganisms comprise common and unique lipid species that can be modified to avoid immune detection and aid in antimicrobial resistance. Moreover, the host receptors that interact with lipids are equally diverse in their structure and function, driving both beneficial and pathogenic responses depending on the location, strength, and duration of signaling. The following review will discuss all the aforementioned aspects of lipids at the host-pathogen interface, which should be expanded upon in future studies to develop novel therapeutics that consider lipids as distinct immune modulators.

Keywords:  host-pathogen interactions; immune mechanisms; infectious disease; lipid signaling

DOI:  https://doi.org/10.1128/iai.00506-24
PLoS Pathog. 2025 Jun 09. 21(6): e1013208

Antigen-specific CD4+ T cells promote monocyte recruitment and differentiation into glycolytic lung macrophages to control Mycobacterium tuberculosis.

Samuel H Becker, Christine E Ronayne, Tyler D Bold, Marc K Jenkins.

Although lung myeloid cells provide an intracellular niche for Mycobacterium tuberculosis (Mtb), CD4+ T cells limit Mtb growth in these cells to protect the host. The CD4+ T cell activities including interferon-γ (IFN-γ) production that account for this protection are poorly understood. Using intravenous antibody labeling and lineage-tracing reporter mice, we show that monocyte-derived macrophages (MDMs), rather than phenotypically similar monocytes or dendritic cells, are preferentially infected with Mtb in murine lungs. MDMs were recruited to the lungs by Mtb-specific CD4+ T cells via IFN-γ, which promoted the extravasation of monocyte precursors from the blood. It was possible that CD4+ T cells recruited infectable MDMs because these cells are uniquely poised to receive cognate MHCII-mediated help to control intracellular bacteria. Mice with MHCII deficiency in monocyte-derived cells had normal Mtb-specific CD4+ T cell activation, expansion and differentiation but the CD4+ T cells were unable to attenuate Mtb growth. Using single cell RNA sequencing, we showed that MDMs receiving cognate MHCII-mediated help from CD4+ T cells upregulated glycolytic genes associated with Mtb control. Overall, the results indicate that CD4+ T cells recruit infectable MDMs to the lungs and then trigger glycolysis-dependent bacterial control in the MDMs by engaging their MHCII-bound Mtb peptides. Moreover, the results suggest that cognate MHCII-mediated help to promote MDM glycolysis is an essential, IFN-γ-independent effector function of Mtb-specific CD4+ T cells.

DOI: https://doi.org/10.1371/journal.ppat.1013208
Cell Host Microbe. 2025 06 03. pii: S1931-3128(25)00198-2. [Epub ahead of print]

Interferon-epsilon, an estrogen-induced type I interferon, is uniquely exploited by Neisseria gonorrhoeae via effects on sialic acid metabolism

Evelyn A Kurt-Jones, Sunita Gulati, Michael King, Rosane B de Oliveira, Peter A Rice, Bo Zheng, Jutamas Shaughnessy, Jennifer L Edwards, Paul J Hertzog, Sanjay Ram, Douglas T Golenbock.

  The female genital mucosa expresses the hormone-dependent type I interferon (IFN), IFN-epsilon (IFN-ε), which protects against chlamydia and herpes infection. Surprisingly, we found that IFN-ε knockout (Ifnε-/-) mice and type I IFN receptor knockout (Ifnar1-/-) mice exhibited enhanced clearance of Neisseria gonorrhoeae (Ng). This result was phenocopied using blocking anti-IFNAR monoclonal antibody (mAb). Ng colonization of the Ifnε-/- urogenital tract was restored by exogenous recombinant IFN-ε or IFN-β. Clearance of Ng in anti-IFNAR-treated mice required the expression of the cathelicidin mCRAMP. Ng deploys a unique mechanism to evade cathelicidins and other innate defenses by sialylating its lipooligosaccharide (LOS) using host-derived cytidine-5'-monophospho-N-acetylneuraminic acid (CMP-Neu5Ac or CMP-sialic acid). Ifnε-/- mice expressed reduced levels of CMP-sialic acid synthetase mRNA in genital tissues. Accordingly, Ng recovered from IFN-deficient mice were hyposialylated. In conclusion, Ng exploits type I IFNs to obtain CMP-sialic acid for LOS sialylation, resulting in innate immune evasion and enhanced colonization.

