bims-bac4me 2025-02-09 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2025–02–09
thirty-two papers selected by
Chun-Chi Chang, Universitäts Spital Zürich

Innate Immune Memory is Stimulus Specific.
Tolerance during infection.
Trained immunity in chronic inflammatory diseases and cancer.
The Microbiome and Pulmonary Immune Function.
Staphylococcus aureus induces mitophagy via the HDAC11/IL10 pathway to sustain intracellular survival.
Metabolic deficiencies underlie reduced plasmacytoid dendritic cell IFN-I production following viral infection.
Rev-erb-α antagonism in alveolar macrophages protects against pneumococcal infection in elderly mice.
Occurrence of Staphylococcus aureus, Staphylococcus epidermidis, and Staphylococcus pseudintermedius colonization among veterinarians in the province of Malaga, Spain.
Increased NFAT and NFκB signalling contribute to the hyperinflammatory phenotype in response to Aspergillus fumigatus in a mouse model of cystic fibrosis.
Lipid metabolism in myeloid cell function and chronic inflammatory diseases.
Role of the Microbiome in Neonatal Infection: Pathogenesis and Implications for Management.
Nasal Mucociliary Epithelial Cell Culture Models for Studying Viral Infections.
Development and Assessment of Intracellular Infection Models for Staphylococcus aureus.
The impaired response of nasal epithelial cells to microplastic stimulation in asthma and COPD.
Regulation of IL-10 production in dendritic cells is controlled by the co-activation of TLR2 and Mincle by Lactiplantibacillus plantarum OLL2712.
Bacterial metabolism in the host and its association with virulence.
Lactobacillus rhamnosus GG induces STING-dependent IL-10 in intestinal monocytes and alleviates inflammatory colitis in mice.
Metabolic analysis of the Mode-of-Action (MoA) and Mode-of-Resistance (MoR) of fusidic acid against S.aureus.
Author Correction: β-Glucan reprograms neutrophils to promote disease tolerance against influenza A virus.
Engineered nose bacteria sneak drugs into the brain.
Impact of cryopreservation on immune cell metabolism as measured by SCENITH.
RUNX2 promotes fibrosis via an alveolar-to-pathological fibroblast transition.
[Preliminary study on the role of siglec-9 expression in peripheral blood of acute respiratory distress syndrome patients].
Path of differentiation defines human macrophage identity.
Is systemic dissemination of BCG following neonatal vaccination required for protection against M. tuberculosis?
MHC class II of different non-professional antigen-presenting cells mediate multiple effects of crosstalk with CD4+T cells in lung diseases.
NOD1: a metabolic modulator.
Effect of Saccharomyces cerevisiae β-glucan on the T helper cytokine profile.
Plasma-derived extracellular vesicles prime alveolar macrophages for autophagy and ferroptosis in sepsis-induced acute lung injury.
Mitochondrial heterogeneity: subpopulations with distinct metabolic activities.
A mathematical model of microglia glucose metabolism and lactylation with positive feedback.
Thiamine deficiency aggravates experimental colitis in mice by promoting glycolytic reprogramming in macrophages.

bioRxiv. 2025 Jan 24. pii: 2025.01.22.634275. [Epub ahead of print]

Innate Immune Memory is Stimulus Specific.

Aoife O'Farrell, Zijian Niu, Jingxin Li, Laura C Van Eyndhoven, Kavitha Sarma, Arjun Raj.

Innate immune memory (also termed trained immunity) is defined in part by its ability to cross-protect against heterologous pathogens, and can be generated by many different stimuli, suggesting a "universal" trained state. However, different stimuli could form distinct memories, leading to stimulus-specific trained responses. Here, we use primary human monocyte-derived macrophages to demonstrate phenotypic and epigenetic stimulus specificity of innate immune memory six days after initial exposure. Quantification of cytokine production with single-molecule RNA imaging demonstrates stimulus-specific patterns of response to restimulation at the single cell level. Differential licensing of inflammatory transcription factors is associated with encoding of specificities in chromatin. Trained cells show stronger responses to secondary stimuli that are more similar to the initial stimulus they experienced, suggesting a functional role for these stimulus-specific memories. Rather than activating a universal training state, our findings demonstrate that different stimuli impart specific memories that generate distinct training phenotypes in macrophages.

