bims-bac4me 2025-09-21 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2025–09–21
38 papers selected by
Chun-Chi Chang, Lunds universitet

Gut commensal Lactobacillus strain induces a balanced trained immunity phenotype to enhance vaccine efficacy through JAK-STAT-SOCS pathway.
Recent Advances of Trained immunity in Macrophages.
Cysteine reactivity profiling identifies host regulators of Mycobacterium tuberculosis replication in human macrophages.
Microbiota-mediated mechanisms of mucosal immunity across the lifespan.
Mechanisms of 10-hydroxyoctadecanoic acid resistance in Streptococcus pneumoniae.
Staphylococcus aureus transcriptomics and single-cell sequencing approaches.
Defects in anaplerotic metabolism sensitize Staphylococcus aureus small colony variants to bicarbonate.
Lactate metabolic checkpoint in immuno-oncology: mechanisms and therapeutic implications.
Intestinal epithelial PTPN2 limits pathobiont colonization by immune-directed antimicrobial responses.
Reprogramming immunity with itaconate: metabolic mechanisms and therapeutic perspectives.
Post-COVID-19 disruption of the respiratory microbiome modulates Mycoplasma pneumoniae: a multi-center retrospective investigation study.
The joint action of antibiotics, bacteriophage, and the innate immune response in the treatment of bacterial infections.
Tissue resident memory B cells mediate protective immunity to respiratory pathogens in the airways.
Limited nasal interferon production contributes to delayed respiratory virus clearance and suboptimal vaccine responses.
Lactate and lactylation in tumor immunity.
NRC31 limits the imprinting of astrocyte epigenetic inflammatory memory early in life.
Innate immune molecular landscape following controlled human influenza virus infection.
Concordance of Pathogenic Bacteria in the Upper and Lower Airway in Children With Severe Viral Lower Respiratory Tract Infections.
MicrobiomeKG: bridging microbiome research and host health through knowledge graphs.
Export by a quorum sensing-controlled drug exporter underlies rifampicin's strong activity against staphylococcal biofilms.
Deficiency of cannabinoid receptors enhances host susceptibility to bacterial infection.
Regulatory roles of intestinal CD4+ T cells in inflammation and their modulation by the intestinal microbiota.
Depletion of Mycobacterium tuberculosis transmembrane protein Rv3737 reduces pathogen survival and induces M1 macrophage polarization against tuberculosis.
Delaying pyroptosis with an AI-screened gasdermin D pore blocker mitigates inflammatory response.
Significance of the LL-37 Peptide Delivered from Human Cathelicidin in the Pathogenesis, Treatment, and Diagnosis of Sepsis.
Autoinducing Peptide-Mediated Bacterial Keratitis Therapy by Camouflaged Staphylococcus aureus.
Sepsis-induced lipid droplet accumulation enhances antibacterial innate immunity through mechanisms dependent on DGAT-1 and interferon-beta.
Inflammatory modalities shape the IgA repertoire via stochastic processes.
The impact of mycobacteria-induced trained immunity on SARS-CoV-2 vaccine responses.
Interorgan Communication Between Lung and Colorectal Epithelial Cells Studied Using a Novel Multi-Organ-On-Chip System.
Decoding immunometabolism with next-generation tools: lessons from dendritic cells and T cells.
Bacterial skin colonization and systemic antibiotic treatment in patients with cutaneous T-cell lymphoma.
Disruption to the gut microbiome by non-antibiotics is linked to infection risk.
Nasal Microbiota as a Potential Therapeutic Target for Allergic Rhinitis: An Emerging Perspective.
Upper respiratory tract immunization with Pam2Cys-adjuvanted spike protein vaccine achieves sterilizing protection against SARS-CoV-2.
Long-chain unsaturated fatty acids released during immune responses stimulate host-microbe trans-kingdom communication.
A fungal pathobiont promotes Streptococcus agalactiae vaginal persistence and pathogenesis through physical and metabolic interactions.
Non-hematopoietic tryptophan metabolism is a driver of ineffective T cell responses during secondary pulmonary bacterial infection.

Probiotics Antimicrob Proteins. 2025 Sep 18.

Gut commensal Lactobacillus strain induces a balanced trained immunity phenotype to enhance vaccine efficacy through JAK-STAT-SOCS pathway.

Lingdi Niu, Hai Li, Junjie Guo, Zheng Jia, Qingru Chang, Ning Liu, Shuhe Zhang, Junwei Ge.

  The gut microbiota plays a complex role in immune system maturation and function. The induction of memory in innate immune cells appears to be part of a co-adaptation between the host and microbiome. As important gut commensals, certain Lactobacillus have been shown to induce innate immune memory. However, the universality, phenotypic characteristics, mechanisms of Lactobacillus-induced innate immune memory, and its potential applications in vaccine immunology remain poorly understood. Here, we discovered that specific strains of the gut commensal Lactobacillus can induce innate immune memory, resulting in a more balanced trained immunity phenotype through SOCS activation. Upon secondary stimulation, macrophages exhibited increased expression of IL-6, IL-1β, IL-10, IL-12, IFN-β, and TGF-β. Peptidoglycan and components in the secretome sensitive to pancreatic enzymes were identified as key elements in inducing trained immunity. Furthermore, mice that underwent training demonstrated rapid resistance to S. aureus infection. Additionally, Lactobacillus-induced trained immunity significantly enhanced the protective efficacy of vaccines against MRSA. Our findings demonstrate that certain Lactobacillus strains can activate non-classical trained immunity, offering potential for enhancing vaccine efficacy. Our study provides new insights into the role of some gut commensals in immune modulation and suggests a novel approach to vaccine enhancement through trained immunity induced by specific gut commensals.

Keywords:   Levilactobacillus brevis 23,017 ; S. aureus ; Macrophages; Trained immunity

DOI:  https://doi.org/10.1007/s12602-025-10769-y
Int J Biol Sci. 2025 ;21(12): 5258-5283

Recent Advances of Trained immunity in Macrophages.

Peizhi Li, Manman Liu, Yakun Liu, Jing Guo, Jingfeng Jiang, Guidan Wang, Chenlong Cao, Xinru Wang, Junxing Qu, Zhiheng Sun.

  Trained immunity (TI), also known as innate immune memory, is the long-term change in the functional program of innate immune cells after transient stimulation through epigenetic and metabolic alterations. This reprogramming augments the response to secondary challenges fueled by various stimulus and contributes to the resistance of cancer, infectious diseases, auto-inflammatory disorders, and other diseases. Macrophages, which are versatile innate immune cells with remarkable plasticity, can adapt to different microenvironments and perform diverse functions. TI of macrophages has been deeply involved in pathogen infection. However, current understandings in the effect of TI are still incomplete and require further investigation and summarization. In this review, we summarized the existing knowledge in this field including the hallmark and mechanism of TI, its impact on health and disease, as well as the potential as a therapeutic tool. This study provides new perspectives for a comprehensive insight of TI.

Keywords:  Autoimmune diseases.; Cancer; Infectious disease; Macrophage; TI

DOI:  https://doi.org/10.7150/ijbs.115515
bioRxiv. 2025 Sep 03. pii: 2025.08.30.673236. [Epub ahead of print]

Cysteine reactivity profiling identifies host regulators of Mycobacterium tuberculosis replication in human macrophages.

John Neff, Kristen E DeMeester, Paola K Parraga, Radu Suciu, Melissa Dix, Gabriel Simon, Max A Gianakopoulos, Bruno Melillo, Benjamin F Cravatt, Michael U Shiloh.

  Innate immune cells such as monocytes and macrophages provide the earliest defense against infection by intracellular pathogens by initiating signaling pathways and restricting pathogen replication. However, the full complement of proteins that mediate cell-autonomous immunity remains incompletely defined. Here, we applied cysteine-directed activity-based protein profiling (ABPP) to map proteome-wide cysteine reactivity changes in THP-1 monocytes and primary human monocyte-derived macrophages during Mycobacterium tuberculosis (Mtb) infection. Across both cell types, we quantified 148 cysteine residues with altered reactivity. Genetic perturbation of a subset of proteins harboring these changes significantly impacted Mtb replication, revealing functional links between site-specific cysteine reactivity and antimicrobial defense. These data define previously unrecognized host protein changes during Mtb infection and provide a resource for investigating post-translational events that regulate innate immune responses to intracellular bacteria.

Keywords:  Mycobacterium tuberculosis; chemical proteomics; covalent probes; cysteine; innate immunity; macrophage; mass spectrometry

DOI:  https://doi.org/10.1101/2025.08.30.673236
Nat Immunol. 2025 Sep 16.

Microbiota-mediated mechanisms of mucosal immunity across the lifespan.

Iliyan D Iliev, J Magarian Blander, Nicholas Collins, Chun-Jun Guo, Randy S Longman, Gregory F Sonnenberg, Melody Y Zeng, David Artis.

