bims-bac4me 2025-09-28 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2025–09–28
27 papers selected by
Chun-Chi Chang, Lunds universitet

Primary human nasal, nasopharyngeal, and bronchial epithelia show distinct immune responses to various pathogens.
Targeting Innate Immune Memory for Stroke Prevention and Prognosis.
Trained immunity modulators: A new frontier in immunoregulation and disease intervention.
Innate Immune Surveillance and Recognition of Epigenetic Marks.
The epigenomic landscape of bronchial epithelial cells reveals the establishment of trained immunity.
Cell Death and Infection: Implications for Host and Microbe.
Elevated glucose increases Staphylococcus aureus antibiotic resistance in a cystic fibrosis airway epithelial cell infection model.
Nasal Staphylococcus aureus carriage promotes depressive behaviour in mice via sex hormone degradation.
Human CD4+ T cells recognize Mycobacterium tuberculosis-infected macrophages amid broader responses.
Macrophage-derived amphiregulin induces myofibroblast transition in adipogenic lineage precursors near Staphylococcus aureus abscess in bone marrow.
Type 1 conventional dendritic cells regulate innate immunity during fungal pneumonia.
IgA-dependent cell phagocytosis of HIV-infected cells elicits cross-presentation to CD8+T cells and immune memory in effector monocytes.
Beyond energy: how TCA cycle-derived metabolites regulate gene expression and inflammation in the nucleus.
Resolved versus uncontrolled inflammation: a mathematical model to decipher the role of innate immunity.
Involvement of (trained) immunity in cardioprotection.
Metabolic regulation of host defence against viral infection through sensing oxaloacetate.
Atopic skin resists colonization by beneficial bacteria: A first-in-human analysis of the rate of elimination of topically applied bacteria.
Microbiota in Health and Disease.
Human Microbiome as an Immunoregulatory Axis: Mechanisms, Dysbiosis, and Therapeutic Modulation.
Pneumolysin-dependent and independent non-canonical autophagy processes mediate host defense against pneumococcal infection.
Proteomic profiling of macrophages: effects of inflammatory activation and anti-inflammatory treatment with IBD therapeutics.
Microbe-responsive human γδ T cells: the peculiar case of Staphylococcus aureus.
A Mechanistic Framework for Repurposing FDA-Approved Drugs to Combat Antimicrobial Resistance: The Case of Staphylococcus aureus.
A programmable, selection-free CRISPR interference system in Staphylococcus aureus for long-term host interaction studies.
Type I IFN drives neutrophil swarming, impeding lung T cell-macrophage interactions and TB control.
CGRP Suppresses Protective SiglecFhi Neutrophil Development in Neonatal Group B Streptococcus Pneumonia.
Lactate metabolism is exploited by Francisella tularensis via its O-antigen capsule to limit macrophage-mediated activation and cell death.

Pathog Dis. 2025 Sep 24. pii: ftaf011. [Epub ahead of print]

Primary human nasal, nasopharyngeal, and bronchial epithelia show distinct immune responses to various pathogens.

E van Woudenbergh, A J Lakerveld, N van Heerbeek, J Honings, P B van Kasteren, M I de Jonge, G den Hartog.

  The respiratory epithelium serves as initial defense against airborne pathogens through its barrier function and induction of immune responses. To study epithelial-pathogen interactions we used primary epithelial models that closely resembled the epithelia of the airways, for which we collected nasal (n = 7), nasopharyngeal (n = 3), and bronchial (n = 4) epithelial cells from different donors. We cultured these epithelial cells on an air-liquid interface and evaluated their differentiation status. To assess how the different epithelial models respond to distinct types of exposures, the cells were stimulated with IFN-γ, Streptococcus pneumoniae, Neisseria meningitidis or respiratory syncytial virus (RSV) for 72 hours. The nasopharyngeal epithelium was distinct from nasal and bronchial cells with respect to morphology, pathogen load, and induction of cytokine responses, while nasal and bronchial epithelial cells had similar, but not identical cytokine profiles. Each tissue type and stimulus showed specific cytokine patterns. Interestingly, donor-specific differences for IFN-λ2,3 and IL-6 responses were found during meningococcal and RSV infections. Our data highlight morphological differences and a broad variety of epithelial cytokine responses in the different regions of the upper respiratory tract. These different epithelial models will help unravel why some pathogens target specific respiratory regions and why certain individuals are more susceptible to infections.

Keywords:   Neisseria meningitidis; RSV; Streptococcus pneumoniae ; Cytokine and chemokine responses; Mucosal host-pathogen interactions; Nasal, bronchial, nasopharyngeal epithelium

DOI:  https://doi.org/10.1093/femspd/ftaf011
Stroke. 2025 Oct;56(10): 3095-3098

Targeting Innate Immune Memory for Stroke Prevention and Prognosis.

Aurora Semerano, Juan F Arenillas, Louise D McCullough, María Ángeles Moro.



Keywords:  atherosclerosis; cardiovascular diseases; immune tolerance; ischemic stroke; myeloid cells; prognosis; trained immunity

DOI:  https://doi.org/10.1161/STROKEAHA.125.049900
J Adv Res. 2025 Sep 18. pii: S2090-1232(25)00734-9. [Epub ahead of print]

Trained immunity modulators: A new frontier in immunoregulation and disease intervention.

Jiao Chen, Chenxi Wang, Shilin Chen, Hui Cai, Mengke Wang, Jingjie Chang, Xueting Cai, Jie Yang, Peng Cao.