DOI: https://doi.org/10.1101/2025.01.22.634275
Nat Immunol. 2025 Feb;26(2): 149

Tolerance during infection.

Stephanie Houston.

DOI: https://doi.org/10.1038/s41590-025-02083-0
Nat Rev Immunol. 2025 Jan 31.

Trained immunity in chronic inflammatory diseases and cancer.

George Hajishengallis, Mihai G Netea, Triantafyllos Chavakis.

A decade after the term 'trained immunity' (TRIM) was coined to reflect the long-lasting hyper-responsiveness of innate immune cells with an epigenetically imprinted 'memory' of earlier stimuli, our understanding has broadened to include the potential implications of TRIM in health and disease. Here, after summarizing the well-documented beneficial effects of TRIM against infections, we discuss emerging evidence that TRIM is also a major underlying mechanism in chronic inflammation-related disorders such as periodontitis, rheumatoid arthritis and cardiovascular disease. Furthermore, mounting evidence indicates that the induction of TRIM by certain agonists confers protective antitumour responses. Although the mechanisms underlying TRIM require further study, the current knowledge enables the experimental development of innovative therapeutic approaches to stimulate or inhibit TRIM in a context-appropriate manner, such as the stimulation of TRIM in cancer or its inhibition in inflammatory disorders.

DOI: https://doi.org/10.1038/s41577-025-01132-x
Clin Chest Med. 2025 Mar;pii: S0272-5231(24)00095-9. [Epub ahead of print]46(1): 77-91

The Microbiome and Pulmonary Immune Function.

Jennifer M Baker, Robert P Dickson.

  In the last decade, the lung microbiome field has matured into a promising area of translational and clinical research due to emerging evidence indicating a role for respiratory microbiota in lung immunity and pathogenesis. Here, we review recent insights pertaining to the lung microbiome's relationship with pulmonary immune function. We discuss areas of future investigation that will be essential to the development of immunomodulatory therapies targeting the respiratory microbiome.

Keywords:  Immunocompromised host; Lung microbiome; Microbial ecology; Pulmonary immunity

DOI:  https://doi.org/10.1016/j.ccm.2024.10.006
J Transl Med. 2025 Feb 04. 23(1): 156

Staphylococcus aureus induces mitophagy via the HDAC11/IL10 pathway to sustain intracellular survival.

Yaji Yang, Haotian Zhou, Feilong Li, Yanhao Zhang, Jianye Yang, Yidong Shen, Ning Hu, Quanming Zou, Leilei Qin, Hao Zeng, Wei Huang.

   BACKGROUND: The immune evasion and prolonged survival of Staphylococcus aureus (S. aureus) within macrophages are key factors contributing to the difficulty in curing osteomyelitis. Although macrophages play a vital role as innate immune cells, the mechanisms by which S. aureus survives within them and suppresses host immune functions remain incompletely understood.
METHODS: This study employed confocal microscopy, flow cytometry, ELISA, and siRNA technology to assess the survival capacity of S. aureus within macrophages and the impact of inflammatory cytokines on its persistence. Proteomics was used to investigate the potential mechanisms and differential proteins involved in S. aureus intracellular survival. Additionally, confocal microscopy, flow cytometry, Mdivi-1 intervention, and Western blot were utilized to validate the role of mitophagy in supporting S. aureus survival. The study further explored how the HDAC11/IL10 axis enhances mitophagy to promote intracellular S. aureus survival by using HDAC11 overexpression, siRNA, and rapamycin intervention combined with confocal microscopy and flow cytometry.
RESULTS: The findings demonstrated that IL10 promotes mitophagy to clear mitochondrial reactive oxygen species (mtROS), thereby enhancing the intracellular survival of S. aureus within macrophages. Additionally, we discovered that the transcriptional repressor of IL10, HDAC11, was significantly downregulated during S. aureus infection. Overexpression of HDAC11 and the use of the autophagy activator rapamycin further validated that the HDAC11/IL10 axis regulates mitophagy via the mTOR pathway, which is essential for supporting S. aureus intracellular survival.
CONCLUSION: This study reveals that S. aureus enhances IL10 production by inhibiting HDAC11, thereby promoting mitophagy and mtROS clearance, which supports its survival within macrophages. These findings offer new insights into the intracellular survival mechanisms of S. aureus and provide potential therapeutic approaches for the clinical management of osteomyelitis.