The microbiota has a fundamental role in regulating homeostasis and inflammation across the barrier surfaces of the body. The gut is a unique bioreactor where the high concentration of microorganisms, microbial and dietary metabolites, microbial-derived molecular structures, immune cells, stroma and neurons form a complex, highly interactive and precisely regulated system. The mucosal immune system in the gut has profound local and systemic effects, influencing both health and disease. A critical period of immune imprinting occurs early in life, shaped by the neonatal microbiota and nutrition, to influence immune development and long-term disease susceptibility. Microbiota-derived metabolites have crucial roles in immune modulation, influencing epithelial integrity, oral tolerance and inflammatory responses. This Review explores the interactions between the microbiota and the mucosal immune system from infancy to adulthood, highlighting the impact on health and disease. We also discuss therapeutic interventions, including microbiota-derived molecules, dietary metabolites and emerging microbiome-based co-therapies.

DOI: https://doi.org/10.1038/s41590-025-02281-w
J Bacteriol. 2025 Sep 19. e0022325

Mechanisms of 10-hydroxyoctadecanoic acid resistance in Streptococcus pneumoniae.

Cydney N Johnson, Matthew W Frank, Chrispin Chaguza, Brendan T Morrow, Qidong Jia, Christopher D Radka, Jason W Rosch.

  Profiles of human nasal colonization consistently demonstrate that Staphylococcus aureus and Streptococcus pneumoniae can co-exist in the nasopharynx. Several studies have demonstrated the antagonist relationship between the two organisms via several molecular mechanisms, including competition for nutrients as well as via direct killing by hydrogen peroxide. During nasal colonization, the pneumococcus is in direct contact with the fatty acid h18:0, which is released into the extracellular environment by S. aureus. We report that h18:0 is specifically toxic to the pneumococcus among the pathogenic streptococci, providing a unique mechanism for interspecies competition during colonization. Exposure of cells to h18:0 revealed that S. pneumoniae could rapidly adapt to and overcome the observed toxicity. Whole-genome analysis revealed the mechanism underlying this resistance being linked to a truncation of a glycosyltransferase in the capsule biosynthesis locus and a genomic inversion in the phase variation locus, leading to altered cell surface charge and membrane lipid composition. These physiological differences in the resistant isolates may aid in repelling toxic, charged fatty acids such as h18:0 from the cell membrane.IMPORTANCEThe pneumococcus and S. aureus are two of the most well-characterized residents of the human nasopharynx; yet much remains unknown regarding how the two bacteria interact. Here, we describe the potential of S. aureus-produced h18:0, whose function and biological impact are still being described, to act as an interspecies competition molecule against S. pneumoniae, and how the pneumococcus can adapt to overcome its toxicity.

Keywords:  Streptococcus pneumoniae; cell charge; fatty acid resistance; glycosyltransferase; hydroxy fatty acid; lipid profile; membrane composition; phase variation; recombinase

DOI:  https://doi.org/10.1128/jb.00223-25
Infect Immun. 2025 Sep 15. e0041125

Staphylococcus aureus transcriptomics and single-cell sequencing approaches.

Natalia Malachowa, Frank R DeLeo.

  Staphylococcus aureus is an important cause of human infections globally and ranks among the top causes of death by bacteria. In addition, the microbe is notorious for developing resistance to antibiotics. Methicillin-resistant S. aureus is endemic in healthcare facilities and the community in many regions of the world. Although our understanding of S. aureus as a human commensal organism and opportunistic pathogen remains incomplete, the use of genomics and transcriptomics approaches for S. aureus research has advanced this knowledge significantly over the past 20 years. This article reviews genomics approaches, with special emphasis on transcriptomics and single-cell sequencing, used to study S. aureus, past and present, and highlights selected discoveries made with these methods and new applications moving forward.

Keywords:  RNA-seq; microarrays; single-cell sequencing; transcriptomics

DOI:  https://doi.org/10.1128/iai.00411-25
Microbiol Spectr. 2025 Sep 17. e0168525

Defects in anaplerotic metabolism sensitize Staphylococcus aureus small colony variants to bicarbonate.

Asif Iqbal, Zannatul H Tumpa, Wyatt W Wittliff, Bennett J Blank, Basel H Abuaita, William N Beavers.

  Staphylococcus aureus is a facultative anaerobe that can generate energy through oxidative phosphorylation or solely glycolysis, and inhibiting oxidative phosphorylation results in the formation of small colony variants (SCVs). SCVs lack a proton motive force (PMF), increasing antibiotic tolerance and contributing to persistent infection in the host. Bicarbonate is an abundant antimicrobial compound in the human host that S. aureus encounters during infection. Bicarbonate alters the PMF, enhancing antibiotic susceptibility in S. aureus, but its impact on S. aureus SCVs remains unexplored. We report that bicarbonate inhibits the growth of S. aureus SCVs at concentrations that do not affect S. aureus wild type, due to defective bicarbonate anaplerotic metabolism, resulting in increased cytoplasmic pH and alkaline toxicity. Inactivation of pyruvate carboxylase (Pyc), a critical enzyme in bicarbonate anaplerotic metabolism that combines bicarbonate and pyruvate to form oxaloacetate, increases bicarbonate sensitivity in S. aureus, indicating that bicarbonate anaplerotic metabolism plays a vital role in bicarbonate detoxification. While SCVs upregulate Pyc in response to bicarbonate, cellular pyruvate levels are insufficient to sustain bicarbonate anaplerotic metabolism. Exogenous pyruvate restores bicarbonate anaplerotic metabolism and lowers the cytoplasmic pH, protecting SCVs from bicarbonate toxicity. Cytoplasmic pH alterations by bicarbonate also resensitize SCVs to aminoglycosides. S. aureus treated with bicarbonate is more susceptible to neutrophil killing, indicating that bicarbonate decreases the virulence of S. aureus. This study identifies bicarbonate anaplerotic metabolism as a S. aureus detoxification mechanism for bicarbonate toxicity and demonstrates that modulating anaplerotic metabolism may be an effective treatment for S. aureus infections.
IMPORTANCE: Staphylococcus aureus is one of the major bacterial contributors to human deaths around the world. Metabolic flexibility allows S. aureus to alter energy generation and resist oxidative and antibiotic killing, facilitating persistence in the host. Bicarbonate has been used for over a century for cleaning and hygiene without completely understanding its antimicrobial properties. We report that small colony variants (SCVs) are defective for bicarbonate anaplerotic metabolism, which is required to detoxify bicarbonate. As a result, bicarbonate inhibits the growth of SCVs by alkalinizing the cytoplasm. Cytoplasmic alkalinization also resensitizes SCVs to aminoglycoside killing, implicating bicarbonate as an effective antimicrobial adjuvant for treating glycolytic S. aureus. Our study defines the impacts of bicarbonate on the growth of SCVs and the metabolic pathways involved in detoxification, indicating that bicarbonate could be effective at controlling chronic S. aureus infections.

Keywords:  Staphylococcus aureus; anaplerotic metabolism; bicarbonate; oxaloacetate; pyruvate; small colony variants

DOI:  https://doi.org/10.1128/spectrum.01685-25
Cancer Lett. 2025 Sep 11. pii: S0304-3835(25)00608-1. [Epub ahead of print]633 218038

Lactate metabolic checkpoint in immuno-oncology: mechanisms and therapeutic implications.

Zhe Wang, Ziyan Gu, Wendi Mo, Haijun Zhang.

  Immuno-Oncology has transformed cancer therapeutics, yet its clinical efficacy remains limited by the immunosuppressive tumor microenvironment (TME). Once considered merely a metabolic byproduct of glycolysis, lactate is now recognized as a critical regulator of immune TME through both direct metabolic effects and its derivative modification, histone lysine lactylation (Kla). Within the TME, lactate and Kla reprogram signaling pathways that impair immune function, thereby facilitating tumor immune escape. This review synthesizes emerging evidence positioning lactate metabolism and histone Kla as pivotal immunosuppressive modulators within the TME. Tumor-derived lactate, produced through the Warburg effect, acidifies the TME and disrupts immune cell function via two interconnected mechanisms: direct metabolic interference and epigenetic reprogramming via Kla. Histone Kla represents a novel post-translational modification that drives immunosuppressive signaling in immune cells, serving as a prognostic biomarker across multiple cancers. Moreover, we highlight therapeutic strategies targeting lactate metabolism, which show considerable promise in overcoming the current limitations of immunotherapy and enhancing its clinical efficacy.

Keywords:  Immunotherapy; Lactate; Lactylation; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.canlet.2025.218038
Gut Microbes. 2025 Dec;17(1): 2559029

Intestinal epithelial PTPN2 limits pathobiont colonization by immune-directed antimicrobial responses.

Pritha Chatterjee, Marianne R Spalinger, Charly Acevedo, Alina N Santos, Casey M Gries, Salomon M Manz, Vinicius Canale, Ali Shawki, Anica Sayoc-Becerra, Hillmin Lei, Meli'sa S Crawford, Lars Eckmann, James Borneman, Declan F McCole.

