bims-bac4me 2025-03-02 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2025–03–02
37 papers selected by
Chun-Chi Chang, Universitäts Spital Zürich

Innate Immune Sensors and Cell Death-Frontiers Coordinating Homeostasis, Immunity, and Inflammation in Skin.
Lung Microbiota: From Healthy Lungs to Development of Chronic Obstructive Pulmonary Disease.
Extracellular vesicles transport gasdermin pores, amplifying inflammatory cell death.
Gasdermin D mediates a fast transient release of ATP after NLRP3 inflammasome activation before ninjurin 1-induced lytic cell death.
Culturing of Airway Stem Cells Obtained from COPD Patients to Assess the Effects of Rhinovirus Infection.
Endogenous nitric oxide promotes Staphylococcus aureus virulence by activating autophagy.
CD4+ T cell-innate immune crosstalk is critical during Staphylococcus aureus craniotomy infection.
Beyond Tuberculosis: The Surprising Immunological Benefits of the Bacillus Calmette-Guérin (BCG) Vaccine in Infectious, Auto-Immune, and Inflammatory Diseases.
Interferon-gamma receptor signaling regulates innate immunity during Staphylococcus aureus craniotomy infection.
Perturbation of EPHA2 and EFNA1 trans binding amplifies inflammatory response in airway epithelial cells.
Cardio-systemic Stress and Trained Innate Immune Memory in Heart Failure.
The immune response of upper and lower airway epithelial cells to Aspergillus fumigatus and Candida albicans-derived β-glucan in Th17 type cytokine environment.
Evaluating the evidence for GM-CSF as a host-directed therapy in respiratory infections.
Macrophages recycle phagocytosed bacteria to fuel immunometabolic responses.
Commensal acidification of specific gut regions produces a protective priority effect against enteropathogenic bacterial infection.
Analysis of Adherence Junctions in Rhinovirus-Infected Airway Epithelial Cells.
Microbiota and Inflammatory Markers: A Review of Their Interplay, Clinical Implications, and Metabolic Disorders.
Sensory neurons on guard: roles in pathogen defense and host immunity.
"Mannose glycans as key players in trained immunity: A novel anti-tumoral catalyst".
Interactions of the maternal microbiome with diet, stress, and infection influence fetal development.
Matriptase-mediated PAR2 activation drives monocyte-to-macrophage differentiation and polarization under hypoxic conditions.
Corrigendum: Recognition of Staphylococcus aureus by the pattern recognition molecules langerin, mannan-binding lectin, and surfactant protein D: the influence of capsular polysaccharides and wall teichoic acid.
Development of a Widely Accessible, Advanced Large-Scale Microfluidic Airway-on-Chip.
The MicroMap is a network visualisation resource for microbiome metabolism.
Inhibition of pneumococcal growth and biofilm formation by human isolates of Streptococcus mitis and Streptococcus oralis.
Implant-Derived S. aureus Isolates Drive Strain-Specific Invasion Dynamics and Bioenergetic Alterations in Osteoblasts.
A bladder-blood immune barrier constituted by suburothelial perivascular macrophages restrains uropathogen dissemination.
Human respiratory airway progenitors derived from pluripotent cells generate alveolar epithelial cells and model pulmonary fibrosis.
Dual RNA-seq reveals the complement protein C3-mediated host-pathogen interaction in the brain abscess caused by Staphylococcus aureus.
Mitochondrial superoxide regulates pro-inflammatory macrophages.
Crosstalk between autophagy and other forms of programmed cell death.
GSDMD-mediated pyroptosis: molecular mechanisms, diseases and therapeutic targets.
Editorial: New techniques in microbiome research - volume II: Host-microbiome interactions using 'meta-omics' techniques.
Listeria monocytogenes Modulates Macrophage Inflammatory Responses to Facilitate Its Intracellular Survival by Manipulating Macrophage-Derived Exosomal ncRNAs.
Amoxicillin-induced bacterial gut dysbiosis decreases IL-1β and IL-6 expression but exacerbate lung inflammatory response against Mycobacterium bovis-Bacille Calmette-Guérin (BCG).
Interferon-responsive intestinal BEST4/CA7+ cells are targets of bacterial diarrheal toxins.
Microbial Community and Immune Modulation Enable Effective Treatment of Methicillin-resistant Staphylococcus aureus Skin Infections with Linalool.

Viruses. 2025 Feb 10. pii: 241. [Epub ahead of print]17(2):

Innate Immune Sensors and Cell Death-Frontiers Coordinating Homeostasis, Immunity, and Inflammation in Skin.

Ye Mon Soe, Seen Ling Sim, Snehlata Kumari.

  The skin provides a life-sustaining interface between the body and the external environment. A dynamic communication among immune and non-immune cells in the skin is essential to ensure body homeostasis. Dysregulated cellular communication can lead to the manifestation of inflammatory skin conditions. In this review, we will focus on the following two key frontiers in the skin: innate immune sensors and cell death, as well as their cellular crosstalk in the context of skin homeostasis and inflammation. This review will highlight the recent advancements and mechanisms of how these pathways integrate signals and orchestrate skin immunity, focusing on inflammatory skin diseases and skin infections in mice and humans.

Keywords:  NF-κB; PANoptosis; apoptosis; inflammation; innate immune sensors; necroptosis; programmed cell death; pyroptosis; skin homeostasis

DOI:  https://doi.org/10.3390/v17020241
Int J Mol Sci. 2025 Feb 07. pii: 1403. [Epub ahead of print]26(4):

Lung Microbiota: From Healthy Lungs to Development of Chronic Obstructive Pulmonary Disease.

Marija M Stankovic.

  Lung health is dependent on a complex picture of the lung microbiota composed of bacteriobiota, mycobiota, and virome. The studies have demonstrated that the lung microbiota has a crucial role in host protection by regulating innate and adaptive lung immunity. Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease featuring changed microbiota composition and diversity, known as a dysbiosis. The lung dysbiosis increases with the progress of COPD and during exacerbation. Two models of dysbiosis have been proposed: dysbiosis and inflammation cycles and the disturbance of bacterial interactome. Still, it is unknown if the driving factor of the pathogenesis of COPD belongs to the host or microbiota. Recently, host-microbiota and microbe-microbe interactions have been highlighted in COPD, but the mechanisms behind these interactions need further exploration. The function of the gut-lung axis is crucial for the maintenance of lung health and is affected in COPD. The application of probiotics has resulted in host-beneficial effects, and it is likely that future progress in this field will aid in the therapy of COPD. In this review, the composition of the lung microbiota, molecular mechanisms, and clinical aspects relating to host and microbiota in health and COPD are comprehensively provided.

Keywords:  bacteriobiota; chronic obstructive pulmonary disease; host-microbiota interaction; lung microbiota; mycobiota; therapy; virome

DOI:  https://doi.org/10.3390/ijms26041403
Trends Immunol. 2025 Feb 26. pii: S1471-4906(25)00031-6. [Epub ahead of print]

Extracellular vesicles transport gasdermin pores, amplifying inflammatory cell death.

Bhesh Raj Sharma, Thirumala-Devi Kanneganti.

Lytic cell death is crucial for antimicrobial and antitumor immunity; however, unchecked pyroptosis drives pathology in sepsis. Wright et al. demonstrate that widespread cell death following pyroptosis is propagated by extracellular vesicles (EVs) carrying gasdermin D (GSDMD) pores that become integrated into the membrane of neighboring cells, driving inflammatory cell death.

DOI: https://doi.org/10.1016/j.it.2025.02.004
Cell Rep. 2025 Feb 25. pii: S2211-1247(25)00004-X. [Epub ahead of print]44(2): 115233

Gasdermin D mediates a fast transient release of ATP after NLRP3 inflammasome activation before ninjurin 1-induced lytic cell death.

Julieta Schachter, Adriana Guijarro, Diego Angosto-Bazarra, Miriam Pinilla, Laura Hurtado-Navarro, Etienne Meunier, Ana B Pérez-Oliva, Pablo J Schwarzbaum, Pablo Pelegrin.