   BACKGROUND: Immunotherapy has emerged as one of the most revolutionary approaches in disease treatments. However, most current and emerging immunotherapeutic strategies primarily target the adaptive immune system. Recent studies have elucidated that innate immune myeloid cells can develop sustained phenotypic modifications upon exposure to specific immunomodulators, mediated through coordinated metabolic alterations and epigenetic reprogramming. These changes lead to either hyperresponsive or hyporesponsive innate immune cells when exposed to secondary stimuli, a phenomenon termed "trained immunity". Over the past decade, trained immunity has garnered increasing attention for its potential to enhance host defense. While numerous studies have investigated trained immunity modulators, comprehensive reviews-especially those focusing on recently identified modulators-are still lacking.
AIM OF REVIEW: This review aims to elucidate the molecular mechanisms underlying trained immunity and its dual roles in various pathological conditions. We provide a comprehensive summary of the classifications and mechanisms of trained immunity inducers and suppressors identified in the past decade, emphasizing their therapeutic potential in immune-related diseases. Additionally, we discuss the limitations of these trained immunity modulators and offer insights into future directions for developing novel therapies targeting trained immunity. Key scientific concepts of review: This review first provide an overview of the molecular mechanisms underlying trained immunity, highlighting both its beneficial and detrimental effects on various diseases. Then it focuses on summarizing the classification and mechanisms of trained immunity modulators, including vaccines, polysaccharides, nanobiologics, endogenous mediators and other non-canonical modulators. Finally, the limitations of current trained immunity modulators and insights into future directions for developing novel therapies targeting trained immunity are proposed.

Keywords:  Inducer; Polysaccharide; Suppressor; Trained immunity; Vaccine

DOI:  https://doi.org/10.1016/j.jare.2025.09.029
Epigenomes. 2025 Sep 05. pii: 33. [Epub ahead of print]9(3):

Innate Immune Surveillance and Recognition of Epigenetic Marks.

Yalong Wang.

  The innate immune system protects against infection and cellular damage by recognizing conserved pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Emerging evidence suggests that aberrant epigenetic modifications-such as altered DNA methylation and histone marks-can serve as immunogenic signals that activate pattern recognition receptor (PRR)-mediated immune surveillance. This review explores the concept that epigenetic marks may function as DAMPs or even mimic PAMPs. I highlight how unmethylated CpG motifs, which are typically suppressed using host methylation, are recognized as foreign via Toll-like receptor 9 (TLR9). I also examine how cytosolic DNA sensors, including cGAS, detect mislocalized or hypomethylated self-DNA resulting from genomic instability. In addition, I discuss how extracellular histones and nucleosomes released during cell death or stress can act as DAMPs that engage TLRs and activate inflammasomes. In the context of cancer, I review how epigenetic dysregulation can induce a "viral mimicry" state, where reactivation of endogenous retroelements produces double-stranded RNA sensed by RIG-I and MDA5, triggering type I interferon responses. Finally, I address open questions and future directions, including how immune recognition of epigenetic alterations might be leveraged for cancer immunotherapy or regulated to prevent autoimmunity. By integrating recent findings, this review underscores the emerging concept of the epigenome as a target of innate immune recognition, bridging the fields of immunology, epigenetics, and cancer biology.

Keywords:  DAMPs; PAMPs; PRRs; cancer immunotherapy; epigenetics; immune recognition; viral mimicry

DOI:  https://doi.org/10.3390/epigenomes9030033
Genes Immun. 2025 Sep 24.

The epigenomic landscape of bronchial epithelial cells reveals the establishment of trained immunity.

Jeanne Bigot, Rachel Legendre, Juliette Hamroune, Sébastien Jacques, Mathieu Le Gars, Nicolas Millet, Loïc Guillot, Harriet Corvol, Christophe Hennequin, Juliette Guitard, Jean-Yves Coppée, Viviane Balloy, Claudia Chica.

Innate immune memory, also called trained immunity, refers to the ability of innate immune cells to gain memory characteristics after transient stimulation, resulting in a nonspecific modified inflammatory response upon secondary remote challenge. Bronchial epithelial cells (BECs) participate in innate immune defence and are the first cells of the lower respiratory tract to encounter inhaled pathogens. We recently showed that BECs are capable of innate immune memory after preexposure to Pseudomonas aeruginosa flagellin through epigenetic mechanisms. In the present study, we investigated such mechanisms through the modification of chromatin architecture induced by flagellin preexposure that results in subsequent changes of gene expression. By conducting an unsupervised approach to jointly analyse chromatin accessibility and gene expression, we mapped the remodelling of the epigenomic and transcriptomic profiles during the establishment of BECs memory. We identified a Memory regulatory profile induced by flagellin exposure. It includes clusters of upregulated genes related to inflammation that are linked to a sustainable gain in chromatin accessibility and with an increased activity of specific transcription factors (TFs) whose binding may drive this process. In summary, we demonstrated that flagellin exposure induced changes in chromatin condensation in BECs, which sustains the reprogramming of transcriptional patterns.

DOI: https://doi.org/10.1038/s41435-025-00357-z
Adv Exp Med Biol. 2025 ;1481 207-240

Cell Death and Infection: Implications for Host and Microbe.

Anna Davey, Thibaut Sanchez, Christopher D Lucas, Christopher J Anderson.