  Loss of activity of the inflammatory bowel disease (IBD) susceptibility gene, protein tyrosine phosphatase non-receptor type 2 (PTPN2), is associated with altered microbiome composition in both human subjects and mice. Furthermore, expansion of the bacterial pathobiont, adherent-invasive E. coli (AIEC), is strongly linked to IBD pathogenesis. The mechanism by which intestinal epithelial cells (IEC) maintain equilibrium between commensal microbiota and immune cells to restrict invading pathobionts is poorly understood. Here, we investigated the role of IEC-specific PTPN2 in regulating AIEC colonization. Tamoxifen-inducible, intestinal epithelial cell-specific Ptpn2 knockout mice (Ptpn2∆IEC) and control Ptpn2fl/fl mice were infected with either noninvasive E. coli K12, or fluorescent-tagged mAIEC (mAIECred) for four consecutive days or administered PBS. Subsequently, bacterial colonization in mouse tissues was quantified. mRNA and protein expression were assayed in intestinal epithelial cells (IECs) or whole tissue lysates by PCR and Western blot. Tissue cytokine expression was determined by ELISA. Intestinal barrier function was determined by in vivo administration of 4 kDa FITC-dextran (FD4) or 70kDa Rhodamine-B dextran (RD70) fluorescent probes. Confocal microscopy was used to determine the localization of tight-junction proteins. Ptpn2∆IEC mice exhibited increased mAIECred - but not K12 - bacterial load in the distal colon compared to infected Ptpn2fl/fl mice. The higher susceptibility to mAIECred infection was associated with altered levels of antimicrobial peptide (AMPs). Ileal RNA expression of the alpha-defensin AMPs, Defa5, and Defa6, as well as MMP7, was significantly lower in Ptpn2∆IEC vs. Ptpn2fl/fl mice, after mAIECred but not K12 infection. Furthermore, we observed an increased tight junction-regulated permeability determined by elevated in vivo FD4 but not RD70 permeability in Ptpn2∆IEC-K12 mice compared to their respective controls. This effect was further exacerbated in Ptpn2∆IEC mAIEC-infected mice. Further, Ptpn2∆IEC mice displayed lower IL-22, IL-6, IL-17A cytokine expression post mAIEC infection compared to Ptpn2fl/fl controls. Recombinant IL-22 reversed the FD4 permeability defect and reduced bacterial burden in Ptpn2∆IEC mice post mAIEC challenge. Our findings highlight that the intestinal epithelial PTPN2 is crucial for mucosal immunity and gut homeostasis by promoting anti-bacterial defense mechanisms involving coordinated epithelial-immune responses to restrict pathobiont colonization.

Keywords:  Adherent-invasive E. coli (AIEC); Antimicrobial Peptide; Barrier Function; Interleukin-22; Intestinal Permeability; Pathobiont; Tight Junctions

DOI:  https://doi.org/10.1080/19490976.2025.2559029
Inflamm Res. 2025 Sep 16. 74(1): 128

Reprogramming immunity with itaconate: metabolic mechanisms and therapeutic perspectives.

Hanlin Gao, Minting Ding, Yunchen Liu, Yiying Wang, Susu Zhao, Junyao Chen, Zhi Chen, Gang Wang.

  Itaconate, a mitochondrial metabolite generated from cis-aconitate via IRG1 (ACOD1), has emerged as a key immunometabolic signal that links metabolic reprogramming with immune regulation. Beyond its origin in the tricarboxylic acid (TCA) cycle, itaconate exemplifies how metabolic intermediates can reshape cell fate and function under stress and inflammation. Upon inflammatory stimulation, immune cells-particularly macrophages-undergo profound metabolic rewiring. Itaconate orchestrates this shift by inhibiting succinate dehydrogenase (SDH), accumulating succinate, activating nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant responses, and modulating glycolytic flux, thus balancing inflammatory output and oxidative stress. This review provides an integrative overview of itaconate biosynthesis, metabolic regulation, and functional mechanisms across diverse physiological and pathological contexts. Itaconate and its derivatives, such as 4-octyl itaconate (4-OI), exhibit promising effects in preclinical models of sepsis, acute lung injury, autoimmune diseases (e.g., SLE and RA), ischemia-reperfusion injury, infection (bacterial and viral), and cancer. These effects are closely linked to itaconate's capacity to reprogram immune metabolism and modulate signaling pathways such as NF-κB, NLRP3, and JAK/STAT. Importantly, recent findings suggest that itaconate not only modulates inflammation but also affects immune cell death pathways, ferroptosis susceptibility, and tumor immune evasion. These multifaceted roles make itaconate a potential metabolic checkpoint in the development of new therapeutic strategies. However, challenges such as metabolic instability, limited bioavailability, and potential off-target effects remain to be addressed. In summary, itaconate represents a powerful endogenous modulator of immunometabolism. Its therapeutic utility, as a direct drug, as a scaffold for derivative design, or as a biomarker for inflammation resolution, holds significant promise for treating inflammation-driven diseases through the lens of metabolic reprogramming. This review summarizes itaconate biosynthesis, its molecular mechanisms in health and disease, and recent advances across multiple conditions, providing a foundation for future immunometabolic therapies.

Keywords:  Immunometabolism; Inflammation; Itaconate; Metabolic reprogramming; Therapeutic potential

DOI:  https://doi.org/10.1007/s00011-025-02087-4
Emerg Microbes Infect. 2025 Sep 15. 2562053

Post-COVID-19 disruption of the respiratory microbiome modulates Mycoplasma pneumoniae: a multi-center retrospective investigation study.

Shiyu Huang, Shengkai Li, Ruike Zhao, Huajiang Yang, Yina Liu, Xinyi Wang, Jiaqi Zhang, Chen Shen, Feina Li, Hua Xu, Changyuan Guo, Xin Ni, Heng Li, Qing Cao, Zhemin Zhou.

  Since the COVID-19 pandemic, there has been a notable resurgence of Mycoplasma pneumoniae pneumonia (MPP) in children, with a concerning rise in the severity of cases. Although changes in post-pandemic respiratory infection patterns have been documented, the reasons behind the increased severity of MPP, especially concerning shifts in the respiratory microbiota, are not well understood. This study aims to explore how pandemic-associated disruptions in respiratory microbiota contribute to MPP severity. Through analysis of multiple independent cohorts, we found that the depletion of protective respiratory microbiota exacerbates MPP severity by reducing colonization resistance against M. pneumoniae. We identified two antagonistic microbiota modules with distinct metabolic features and community structures that regulate pathogen colonization and disease severity. Using a Susceptible-Infected-Recovered (SIR) model, we simulated M. pneumoniae infection dynamics across different microbiota states. Additionally, a machine-learning model based on eight key microbes effectively distinguished between cases and controls and predicted infection severity, offering insights into post-pandemic respiratory infections. This study underscores the essential role of the respiratory microbiota in influencing the severity of M. pneumoniae infections. Our findings offer a framework for managing respiratory infections in the post-pandemic era, highlighting the significance of understanding microbial community dynamics in determining disease outcomes. These insights could guide the development of therapeutic strategies focused on restoring or enhancing the protective microbiota, which may offer an effective strategy for the management of MPP and other respiratory infections.

Keywords:  Mycoplasma pneumoniae; Pediatrics; Respiratory Infection; Severity Risk Model; Susceptible-Infected-Recovered Model

DOI:  https://doi.org/10.1080/22221751.2025.2562053
Front Microbiol. 2025 ;16 1632267

The joint action of antibiotics, bacteriophage, and the innate immune response in the treatment of bacterial infections.

Brandon A Berryhill, Teresa Gil-Gil, Bruce R Levin.

  Studies of antimicrobial therapeutics have traditionally neglected the contribution of the host in determining the course of treatment and its outcome. One critical host element, which shapes the dynamics of treatment is the innate immune system. Studies of chemotherapeutics and complementary therapies such as bacteriophage (phage), are commonly performed with mice that purposely have an ablated innate immune system. Here, we generate a mathematical and computer-simulation model of the joint action of antibiotics, phage, and phagocytes. Our analysis of this model highlights the need for future studies to consider the role of the host's innate immune system in determining treatment outcomes. Critically, our model predicts that the conditions under which resistance to the treatment agent(s) will emerge are much narrower than commonly anticipate. We also generate a second model to predict the dynamics of treatment when multiple phages are used. This model provides support for the application of cocktails to treat infections rather than individual phages. Overall, this study provides hypotheses that can readily be tested experimentally with both in vitro and in vivo experiments.

Keywords:  Innate immunity; antibiotic resistance; antibiotics; bacteriophages; infection dynamics; mathematical and computer-simulation modeling; phage resistance

DOI:  https://doi.org/10.3389/fmicb.2025.1632267
Immunol Lett. 2025 Sep 16. pii: S0165-2478(25)00124-5. [Epub ahead of print]277 107091

Tissue resident memory B cells mediate protective immunity to respiratory pathogens in the airways.

Ivy M Akehurst, Louisa K James.