  Pyroptosis is a lytic cell death triggered by the cleavage of gasdermin (GSDM) proteins and subsequent pore formation by the N-terminal domain oligomerization in the plasma membrane. GSDMD is cleaved by caspase-1/-4/-5/-11 upon inflammasome activation and mediates interleukin (IL)-1β and IL-18 release. GSDMD pores favor ninjurin 1 (NINJ1)-induced plasma membrane rupture and cell death. Here, we demonstrate that GSDMD mediates early ATP release upon NLRP3 inflammasome activation independently of NINJ1, occurring before IL-1β release and cell death and constituting an early danger signal. The release of ATP is a transient signal terminated before the cells continue to permeabilize and die. The different N termini of GSDMA to -E are also able to release ATP and induce monocyte migration toward pyroptotic cells. This study reveals ATP release as an early and transient danger signal depending on GSDMD plasma membrane permeabilization, independently of the late stages of lytic cell death.

Keywords:  CP: Immunology; caspase-1; danger signal; extracellular nucleotide; inflammation; macrophage; nigericin; ninjurin 1; purinergic singaling; pyroptosis

DOI:  https://doi.org/10.1016/j.celrep.2025.115233
Methods Mol Biol. 2025 ;2903 97-111

Culturing of Airway Stem Cells Obtained from COPD Patients to Assess the Effects of Rhinovirus Infection.

Mohsen Tabasi, Tyler Markward, Umadevi Sajjan.

  Rhinovirus primarily infects airway epithelial cells lining the conductive airways. Mucociliary-differentiated airway epithelial cell cultures, established from airway basal cells, are relevant in vitro model systems to examine the rhinovirus-stimulated innate immune responses and changes in barrier function. The airway epithelium in patients with chronic respiratory diseases such as asthma, cystic fibrosis, and chronic obstructive pulmonary disease often shows remodeling, such as goblet cell metaplasia, squamous metaplasia, and basal cell hyperplasia. Such changes profoundly affect the airway epithelial responses to rhinovirus infection. Previously, we have demonstrated that mucociliary-differentiated cell cultures, established from airway basal cells isolated from COPD patients, show goblet cell and basal cell hyperplasia similar to that observed in patients. These cultures also show a pro-inflammatory phenotype and abnormal innate immune responses to rhinovirus infection. We describe a culturing method that maintains these in vivo features.

Keywords:  Airway basal cells; Chronic obstructive pulmonary disease; Innate immunity; Mucociliary differentiation

DOI:  https://doi.org/10.1007/978-1-0716-4410-2_9
mBio. 2025 Feb 25. e0400624

Endogenous nitric oxide promotes Staphylococcus aureus virulence by activating autophagy.

Nadira Nurxat, Qichen Wang, Na Zhao, Yanan Guo, Xilong Zhang, Yanan Wang, Ying Jian, Hua Wang, Shengbing Yang, Min Li, Qian Liu.

  Endogenous nitric oxide (NO) is a small molecule that has been demonstrated to affect the physiology and survival of bacteria. The role of endogenous NO for Staphylococcus aureus survival inside host cells remains unclear. Here, we show that the production of endogenous NO by bacterial nitrate reductase (NR) is affected by molybdopterin biosynthesis protein A (MoeA), which is essential for molybdenum cofactor synthesis in S. aureus. During the infection, the production of endogenous NO promotes S. aureus survival inside macrophages by initiating cellular autophagy. Mechanistically, bacterial endogenous NO can modify the host regulatory protein thioredoxin vis S-nitrosylation, subsequently triggering the phosphorylation of the JNK-Bcl-2 pathway and promoting the initiation of autophagy through the release of Beclin1. Moreover, we confirmed the critical role of MoeA in bacterial survival in vivo by using bloodstream infection, pneumonia, and skin abscess model on both wild-type and autophagy-deficient mice. Interestingly, we observed the significantly increased production of NO and activation of cellular autophagy of sequence type (ST)5 compared with ST239, suggesting that the initiation of autophagy is involved in the clone shift of S. aureus. Our data offered new insights on the role of bacterial endogenous NO in regulating the host signal pathway during infection inside host cells.IMPORTANCEUnderstanding the mechanism underlying Staphylococcus aureus pathogenesis is essential for developing innovative strategies for the prevention and treatment of infection. In this study, we underscore the critical role of molybdopterin biosynthesis protein A and nitric oxide (NO) in inducing autophagy during S. aureus survival within macrophage and in vivo infection. We demonstrate that host regulatory protein can be modified by bacterial metabolites, which may influence cellular processes. Furthermore, our findings indicated that increased endogenous NO production may contribute to the stable prevalence of S. aureus ST5 in the healthcare-associated environment. These findings highlight the significance of bacterial metabolism in modulating the host immune system, thereby facilitating S. aureus survival and persistence.

Keywords:  Staphylococcus aureus; autophagy; metabolism; nitric oxide; virulence

DOI:  https://doi.org/10.1128/mbio.04006-24
JCI Insight. 2025 Feb 24. pii: e183327. [Epub ahead of print]10(4):

CD4+ T cell-innate immune crosstalk is critical during Staphylococcus aureus craniotomy infection.

Gunjan Kak, Zachary Van Roy, Rachel W Fallet, Lee E Korshoj, Tammy Kielian.

  Access to the brain for treating neurological sequalae requires a craniotomy, which can be complicated by infection. Staphylococcus aureus accounts for half of craniotomy infections, increasing morbidity in a medically fragile patient population. T cells preferentially traffic to the brain during craniotomy infection; however, their functional importance is unknown. Using a mouse model of S. aureus craniotomy infection, CD4+ T cells were critical for bacterial containment, as treatment of WT animals with anti-CD4 exacerbated infection that was similar to phenotypes in Rag1-/- mice. Single-cell RNA-Seq (scRNA-Seq) revealed transcriptional heterogeneity in brain CD3+ infiltrates, with CD4+ cells most prominent that displayed Th1- and Th17-like characteristics, and adoptive transfer of either subset in Rag1-/- animals during early infection prevented S. aureus outgrowth. scRNA-Seq identified a robust IFN signature in several innate immune clusters, and examination of cell-to-cell interactions revealed extensive T cell crosstalk with monocytes/macrophages that was also observed in human craniotomy infection. A cooperative role for Th1 and Th17 responses was demonstrated by treatment of Ifng-/- mice with IL-17A neutralizing antibody that recapitulated phenotypes in Rag1-/- animals. Collectively, these findings implicate Th1- and Th17-mediated proinflammatory responses in shaping the innate immune landscape for S. aureus containment during craniotomy infection.

Keywords:  Bacterial infections; Immunology; Infectious disease; Innate immunity; T cells

DOI:  https://doi.org/10.1172/jci.insight.183327
Pathogens. 2025 Feb 15. pii: 196. [Epub ahead of print]14(2):

Beyond Tuberculosis: The Surprising Immunological Benefits of the Bacillus Calmette-Guérin (BCG) Vaccine in Infectious, Auto-Immune, and Inflammatory Diseases.

Magdalena Jurczak, Magdalena Druszczynska.

  The Bacillus Calmette-Guérin (BCG) vaccine, best known for its role in preventing tuberculosis, has recently garnered attention for its broader immunomodulatory effects. By inducing trained immunity, BCG reprograms innate immune cells, enhancing their responses to various pathogens. This process, driven by epigenetic and metabolic reprogramming, suggests that BCG may have therapeutic potential far beyond tuberculosis. Emerging evidence points to its potential benefits in conditions such as autoimmune diseases, cancer, and viral infections. Furthermore, by modulating immune activity, BCG has been proposed to reduce chronic inflammation and promote immune tolerance. This review delves into the multifaceted role of BCG, highlighting its potential as a versatile therapeutic tool for managing a wide range of diseases.

Keywords:  Bacillus Calmette–Guérin; non-specific BCG effect; trained immunity

DOI:  https://doi.org/10.3390/pathogens14020196
J Neuroinflammation. 2025 Feb 22. 22(1): 46

Interferon-gamma receptor signaling regulates innate immunity during Staphylococcus aureus craniotomy infection.