Keywords:  IFNAR; Neisseria gonorrhoeae; cathelicidin; cytidine-5'-monophospho-N-acetylneuraminic acid; interferon-epsilon; lipooligosaccharide; sialylation; type I interferon

DOI:  https://doi.org/10.1016/j.chom.2025.05.015
Immunol Res. 2025 Jun 11. 73(1): 95

Staphylococcus aureus α-hemolysin induces DNA methylation changes in human Th1 cells.

Iwona Karwaciak, Joanna Pastwińska, Anna Sałkowska, Kaja Karaś, Marta Sobalska-Kwapis, Jarosław Dastych, Marcin Ratajewski.

  α-Hemolysin is one of the most dangerous virulence factors produced by Staphylococcus aureus. Among the immune cells that respond to this pathogenic bacterium, Th1 lymphocytes play a critical role. In our study, we investigated the impact of α-hemolysin on the methylation of the Th1 cell genome. Our findings revealed that α-hemolysin upregulates HELLS and DNMT3A expression while downregulating DNMT3L expression at the protein level. Whole-genome bisulfite sequencing analysis revealed significant alterations in DNA methylation, particularly in regions outside CpG sequences. These results suggest that bacterial proteins can act as potent epigenetic modulators in human cells, influencing their activity, plasticity, and phenotype.

Keywords:   Staphylococcus aureus ; DNA methylation; Th1; α-Hemolysin

DOI:  https://doi.org/10.1007/s12026-025-09647-0
bioRxiv. 2025 Jun 03. pii: 2025.05.30.657106. [Epub ahead of print]

Spatial Heterogeneity of Macrophages in the Human Lung.

Patrick S Hume, Katelyn H Lyn-Kew, Elizabeth A Wynn, Benjamin Steinhart, Jennifer Driscoll, Sean Jacobson, Peter M Henson, Kara J Mould, Camille M Moore, William J Janssen.

Rationale: Transcriptionally-defined populations of interstitial macrophages (IMs) and airspace macrophages (AMs) have recently been identified in the human lung. However, the anatomic locations occupied by these populations (i.e. alveoli, pleura, airways, or arteries) have not been fully defined.
Objectives: To determine the distribution of transcriptionally-defined human macrophages in the major anatomical lung structures and to identify alterations in their distribution and programming induced by cigarette smoking.
Methods: Single-cell RNA sequencing was performed on lung tissue from eight human donors without pulmonary disease (four smokers and four nonsmokers). Microdissection was used to isolate distinct pulmonary anatomical structures from each lung: alveoli, pleura, airways, and arteries. Transcriptional profiles of subpopulations of interstitial macrophages (IMs) and alveolar macrophages (AMs) were analyzed based on their anatomical structure of origin and smoking status.
Measurements and Main Results: Five major IM and five AM subpopulations in human lungs are identified. We demonstrate significant differences in the accumulation patterns of each macrophage subset within anatomical structures, though each subset was detected in each. Immunofluorescent microscopy confirmed anatomical structure-specific accumulation patterns of IMs.
Conclusions: In this study, we highlight key differences in the accumulation of lung macrophage subpopulations in anatomical structures but find programming within macrophage subpopulations is largely conserved, regardless of structure of origin or smoking status. We also detect populations of inflammatory AMs and IMs which accumulate within the airways, but not the alveolar parenchyma, of human cigarette smokers. We introduce a novel three-tiered hierarchy nomenclature to distinguish transcriptionally defined human lung IM subsets as 1°) Monocyte-like vs Antigen Presenting, 2°) Quiescent vs Inflammatory, and 3°) FOLR2 high vs FOLR2 low . This study is the first to report the fractional accumulation of human lung macrophage subsets by lung anatomical structure.
Summary: Lung anatomical structure-specific single cell RNA sequencing is introduced to identify and determine the local composition of human lung leukocytes, including 5 populations of human interstitial macrophages.

DOI: https://doi.org/10.1101/2025.05.30.657106
Cell Rep. 2025 Jun 12. pii: S2211-1247(25)00631-X. [Epub ahead of print]44(6): 115860

Airway basal stem cells are necessary for the maintenance of functional intraepithelial airway macrophages.