  Respiratory pathogens pose a significant risk to public health and are responsible for burdening health care by causing worldwide morbidity and mortality. The immune environment in the airway is critical for protection from respiratory pathogens and comprises several specialist subsets of resident lymphocytes and myeloid cells. Tissue resident-memory B cells (BRM) are a subset of memory B cell which reside in mucosal tissues, including the airways. Although, BRM have only recently been characterised, they have a crucial role in generating robust and localised immune responses to respiratory infections, particularly secondary responses, by rapidly differentiating into antibody-secreting cells. A greater understanding of their role in protecting the airways from respiratory pathogens will enable the development of immunisation strategies against respiratory disease. This mini-review aims to summarise the current knowledge of BRM and highlight areas for future research.

Keywords:  Antibodies; B cells; Immune memory; Immunoglobulin; Respiratory; Tissue resident B cells

DOI:  https://doi.org/10.1016/j.imlet.2025.107091
JCI Insight. 2025 Sep 16. pii: e182836. [Epub ahead of print]

Limited nasal interferon production contributes to delayed respiratory virus clearance and suboptimal vaccine responses.

Jorna Sojati, Olivia B Parks, Taylor Eddens, Jie Lan, Monika Johnson, John V Williams.

  Acute lower respiratory infections are the primary cause of global mortality in post-neonatal children. Most respiratory viruses primarily involve upper airway infection and inflammation, yet nasal responses are poorly characterized. Using a mouse model of human metapneumovirus (HMPV), we found viral burden was higher in nasal airways and exhibited delayed clearance. Despite high burden, there was low nasal expression of type I and III interferon (IFN). Single-cell RNA-sequencing (scRNA-seq) from HMPV-infected mice showed lower nasal interferon-stimulated gene (ISG) expression and nasal enrichment of genes negatively regulating IFN. scRNA-seq of COVID-19 patients confirmed lower ISG expression in upper airways. HMPV infection downregulated nasal expression of interferon regulatory factor-3, suggesting a mechanism for limited response. To rescue the quiescent environment, we administered type I or III IFN to upper airways early post-infection, leading to lower nasal HMPV titer and virus-specific CD8+ T-cell upregulation. Intranasal immunization adjuvanted with type I or III IFN improved immune response, reduced clinical disease, and enhanced viral clearance in HMPV and influenza infection. IFN adjuvant increased recruitment of dendritic cells, resident-memory T-cells, and neutralizing antibodies. These findings reveal locally suppressed IFN production contributes to a quiescent nasal immune landscape that delays viral clearance and impairs mucosal vaccine responses.

Keywords:  Immunology; Infectious disease; Influenza; Innate immunity; Vaccines; Virology

DOI:  https://doi.org/10.1172/jci.insight.182836
Front Med. 2025 Sep 20.

Lactate and lactylation in tumor immunity.

Liu Song, Lingjuan Sun, Song Chen, Peixiang Lan.

  The Warburg effect, originally discovered by Otto Warburg, refers to the metabolic reprogramming of tumor cells from aerobic oxidation to glycolysis, enabling rapid energy production to support their growth and metastasis. This process is accompanied by the massive production and accumulation of lactate both intracellularly and extracellularly. The resulting acidic microenvironment impairs the normal physiological functions of immune cells and promotes tumor progression. An increasing number of studies indicate that lactate, a key metabolite in the tumor microenvironment (TME), acts as a pivotal immunosuppressive signaling molecule that modulates immune cell function. This review aims to comprehensively examine lactate's role as an immunosuppressive molecule in TME. It focuses on mechanisms such as membrane receptor binding, functional reshaping of immune cells via lactate shuttle transport, epigenetic regulation of gene expression through histone lactylation, and modulation of protein structure and function through nonhistone lactylation, emphasizing lactate's importance in immune regulation within the TME. Ultimately, this review offers novel insights into immunosuppressive therapies aimed at targeting lactate function.

Keywords:  TME; immunosuppressive immune cells; lactate; lactylation; tumor immunity

DOI:  https://doi.org/10.1007/s11684-025-1148-0
Nat Commun. 2025 Sep 17. 16(1): 8302

NRC31 limits the imprinting of astrocyte epigenetic inflammatory memory early in life.

Hong-Gyun Lee, Francisco J Quintana.

DOI: https://doi.org/10.1038/s41467-025-64102-w
Cell Rep. 2025 Sep 16. pii: S2211-1247(25)01083-6. [Epub ahead of print]44(10): 116312

Innate immune molecular landscape following controlled human influenza virus infection.

William Thistlethwaite, Sindhu Vangeti, Wan-Sze Cheng, Pankaj Agarwal, Antonio Cappuccio, Wenliang Wang, Bei Wei, Rachel Myers, Aliza B Rubenstein, Daniel Chawla, Manoj Hariharan, Micah T McClain, Thomas W Burke, Steven H Kleinstein, Joseph R Ecker, Christopher W Woods, William J Greenleaf, Xi Chen, Irene Ramos, Elena Zaslavsky, Thomas G Evans, Olga G Troyanskaya, Stuart C Sealfon.

  Viral infections can induce prolonged changes in innate immunity. Here, we use blood samples from a human influenza H3N2 challenge study (NCT03883113) to perform comprehensive multi-omics analyses. We detect remodeling of immune programs in circulating innate immune cells that persist after resolution of the infection. We find changes associated with suppressed inflammation, including decreased cytokine and AP-1 gene expression as well as decreased accessibility at AP-1 targets and interleukin-related gene promoter regions. We also find decreased histone deacetylase gene expression, increased MAP kinase gene expression, and increased accessibility at interferon-related gene promoter regions. Genes involved in inflammation and methylation remodeling show modulation of gene-chromatin site regulatory circuit activity. These results reveal a coordinated rewiring of the molecular landscape in innate immune cells induced by mild influenza virus infection.

Keywords:  CP: Immunology; CP: Molecular biology; human challenge; influenza; innate immunity; multi-omics; scATAC-seq; scRNA-seq; transcriptomics

DOI:  https://doi.org/10.1016/j.celrep.2025.116312
Pediatr Infect Dis J. 2025 Sep 18.

Concordance of Pathogenic Bacteria in the Upper and Lower Airway in Children With Severe Viral Lower Respiratory Tract Infections.

Katherine Bline, Takaharu Karube, Jeffrey Naples, Melissa Moore-Clingenpeel, Josey Hensley, Chi-Sian Dai, Li Tang, Mark W Hall, Will Ray, Octavio Ramilo, Asuncion Mejias.

   BACKGROUND: Viral lower respiratory tract infections (LRTIs) are a leading cause of mortality among children. Bacterial coinfections in viral LRTI are associated with severe clinical outcomes. Identifying lower airway bacterial involvement in viral LRTI is challenging. Our objective was to define the concordance of bacterial detection between paired upper nasopharyngeal (NP) swabs and lower endotracheal airway samples (ETAs) in children with severe viral LRTI.
METHODS: Convenience sample of children <5 years intubated with LRTI. Children were enrolled within 48 hours of ICU admission, and NP/ETAs were obtained for the detection of Moraxella catarrhalis, Streptococcus pneumoniae, Haemophilus influenzae and Staphylococcus aureus. Concordance was assessed via intraclass correlation coefficient (ICC), according to the respiratory virus and age. Clinical outcomes were also assessed.
RESULTS: From 2017 to 2021, we enrolled 76 children [median age: 2.1 (1.2-4.3) months]. The most common respiratory virus was respiratory syncytial virus (RSV) (73.7%). Overall concordance for bacterial detection was high for M. catarrhalis, H. influenzae, and S. pneumoniae (ICC ≥0.75) but low for S. aureus (ICC 0.36). Detection rates varied by viral pathogen, with M. catarrhalis and S. pneumoniae showing the highest agreement in children with RSV. Agreement was higher in infants <6 months. Prolonged intubation was observed in children with RSV and NP codetection of S. pneumoniae or H. influenzae.
CONCLUSIONS: Concordance was high for M. catarrhalis, H. influenzae, and S. pneumoniae, but not for S. aureus, and was influenced by the viral etiology and age. These findings suggest the applicability of NP swabs as surrogates for lower airway cultures for specific bacterial-virus combinations in children with severe LRTI.

Keywords:  bacterial detection; critical care; immunology; mechanical ventilation; pediatric; respiratory infection

DOI:  https://doi.org/10.1097/INF.0000000000005009
Front Syst Biol. 2025 ;5 1544432

MicrobiomeKG: bridging microbiome research and host health through knowledge graphs.

Skye L Goetz, Amy K Glen, Gwênlyn Glusman.

  The microbiome represents a complex community of trillions of microorganisms residing in various body parts and plays critical roles in maintaining host health and wellbeing. Understanding the interactions between microbiota and their host offers valuable insights into potential strategies for promoting health, including microbiome-targeted interventions. We have created MicrobiomeKG, a knowledge graph for microbiome research, that bridges various taxa and microbial pathways with host health. This novel knowledge graph derives algorithmically generated knowledge assertions from the supplementary tables that support published microbiome papers. By identifying knowledge assertions from supplementary tables and expressing them as knowledge graphs, we are casting this valuable content into a format that is ideal for hypothesis generation. To address the high heterogeneity of study contexts, methodologies, and reporting standards, we leveraged neural networks to implement a standardized edge scoring system, which we use to perform centrality analyses. We present three example use cases: linking helminth infections with non-alcoholic fatty-liver disease via microbial taxa, exploring connections between the Alistipes genus and inflammation, and identifying the Bifidobacterium genus as the most central connection with attention deficit hyperactivity disorder. MicrobiomeKG is deployed for integrative analysis and hypothesis generation, both programmatically and via the Biomedical Data Translator ecosystem. By bridging data gaps and facilitating the discovery of new biological relationships, MicrobiomeKG will help advance personalized medicine through a deeper understanding of the microbial contributions to human health and disease mechanisms.