  Cell death is a part of life. Every day, billions of cells undergo programmed cell death within the human body as part of normal tissue turnover and homeostasis. The factors that initiate programmed cell death, the resulting signalling pathways that occur within the dying cell, the means to dispose of the dying cell, and the response of the neighbouring tissue to the dying cell are all highly evolutionarily conserved and tightly regulated processes. Decades of outstanding research have identified critical components of programmed cell death initiation, corpse clearance, and tissue response, particularly in the context of homeostatic cell death or sterile injury-induced cell death; however, multiple tissues are not sterile under homeostasis. In particular, the intestinal and respiratory tracts are 'external environment-facing' tissues that are in constant contact with commensal microorganisms and are also frequently exposed to invading pathogenic microbes. Indeed, many pathogenic microbes are capable of inducing or inhibiting various forms of cell death during infection, and some go as far as to utilise the metabolites released to the environment during apoptosis for their own growth. The primary emphasis of the field has been on the identification of what form of programmed cell death is initiated during infection and what the immunological consequences are. In contrast, less is known about how the critical stages of cell death and cell clearance directly or indirectly impact the microbes (both commensal and pathogenic) themselves. In this review, we will pay particular attention to the host cell-cell communication events occurring downstream of programmed cell death and highlight new research and new questions surrounding how these fundamental host processes interact with the bacterial communities, with a particular focus on the intestine and the lung.

Keywords:  Apoptosis; Bacteria; Host-microbe interactions; Metabolism

DOI:  https://doi.org/10.1007/978-3-031-92785-0_7
Infect Immun. 2025 Sep 22. e0017825

Elevated glucose increases Staphylococcus aureus antibiotic resistance in a cystic fibrosis airway epithelial cell infection model.

Emily M Hughes, Meghan J Hirsch, Joshua T Huffines, Stefanie Krick, Megan R Kiedrowski.

  In a healthy lung, the airway epithelium regulates glucose transport to maintain low glucose concentrations in the airway surface liquid (ASL). However, hyperglycemia and chronic lung diseases, such as cystic fibrosis (CF), can result in increased glucose in bronchial aspirates. People with CF are also at increased risk of lung infections caused by bacterial pathogens, including methicillin-resistant Staphylococcus aureus. Yet, it is not known how increased airway glucose availability affects bacteria in chronic CF lung infections or impacts treatment outcomes. To model the CF airways, we cultured immortalized CF (CFBE41o-) and non-CF (16HBE) human bronchial epithelial cells at the air-liquid interface (ALI). Glucose concentrations in the basolateral media were maintained at 5.5 or 12.5 mM to mimic a normal and hyperglycemic milieu, respectively. We found that glucose concentrations in the ASL of ALI cultures maintained in normal or high glucose mimicked levels measured in breath condensate assays from people with CF and hyperglycemia. Additionally, we found hyperglycemia increased S. aureus aggregation and antibiotic resistance during infection of cells maintained in high glucose compared to normal glucose conditions. Heightened antibiotic resistance was not observed during in vitro growth with elevated glucose. Limiting glucose with 2-deoxyglucose both decreased aggregation and reduced antibiotic resistance back to levels comparable to non-hyperglycemic conditions. These data indicate that hyperglycemia alters S. aureus growth during infection and may reduce efficacy of antibiotic treatment. Glucose restriction is a potential option that could be explored to limit bacterial growth and improve treatment outcomes in chronic airway infections.

Keywords:  CF-related diabetes; Staphylococcus aureus; antibiotic resistance; bacterial aggregation; biofilm; cystic fibrosis

DOI:  https://doi.org/10.1128/iai.00178-25
Nat Microbiol. 2025 Sep 22.

Nasal Staphylococcus aureus carriage promotes depressive behaviour in mice via sex hormone degradation.

Guoxiu Xiang, Yanan Wang, Kaiji Ni, Huoqing Luo, Qian Liu, Yan Song, Ping Miao, Lei He, Ying Jian, Ziyu Yang, Tianchi Chen, Ke Xu, Xia Sun, Zhen Shen, Chenfeng Ji, Na Zhao, Mengxin He, Yan Pan, Yanli Luo, Ji Hu, Michael Otto, Min Li.

The human microbiome has a pronounced impact on human physiology and behaviour. Despite its unique anatomical connection to the brain, the role of the nasal microbiome in neurological diseases is understudied. Here, using human data and experiments in mice, we show that nasal Staphylococcus aureus is linked to depression. Nasal microbiome analyses revealed a positive correlation between depression scores and S. aureus abundance among patients with depression and healthy controls. Metabolomics of the nasal cavity showed decreased sex hormones, estradiol and testosterone in patients with depression versus controls. Nasal microbiota transplants from patients reproduced depression-like behaviour in mice with differential abundance of S. aureus. Further homology and mutational analysis uncovered an S. aureus sex hormone-degrading enzyme, 17b-hydroxysteroid dehydrogenase (Hsd12), which degraded testosterone and estradiol in mice, leading to lower levels of dopamine and serotonin in the murine brain. These findings reveal a nasal commensal that influences depressive behaviour and provides insights into the nose-brain axis.

DOI: https://doi.org/10.1038/s41564-025-02120-6
J Exp Med. 2025 Dec 01. pii: e20250460. [Epub ahead of print]222(12):

Human CD4+ T cells recognize Mycobacterium tuberculosis-infected macrophages amid broader responses.

Volodymyr Stetsenko, Daniel P Gail, Scott M Reba, Vinicius G Suzart, Robert Schauner, Avinaash K Sandhu, Alessandro Sette, Mohammad Haj Dezfulian, Cecilia S Lindestam Arlehamn, Stephen M Carpenter.