Tristan Kooistra, Borja Saez, Marly Roche, Alejandro Egea-Zorrilla, Dongzhu Li, Dilanjan Anketell, Nhan Nguyen, Jorge Villoria, Jacob Gillis, Eva Petri, Laura Vera, Zuriñe Blasco-Iturri, Neal P Smith, Jehan Alladina, Yanting Zhang, Vladimir Vinarsky, Manjunatha Shivaraju, Susan L Sheng, Michelle Chen, Meryem Gonzalez-Celeiro, Hongmei Mou, Avinash Waghray, Brian Lin, Azadeh Paksa, Kilangsungla Yanger, Purushotama Rao Tata, Rui Zhao, Benjamin Causton, Javier J Zulueta, Felipe Prosper, Josalyn L Cho, Alexandra-Chloe Villani, Adam Haber, Jayaraj Rajagopal, Benjamin D Medoff, Ana Pardo-Saganta.

  Stem cells are known to provide signals that contribute to the maintenance and function of neighboring cells. We demonstrate that Notch signaling arising from airway basal stem cells is necessary for the function of a unique population of intraepithelial airway macrophages (IAMs) in the murine trachea. Without this stem cell signaling, IAMs lose MHC II expression, which in turn prevents antigen-induced allergic inflammation. Distal murine airways do not harbor basal stem cells, and, in this region of the lung, allergic inflammation proceeds unperturbed. We speculate that the functional coupling of specific anatomically restricted stem cell populations and adjacent immune cells is one mechanism for ensuring that inflammatory responses are compartmentalized to regions of injury. Basal stem cells are found throughout the human airway tree and we demonstrate the existence of human IAM-like cells, suggesting that their interaction may influence airways disease.

Keywords:  CP: Stem cell research; Notch pathway; airway basal stem cells; allergic inflammation; intraepithelial immune cells; macrophages

DOI:  https://doi.org/10.1016/j.celrep.2025.115860
Cell Host Microbe. 2025 Jun 11. pii: S1931-3128(25)00197-0. [Epub ahead of print]33(6): 820-835

Unlocking the power of human milk and infant feeding: Understanding how nutrition and early microbiota interaction shapes health programming.

Alexandra Zhernakova, Moran Yassour, Lindsay J Hall, Maria Carmen Collado.

  Human milk represents a highly evolved bioactive system that promotes colonization by infant microbial pioneers, supports immune maturation, and fosters infant development. Beyond providing nutrition, human milk contains key bioactive components, such as microbes, metabolites, human milk oligosaccharides, immunoglobulins, lactoferrin, and antimicrobial peptides. These factors influence colonization of the infant gut microbiome and facilitate immune development and metabolic health, with implications for health outcomes and risk of non-communicable diseases. In this review, we highlight the impact of infant feeding, human milk constituents (especially bioactive compounds), and weaning on infant microbial trajectories. By understanding how early-life nutrition influences microbial colonization and nutrient sensing, i.e., "how we feed our microbes," we can develop targeted interventions and personalized diets to support proper gut maturation and disease prevention from infancy to adulthood, as well as explore the therapeutic potential of human milk bioactives beyond infancy, offering new strategies for disease prevention and treatment.

Keywords:  HMOs; bioactive compounds; biotics; breastfeeding; human milk; infancy; microbiome

DOI:  https://doi.org/10.1016/j.chom.2025.05.014
Microb Pathog. 2025 Jun 04. pii: S0882-4010(25)00510-8. [Epub ahead of print] 107785

Protective mechanism of Bifidobacterium on intestinal mucosal barrier in sepsis.

Kai-Jun Zhang, Yi-Feng Chang, Yi-Fan Liu, Shi-Xue Dai, Jie Li.

  Prior research has examined the advantageous impacts of probiotics in preventing and treating sepsis; however, the protective actions of Bifidobacterium against sepsis are still not understood. In this review, we innovatively discussed the mechanisms by which Bifidobacterium can prevent and treat sepsis by regulating the intestinal mucosal barrier during homeostasis and when damaged. Surprisingly, we found that the mechanisms include blocking NF-κB and p38MAPK signaling pathways, regulating AHR/NRF2/NLRP3 inflammasome pathways, inhibiting NLRP3/ASC/Caspase1 signaling pathways, regulating enteric glial cells (EGCs) network development, regulating immunity, and restoring intestinal symbiosis, etc. Through continued pathway researches into mechanisms of probiotics on sepsis, we try to get more evidence of Bifidobacterium on the prevention and treatment of sepsis.

Keywords:  Bifidobacterium; gut microbiota; intestinal mucosal barrier; microbial therapy; sepsis

DOI:  https://doi.org/10.1016/j.micpath.2025.107785