Keywords:  data integration; health informatics; hypothesis generation; knowledge representation; neural networks; supplementary data; systems biology; table mining

DOI:  https://doi.org/10.3389/fsysb.2025.1544432
Sci Transl Med. 2025 Sep 17. 17(816): eadq8328

Export by a quorum sensing-controlled drug exporter underlies rifampicin's strong activity against staphylococcal biofilms.

Yao Liu, Lei He, Ryan Liu, Dylan J Burgin, Min Li, Michael Otto.

Biofilm infections on indwelling medical devices are a major cause of health care-associated infection and mortality. Most of these infections are caused by staphylococci. Biofilm formation presents a continued clinical challenge because of the association with dramatically increased nonspecific antimicrobial resistance. Unlike most antibiotics, rifampicin is active against staphylococcal biofilm infections; however, the mechanism is unknown. Using in vitro assays and mouse models of biofilm infection, we show here that rifampicin is more effective than other antibiotics against staphylococcal agr mutants, which are linked to serious biofilm infections because they produce extended biofilms. We found that this superiority results from an Agr-controlled rifampicin efflux system, which makes agr mutant biofilms less resistant to rifampicin, rather than more resistant, than they are to other antibiotics. Our study provides a scientific rationale supporting the use of rifampicin in staphylococcal biofilm infections and emphasizes the importance of understanding genetic adaptations during infection for the use and development of biofilm therapeutics.

DOI: https://doi.org/10.1126/scitranslmed.adq8328
mBio. 2025 Sep 18. e0208825

Deficiency of cannabinoid receptors enhances host susceptibility to bacterial infection.

Hailey A Barker, Saloni Bhimani, Deyaneira Tirado, Jorge J Canas, Leandro Nascimento Lemos, Luiz F W Roesch, Mariola J Ferraro.

  Host resilience to bacterial infection depends on tightly regulated immune responses, which can be shaped by metabolic cues, including the contribution from bioactive lipids. The endocannabinoid system (ECS), a lipid signaling network known for its neuromodulatory roles, also influences immunity; however, the receptor-specific contributions of cannabinoid receptor 1 (CB1R) and cannabinoid receptor 2 (CB2R) in host-pathogen interactions remain incompletely defined in this context. Using receptor-deficient mouse models, we investigated how CB1R and CB2R modify immune responses to Salmonella Typhimurium. CB1R-deficient (CB1R-KO) mice exhibited heightened systemic inflammation, impaired bacterial clearance, and reduced survival in systemic infection, associated with dysregulated macrophage polarization and diminished neutrophil recruitment. In contrast, CB2R-KO mice showed increased susceptibility in both systemic and mucosal infection models, marked by a pro-inflammatory macrophage profile, enhanced neutrophilia, and microbiota dysbiosis. Shotgun metagenomic analysis revealed a reduced abundance of specific protective commensals and altered microbial metabolic pathway profiles in CB2R-KO mice, suggesting a role for CB2R in maintaining mucosal immune-microbiota homeostasis. Collectively, these findings highlight non-redundant roles for CB1R and CB2R in regulating immune dynamics and salmonellosis disease severity, and they point to the ECS as a potential target for host-directed immunomodulatory therapies.IMPORTANCEEffective immunity against bacterial pathogens requires a delicate balance between microbial clearance and the containment of inflammatory damage encountered during many infections. The molecular pathways that regulate this equilibrium remain incompletely defined, and the involvement of bioactive lipid signaling mechanisms also needs to be better described. Here, we show that the endocannabinoid receptors CB1R and CB2R play non-redundant roles in host defense against Salmonella infection. CB1R deficiency results in exacerbated systemic inflammation, defective bacterial clearance, and dysregulated macrophage polarization. In contrast, CB2R deficiency leads post-infection to gut dysbiosis and has been found to negatively affect the outcome for the host in both systemic and mucosal infection with Salmonella. By describing cannabinoid receptor-specific contributions to immune regulation and microbiota dynamics, our findings reveal a previously underappreciated axis of host-pathogen interaction. This study broadens our understanding of lipid-mediated immune modulation and identifies CB1R and CB2R as potential targets for therapies aimed at restoring immune homeostasis and improving infectious disease outcomes.

Keywords:  Salmonella infection; cannabinoid receptors; endocannabinoid system; immune response; macrophage; microbiome

DOI:  https://doi.org/10.1128/mbio.02088-25
Gut Microbes. 2025 Dec;17(1): 2560019

Regulatory roles of intestinal CD4+ T cells in inflammation and their modulation by the intestinal microbiota.

Ziyu Ma, Zixu Wang, Jing Cao, Yulan Dong, Yaoxing Chen.

  Intestinal inflammation is a major global health challenge, driving the pathogenesis of inflammatory bowel disease (IBD) and imposing a significant socioeconomic burden. Dysregulated homeostasis of intestinal CD4+ T cell subsets, particularly the imbalance between pro-inflammatory T helper cells (Th1, Th2, Th17, Th9) and regulatory T cells (Tregs), is a key trigger of intestinal inflammation. These immune cells orchestrate immune responses through distinct cytokine profiles (IFN-γ/IL-4/IL-17/IL-9 vs. IL-10/TGF-β). Recent studies highlight the pivotal role of the intestinal microbiota in regulating this immune axis via three primary mechanisms: 1, Short-chain fatty acids (SCFAs) induce epigenetic reprogramming by inhibiting HDACs, promoting Treg differentiation and inhibit the differentiation of Th17/Th9 cells; 2, Secondary bile acids (BAs) suppress Th17 polarization through FXR/TGR5/PXR signaling; 3, Tryptophan metabolites (indole, kynurenine) balance Th17/Treg ratios via AhR-IL-22 signaling. Microbial dysbiosis disrupts this network by secreting pathogen-associated molecular patterns (PAMPs), such as Lipopolysaccharide (LPS) and peptidoglycan (PG), which activate pathogen pattern recognition receptors (PRRs), such as TLR4/NOD2/NF-κb signaling, driving Th1/Th17 differentiation. This review summarizes recent advances in the microbiota-CD4+ T cell interaction and discusses therapeutic strategies to modulate the intestinal microbiota, aiming to enhance understanding of IBD pathogenesis and identify potential clinical interventions.

Keywords:  Intestinal CD4+ T cells; inflammation; intestinal microbiota; microbiota metabolites

DOI:  https://doi.org/10.1080/19490976.2025.2560019
Front Cell Infect Microbiol. 2025 ;15 1592296

Depletion of Mycobacterium tuberculosis transmembrane protein Rv3737 reduces pathogen survival and induces M1 macrophage polarization against tuberculosis.

Zhangli Peng, Chao Xu, Taixian You, Chengjie Shu, Qing Li, Nana Li, Renzhong He, Ling Chen, Lin Xu.

   Objectives: Mycobacterium tuberculosis (Mtb) modulates macrophage polarization to evade host immunity and enhance intracellular survival. Rv3737, a probable conserved transmembrane protein in Mtb, has an unclear biological function. This study investigates the role of Rv3737 in regulating macrophage polarization and Mtb survival within host cells.
Methods: The structure of Rv3737 was predicted using bioinformatics tools. Macrophage polarization markers were assessed by real-time PCR for M1/M2-associated cytokines, and flow cytometry for CD86+/CD206+ expression. RNA sequencing, along with KEGG and GO analyses, was used to explore underlying regulatory pathways. Western blotting evaluated the phosphorylation status of NF-κB (P65, IκB) and MAPK (ERK, P38, JNK) signaling components. Colony-forming units (CFUs) and inducible nitric oxide synthase (iNOS) levels were examined in H37RvΔRv3737-infected macrophages pretreated with specific inhibitors (JSH-23, U0126-EtOH, SB203580, SP600125).
Results: Rv3737 is predicted to contain 10 transmembrane segments enriched in aliphatic amino acids. Deletion of Rv3737 in H37Rv (H37RvΔRv3737) led to upregulation of M1 markers (TNF-α, IL-1β, IL-6, iNOS, MCP-1, CD86) and downregulation of M2 markers (Arg-1, IL-10, TGF-β, CD206). Conversely, overexpression of Rv3737 (MS_Rv3737) promoted M2 polarization. RNA sequencing indicated NF-κB pathway activation in macrophages infected with H37RvΔRv3737, along with increased phosphorylation of P65, IκB, ERK, and P38. Inhibition of NF-κB (with JSH-23) and P38 MAPK (with SB203580) reduced iNOS levels and partially restored Mtb survival, indicating that Rv3737 deletion enhances the macrophage antimicrobial response.
Conclusions: Rv3737 suppresses M1 macrophage polarization to promote Mtb survival. Its deletion enhances host antimicrobial activity by activating NF-κB and MAPK signaling pathways. Targeting Rv3737 may represent a novel strategy for tuberculosis therapy.