CD4+ T cell-mediated control of tuberculosis (TB) requires recognition of macrophages infected with Mycobacterium tuberculosis (Mtb). Yet, not all Mtb-specific T cells recognize infected macrophages. Using infected monocyte-derived macrophages and autologous memory CD4+ T cells from individuals with stable latent Mtb infection (LTBI), we quantify the frequency of activated T cells. T cell antigen receptor (TCR) sequencing revealed >70% of unique and >90% of total Mtb-specific TCR clonotypes in LTBI are linked to recognition of infected macrophages, while a subset required exogenous antigen exposure, suggesting incomplete recognition. Clonotypes specific for multiple Mtb antigens, and other pathogens, were identified. Remarkably, antigen screening revealed all TCRs to be specific for type VII secretion system (T7SS) substrates. Mtb-specific clonotypes expressed signature effector functions dominated by IFNγ, TNF, IL-2, and GM-CSF or chemokine production and signaling. We propose that TB vaccines, which elicit T cells specific for T7SS substrates, recognize infected macrophages, and express canonical effector functions, will offer protection against TB.

DOI: https://doi.org/10.1084/jem.20250460
Nat Commun. 2025 Sep 25. 16(1): 8409

Macrophage-derived amphiregulin induces myofibroblast transition in adipogenic lineage precursors near Staphylococcus aureus abscess in bone marrow.

Bingsheng Yang, Jianwen Su, Jichang Wu, Zhongwen Wang, Jin Hu, Mankai Yang, Yihuang Lin, Mingchao Jin, Xiaochun Bai, Bin Yu, Xianrong Zhang.

The formation of Staphylococcus aureus (S. aureus) abscesses is a well-established determinant of persistent skeletal infections, yet the mechanisms underlying bacterial persistence remain elusive. Here, we demonstrate that bone marrow adiponectin-positive (Adipoq+) precursors are mobilized to surround S. aureus abscesses and undergo myofibroblast differentiation. This phenotypic transition induces vascular constriction, thereby impairing local perfusion and impeding effective bacterial clearance. Mechanistically, macrophage-derived amphiregulin (AREG) activates EGFR signaling on Adipoq+ cells, triggering the mTOR/YAP pathway to drive their myofibroblast transition. Importantly, genetic ablation of Adipoq+ cells, cell-specific deletion of the AREG/EGFR axis, or pharmacological inhibition of EGFR/mTOR signaling effectively alleviates fibrosis, restores vascular perfusion and antibiotic delivery, and promotes bacterial eradication from abscesses. Our findings implicate a macrophage-Adipoq+ cell regulatory axis that sustains S. aureus persistence in osteomyelitis and identify therapeutic targeting of this axis as a strategy to enhance antibiotic efficacy against S. aureus skeletal infections.

DOI: https://doi.org/10.1038/s41467-025-63551-7
mBio. 2025 Sep 22. e0256425

Type 1 conventional dendritic cells regulate innate immunity during fungal pneumonia.

Pari M Dhruva, Thomas E Draper, Camille A Chiller, MaryJane Jones, Chad Steele.

  Aspergillus fumigatus is a ubiquitous mold that is the primary etiological agent of invasive pulmonary aspergillosis (IPA), a severe lung infection in immunocompromised patients with extreme mortality. Innate immunity is critical for controlling the severity of IPA. Regarding dendritic cells (DCs), studies have shown protective roles for monocyte-derived DCs and plasmacytoid DCs during IPA. Here, we examined the role of type 1 conventional dendritic cells (cDC1s) during A. fumigatus lung infection. We first show that global depletion of DCs resulted in impaired lung clearance of A. fumigatus, indicating a protective role for DCs, as expected. Unexpectedly, however, mice lacking cDC1s (Batf3-/-) cleared A. fumigatus more efficiently than wild-type C57BL/6 control mice. Enhanced fungal clearance was also observed in two additional cDC1-deficient strains, Cd11cCre/Irf8flox/flox mice and interferon regulatory factor 8 +32-/- mice. Batf3-/- mice displayed an enhanced type 17 immune response, which we have shown to be required for optimal immunity during IPA. Moreover, elevated type 17 responses correlated with differential production of IL-33 (decreased in Batf3-/-) and PGE2 (increased in Batf3-/-), an axis we have reported to promote type 17 responses during IPA. We further show that alveolar macrophages from Batf3-/- mice had increased fungicidal activity against A. fumigatus. In contrast, alveolar macrophages cultured in the presence of bone marrow-derived cDC1s had lower fungicidal activity compared to alveolar macrophages cultured alone, suggesting that cDC1s restrict alveolar macrophage function. Taken together, our data identify cDC1s as a regulator of innate immune responsiveness during IPA.IMPORTANCEFungal infections have increased at an alarming rate as a result of increased usage of immunosuppressive therapies, growing resistance to antifungal drugs, and global warming. This recently prompted the World Health Organization to publish the first-ever fungal priority pathogens list, which focused on 19 organisms, ultimately deeming 4 pathogens of critical importance based on perceived public health importance. Among these four was the opportunistic mold Aspergillus fumigatus, the etiological agent of the most lethal fungal infection known to humans, IPA. Innate immunity is paramount for controlling IPA with protective roles identified for multiple myeloid cell types. In the current report, employing three complementary animal models, we show that cDC1s hinder the clearance of A. fumigatus from the lung. We further identified specific responses that are regulated by cDC1s. Overall, our study uncovers a new mechanism of immune regulation during IPA.

Keywords:  fungal; innate immunity; lung

DOI:  https://doi.org/10.1128/mbio.02564-25
Mucosal Immunol. 2025 Sep 18. pii: S1933-0219(25)00094-7. [Epub ahead of print]

IgA-dependent cell phagocytosis of HIV-infected cells elicits cross-presentation to CD8+T cells and immune memory in effector monocytes.