Zachary Van Roy, Gunjan Kak, Rachel W Fallet, Tammy Kielian.

  A craniotomy is a neurosurgical procedure performed to access the intracranial space. In 3-5% of cases, infections can develop, most caused by Staphylococcus aureus biofilm formation on the skull surface. Medical management of this infection is difficult, as biofilm properties confer immune and antimicrobial recalcitrance to the infection and necessitate additional surgical procedures. Furthermore, treatment failure rates can be appreciably high. These factors, compounded with rapidly expanding rates of antimicrobial resistance, highlight the need to develop alternative treatment strategies to target and reverse the immune dysfunction that occurs during biofilm infection. Our recent work has identified CD4+ Th1 and Th17 cells as potent regulators of innate immune cell activation during craniotomy infection. Here, we report the role of IFN-γ, versus other Th1- and Th17-derived cytokines, in programing the immune response to biofilm infection using both global and cell type-specific IFN-γR1-deficient (Ifngr1-/-) mice. Bacterial burdens were significantly higher in Ifngr1-/- relative to WT animals despite few changes in immune cell abundance. Single-cell transcriptomics identified candidate explanations for this phenotype as alterations in cell death pathways, innate immune cell activation, MHC-II expression, and T cell responses were significantly reduced in Ifngr1-/- mice. While caspase-1 activation in PMNs and macrophage/microglial MHC-II expression were regulated by IFN-γ signaling, no phenotypes were observed with either granulocyte- or macrophage/microglia Ifngr1-/- conditional knockout mice, suggestive of redundancy. Instead, a decreased Th1/Th17 ratio was identified in Ifngr1-/- animals that was corroborated by elevated IL-17 levels and correlated with dysfunctional T cell-innate immune communication. Further, Th17 cells were less effective than Th1 cells in promoting S. aureus bactericidal activity in microglia and macrophages. Collectively, this work identifies a key protective role for IFN-γ during craniotomy infection by enhancing macrophage and microglial antibacterial activity. Therefore, controlled programming of IFN-γ responses may represent a novel therapeutic strategy for chronic craniotomy infections.

Keywords:  Biofilm; Craniotomy; Granulocyte; IFN-γR; Infection; Macrophage; Microglia; T cells; Th1; Th17

DOI:  https://doi.org/10.1186/s12974-025-03376-9
iScience. 2025 Feb 21. 28(2): 111872

Perturbation of EPHA2 and EFNA1 trans binding amplifies inflammatory response in airway epithelial cells.

Ryosuke Fukuda, Shiori Beppu, Daichi Hinata, Yuka Kamada, Tsukasa Okiyoneda.

  The interactions between EPH receptors and ephrin (EFN) ligands play a crucial role in maintaining epithelial integrity and aiding in defense against infections. However, it remains unclear how the EPH-EFN trans-binding changes during infections and how this alteration affects inflammatory response. Here we report that pathogen-associated molecular patterns (PAMPs) disrupt the EPHA2-EFNA1 trans-binding in airway epithelial cells (AECs). Mechanistically, flagellin induces the TLR5-dependent EFNA1 cleavage through the metalloproteinase ADAM9 concomitant with the activation of ligand-independent EPHA2 signaling. We found that the ablation of EPHA2 reduced the responsiveness of respiratory inflammation induced by flagellin and Pseudomonas aeruginosa both in vitro and in vivo. Notably, even in the absence of PAMPs, the inflammatory response in AECs was stimulated by forcibly induced EFNA1 shedding. These findings illustrate that the perturbation of the EPHA2-EFNA1 trans-binding acts as a sensing mechanism for infections and amplifies the inflammatory response, providing a defense mechanism for respiratory epithelia.

Keywords:  Biochemistry; Biological sciences; Cell biology

DOI:  https://doi.org/10.1016/j.isci.2025.111872
Transplantation. 2024 Nov 15.

Cardio-systemic Stress and Trained Innate Immune Memory in Heart Failure.

Ameesh Isath, Mandeep R Mehra.

DOI: https://doi.org/10.1097/TP.0000000000005278
Arch Microbiol. 2025 Feb 24. 207(4): 70

The immune response of upper and lower airway epithelial cells to Aspergillus fumigatus and Candida albicans-derived β-glucan in Th17 type cytokine environment.

Murat Turkbey, Dilara Karaguzel, Ali Doruk Uzunkaya, Yusuf Doruk Aracagok, Cagatay Karaaslan.

  The fungal cell wall component β-glucan activates inflammation via the Dectin-1 receptor and IL-17 coordinates the antifungal immunity. However, the molecular crosstalk between IL-17, Dectin-1, and β-glucan in epithelial cells and fungal immunity remains unclear. We investigated the impact of A.fumigatus-derived β-glucan (AFBG) and C.albicans-derived β-glucan (CABG) on Dectin-1 and cytokines in nasal epithelial cells (NECs) and bronchial epithelial cells (BECs) in the presence of IL-17. CABG reduced BEC viability more than AFBG despite similar Dectin-1 expression. IL-17 reduced β-glucan-dependent Dectin-1 expression in NECs but increased it in BECs after 12 h. AFBG synergized with IL-17, enhancing pro-inflammatory cytokines and chemokine expressions. IL-6 and IL-8 production increased in the presence of IL-17. Th17 cytokine influenced the Dectin-1 response to fungal β-glucan in NECs and BECs, impacting the initiation and nature of epithelial cell reactions to AFBG and CABG. Uncovering the molecular mechanisms of fungal β-glucans in the respiratory tract could lead to novel strategies for preventing fungal diseases.

Keywords:   Aspergillus fumigatus ; Candida albicans ; Cytokine; Dectin-1; Epithelial cell; β-glucan

DOI:  https://doi.org/10.1007/s00203-025-04266-7
Cytokine. 2025 Feb 24. pii: S1043-4666(25)00049-3. [Epub ahead of print]189 156902

Evaluating the evidence for GM-CSF as a host-directed therapy in respiratory infections.

Camille David, Charles Verney, Mustapha Si-Tahar, Antoine Guillon.

  Novel therapeutic approaches are needed to treat respiratory infections due to the rising antimicrobial resistance and the lack of effective antiviral therapies. A promising avenue to overcome treatment failure is to develop strategies that target the host immune response rather than the pathogen itself. Granulocyte-macrophage colony-stimulating factor (GM-CSF) plays a critical role in controlling homeostasis in lungs, alveolar macrophages being the most sensitive cells to GM-CSF signaling. In this review, we discuss the importance of GM-CSF secretion for lung homeostasis and its alteration during respiratory infections. We also present the pre-clinical evidence and clinical investigations evaluating GM-CSF-based treatments (administration or inhibition) as a therapeutic strategy for treating respiratory infections, highlighting both supporting and contradictory findings.

Keywords:  Community acquired pneumonia; Granulocyte-macrophage colony-stimulating factor; Influenza virus; Respiratory infection; SARS-CoV-2 virus

DOI:  https://doi.org/10.1016/j.cyto.2025.156902
Nature. 2025 Feb 26.

Macrophages recycle phagocytosed bacteria to fuel immunometabolic responses.

Juliette Lesbats, Aurélia Brillac, Julie A Reisz, Parnika Mukherjee, Charlène Lhuissier, Mónica Fernández-Monreal, Jean-William Dupuy, Angèle Sequeira, Gaia Tioli, Celia De La Calle Arregui, Benoît Pinson, Daniel Wendisch, Benoît Rousseau, Alejo Efeyan, Leif Erik Sander, Angelo D'Alessandro, Johan Garaude.