Keywords:  Histone deacetylase 11; Interleukin 10; Intracellular survival; Macrophage; Mitochondrial reactive oxygen species; Mitophagy; Staphylococcus aureus

DOI:  https://doi.org/10.1186/s12967-025-06161-7
Nat Commun. 2025 Feb 07. 16(1): 1460

Metabolic deficiencies underlie reduced plasmacytoid dendritic cell IFN-I production following viral infection.

Trever T Greene, Yeara Jo, Carolina Chiale, Monica Macal, Ziyan Fang, Fawziyah S Khatri, Alicia L Codrington, Katelynn R Kazane, Elizabeth Akbulut, Shobha Swaminathan, Yu Fujita, Patricia Fitzgerald-Bocarsly, Thekla Cordes, Christian Metallo, David A Scott, Elina I Zúñiga.

Type I Interferons (IFN-I) are central to host protection against viral infections, with plasmacytoid dendritic cells (pDC) being the most significant source, yet pDCs lose their IFN-I production capacity following an initial burst of IFN-I, resulting in susceptibility to secondary infections. The underlying mechanisms of these dynamics are not well understood. Here we find that viral infection reduces the capacity of pDCs to engage both oxidative and glycolytic metabolism. Mechanistically, we identify lactate dehydrogenase B (LDHB) as a positive regulator of pDC IFN-I production in mice and humans; meanwhile, LDHB deficiency is associated with suppressed IFN-I production, pDC metabolic capacity, and viral control following infection. In addition, preservation of LDHB expression is sufficient to partially retain the function of otherwise exhausted pDCs, both in vitro and in vivo. Furthermore, restoring LDHB in vivo in pDCs from infected mice increases IFNAR-dependent, infection-associated pathology. Our work thus identifies a mechanism for balancing immunity and pathology during viral infections, while also providing insight into the highly preserved infection-driven pDC inhibition.

DOI: https://doi.org/10.1038/s41467-025-56603-5
Cell Rep. 2025 Feb 04. pii: S2211-1247(25)00044-0. [Epub ahead of print]44(2): 115273

Rev-erb-α antagonism in alveolar macrophages protects against pneumococcal infection in elderly mice.

Fabiola Silva Angulo, Claudine Vanessa Joseph, Lou Delval, Lucie Deruyter, Séverine Heumel, Marie Bicharel, Patricia Brito Rodrigues, Valentin Sencio, Tom Bourguignon, Marina Gomes Machado, Marie Fourcot, Stéphane Delhaye, Sophie Salomé-Desnoulez, Philippe Valet, Serge Adnot, Isabelle Wolowczuk, Jean-Claude Sirard, Muriel Pichavant, Bart Staels, Joel T Haas, Ruxandra Gref, Jimmy Vandel, Arnaud Machelart, Hélène Duez, Benoit Pourcet, François Trottein.