Andrea Cottignies-Calamarte, Annouk Dauvilliers, Lucie Adoux, Benjamin Saint-Pierre, Franck Letourneur, Sylvain Cardinaud, Daniela Tudor, Morgane Bomsel.

  Mucosal IgA antibodies are the first defence against mucosal infections. Besides targeting specific antigens by their Fab-region, IgA also mediates antiviral functions via their Fc-domain, allowing infected cells destruction by antibody-dependent cellular phagocytosis (ADCP). Passive immunisation with anti-HIV-1 IgG protected Non-Human Primates in a CD8+ T cell-dependent manner, a process likely involving ADCP. Here, we unravel the consequences of ADCP of HIV-1-infected cells mediated by anti-HIV envelope IgA compared to IgG. We found that IgA-mediated ADCP, not IgG, drives viral antigen cross-presentation to HIV-1-specific cytotoxic CD8+ T cells. IgA effector function reprogrammed ADCP effector monocytes into activated macrophages exhibiting a mixed pro- and anti-inflammatory profile combined with increased pro-inflammatory chemokines. IgA-mediated ADCP sensitizes monocytes to respond to a novel bacterial challenge by secreting IL-6 and TNFα, indicative of acquired trained immunity. Altogether, these data establish a bridge between humoral and cellular immunity that could be exploited in HIV preventive strategies.

Keywords:  Antibody-dependent cell phagocytosis; Cross-presentation; HIV-1; IgA; Trained immunity

DOI:  https://doi.org/10.1016/j.mucimm.2025.09.004
J Inflamm (Lond). 2025 Sep 26. 22(1): 39

Beyond energy: how TCA cycle-derived metabolites regulate gene expression and inflammation in the nucleus.

Jaiya Randhawa, Eva M Pålsson-McDermott.

  Immune cells can rewire their metabolism in response to various stimuli. Crosstalk between the nucleus and mitochondria allows for tight regulation of this metabolic reprogramming. Research has emerged showing several TCA cycle-derived metabolites exhibiting moonlighting functions in the nucleus, modulating chromatin modifications in order to control inflammation. These TCA cycle-derived metabolites include acetyl-CoA, α-ketoglutarate, succinate, fumarate, itaconate, and succinyl-CoA which can modify DNA or histone to drive or inhibit gene expression. In this review, we look at the mechanisms of TCA cycle metabolites' non-canonical functions in the nucleus in the context of inflammation. In addition, we discuss the known and possible links between these metabolites' nuclear moonlighting functions and the pathogenesis of diseases, including inflammatory diseases and cancers.

Keywords:  Epigenetics; Immunometabolism; Inflammation; Metabolites; TCA cycle

DOI:  https://doi.org/10.1186/s12950-025-00461-x
J Leukoc Biol. 2025 Sep 26. pii: qiaf132. [Epub ahead of print]

Resolved versus uncontrolled inflammation: a mathematical model to decipher the role of innate immunity.

Karina García-Martínez, Nuris Ledón, Agustín Lage.

  Understanding the impact of Neutrophils and Macrophages in the dynamic outcome of resolution vs uncontrolled response is still an open debate. Here, we develop a mathematical model that describe the dynamic of the innate immune response after an acute damage. Our model includes all the described processes that mediate this response, including the regulatory mechanisms carried out by type-2 Macrophages (M2). Additionally, we estimate the resolution indices to quantify the efficiency of resolution mechanisms by controlling the initial expansion of Neutrophils and/or the subsequent contraction kinetics of the cell response. We predict that the partial reduction of Neutrophil influx and the increase of type-1 Macrophage (M1)-mediated efferocytosis rate are the best strategies to control the Neutrophil initial expansion. On the other hand, the partial reduction of M1 cells influx or the increase of Neutrophil apoptosis rate are predicted as good strategies to accelerate the Neutrophils decay during the contraction phase of the response.

Keywords:  Macrophage; Neutrophil; acute inflammation; mathematical model; resolution indices

DOI:  https://doi.org/10.1093/jleuko/qiaf132
Cardiovasc Res. 2025 Sep 24. pii: cvaf170. [Epub ahead of print]

Involvement of (trained) immunity in cardioprotection.

Gerd Heusch, Petra Kleinbongard.

DOI: https://doi.org/10.1093/cvr/cvaf170
Nat Microbiol. 2025 Sep 25.

Metabolic regulation of host defence against viral infection through sensing oxaloacetate.

DOI: https://doi.org/10.1038/s41564-025-02129-x
J Invest Dermatol. 2025 Sep 23. pii: S0022-202X(25)02442-X. [Epub ahead of print]

Atopic skin resists colonization by beneficial bacteria: A first-in-human analysis of the rate of elimination of topically applied bacteria.

Richard L Gallo, Teruaki Nakatsuji, Andrea Roso Mares, June Moon, Olive Osuoji, Victoria Li, Alexandra Fernandez-Desoto, Angie Wu, Michael Nodzenski, Gloria David, Amaziah Coleman, Tissa R Hata.



Keywords:  Atopic Dermatitis; Bacteriotherapy; Microbiome; Probiotic; Staphylococcus

DOI:  https://doi.org/10.1016/j.jid.2025.09.014
Life (Basel). 2025 Aug 29. pii: 1374. [Epub ahead of print]15(9):

Microbiota in Health and Disease.

Amélia Sarmento, Catarina D Simões.

In recent years microbiota has been shown to strongly influence host metabolism and immunity, resulting in a huge impact in human physiology [...].

DOI: https://doi.org/10.3390/life15091374
Microorganisms. 2025 Sep 14. pii: 2147. [Epub ahead of print]13(9):

Human Microbiome as an Immunoregulatory Axis: Mechanisms, Dysbiosis, and Therapeutic Modulation.