Keywords:  Mycobacterium tuberculosis; Rv3737; intracellular survival; macrophage polarization; transmembrane protein

DOI:  https://doi.org/10.3389/fcimb.2025.1592296
Nat Immunol. 2025 Sep 15.

Delaying pyroptosis with an AI-screened gasdermin D pore blocker mitigates inflammatory response.

Jianhui Sun, Jun Yang, Jie Tao, Yifan Yang, Rui Wang, Huacai Zhang, Wenyi Liu, Shulin Zhao, Runze Shao, Yuhui He, Shaolin Tao, Yaxiong Li, Hai Qu, Di Liu, Jingwen Li, Jianxin Jiang, Bo Deng, Chu Gao, Ping Lin, Ling Zeng, Ping Meng, Gan Wang.

The formation of membrane pores by cleaved N-terminal gasdermin D (GSDMD-NT) results in the release of cytokines and inflammatory cell death, known as pyroptosis. Blocking GSDMD-NT pores is an attractive and promising strategy for mitigating inflammation. Here we demonstrate that SK56, an artificial intelligence-screened peptide, effectively obstructs GSDMD-NT pores and inhibits pyroptosis and cytokine release in macrophages and human peripheral blood leukocyte-induced pyroptosis. SK56 prevents septic death induced by lipopolysaccharide or cecal ligation and puncture surgery in mice. SK56 does not influence cleavage of interleukin-1β or GSDMD. Instead, SK56 inhibits the release of cytokines from pyroptotic macrophages, mitigates the activation of primary mouse dendritic cells triggered by incubation with pyroptotic cytomembranes and prevents widespread cell death of human alveolar organoids in an organoid-macrophage coculture model. SK56 blocks GSDMD-NT pores on lipid-bilayer nanoparticles and enters pyroptotic macrophages to inhibit mitochondrial damage. SK56 presents new therapeutic possibilities for counteracting inflammation, which is implicated in numerous diseases.

DOI: https://doi.org/10.1038/s41590-025-02280-x
Arch Immunol Ther Exp (Warsz). 2025 Jan 01. 73(1):

Significance of the LL-37 Peptide Delivered from Human Cathelicidin in the Pathogenesis, Treatment, and Diagnosis of Sepsis.

Angelika Mańkowska, Paulina Paprocka, Grzegorz Król, Agata Lesiak, Jakub Spałek, Ewelina Piktel, Sławomir Okła, Piotr Bijak, Wiesława Niklińska, Bonita Durnaś, Robert Bucki.

  Antimicrobial peptides, which function as the first line of host immune defense, have recently been identified as important immunomodulators of inflammation, and are involved as regulatory molecules in infections, including sepsis. Treatment of sepsis is very complex and remains largely challenging and sometimes ineffective. This creates a need to develop new therapeutic strategies focusing not only on the elimination of sepsis-causing microorganisms, which can be achieved with antibiotics, but also on the control of the immune system and its overactive response resulting in increased vascular endothelial permeability. One approach to develop new treatments for patients with sepsis is to better understand the pleiotropic function of the human LL-37 peptide that originates from the human cathelicidin antibacterial protein (h-CAP18). An increasing number of studies indicate high dynamics of changes in LL-37 concentration in the blood during sepsis. Additionally, in animal models, administration of exogenous LL-37 peptide to mice with experimentally induced sepsis increases their survival. It can therefore be assumed that knowledge of the molecular mechanism of cathelicidin LL-37 action, as well as the synthesis of its stable analogs, will result in progress in the diagnosis and therapy of sepsis.

Keywords:  Bacteria; Cathelicidins; LL-37 peptide; Sepsis

DOI:  https://doi.org/10.2478/aite-2025-0025
ACS Nano. 2025 Sep 15.

Autoinducing Peptide-Mediated Bacterial Keratitis Therapy by Camouflaged Staphylococcus aureus.

Xiaojie Wu, Xin Wang, Jing Kang, Alideertu Dong, Ying-Wei Yang.

  Staphylococcus aureus (S. aureus) is a prevalent and highly virulent pathogen responsible for microbial keratitis, which can lead to stromal damage, corneal perforation, and even blindness. In the postantibiotic era, the escalating prevalence of antibiotic-resistant S. aureus has rendered conventional antibiotic treatments increasingly ineffective, particularly due to autoinducing peptide-mediated signaling. Meanwhile, antibiotics disrupt the balance of the microbiota, which can further trigger ocular complications. To address these challenges, we designed and prepared a camouflaged bacterial system, supramolecular-coated S. aureus (SMCS), which can identify and aggregate with the matching pathogenic S. aureus through autoinducing peptide-mediated signaling. Upon the addition of amantadine, competitive host-guest interactions trigger the release of the antibacterial agent, enabling efficient and selective sterilization against pathogenic S. aureus with a fourfold higher efficacy than that against beneficial bacteria. In a rat model of bacterial keratitis, the proportion of Staphylococcus is 13.71% in the cornea after SMCS treatment, which is comparable to that in the healthy cornea (7.40%). SMCS+amantadine treatment can effectively eradicate bacteria, increase the diversity and abundance of corneal microorganisms, and preserve the balance of the corneal microbiota, providing promising clinical prospects in bacterial infection treatments and bacterial-mediated bioapplications.

Keywords:  bacterial keratitis; biomaterials; cucurbiturils; host−guest chemistry; supramolecular materials

DOI:  https://doi.org/10.1021/acsnano.5c08838
Metabolism. 2025 Sep 17. pii: S0026-0495(25)00258-6. [Epub ahead of print] 156389

Sepsis-induced lipid droplet accumulation enhances antibacterial innate immunity through mechanisms dependent on DGAT-1 and interferon-beta.

Filipe S Pereira-Dutra, Julia Cunha Santos, Ellen Kiarely Souza, Rodrigo Vieira Savi, Tamyris S Souza, Helen Gil, Hugo Espinheira-Silva, Felipe Ferraro-Moreira, Guilherme Iack, Tamires Cunha-Fernandes, Tathiany Igreja-Silva, Lohanna Palhinha, Mariana Macedo Campos, Ester Fernanda Terra Souza, Amanda França Cordeiro, Pablo Andrade-Dos-Santos, Douglas Mathias Oliveira, Vinicius Soares Cardoso, Matheus A Rajão, Livia Teixeira, Luciana Souza-Moreira, Maria Fernanda Souza Costa, Patrícia Alves Reis, Patrícia T Bozza.

  Lipid droplets (LDs) are lipid-rich organelles recognized as central players in lipid homeostasis, signaling, and inflammation. While their functions in inflammation are well-documented, the mechanisms of LDs in antibacterial immunity and infection resistance remain less understood. Our results show that E. coli-infection trigger immunometabolic reprogramming and LD accumulation in macrophages. Moreover, purified LDs from LPS-stimulated and E. coli-infected macrophages exhibited direct E. coli anti-bacterial activity. Pharmacological inhibition or genetic knockdown of DGAT1, a key enzyme in triglyceride synthesis, reduced LD formation, bacterial clearance, and pro-inflammatory responses (nitric oxide, PGE2, CCL2, IL-6). Notably, DGAT1 inhibition impaired the expression of IFN-β and several interferon-stimulated genes (ISGs), including viperin, iNOS, cathelicidin and IGTP, in E. coli-infected macrophages. In a cecal-ligation and puncture model of sepsis in C57BL/6 mice, DGAT1 inhibition reduced sepsis-induced LD accumulation in peritoneal cells and decreased levels of IFN-β, CCL2, nitric oxide, and lipid mediators (PGE2, LTB4, and RvD1). Furthermore, DGAT1 inhibition accelerated sepsis-related mortality, coinciding with elevated bacterial loads in the peritoneum and bloodstream at 6- and 24-h post-sepsis. Our results demonstrate that LDs are critical regulators of innate immunity infection resistance, contributing to both bacterial clearance and the coordination of a protective proinflammatory response during sepsis through mechanisms dependent on DGAT-1 and Type I IFN.

Keywords:  Immunometabolism; Lipid droplets; Lipid metabolism; Resistence to infection

DOI:  https://doi.org/10.1016/j.metabol.2025.156389
Cell Rep. 2025 Sep 16. pii: S2211-1247(25)01078-2. [Epub ahead of print]44(10): 116307

Inflammatory modalities shape the IgA repertoire via stochastic processes.

Christian Melcher, Chaim A Schramm, Laura Kampe, Yushu Zhang, Katrin Westphal, Martina Krautkrämer, Xiameng Shen, Korbinian Brand, Peter Franz, Marius Vital, Daniel C Douek, Niko Föger, Kyeong-Hee Lee.