Macrophages specialize in phagocytosis, a cellular process that eliminates extracellular matter, including microorganisms, through internalization and degradation1,2. Despite the critical role of phagocytosis during bacterial infection, the fate of phagocytosed microbial cargo and its impact on the host cell are poorly understood. In this study, we show that ingested bacteria constitute an alternative nutrient source that skews immunometabolic host responses. By tracing stable isotope-labelled bacteria, we found that phagolysosomal degradation of bacteria provides carbon atoms and amino acids that are recycled into various metabolic pathways, including glutathione and itaconate biosynthesis, and satisfies the bioenergetic needs of macrophages. Metabolic recycling of microbially derived nutrients is regulated by the nutrient-sensing mechanistic target of rapamycin complex C1 and is intricately tied to microbial viability. Dead bacteria, as opposed to live bacteria, are enriched in cyclic adenosine monophosphate, sustain the cellular adenosine monophosphate pool and subsequently activate adenosine monophosphate protein kinase to inhibit the mechanistic target of rapamycin complex C1. Consequently, killed bacteria strongly fuel metabolic recycling and support macrophage survival but elicit decreased reactive oxygen species production and reduced interleukin-1β secretion compared to viable bacteria. These results provide a new insight into the fate of engulfed microorganisms and highlight a microbial viability-associated metabolite that triggers host metabolic and immune responses. Our findings hold promise for shaping immunometabolic intervention for various immune-related pathologies.

DOI: https://doi.org/10.1038/s41586-025-08629-4
bioRxiv. 2025 Feb 13. pii: 2025.02.12.637843. [Epub ahead of print]

Commensal acidification of specific gut regions produces a protective priority effect against enteropathogenic bacterial infection.

Jane L Yang, Haolong Zhu, Puru Sadh, Kevin Aumiller, Zehra T Guvener, William B Ludington.

The commensal microbiome has been shown to protect against newly introduced enteric pathogens in multiple host species, a phenomenon known as a priority effect. Multiple mechanisms can contribute to this protective priority effect, including antimicrobial compounds, nutrient competition, and pH changes. In Drosophila melanogaster , Lactiplantibacillus plantarum has been shown to protect against enteric pathogens. However, the strains of L. plantarum studied were derived from laboratory flies or non-fly environments and have been found to be unstable colonizers of the fly gut that mainly reside on the food. To study the priority effect using a naturally occurring microbial relationship, we isolated a wild-fly derived strain of L. plantarum that stably colonizes the fly gut in conjunction with a common enteric pathogen, Serratia marcescens . Flies stably associated with the L. plantarum strain were more resilient to oral Serratia marcescens infection as seen by longer lifespan and lower S. marcescens load in the gut. Through in vitro experiments, we found that L. plantarum inhibits S. marcescens growth due to acidification. We used gut imaging with pH-indicator dyes to show that L. plantarum reduces the gut pH to levels that restrict S. marcescens growth in vivo . In flies colonized with L. plantarum prior to S. marcescens infection, L. plantarum and S. marcescens are spatially segregated in the gut and S. marcescens is less abundant where L. plantarum heavily colonizes, indicating that acidification of specific gut regions is a mechanism of a protective priority effect.

DOI: https://doi.org/10.1101/2025.02.12.637843
Methods Mol Biol. 2025 ;2903 77-96

Analysis of Adherence Junctions in Rhinovirus-Infected Airway Epithelial Cells.

Kevin Looi, Liisa M Hirvonen, Anthony Kicic.

  The airway mucosal epithelium is the main gateway of entry for numerous human respiratory viruses, including human influenza virus, respiratory syncytial virus (RSV), coronavirus, and rhinoviruses (RV). For respiratory viruses to perpetuate infection, they must be able to traverse the airway mucosal epithelium and then spread into distal sites of the respiratory tract and lung parenchyma. However, this cellular interface has evolved well-developed apical junctional complexes (AJCs), including tight and adherens junctions, that bridge adjacent epithelial cells together. The resulting structure not only provides a strong physical barrier but also plays an active role in preventing and/or limiting the spread and dissemination of viral pathogens. Respiratory viruses, such as RVs, have been shown to target various components of these AJCs, either directly or indirectly, thus facilitating paracellular viral penetration, resulting in airway epithelial barrier dysfunction. Disruption of these AJCs may also result in unintended contact with hidden viral receptors, further enabling viral infection of the airway epithelium. Here we describe the various models of RV-infected airway epithelial cells and the methods used for the characterization and analysis of AJCs following RV infection.

Keywords:  Adherens junctions; Apical junctional complex; Barrier disruption; Confocal microscopy; Epithelial barrier; Epithelial permeability; In-Cell Western™; Rhinovirus; Super-resolution microscopy; Tight junctions; Transepithelial electrical resistance; Viral infection

DOI:  https://doi.org/10.1007/978-1-0716-4410-2_8
Int J Mol Sci. 2025 Feb 19. pii: 1773. [Epub ahead of print]26(4):

Microbiota and Inflammatory Markers: A Review of Their Interplay, Clinical Implications, and Metabolic Disorders.

Emiliano Peña-Durán, Jesús Jonathan García-Galindo, Luis Daniel López-Murillo, Alfredo Huerta-Huerta, Luis Ricardo Balleza-Alejandri, Alberto Beltrán-Ramírez, Elsa Janneth Anaya-Ambriz, Daniel Osmar Suárez-Rico.

  The human microbiota, a complex ecosystem of microorganisms, plays a pivotal role in regulating host immunity and metabolism. This review investigates the interplay between microbiota and inflammatory markers, emphasizing their impact on metabolic and autoimmune disorders. Key inflammatory biomarkers, such as C-reactive protein (CRP), interleukin-6 (IL-6), lipopolysaccharides (LPS), zonulin (ZO-1), and netrin-1 (Ntn1), are discussed in the context of intestinal barrier integrity and chronic inflammation. Dysbiosis, characterized by alterations in microbial composition and function, directly modulates the levels and activity of these biomarkers, exacerbating inflammatory responses and compromising epithelial barriers. The disruption of microbiota is further correlated with increased intestinal permeability and chronic inflammation, serving as a precursor to conditions like type 2 diabetes (T2D), obesity, and non-alcoholic fatty liver disease. Additionally, this review examines therapeutic strategies, including probiotics and prebiotics, designed to restore microbial balance, mitigate inflammation, and enhance metabolic homeostasis. Emerging evidence positions microbiota-targeted interventions as critical components in the advancement of precision medicine, offering promising avenues for diagnosing and treating inflammatory and metabolic disorders.

Keywords:  biomarkers; chronic diseases; dysbiosis; inflammation; insulin resistance; microbiota; probiotics

DOI:  https://doi.org/10.3390/ijms26041773
Curr Opin Immunol. 2025 Feb 26. pii: S0952-7915(25)00017-2. [Epub ahead of print]93 102541

Sensory neurons on guard: roles in pathogen defense and host immunity.

Ozge Erdogan, Xiao-Qian Hu, Isaac M Chiu.

The nervous system, like the immune system, constantly interfaces with the environment, encountering threats, including pathogens. Recent discoveries reveal an emerging role for sensory neurons in host defense and immunity. Sensory neurons detect infections either by directly sensing microbial signals or through immune mediators. Beyond pathogen detection, they modulate immune responses and local inflammation by interacting with immune cells, influencing inflammation and pathogen clearance. Additionally, sensory neurons trigger protective reflexes - such as pain, coughing, sneezing, and itching - that can help expel pathogens but may also facilitate their spread. Sensory neurons may also encode and shape long-term immunity. Understanding the roles of neurons in pathogen defense could offer new insights into infectious diseases and highlight therapeutic opportunities for immune modulation.

DOI: https://doi.org/10.1016/j.coi.2025.102541
Biochim Biophys Acta Gen Subj. 2025 Feb 21. pii: S0304-4165(25)00024-8. [Epub ahead of print] 130779

"Mannose glycans as key players in trained immunity: A novel anti-tumoral catalyst".

Pedro Almeida, Inês Alves, Ângela Fernandes, Cláudia Lima, Rui Freitas, Isaac Braga, Jorge Correia, Carmen Jerónimo, Salomé Pinho.