Matías Cortés, Paula Olate, Rodrigo Rodriguez, Rommy Diaz, Ailín Martínez, Genisley Hernández, Nestor Sepulveda, Erwin A Paz, John Quiñones.

  The human microbiome plays a central role in modulating the immune system and maintaining immunophysiological homeostasis, contributing to the prevention of immune-mediated diseases. In particular, the gut microbiota is a key ecosystem for immune system maturation, especially in early life. This review aimed to analyze the molecular and cellular mechanisms linking the microbiome to immune and neuronal functions, as well as the impact of dysbiosis and emerging therapeutic strategies targeting the microbiome. The analysis was based on scientific databases, prioritizing studies published since 2000, with special emphasis on the past decade. The microbiome influences immune signaling through microorganism-associated molecular patterns (MAMPs) and pattern recognition receptors (PRRs), including Toll-like receptors (TLRs). Additionally, microbial metabolites-such as short-chain fatty acids (SCFAs), tryptophan derivatives, and secondary bile acids-exert significant immunomodulatory effects. The intestinal epithelial barrier is also described as an active immunological interface contributing to systemic regulation. The literature highlights innovative therapies, including fecal microbiota transplantation (FMT), probiotics, and microbiome editing with CRISPR-Cas technologies. These strategies aim to restore microbial balance and improve immune outcomes. The growing body of evidence positions the microbiome as a valuable clinical and diagnostic target, with significant potential for application in personalized medicine.

Keywords:  dysbiosis; human microbiome; immune homeostasis; immunomodulation; microbiome-based therapies

DOI:  https://doi.org/10.3390/microorganisms13092147
Autophagy. 2025 Sep 23. 1-20

Pneumolysin-dependent and independent non-canonical autophagy processes mediate host defense against pneumococcal infection.

Bartosz J Michno, Niedharsan Pooranachandran, Tonisha C Smith, Erin Faught, Sandra Lipowská, Andrew K Fenton, Annemarie H Meijer, Tomasz K Prajsnar.

  Streptococcus pneumoniae is an opportunistic pathogen responsible for life-threatening diseases including pneumonia and meningitis. The host defense against pneumococci relies heavily on macrophages, which can effectively internalize and degrade bacteria. Recent studies have implicated both canonical and non-canonical autophagy-related processes in bacterial clearance, but the precise pathways mediating defense against S. pneumoniae remain unknown. Here, we utilize a well-established zebrafish larval infection model to investigate the role of autophagy in host defense against pneumococci in vivo. Using a transgenic macroautophagy/autophagy reporter line, we found the autophagy marker Map1lc3/Lc3 being recruited to pneumococci-containing vesicles upon bacterial internalization by zebrafish macrophages. The genetic inhibition of core autophagy gene atg5 led to loss of the Lc3 associations and their impaired acidification, significantly delaying bacterial clearance. This Lc3 recruitment is partially mediated by LC3-associated phagocytosis (LAP), as knockdown of cyba and rubcn moderately reduced Lc3 association with phagosomes and diminished pneumococcal degradation. Interestingly, we observed no involvement of xenophagy components in S. pneumoniae-infected macrophages, suggesting the activation of another non-canonical autophagy pathway, distinct from LAP, targeting pneumococci-containing phagosomes. Instead, we found that the pneumococcal pore-forming toxin pneumolysin induces ROS-independent CASM pathways, one of which is abolished by knockdown of tecpr1a indicating the involvement of sphingomyelin-Tecpr1-induced LC3 lipidation (STIL). Collectively, our observations shed new light on the host immune response against S. pneumoniae, demonstrating that several distinct non-canonical autophagy pathways mediate bacterial degradation by macrophages and providing potential targets for the development of novel therapies to combat pneumococcal infections.Abbreviations: ATG: autophagy related; BMDM: bone marrow-derived macrophage; CASM: conjugation of ATG8 to single membranes; CFU: colony-forming units; Cyba: cytochrome b-245, alpha polypeptide; DPI: diphenyleneiodonium, GFP: green fluorescent protein; hpf: hours post-fertilization; hpi: hours post-infection; LAP: LC3-associated phagocytosis; Map1lc3/Lc3: microtubule-associated protein 1 light chain 3; MEF: mouse embryonic fibroblast; NADPH: nicotinamide adenine dinucleotide phosphate; Optn: optineurin; PINCA: pore-forming toxin-induced non-canonical autophagy; Ply: pneumolysin; ROS: reactive oxygen species; SLR: sequestosome-like receptors; Sqstm1: sequestosome 1; STIL: sphingomyelin-TECPR1-induced LC3 lipidation; Tecpr1: tectonin beta-propeller repeat containing 1.

Keywords:  LAP; STIL; Streptococcus; macrophage; pneumoniae; zebrafish

DOI:  https://doi.org/10.1080/15548627.2025.2559728
Eur J Pharm Biopharm. 2025 Sep 18. pii: S0939-6411(25)00246-2. [Epub ahead of print] 114869

Proteomic profiling of macrophages: effects of inflammatory activation and anti-inflammatory treatment with IBD therapeutics.

Simone Lichtner, Kathrin Schunck, Johanna Frey, Janina Osti, Selina Dannheimer, Sabrina Schnur, Claus-Michael Lehr, Marc Schneider, Marius Hittinger.