  Mucosal B cell immunity relies on the constant induction of immunoglobulin A (IgA) in the intestine. In spite of abundant homeostatic IgA, here we present further amplification of IgA plasma cells during intestinal inflammation that was linked to massive clonal expansion of dominant B lineages. We characterized the inducible B cell response during colitis and show the properties of intestinal IgA produced by adaptive and innate B cell subsets. Fab-dependent specific recognition of individual commensal taxa by inflammation-induced IgA was associated with signs of affinity maturation and cross-reactivity to cellular autoantigens. However, despite the principal ability of mucosal B cells to specifically induce microbiota-targeting IgA, the vast majority of inflammation-induced intestinal IgA was microbiota non-reactive, generated upon clonal burst of germline-encoded bystanders. Unpredictable variation in the prevalence of microbiota- and auto-reactive IgA in individual colitic mice was indicative of stochastic selection of random B lineages in the inflammatory environment with potentially unforeseeable pathophysiological consequences.

Keywords:  CP: Immunology; IgA; inflammatory bowel disease; microbiota; mucosal B cell immunity

DOI:  https://doi.org/10.1016/j.celrep.2025.116307
Front Immunol. 2025 ;16 1633977

The impact of mycobacteria-induced trained immunity on SARS-CoV-2 vaccine responses.

Lidia Sánchez-Morales, Néstor Porras, Andrea Pérez-Domingo, Marta Pérez-Sancho, Teresa García-Seco, Marta Diaz-Frutos, Aranzazu Buendia, Inmaculada Moreno, Leydis Zamora, Ana Balseiro, M A Risalde, Antonio Rodriguez-Bertos, Christian Gortázar, Mercedes Domínguez, Lucas Domínguez.

   Introduction: Beyond the role of Bacillus Calmette-Guérin (BCG) for tuberculosis prevention, BCG has demonstrated heterologous protective effects. The global health crisis caused by the SARS-CoV-2 virus led to research on whether BCG-induced trained immunity could strengthen antiviral defenses. However, studies reported quite different results on its effect against COVID-19.
Methods and results: In this study, we evaluated the impact of pre-existing trained immunity induced by a BCG-derived Mycobacterium bovis strain (dpB), in both live and inactivated forms, in combination with SARS-CoV-2 vaccination prior to challenge in a mouse model. While the SARS-CoV-2 vaccine was enough for protection in morbidity and mortality terms, its combination with live dpB significantly enhanced immune responses reflected in higher levels of pro-inflammatory cytokines, reduced pulmonary viral loads, and improved histopathological outcomes. Additionally, the formation of inducible bronchus-associated lymphoid tissue (iBALT) in lungs in vaccinated animals pre-exposed to live dpB points to a potential mechanism for long-term immune surveillance in the respiratory tract.
Conclusions: These immunological findings highlight the potential benefits of integrating trained immunity inducers with pathogen-specific vaccines to enhance immune responses and protection. Further research is needed to optimize immunomodulation strategies, dosing regimens and administration routes to maximize these synergistic effects and prevent potential negative effects.

Keywords:  SARS-CoV-2 vaccine; adaptative immunity; innate memory; mycobacteria; trained immunity

DOI:  https://doi.org/10.3389/fimmu.2025.1633977
Compr Physiol. 2025 Oct;15(5): e70051

Interorgan Communication Between Lung and Colorectal Epithelial Cells Studied Using a Novel Multi-Organ-On-Chip System.

Brady Rae, Verena Bood, Hye-Jin Dijk, Gwenda F Vasse, Barbro N Melgert, Anika Nagelkerke, Janette K Burgess, Dirk-Jan Slebos, Irene H Heijink, Simon D Pouwels.

  Chronic Obstructive Pulmonary Disease (COPD), a severe lung disease caused by chronic inhalation of toxic gases and particles, is often accompanied by extrapulmonary comorbidities. These are characterized by systemic inflammation and activation of the bi-directional lung-gut axis, in which communication takes place between lung and intestinal cells. The mechanisms of interorgan communication in COPD are largely unknown, partly due to the lack of suitable in vitro models to study interorgan communication. In the current study, we developed a novel unidirectional millifluidic multi-organ-on-chip (MOoC) device, in which stimulated lung epithelial cells were connected to colorectal cells. Human lung epithelial A549 cells were exposed to cigarette smoke extract and nylon microplastic fibers, mimicking inhaled pollutants that induce lung epithelial damage and can contribute to the development of COPD. Once exposed, A549 cells were connected to naïve colorectal DLD-1 cells within our MOoC system to study interorgan communication mediated by released factors such as cytokines, chemokines, or Damage Associated Molecular Patterns (DAMPs). A549 cells treated with inhalable pollutants released communication mediators, such as the DAMP galectin-3. Naïve DLD-1 cells responded to these released factors from stimulated A549 cells by inducing pro-inflammatory responses, demonstrated by increased IL-6 mRNA expression and decreasing barrier integrity, as demonstrated by decreased CDH1 mRNA expression and delocalization from the cell membrane of E-cadherin and ZO-1 proteins. This study introduces a novel chip platform that can be used to study communication between cells derived from different organs. This study also provides relevant insight into the mediators involved in lung-gut axis communication.

Keywords:  COPD; interorgan communication; lung‐gut axis; microplastics; multi‐organ‐on‐chip

DOI:  https://doi.org/10.1002/cph4.70051
EMBO J. 2025 Sep 16.

Decoding immunometabolism with next-generation tools: lessons from dendritic cells and T cells.

Yi-Hao Wang, Limei Wang, Ping-Chih Ho.

  Cellular metabolism plays a pivotal role in regulating the effector functions and fate decisions of immune cells, shaping immune responses in homeostasis and disease. Metabolic pathways also serve as critical signaling hubs governing immune cell behavior. Deregulated metabolic pathways contribute to immune dysfunction, fueling disease progression and creating challenges for therapeutic interventions. The recent development of advanced technologies to delineate immunometabolic regulation has revolutionized our understanding of immune cell biology. These tools, ranging from quantitative single-cell metabolomics to in vivo spatial tissue profiling and DC-based metabolic therapy, have shifted the focus from broad nutrient pathways to a detailed exploration of metabolic reprogramming within disease microenvironments, revealing how metabolic changes drive immune cell activation, differentiation, and effector responses. The integration of immunometabolic insights into clinical practice holds strong potential for advancing precision medicine and developing targeted therapies that restore immune balance in pathological conditions. Here, we summarize emerging cutting-edge technologies related to immunometabolism and critically reflect on their current limitations. Finally, we discuss potential needs for developing novel methods that can uncover the intricate interplay between metabolism and immune cell function.

Keywords:  Dendritic Cells; Immunometabolism; Metabolic Reprogramming; T Cells; Technological Advances

DOI:  https://doi.org/10.1038/s44318-025-00569-z
J Dtsch Dermatol Ges. 2025 Sep 19.

Bacterial skin colonization and systemic antibiotic treatment in patients with cutaneous T-cell lymphoma.

Huizhong Wang, Shanshan Li, Yujie Wen, Zhuojing Chen, Beini Lyu, Yang Wang, Jingru Sun.

   BACKGROUND AND OBJECTIVES: Bacterial colonization, particularly by Staphylococcus aureus (SA), is prevalent on the skin of patients with primary cutaneous T-cell lymphoma (CTCL). This study aimed to investigate risk factors for cutaneous bacterial and Staphylococcus aureus colonization and to evaluate their impact, together with systemic antibiotic use, on the prognosis of patients with CTCL.
METHODS: This retrospective study included 113 CTCL patients who underwent skin swab testing at Peking University First Hospital from 2010 to 2024.
RESULTS: Eighty-five patients (75.2%) tested positive for bacterial skin colonization (SA, 60.2%). Ulcerated lesions significantly increased the likelihood of a positive result in bacterial/SA skin cultures (multivariate analysis). Additionally, advanced stages, the presence of tumors, erythroderma, lymphopenia, and eosinophilia were associated with an increased risk of positive skin cultures (Univariate analysis). Cox regression analysis indicated that skin bacterial/SA colonization and antibiotic intervention, were not correlated with overall survival (p > 0.05).
CONCLUSIONS: This retrospective study presents data on the prevalence of bacterial skin colonization in Asian CTCL patients. Ulcerated lesions emerged as the most significant risk factor associated with cutaneous bacterial/SA colonization. In Asian patients with CTCL, neither bacterial or Staphylococcus aureus skin colonization was associated with a poorer prognosis, nor did short-term systemic antibiotic therapy improve outcomes.

Keywords:  Bacterial colonization; Cutaneous T‐cell lymphoma; Prognosis; Staphylococcus aureus; Systemic antibiotics

DOI:  https://doi.org/10.1111/ddg.15865
Cell Chem Biol. 2025 Sep 18. pii: S2451-9456(25)00261-2. [Epub ahead of print]32(9): 1102-1105

Disruption to the gut microbiome by non-antibiotics is linked to infection risk.

Caroline Tawk, Till Strowig.

Human-targeted drugs alter the composition and function of the gut microbiome, but their effect on the risk of gastrointestinal infection has received little attention. In two studies, Grieβhammer et al.1 and Kumar et al.2 identified non-antibiotic drugs that affect the microbiome's natural defense against enteropathogen colonization and subsequent host infection.