  Cell wall glycans isolated from microorganisms are long known to provoke strong immune responses piloted by innate immune cell populations, including monocytes, in the context of Trained Immunity (TI). However, the contribution of yeast-derived mannan in the reprogramming of monocytes remains ill-defined. Here, we demonstrated that TI is often accompanied by an altered gene expression profile of selected glycan-binding proteins expressed by monocytes, including DC-SIGN and Dectin-2. Additionally, we showed that mannan, a mannose rich glycan, can trigger an enhanced immune phenotype compatible with TI in healthy monocytes, with glycan-primed cells exhibiting enhanced pro-inflammatory cytokine secretion (TNFα and IL-6) and higher activation (CD86) levels. Furthermore, the glycan-mediated priming of monocytes also imposed alterations to the expression of certain Glycan-Binding Proteins, such as DC-SIGN. Importantly, we established that these mannan-trained immune cells displayed an improved capacity to kill tumor cells in vitro. Lastly, we confirmed that monocytes from non-muscle invasive bladder cancer patients treated with BCG instillations presented a TI phenotype, as was revealed by the higher cytokine production and activation. Altogether, this study lays the foundations for exploiting the immunological potential of glycan-derived pathogens in reprogramming innate immune cells towards an effective anti-tumor immune response.

Keywords:  BCG; Bladder Cancer; Glycan-binding proteins; Glycans; Mannose; Trained immunity

DOI:  https://doi.org/10.1016/j.bbagen.2025.130779
FEBS J. 2025 Feb 23.

Interactions of the maternal microbiome with diet, stress, and infection influence fetal development.

Chloe H Puglisi, Minjeong Kim, Modi Aldhafeeri, Megan Lewandowski, Helen E Vuong.

  Humans and other animals contain multitudes of microorganisms including bacteria, fungi, and viruses, which make up a diverse microbiome. Across body sites including skin, gastrointestinal tract, and oral cavity there are distinct microbial niches that are made up of trillions of microorganisms that have co-evolved to inhabit and interact with the host. The microbiome also interacts with the changing environment. This tripartite interaction between the host, microbiome, and environment suggests microbial communities play a key role in the biological processes of the host, such as development and behaviors. Over the past two decades, emerging research continues to reveal how host and microbe interactions impact nervous system signaling and behaviors, and influence neurodevelopmental, neurological, and neurodegenerative disorders. In this review, we will describe the unique features of the maternal microbiome that exist during the perinatal period and discuss evidence for the function of the maternal microbiome in offspring development. Finally, we will discuss how the maternal environment interacts with the microbiome and nervous system development and then postulate how the maternal microbiome can modify early offspring development to have lasting influence on brain health.

Keywords:  diet; gut microbiome; immune activation; maternal environment; neurodevelopment; offspring development; perinatal period; stress

DOI:  https://doi.org/10.1111/febs.70031
FEBS J. 2025 Feb 27.

Matriptase-mediated PAR2 activation drives monocyte-to-macrophage differentiation and polarization under hypoxic conditions.

Arpana Singh, Avinandan Bhoumick, Prosenjit Sen.

  Within the intricate landscape of the tumour microenvironment (TME), hypoxia stands out as a pivotal factor profoundly shaping immune cell dynamics. Our study delves into this dynamic interplay, uncovering a cascade of events triggered by hypoxia. We unveil the emergence of protease-activated receptor 2 (PAR2; also known as F2R-like trypsin receptor 1 [F2RL1]) expression in monocyte cell lines (THP1) and peripheral blood mononuclear cells (PBMCs), orchestrated by the active serine protease matriptase (TMPRSS2; also known as transmembrane protease serine 2). Hypoxic conditions set the stage for a dual mechanism: lactate accumulation drives extracellular pH reduction, and facilitates matriptase activation from its latent form. A 10 mm lactate threshold activates matriptase, which in turn activates PAR2, driving monocytes towards M1 macrophage differentiation through the AKT2-NF-κβ axis. This triggers miR155 expression, which suppresses cytokine signaling 1 (SOCS1), a key regulator of M1-M2 polarisation, while NF-κβ enhances proinflammatory responses. Notably, our study reveals a temporal switch in this hypoxia-driven process. After 48 h of hypoxia, lactate levels rise to 25 mm, suppressing matriptase activation and driving a shift towards M2 polarisation. This transition, marked by reduced miR155 expression via AKT2-NFκβ axis inactivation, highlights the dynamic nature of macrophage polarisation. Our findings demonstrate matriptase as a key regulator driving macrophage polarisation towards the M1 phenotype within hypoxic microenvironments. This insight into macrophage behaviour under hypoxia suggests new strategies for immune modulation to counter tumour progression.

Keywords:  M1 M2 polarisation; PAR2; differentiation; macrophage; matriptase

DOI:  https://doi.org/10.1111/febs.70046
Front Immunol. 2025 ;16 1568032

Corrigendum: Recognition of Staphylococcus aureus by the pattern recognition molecules langerin, mannan-binding lectin, and surfactant protein D: the influence of capsular polysaccharides and wall teichoic acid.

Kirstine Mejlstrup Hymøller, Stig Hill Christiansen, Anders Grønnegaard Schlosser, Uffe B Skov Sørensen, Jean C Lee, Steffen Thiel.

  [This corrects the article DOI: 10.3389/fimmu.2024.1504886.].

Keywords:  C-type lectins; S. aureus; capsular polysaccharides; innate immunity; langerin; mannan-binding lectin; surfactant protein D; wall teichoic acid

DOI:  https://doi.org/10.3389/fimmu.2025.1568032
Bioengineering (Basel). 2025 Feb 13. pii: 182. [Epub ahead of print]12(2):

Development of a Widely Accessible, Advanced Large-Scale Microfluidic Airway-on-Chip.

Brady Rae, Gwenda F Vasse, Jalal Mosayebi, Maarten van den Berge, Simon D Pouwels, Irene H Heijink.

  On-chip microfluidics are advanced in vitro models that simulate lung tissue's native 3D environment more closely than static 2D models to investigate the complex lung architecture and multifactorial processes that lead to pulmonary disease. Current microfluidic systems can be restrictive in the quantities of biological sample that can be retrieved from a single micro-channel, such as RNA, protein, and supernatant. Here, we describe a newly developed large-scale airway-on-chip model that employs a surface area for a cell culture wider than that in currently available systems. This enables the collection of samples comparable in volume to traditional cell culture systems, making the device applicable to any workflow utilizing these static systems (RNA isolation, ELISA, etc.). With our construction method, this larger culture area allows for easier handling, the potential for a wide range of exposures, as well as the collection of low-quantity samples (e.g., volatiles or mitochondrial RNA). The model consists of two large polydimethylsiloxane (PDMS) cell culture chambers under an independent flow of medium or air, separated by a semi-permeable polyethylene (PET) cell culture membrane (23 μm thick, 0.4 μm pore size). Each chamber carries a 5 × 18 mm, 90 mm2 (92 mm2 with tapered chamber inlets) surface area that can contain up to 1-2 × 104 adherent structural lung cells and can be utilized for close contact co-culture studies of different lung cell types, including airway epithelial cells, fibroblasts, smooth muscle cells, and endothelial cells. The parallel bi-chambered design of the chip allows for epithelial cells to be cultured at the air-liquid interface (ALI) and differentiation into a dense, multi-layered, pseudostratified epithelium under biological flow rates. This millifluidic airway-on-chip advances the field by providing a readily reproducible, easily adjustable, and cost-effective large-scale fluidic 3D airway cell culture platform.

Keywords:  PDMS; airway-on-chip; air–liquid interface; epithelial cells; microfluidics

DOI:  https://doi.org/10.3390/bioengineering12020182
bioRxiv. 2025 Feb 16. pii: 2025.02.13.637616. [Epub ahead of print]

The MicroMap is a network visualisation resource for microbiome metabolism.