  Inflammatory bowel diseases (IBD) are chronic disorders characterized by persistent immune dysregulation in the intestinal mucosa, with macrophages playing a central role in disease pathogenesis. In this study, primary human monocyte-derived macrophages (MDMs) were stimulated with lipopolysaccharide (LPS) to model innate immune activation, and subsequent proteomic changes were analyzed by mass spectrometry. The effects of three established IBD drugs, mesalazine, prednisolone and 6-mercaptopurine (6-MP), were systematically evaluated within this model. LPS stimulation resulted in activation of proteins related to pro-inflammatory pathways, including NF-κB signaling, which was reflected by increased expression of cytokine- and adhesion-related proteins such as IL1B, IL8 and ICAM1. Mesalazine treatment induced a moderate modulation of inflammatory regulators, prednisolone produced a strong suppression of pro-inflammatory and complement proteins, and 6-MP caused broad alterations in ribosomal, metabolic and apoptosis-associated proteins. These results indicate that the LPS-stimulated MDM model can reproduce essential features of macrophage activation in IBD and differentiate drug-specific proteomic signatures that are consistent with known mechanisms of action.

Keywords:  6-Mercaptopurine; Drug response profiling; Label-free quantification; Lipopolysaccharide (LPS) stimulation; Mass spectrometry; Mesalazine; Monocyte-derived macrophages (MDM); Prednisolone; Proteomics

DOI:  https://doi.org/10.1016/j.ejpb.2025.114869
Immunol Cell Biol. 2025 Sep 22.

Microbe-responsive human γδ T cells: the peculiar case of Staphylococcus aureus.

Matthias Eberl, Manuel Mata Forsberg, James E McLaren, Eva Sverremark-Ekström.

  Vγ9/Vδ2 T cells represent the largest γδ T-cell population in human blood and possess a unique responsiveness towards microbial organisms by sensing the metabolite (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP) in the context of the butyrophilin family members BTN2A1 and BTN3A1. Curiously, the bacterium Staphylococcus aureus does not produce HMB-PP but appears to be capable of inducing activation, cytokine expression and proliferation of Vγ9/Vδ2 T cells regardless, through a largely unknown mechanism. We here provide a comprehensive review of the existing literature around Vγ9/Vδ2 T-cell responses to S. aureus and discuss potential pathways, ligands and biological functions.

Keywords:  Staphylococcus aureus; bacteria; immunity; infection; superantigens; γδ T cells

DOI:  https://doi.org/10.1111/imcb.70060
Annu Rev Pharmacol Toxicol. 2025 Sep 25.

A Mechanistic Framework for Repurposing FDA-Approved Drugs to Combat Antimicrobial Resistance: The Case of Staphylococcus aureus.

Daniel Sun, Victor Nizet.

The global rise of antibiotic-resistant bacteria poses a critical threat to healthcare systems, challenging researchers to stay ahead of evolving pathogens. Among the most concerning are invasive infections caused by Staphylococcus aureus (SA), where morbidity and mortality remain high despite advances in care. Resistance in SA has emerged rapidly after the introduction of new antibiotics, limiting treatment options and prompting an urgent need for alternatives. While developing new antimicrobials remains essential, repurposing FDA-approved drugs-originally developed for noninfectious indications-offers a complementary strategy. These agents have known safety and pharmacokinetic profiles and may impact bacterial virulence, antibiotic susceptibility, or host immunity to improve outcomes. This review highlights recent advances in SA drug repurposing, focusing on six mechanistic categories: inhibition of virulence factors, antibiotic resensitization, enhanced susceptibility to innate immunity, host cell protection, augmentation of immune functions, and modulation of pathological inflammation. Together, these strategies offer a multifaceted framework to improve SA infection outcomes using existing therapeutics.

DOI: https://doi.org/10.1146/annurev-pharmtox-062624-014243
iScience. 2025 Sep 19. 28(9): 113420

A programmable, selection-free CRISPR interference system in Staphylococcus aureus for long-term host interaction studies.

Roni Miah, Mona Johannessen, Morten Kjos, Christian S Lentz.

  Common dCas9-based CRISPR interference (CRISPRi) systems for manipulating bacterial gene expression require antibiotic selection and exogenous inducer molecules, limiting their applicability in infection models. For Staphylococcus aureus, we have developed a programmable, selection-free CRISPRi system leveraging the pCM29 plasmid, which is stable without antibiotic selection. In this system, dCas9 expression is regulated by an endogenous promoter, and sgRNA expression is driven by a constitutive promoter, eliminating the need for exogenous inducer molecules. We programmed the system to silence the expression of the coagulase or autolysin genes whenever their respective endogenous promoters were activated. We confirmed selection-free interference with target gene expression for ≥27 generations by qPCR and protein target-dependent in vitro or in vivo phenotypic assays (plasma coagulation, THP-1 cell, and Galleria mellonella infection). The system is suitable for interrogating gene function in long-term studies of S. aureus pathogenesis and represents a blueprint for similar CRISPRi systems in other species.

Keywords:  Biological sciences; Biotechnology; Microbiology; Synthetic biology

DOI:  https://doi.org/10.1016/j.isci.2025.113420
J Exp Med. 2025 Dec 01. pii: e20250466. [Epub ahead of print]222(12):

Type I IFN drives neutrophil swarming, impeding lung T cell-macrophage interactions and TB control.

William J Branchett, Evangelos Stavropoulos, Jessica Shields, Alaa Al-Dibouni, Marcos Cardoso, Ana Isabel Fernandes, Lúcia Moreira-Teixeira, Hubert Slawinski, Anna Mikolajczak, Angela Rodgers, Margarida Saraiva, Anne O'Garra.