DOI: https://doi.org/10.1016/j.chembiol.2025.08.008
Curr Pharm Des. 2025 Sep 11.

Nasal Microbiota as a Potential Therapeutic Target for Allergic Rhinitis: An Emerging Perspective.

Bing-Yu Liang, Yi-Pin Yang, Chun-Ya Pan, Fen-Fen Li, Ping-Ting Zhou, Zi-Yue Fu, Yan-Xun Han, Qin Wang, Hai-Feng Pan, Yu-Chen Liu.

  Allergic Rhinitis (AR) represents a significant global health challenge with extensive prevalence and profound impacts, necessitating the development of novel therapeutic approaches beyond conventional symptomatic treatment. Emerging research has elucidated the crucial role of nasal microbiota dysbiosis in both the pathogenesis and progression of AR. Although the dominant microbial phyla remain largely consistent, significant changes in microbial abundance, composition, and diversity are often observed. In addition, studies have shown a correlation between changes in nasal microbiota and immune markers such as immunoglobulin E levels, suggesting that microbiota changes can reflect the severity of AR. Therefore, targeted modulation of the aberrant nasal microbiota may offer a promising therapeutic approach for this disease. However, further research is crucial for elucidating the causal relationships between specific microbial characteristics, disease severity, and potential comorbidities. This article summarizes recent studies examining the pathogenic role of nasal microbiota dysbiosis, the differential microbial composition across nasal mucosal sites, and potential therapeutic targets in AR. The ultimate goal is to develop precision medicine-based therapeutic interventions that target the underlying pathophysiological mechanisms of AR through specific modulation of dysbiotic nasal microbiota, thereby potentially preventing disease progression and reducing the risk of associated comorbidities.

Keywords:  Allergic rhinitis; allergic reaction; microbiota; nanomaterials.; nasal cavity; targeted therapy

DOI:  https://doi.org/10.2174/0113816128388496250812102820
Front Immunol. 2025 ;16 1654126

Upper respiratory tract immunization with Pam2Cys-adjuvanted spike protein vaccine achieves sterilizing protection against SARS-CoV-2.

Erica L Stewart, Skye Stockdale, Matt D Johansen, Lachlan Smith, Sibel Alca, Joshua W C Maxwell, Duc H Nguyen, Stefan Miemczyk, Guanshu Zhao, Stuart Turville, James A Triccas, Megan Steain, Scott N Byrne, Philip M Hansbro, Richard J Payne, Warwick J Britton, Anneliese S Ashhurst.

  Injected COVID-19 vaccines protect against severe disease, but do not induce robust mucosal immune responses. Nasal vaccines offer the advantage of local immunity to block viral infection and transmission. Previously we showed immunization of a Pam2Cys-adjuvanted SARS-CoV-2 vaccine to the upper and lower respiratory tracts (URT/LRT) induced protective immune responses in the lungs. However, URT/LRT immunization is not representative of nasal vaccines for clinical use that exclusively target the URT. Here, we show that delivery to only the URT with Pam2Cys and spike protein effectively induced strong SARS-CoV-2 specific immune responses in the nasal mucosa. When delivered in a low volume so that vaccine exposure was limited to the URT, Pam2Cys/spike protein induced local SARS-CoV-2-specific Th17 cells and neutralizing antibodies to a similar level to inhaled vaccination reaching both the URT and LRT. We compared URT versus URT/LRT delivery as booster vaccinations following parenteral immunization and found that URT vaccination concentrated the immune response to the URT rather than the lungs. Importantly, URT immunization or boosting induced sterilizing immunity in K18-hACE2 mice challenged with homologous SARS-CoV-2. Thus, booster vaccination to the URT alone with Pam2Cys/spike achieved robust nasal immunity against SARS-CoV-2 and is a promising strategy for clinical development.

Keywords:  COVID-19; SARS-CoV-2; TLR2 agonist; mucosal adjuvant; mucosal immunity; mucosal vaccine; nasal vaccines; subunit vaccination

DOI:  https://doi.org/10.3389/fimmu.2025.1654126
Cell Host Microbe. 2025 Sep 18. pii: S1931-3128(25)00337-3. [Epub ahead of print]

Long-chain unsaturated fatty acids released during immune responses stimulate host-microbe trans-kingdom communication.

Aleksander Czauderna, Grishma Kulkarni, Niccolò Bianchi, Liqing Cheng, Marissa Sim, Nicola R Realini, Joanna Gach, Aurelie Caillon, Joachim Kloehn, Gérard Lambeau, Annika Hausmann, Stefano Serra, Matthew T Sorbara, Simone Becattini.

  Immune responses can significantly alter the structure and function of the gut microbiota, leading to rapid transcriptional and metabolic shifts in commensal microbes. However, the host mediators involved in this process and their effects on bacteria remain poorly elucidated. Here, using a flagellin injection model to induce immune activation, we identified unsaturated long-chain fatty acids (uLCFAs) as broad modulators that are released into the gut lumen and alter bacterial gene expression. Luminal release of uLCFAs is partially mediated by host phospholipases, including PLA2G5. In response to uLCFAs, commensals such as Blautia trigger the expression of ohyA, encoding oleate hydratase, which converts toxic uLCFAs to non-toxic hydroxy fatty acids with immunomodulatory properties. Remarkably, oral administration of uLCFAs to mice replicates many of the bacterial transcriptional changes induced by flagellin. This molecular loop underscores the sophisticated interactions between host and microbiota and sheds light on how immune responses affect gut commensal functions.

Keywords:  Blautia; immune responses; long-chain unsaturated fatty acids; microbiota; oleate hydratase; transcriptomics

DOI:  https://doi.org/10.1016/j.chom.2025.08.011
bioRxiv. 2025 Sep 08. pii: 2025.09.07.674778. [Epub ahead of print]

A fungal pathobiont promotes Streptococcus agalactiae vaginal persistence and pathogenesis through physical and metabolic interactions.

Shirli Cohen, Arianne J Crossen, Melody N Neely, Kirsty Le Doare, Angela H Nobbs, Kyla S Ost, Kelly S Doran.

Complex polymicrobial interactions at the host interface can shape the mucosal landscape and tip the scales between commensalism and pathogenicity. Here, we use a newly adapted murine model of vaginal colonization to show that the human pathobiont Candida albicans (Ca) supports Group B Streptococcus (GBS) fitness in the vaginal tract and ascension to the uterus. GBS frequently colonizes the vagina asymptomatically; however, during pregnancy, colonization can lead to adverse outcomes and neonatal invasive infection. Using human vaginal isolates of Ca and GBS, we demonstrate that physical interactions contribute to persistence. Triple RNA sequencing of Ca, GBS, and a physiologically relevant model of the human vaginal epithelium reveals that GBS induces arginine biosynthesis in Ca. This drives the expression of bacterial virulence factors and primes GBS for adhesion to the epithelium. We show that interkingdom nutrient exchange can increase GBS pathogenic potential and identify a new target for preventative therapies.

DOI: https://doi.org/10.1101/2025.09.07.674778
J Immunol. 2025 Sep 16. pii: vkaf197. [Epub ahead of print]

Non-hematopoietic tryptophan metabolism is a driver of ineffective T cell responses during secondary pulmonary bacterial infection.

Lydia M Roberts, Leanne Arakkal, Tara Wehrly, Claire Poore Fonseka, Pavlina Laskova, Benjamin Schwarz, Eric Bohrnsen, Ronald Germain, Catharine M Bosio, Emily Speranza.

  Pulmonary infections often fail to produce long-lived immune memory and the underlying mechanism(s) for this are unclear. Given the complex interactions between cells within the lung, we predicted intrinsic and extrinsic factors contribute to development of poor memory immune responses. To identify these factors, we used a multiomics approach to determine host-driven responses that undermine or support development of effective immune responses in two mouse models of pulmonary bacterial infections. Single cell RNA analysis and spatial imaging of the lung revealed that, in contrast to Bordetella pertussis driven immunity, subpar responses following Francisella tularensis infection were associated with the inability of T cells to readily proliferate upon re-challenge and absence of formation of iBALT. Further, we also identified that these features were partially a consequence of IFN-γ driven reprogramming of endothelial cells resulting in expression of IDO1 and dysregulated tryptophan metabolism. Interestingly, IDO1 expression and imbalanced tryptophan persisted even after clearance of the primary infection. The importance of expression of IDO1 was confirmed using IDO1 knock out mice. Specifically, these animals could withstand higher doses of the initial infection and developed significantly larger pools of functional T cells compared to wild type controls. Together, these results demonstrate critical crosstalk among cells in the lung that influences spatial organization of immune cells which affects the ability to develop effective memory immune responses against secondary bacterial infection. Our data also underscores the challenge of utilizing a live vaccine strategy against tularemia and the necessity for identifying novel, acellular vaccine candidates.

Keywords:  T cell; bacteria; lung; metabolism

DOI:  https://doi.org/10.1093/jimmun/vkaf197