Cyrille C Thinnes, Renee Waschkowitz, Eoghan Courtney, Eoghan Culligan, Katie Fahy, Ruby A M Ferrazza, Ciara Ferris, Angeline Lagali, Rebecca Lane, Colm Maye, Olivia Murphy, David Noone, Saoirse Ryan, Mihaela Bet, Maria C Corr, Hannah Cummins, David Hackett, Ellen Healy, Nina Kulczycka, Niall Lang, Luke Madden, Lynne McHugh, Ivana Pyne, Ciara Varley, Niamh Harkin, Ronan Meade, Grace O'Donnell, Bram Nap, Filippo Martinelli, Almut Heinken, Ines Thiele.

The human microbiome plays a crucial role in metabolism and thereby influences health and disease. Constraint-based reconstruction and analysis (COBRA) has proven an attractive framework to generate mechanism-derived hypotheses along the nutrition-host-microbiome-disease axis within the computational systems biology community. Unlike for human, no large-scale visualisation resource for microbiome metabolism has been available to date. To address this gap, we created the MicroMap, a manually curated microbiome metabolic network visualisation, which captures the metabolic content of over a quarter million microbial genome-scale metabolic reconstructions. The MicroMap contains 5,064 unique reactions and 3,499 unique metabolites, including for 98 drugs. The MicroMap allows users to intuitively explore microbiome metabolism, inspect microbial metabolic capabilities, and visualise computational modelling results. Further, the MicroMap shall serve as an educational tool to make microbiome metabolism accessible to broader audiences beyond computational modellers. For example, we utilised the MicroMap to generate a comprehensive collection of 257,429 visualisations, corresponding to the entire scope of our current microbiome reconstruction resources, to enable users to visually compare and contrast the metabolic capabilities for different microbes. The MicroMap seamlessly integrates with the Virtual Metabolic Human (VMH, www.vmh.life) and the COBRA Toolbox (opencobra.github.io), and is freely accessible at the MicroMap dataverse (https://dataverse.harvard.edu/dataverse/micromap), in addition to all the generated reconstruction visualisations.

DOI: https://doi.org/10.1101/2025.02.13.637616
Appl Environ Microbiol. 2025 Feb 26. e0133624

Inhibition of pneumococcal growth and biofilm formation by human isolates of Streptococcus mitis and Streptococcus oralis.

João Borralho, Sara Handem, João Lança, Bárbara Ferreira, Catarina Candeias, Adriano O Henriques, N Luisa Hiller, Carina Valente, Raquel Sá-Leão.

  In a world facing the unprecedented threat of antibiotic-resistant bacteria, targeted approaches to control colonization and prevent disease caused by common pathobionts offer a promising solution. Streptococcus pneumoniae (pneumococcus) is a leading cause of infections worldwide, affecting both children and adults despite available antimicrobials and vaccines. Colonization, which occurs in the form of a biofilm in the upper respiratory tract, is frequent and a prerequisite for disease and transmission. The use of live bacterial strains as biotherapeutics for infectious diseases is actively being explored. Here, we investigated the potential of commensal streptococci to control S. pneumoniae. Screening of over 300 human isolates led to the identification of seven strains (one Streptococcus oralis and six Streptococcus mitis, designated A22 to G22) with inhibitory activity against S. pneumoniae of multiple serotypes and genotypes. Characterization of A22 to G22 cell-free supernatants indicated the involvement of secreted proteins or peptides in the inhibitory effect of all S. mitis isolates. Genome analyses revealed the presence of 64 bacteriocin loci, encoding 70 putative bacteriocins, several of which are novel and absent or rare in over 7,000 publicly available pneumococcal genomes. Deletion mutants indicated that bacteriocins partially or completely explained the anti-pneumococcal activity of the commensal strains. Importantly, strains A22 to G22 were further able to prevent and disrupt pneumococcal biofilms, a proxy for nasopharyngeal colonization. These results highlight the intricacy of the interactions among nasopharyngeal colonizers and support the potential of strains A22 to G22 to be used as live biotherapeutics, alone or in combination, to control S. pneumoniae colonization.
IMPORTANCE: Streptococcus pneumoniae (pneumococcus) infections remain a major public health issue despite the use of vaccines and antibiotics. Pneumococci asymptomatically colonize the human upper respiratory tract, a niche shared with several commensal Streptococcus species. Competition for space and nutrients among species sharing the same niche is well documented and tends to be more intense among closely related species. Based on this rationale, a screening of several commensal streptococci isolated from the human upper respiratory tract led to the identification of strains of Streptococcus mitis and Streptococcus oralis capable of inhibiting most pneumococcal strains, across diverse serotypes and genotypes. This inhibition was partially or wholly linked to the expression of novel bacteriocins. The selected S. mitis and S. oralis strains significantly disrupted pneumococcal biofilms, indicating a potential for using commensals as biotherapeutics to control pneumococcal colonization, a key step in preventing disease and transmission.

Keywords:  Streptococcus mitis; Streptococcus oralis; Streptococcus pneumoniae; bacteriocin; biofilm; biotherapeutic; colonization

DOI:  https://doi.org/10.1128/aem.01336-24
Antibiotics (Basel). 2025 Jan 23. pii: 119. [Epub ahead of print]14(2):

Implant-Derived S. aureus Isolates Drive Strain-Specific Invasion Dynamics and Bioenergetic Alterations in Osteoblasts.

Lei Song, Lea-Sophie Schwinn, Juliane Barthel, Vanessa Ketter, Philipp Lechler, Uwe Linne, Ardawan J Rastan, Sebastian Vogt, Steffen Ruchholtz, Jürgen R J Paletta, Madeline Günther.

  Background: Implants are integral to modern orthopedic surgery. The outcomes are good, but infections remain a serious issue. Staphylococcus aureus (S. aureus), along with Staphylococcus epidermidis, are predominant pathogens responsible for implant-associated infections, as conventional antibiotic treatments often fail due to biofilm formation or the pathogens' ability to invade cells and to persist intracellularly. Objectives: This study therefore focused on interactions of S. aureus isolates from infected implants with MG63 and SaOS2 osteoblasts by investigating the adhesion, invasion, and the impact on the bioenergetics of osteoblasts. Methods and Results: We found that the ability of S. aureus to adhere to osteoblasts depends on the isolate and was not associated with a single gene or expression pattern of characteristic adhesion proteins, and further, was not correlated with invasion. However, analysis of invasion capabilities identified better invasion conditions for S. aureus isolates with the SaOS2 osteoblastic cells. Interestingly, metabolic activity of osteoblasts remained unaffected by S. aureus infection, indicating cell survival. In contrast, respiration assays revealed an altered mitochondrial bioenergetic turnover in infected cells. While basal as well as maximal respiration in MG63 osteoblasts were not influenced statistically by S. aureus infections, we found increased non-mitochondrial respiration and enhanced glycolytic activity in the osteoblasts, which was again, more pronounced in the SaOS2 osteoblastic cells. Conclusions: Our findings highlight the complexity of S. aureus-host interactions, where both the pathogen and the host cell contribute to intracellular persistence and survival, representing a major factor for therapeutic failures.

Keywords:  S. aureus; SaOS2 and MG63 osteoblasts; adhesion-, invasion- and survival assay; clinical isolates; implant infections; mitochondrial respiration

DOI:  https://doi.org/10.3390/antibiotics14020119
Immunity. 2025 Feb 21. pii: S1074-7613(25)00069-X. [Epub ahead of print]

A bladder-blood immune barrier constituted by suburothelial perivascular macrophages restrains uropathogen dissemination.

Lu Li, Qiancheng Jiao, Qianqian Yang, Haisen Lu, Xia Zhou, Qing Zhang, Futing Zhang, Hai Li, Zhigang Tian, Zhutian Zeng.

  Urinary tract infections (UTIs) predominantly occur in the bladder and can potentially progress into life-threatening sepsis if uropathogens spread unconstrainedly into the bloodstream. Here, we identified a subset of suburothelial perivascular macrophages (suPVMs) in the bladder that exerted a pivotal barrier function to prevent systemic bacterial dissemination during acute cystitis. During the initial phase of uropathogenic Escherichia coli (UPEC) infection, suPVMs actively captured UPEC invading the laminal propria and maintained the integrity of inflamed vessels. They subsequently underwent METosis to expel macrophage extracellular DNA traps (METs) into the urothelium to sequester bacteria within this avascular compartment. Matrix metallopeptidase-13 was released along with METs to promote neutrophil transuroepithelial migration. Replenished suPVMs from monocytes following a prior infection were functionally competent to confer protection against recurrent UTIs. Our study thus uncovers a bladder-blood immune barrier in restraining uropathogen dissemination, which could have implications for the prevention and treatment of urosepsis.