The early immune mechanisms determining Mycobacterium tuberculosis infection outcome are unclear. Using bulk and scRNA-seq over the first weeks of infection, we describe an unexpected, higher early pulmonary type I IFN response in relatively resistant C57BL/6 as compared with highly TB-susceptible C3HeB/FeJ mice. C57BL/6 mice showed pronounced early monocyte-derived macrophage (MDM) accumulation and extensive CD4+ T cell-MDM interactions in lung lesions, accompanied by high expression of T cell-attractant chemokines by MDMs. Conversely, lesions in C3HeB/FeJ mice were dominated by neutrophils with high expression of pro-inflammatory chemokines, from which CD4+ T cells were spatially segregated. Early type I IFN signaling blockade reduced bacterial load and neutrophil swarming within early TB lesions while increasing CD4+ T cell numbers in both C57BL/6 and C3HeB/FeJ mice, with later more pronounced effects on bacterial load in C3HeB/FeJ mice. These data suggest that early type I IFN signaling during M. tuberculosis infection favors neutrophil accumulation and limits CD4+ T cell infiltration into developing lesions.

DOI: https://doi.org/10.1084/jem.20250466
Microorganisms. 2025 Sep 11. pii: 2119. [Epub ahead of print]13(9):

CGRP Suppresses Protective SiglecFhi Neutrophil Development in Neonatal Group B Streptococcus Pneumonia.

Inês Lorga, Ana Sofia Teixeira, Bárbara Carvalho, Joana Soares, Nuno Ribeiro, Marcos S Cardoso, Joana Cunha, Joana Santos, Regina A Silva, Manuel Vilanova, Elva Bonifácio Andrade.

  Neonatal pneumonia, a leading cause of morbidity and mortality, is frequently caused by Group B Streptococcus (GBS). The mechanisms underlying protective immunity to this pathogen in the neonatal lung remain incompletely understood. Using a clinically relevant neonatal mouse model of GBS pneumonia, we investigated the immune mechanisms influencing disease severity. We demonstrate that neutrophils are effectively recruited to the lungs of infected neonates, but their phenotype differs with disease severity. In pups with moderate disease, we observe significant infiltration of SiglecFhi neutrophils, a phenotype associated with enhanced phagocytic capacity and bacterial clearance. In contrast, pups with severe disease failed to develop SiglecFhi neutrophils, resulting in reduced bacterial clearance and worsened pathology. We further show that severity is associated with increased expression of calcitonin gene-related peptide (CGRP) in the lungs. CGRP suppressed neutrophil activation into the SiglecFhi phenotype, thereby limiting their antibacterial function. Our findings show that GBS exploits the neuroimmune axis to evade host immunity through CGRP-mediated suppression of neutrophil activation.

Keywords:  CGRP; Group B Streptococcus; SiglecF; innate immunity; lung; neonatal immunity; neutrophil; pneumonia

DOI:  https://doi.org/10.3390/microorganisms13092119
mBio. 2025 Sep 22. e0068125

Lactate metabolism is exploited by Francisella tularensis via its O-antigen capsule to limit macrophage-mediated activation and cell death.

Forrest Jessop, Eric Borhnsen, Benjamin Schwarz, Kaitlin A Stromberg, Molly Miltko, Tyler Jones, Tara Wehrly, Catharine M Bosio.

  Intracellular pathogens manipulate host metabolic systems to establish a replicative niche and evade immune responses. However, mechanisms by which metabolism can be altered for successful infection remain poorly understood. Here, we identify a metabolism-based strategy used by the intracellular pathogen Francisella tularensis subsp. tularensis (FTT) to condition its host cell for optimal replication. FTT, through its associated O-antigen capsule, augmented lactate oxidation in macrophages, thereby improving mitochondrial bioenergetics, reducing redox imbalances and production of pro-inflammatory cytokines, and maintaining cellular viability. Heavy isotope tracing and extracellular flux analysis confirmed lactate incorporation into the TCA cycle with increased mitochondrial ATP production, and these outcomes were associated with upregulation of lactate import and conversion systems, specifically monocarboxylate transporter 4 (MCT4) and LDHB, respectively. Targeting MCT4 using the small molecule inhibitor MSC-4381, controlled FTT infection-mediated manipulation of mitochondrial function and increased cell death in infected macrophages, thereby controlling infection. MSC-4381 also directly controlled FTT infection in defined medium implicating a critical role of short-chain carbon intermediates among the bacteria. Ultimately, these data demonstrate that the lactate oxidation metabolic node, including MCT4 activity, is integral for successful FTT infection and contributes to the pleiotropic effects of the FTT capsule on immune evasion.IMPORTANCEFrancisella tularensis subsp. tularensis (FTT) is an extremely virulent pathogen for which antibiotic intervention must be delivered early, often before proper diagnosis and effective, durable vaccines do not exist. Part of what makes FTT so problematic is that it is proficient at manipulating host metabolic pathways that govern immune activation. However, specific mechanisms by which this manipulation occurs have remained elusive. Discovering new ways in which FTT modulates host cell metabolism will reveal new therapeutic targets to help treat this difficult-to-control infection. We show here that FTT, through its O-antigen polysaccharide capsule, increased lactate oxidation, which in turn reduced inflammatory cytokine production, redox imbalance, and cell death. Targeting proteins responsible for lactate transport controlled FTT infection and blocked the capsule's ability to manipulate the host cell. These data are the first to show lactate oxidation as a potential target for pathogen success and may be a therapeutic target for FTT infection.

Keywords:  capsule; intracellular bacteria; lactate; macrophages; metabolism; mitochondria

DOI:  https://doi.org/10.1128/mbio.00681-25