Keywords:  METs; MMP13; bacteremia; extracellular DNA traps; intravital imaging; neutrophils; perivascular macrophages; tissue-resident macrophages; urinary tract infections

DOI:  https://doi.org/10.1016/j.immuni.2025.02.002
Nat Biotechnol. 2025 Feb 24.

Human respiratory airway progenitors derived from pluripotent cells generate alveolar epithelial cells and model pulmonary fibrosis.

Mikael G Pezet, Juan A Torres, Tania A Thimraj, Ivana Matkovic, Nadine Schrode, John W Murray, Anjali Saqi, Kristin G Beaumont, Hans-Willem Snoeck.

Human lungs contain unique cell populations in distal respiratory airways or terminal and respiratory bronchioles (RA/TRBs) that accumulate in persons with lung injury and idiopathic pulmonary fibrosis (IPF), a lethal lung disease. As these populations are absent in rodents, deeper understanding requires a human in vitro model. Here we convert human pluripotent stem cells (hPS cells) into expandable spheres, called induced respiratory airway progenitors (iRAPs), consisting of ~98% RA/TRB-associated cell types. One hPS cell can give rise to 1010 iRAP cells. We differentiate iRAPs through a stage consistent with transitional type 2 alveolar epithelial (AT2) cells into a population corresponding to mature AT1 cells with 95% purity. iRAPs with deletion of Heřmanský-Pudlák Syndrome 1 (HPS1), which causes pulmonary fibrosis in humans, replicate the aberrant differentiation and recruitment of profibrotic fibroblasts observed in IPF, indicating that intrinsic dysfunction of RA/TRB-associated alveolar progenitors contributes to HPS1-related IPF. iRAPs may provide a system suitable for IPF drug discovery and validation.

DOI: https://doi.org/10.1038/s41587-025-02569-0
mSystems. 2025 Feb 26. e0154024

Dual RNA-seq reveals the complement protein C3-mediated host-pathogen interaction in the brain abscess caused by Staphylococcus aureus.

Qiyuan Jin, Yaxuan Zhai, Rui Qiang, Xin Ma, Chenhao Zhao, Jinqi Zhong, Jijie Li, Qi Chen, Mingxiao Han, Hong Du, Qifei Cong, Haifang Zhang.

  This study aimed to elucidate the complement protein C3-mediated host-pathogen interaction in the brain abscess caused by Staphylococcus aureus infection. Dual RNA-seq was employed to analyze the transcriptomic differences between C3 deficiency and wild-type mice of S. aureus-induced brain abscess model, and then we investigated the potential regulatory pathways of S. aureus-host interaction mediated by C3 and S. aureus genes associated with the pathogenesis of brain abscess. Finally, C3 deficient-mice and hla mutants of S. aureus were used to verify the specific pathogen-host interaction. In the S. aureus-induced brain abscess mouse model, the transcriptomic analysis revealed significant changes in bacterial virulence factors, such as hemolysin. Based on these data, we predicted a regulatory network formed by genes like hrcA and dnaK, which represent a possible regulation mechanism of S. aureus responding to the host. Furthermore, we identified that hla was the C3 response gene in S. aureus. From the host perspective, we observed that the absence of C3 significantly impacted the host's inflammatory response, primarily by altering the gene expression of several key immune and inflammatory pathways. These findings suggest that C3 deficiency may impair the host's ability to recognize and respond to external pathogens. To the best of our knowledge, this study proposed that S. aureus may affect host immune response through C3, and C3 plays a critical role in regulating inflammation and immune signaling pathways in the brain abscess caused by S. aureus infection.IMPORTANCEIn this work, we employed immunofluorescence and Western blot analysis to reveal a significant upregulation of microglia-derived C3 in the brain abscess mice model caused by S. aureus infection. By integrating the individual RNA sequencing data of S. aureus and the dual RNA-seq data of S. aureus infection brain abscess mice model, the potential regulatory pathways between S. aureus and host were identified, and host C3 not only affects the immune response but also mediates the regulation network of S. aureus. This study provided the potential novel targets for therapeutic strategies in mitigating the effects of S. aureus infections and improving treatment outcomes.

Keywords:  C3; Staphylococcus aureus; brain abscess; dual RNA-seq; pathogen-host interaction

DOI:  https://doi.org/10.1128/msystems.01540-24
Nat Metab. 2025 Feb 24.

Mitochondrial superoxide regulates pro-inflammatory macrophages.

DOI: https://doi.org/10.1038/s42255-025-01223-y
Eur J Pharmacol. 2025 Feb 20. pii: S0014-2999(25)00168-2. [Epub ahead of print]995 177414

Crosstalk between autophagy and other forms of programmed cell death.

Huaiyuan Wang, Xiran Feng, Huilin He, Lingyu Li, Yiqiong Wen, Xiaofei Liu, Bifeng He, Shu Hua, Shibo Sun.

  Cell death occurs continuously throughout individual development. By removing damaged or senescent cells, cell death not only facilitates morphogenesis during the developmental process, but also contributes to maintaining homeostasis after birth. In addition, cell death reduces the spread of pathogens by eliminating infected cells. Cell death is categorized into two main forms: necrosis and programmed cell death. Programmed cell death encompasses several types, including autophagy, pyroptosis, apoptosis, necroptosis, ferroptosis, and PANoptosis. Autophagy, a mechanism of cell death that maintains cellular equilibrium via the breakdown and reutilization of proteins and organelles, is implicated in regulating almost all forms of cell death in pathological contexts. Notably, necroptosis, ferroptosis, and PANoptosis are directly classified as autophagy-mediated cell death. Therefore, regulating autophagy presents a therapeutic approach for treating diseases such as inflammation and tumors that arise from abnormalities in other forms of programmed cell death. This review focuses on the crosstalk between autophagy and other programmed cell death modalities, providing new perspectives for clinical interventions in inflammatory and neoplastic diseases.

Keywords:  Crosstalk; Disease; Programmed cell death

DOI:  https://doi.org/10.1016/j.ejphar.2025.177414
Mol Biomed. 2025 Feb 25. 6(1): 11

GSDMD-mediated pyroptosis: molecular mechanisms, diseases and therapeutic targets.

Yujuan Li, Bin Guo.

  Pyroptosis is a regulated form of inflammatory cell death in which Gasdermin D (GSDMD) plays a central role as the key effector molecule. GSDMD-mediated pyroptosis is characterized by complex biological features and considerable heterogeneity in its expression, mechanisms, and functional outcomes across various tissues, cell types, and pathological microenvironments. This heterogeneity is particularly pronounced in inflammation-related diseases and tumors. In the context of inflammatory diseases, GSDMD expression is typically upregulated, and its activation in macrophages, neutrophils, T cells, epithelial cells, and mitochondria triggers both pyroptotic and non-pyroptotic pathways, leading to the release of pro-inflammatory cytokines and exacerbation of tissue damage. However, under certain conditions, GSDMD-mediated pyroptosis may also serve a protective immune function. The expression of GSDMD in tumors is regulated in a more complex manner, where it can either promote immune evasion or, in some instances, induce tumor cell death. As our understanding of GSDMD's role continues to progress, there have been advancements in the development of inhibitors targeting GSDMD-mediated pyroptosis; however, these therapeutic interventions remain in the preclinical phase. This review systematically examines the cellular and molecular complexities of GSDMD-mediated pyroptosis, with a particular emphasis on its roles in inflammation-related diseases and cancer. Furthermore, it underscores the substantial therapeutic potential of GSDMD as a target for precision medicine, highlighting its promising clinical applications.

Keywords:  Cell heterogeneity; Disease; GSDMD; Mechanism; Pyroptosis; Therapy

DOI:  https://doi.org/10.1186/s43556-025-00249-8
Front Cell Infect Microbiol. 2025 ;15 1541881

Editorial: New techniques in microbiome research - volume II: Host-microbiome interactions using 'meta-omics' techniques.

Tao Lin.



Keywords:  META-OMICS; human health and diseases; metabolomics; metagenomics; metaproteomics; metatranscriptomics; microbiome; new techniques

DOI:  https://doi.org/10.3389/fcimb.2025.1541881
Microorganisms. 2025 Feb 13. pii: 410. [Epub ahead of print]13(2):

Listeria monocytogenes Modulates Macrophage Inflammatory Responses to Facilitate Its Intracellular Survival by Manipulating Macrophage-Derived Exosomal ncRNAs.

Jian Jiao, Zhongmei Ma, Nengxiu Li, Fushuang Duan, Xuepeng Cai, Yufei Zuo, Jie Li, Qingling Meng, Jun Qiao.

  Exosomes are nanoscale vesicles secreted by cells that play vital regulatory roles in intercellular communication and immune responses. Listeria monocytogenes (L. Monocytogenes, LM) is a notable Gram-positive intracellular parasitic bacterium that infects humans and diverse animal species. However, the specific biological function of exosomes secreted by macrophages during L. Monocytogenes infection (hereafter EXO-LM) remains elusive. Here, we discovered that EXO-LM stimulated the secretion of inflammation-associated cytokines by macrophages, facilitating the intracellular survival of L. monocytogenes within macrophages. Transcriptomic analysis shows that EXO-LM significantly upregulates immune recognition and inflammation-related signaling pathways in macrophages. Furthermore, a ceRNA regulatory network comprising exosomal ncRNAs and macrophage RNAs was constructed through EXO-LM transcriptome sequencing. Utilizing bioinformatics and dual-luciferase reporter assays, we identified two potential binding sites between lncRNA Rpl13a-213 and miR-132-3p. Cell transfection experiments demonstrated that Rpl13a-213 overexpression augmented pro-inflammatory cytokine expression in macrophages, in contrast to the suppression by miR-132-3p overexpression. The decrease in Rpl13a-213 upon EXO-LM stimulation enhances miR-132-3p expression, dampening the inflammatory response in macrophages and aiding L. monocytogenes intracellular survival. This study unveils the immunomodulatory function of exosomal ncRNAs originating from macrophages, which provides fresh perspectives into the mechanisms underlying macrophage inflammatory response regulation by L. monocytogenes-infected cell-derived exosomes.

Keywords:  Listeria monocytogenes; exosome; inflammatory response; intracellular survival; macrophage

DOI:  https://doi.org/10.3390/microorganisms13020410
PLoS One. 2025 ;20(2): e0319382

Amoxicillin-induced bacterial gut dysbiosis decreases IL-1β and IL-6 expression but exacerbate lung inflammatory response against Mycobacterium bovis-Bacille Calmette-Guérin (BCG).

Tatimara M Miyauchi-Tavares, Evandro Neves Silva, Joyce Alves Dos Santos, Priscila V Sousa, Marcos F Teodoro Braga, Caroline M Carminatti, Victoria B Lanza, Bruna C Fagundes, Rômulo Dias Novaes, Leonardo Augusto de Almeida, Patrícia Paiva Corsetti.

Tuberculosis is one of the leading causes of global mortality, and the standard, prolonged, and intensive treatment can affect intestinal homeostasis. This study investigated amoxicillin-induced bacterial gut dysbiosis and its impact on the immune response of C57BL/6 mice to pulmonary infection by Mycobacterium bovis-BCG. It was observed that amoxicillin treatment resulted in bacterial gut dysbiosis, characterized by an increase in the phylum Proteobacteria and a reduction in Bacteroidetes and Firmicutes. This alteration was associated with a decrease in the animals' body weight and a reduction in the expression of pro-inflammatory cytokines such as IL-1β and IL-6, suggesting a compromised immune response. Additionally, microstructural analysis revealed significant alterations in the caecum and pulmonary structure of the mice, indicating tissue damage associated with intestinal dysbiosis. The results indicate that amoxicillin-induced bacterial gut dysbiosis may negatively affect pulmonary immunity and exacerbate M. bovis-BCG infection, highlighting the need to consider the impacts of intestinal microbiota on the development and control of tuberculosis. This study contributes to the understanding of the interaction between intestinal microbiota, antibiotic treatment, and immunity in pulmonary infections.

DOI: https://doi.org/10.1371/journal.pone.0319382
Cell Stem Cell. 2025 Feb 24. pii: S1934-5909(25)00042-6. [Epub ahead of print]

Interferon-responsive intestinal BEST4/CA7+ cells are targets of bacterial diarrheal toxins.

Daisong Wang, Willem Kasper Spoelstra, Lin Lin, Ninouk Akkerman, Daniel Krueger, Talya Dayton, Jeroen S van Zon, Sander J Tans, Johan H van Es, Hans Clevers.

  BEST4/CA7+ cells of the human intestine were recently identified by single-cell RNA sequencing. While their gene expression profile predicts a role in electrolyte balance, BEST4/CA7+ cell function has not been explored experimentally owing to the absence of BEST4/CA7+ cells in mice and the paucity of human in vitro models. Here, we establish a protocol that allows the emergence of BEST4/CA7+ cells in human intestinal organoids. Differentiation of BEST4/CA7+ cells requires activation of Notch signaling and the transcription factor SPIB. BEST4/CA7+ cell numbers strongly increase in response to the cytokine interferon-γ, supporting a role in immunity. Indeed, we demonstrate that BEST4/CA7+ cells generate robust CFTR-mediated fluid efflux when stimulated with bacterial diarrhea-causing toxins and find the norepinephrine-ADRA2A axis as a potential mechanism in blocking BEST4/CA7+ cell-mediated fluid secretion. Our observations identify a central role of BEST4/CA7+ cells in fluid homeostasis in response to bacterial infections.

Keywords:  BEST4/CA7(+) cells; bacterial infection; fluid homeostasis; human intestinal organoids; interferon-γ

DOI:  https://doi.org/10.1016/j.stem.2025.02.003
Microb Pathog. 2025 Feb 23. pii: S0882-4010(25)00131-7. [Epub ahead of print] 107406

Microbial Community and Immune Modulation Enable Effective Treatment of Methicillin-resistant Staphylococcus aureus Skin Infections with Linalool.

Xingyun Xiong, Xin Wen, Yangjing Zhang, Xiaofang Li, Yuping Zhang, Nana Long.

  Methicillin-resistant Staphylococcus aureus (MRSA), as one of the main pathogens causing skin and soft tissue infections, poses challenges in treatment due to its high resistance to antibiotics. As one of the efficacious essential oil components in numerous traditional Chinese medicines, linalool was believed to possess antimicrobial activity against pathogenic microorganisms. Here, we investigated the therapeutic effects of linalool on MRSA-infected mice by examining their post-treatment outcomes. This was done through observations of physiological conditions, pathological sections, inflammatory factors, and changes in the skin microenvironment. We have confirmed the effectiveness of linalool in treating MRSA infections. Mice treated with linalool exhibited more pronounced signs of recovery, such as reduced skin necrosis, increased fibroplasia, greater neovascularization, and resolution of inflammatory infiltration. In addition, there was an improvement in the inflammatory environment, with a decrease in inflammatory factors. The microbial composition on the skin surface also confirmed this improvement. After linalool treatment, mice exhibited better species diversity on the skin, making it easier to maintain the skin's homeostasis. The excellent performance of linalool in combating MRSA infections provides a new direction for the search for new antibiotics against multidrug-resistant bacteria, highlighting the potential of linalool as a promising anti-MRSA drug.

Keywords:  Linalool; Methicillin-resistant Staphylococcus aureus; Microbial community; Skin and soft tissue infection

DOI:  https://doi.org/10.1016/j.micpath.2025.107406