  Circadian rhythms control the diurnal nature of many physiological, metabolic, and immune processes. We hypothesized that age-related impairments in circadian rhythms are associated with high susceptibility to bacterial respiratory tract infections. Our data show that the time-of-day difference in the control of Streptococcus pneumoniae infection is altered in elderly mice. A lung circadian transcriptome analysis revealed that aging alters the daily oscillations in the expression of a specific set of genes and that some pathways that are rhythmic in young-adult mice are non-rhythmic or time shifted in elderly mice. In particular, the circadian expression of the clock component Rev-erb-α and apelin/apelin receptor was altered in elderly mice. In young-adult mice, we discovered an interaction between Rev-erb-α and the apelinergic axis that controls host defenses against S. pneumoniae via alveolar macrophages. Pharmacological repression of Rev-erb-α in elderly mice resulted in greater resistance to pneumococcal infection. These data suggest the causative role of age-associated impairments in circadian rhythms on respiratory infections and have clinical relevance.

Keywords:  CP: Immunology; CP: Microbiology; Rev-erb-α; Streptococcus pneumoniae; aging; alveolar macrophages; apelin; apelin receptor; circadian rhythm; respiratory bacterial infection

DOI:  https://doi.org/10.1016/j.celrep.2025.115273
Vet World. 2024 Dec;17(12): 2719-2724

Occurrence of Staphylococcus aureus, Staphylococcus epidermidis, and Staphylococcus pseudintermedius colonization among veterinarians in the province of Malaga, Spain.

Fernando Fariñas-Guerrero, Antonio J Villatoro, Eduardo Martinez-Manzanares, Rosa López-Gigosos.

   Background and Aim: Staphylococcus pseudintermedius and Staphylococcus aureus are common colonizing pathogens in companion animals. These opportunistic pathogens can cause infections of varying frequency and severity in humans and pets. Studies on Staphylococcus colonization in veterinarians are scarce. This study aimed to investigate the colonization of the nostrils and hands by S. aureus, Staphylococcus epidermidis, and S. pseudintermedius among healthy clinical practice veterinarians in the province of Malaga (Spain), with a particular focus on their potential antibiotic resistance.
Materials and Methods: A request for voluntary participation was extended to professionals from the Official College of Veterinarians of Malaga. Nasal and hand swabs were collected by two trained technicians in January 2024, and all samples were delivered to the laboratory within 24 h. Gram staining, catalase, oxidase, and coagulase tests were performed. The susceptibility of the isolated bacteria to 11 antibiotics was evaluated.
Results: A total of 50 clinical practice veterinarians were enrolled in the study, comprising 36 women and 14 men from 31 veterinary clinics across Málaga province. A total of 32% of the nasal samples yielded S. aureus, whereas 64% were found to contain S. epidermidis. In total, 30% of the hand samples yielded S. aureus and 30% yielded S. epidermidis. The participants did not exhibit any strains of S. pseudintermedius in their nasal samples or hands. Two strains (11.1%) of methicillin-resistant S. aureus were isolated from 18 strains isolated from nostrils. Furthermore, a high prevalence of S. aureus strains resistant to ampicillin (94.4%) and amoxicillin (72.2%) was observed.
Conclusions: The colonization profiles of veterinary professionals were similar to those observed in the general population. Further research is required among veterinary professionals, companion animals, and their owners to better understand the colonization processes and the pet-human interface within a "One Health" approach.

Keywords:  Staphylococcus colonization; antibiotic resistance; drug-resistant Staphylococcus aureus; one health; seroprevalence; veterinarians

DOI:  https://doi.org/10.14202/vetworld.2024.2719-2724
PLoS Pathog. 2025 Feb 04. 21(2): e1012784

Increased NFAT and NFκB signalling contribute to the hyperinflammatory phenotype in response to Aspergillus fumigatus in a mouse model of cystic fibrosis.

Amelia Bercusson, Thomas J Williams, Nicholas J Simmonds, Eric Wfw Alton, Uta Griesenbach, Anand Shah, Adilia Warris, Darius Armstrong-James.

Aspergillus fumigatus (Af) is a major mould pathogen found ubiquitously in the air. It commonly infects the airways of people with cystic fibrosis (CF) leading to Aspergillus bronchitis or allergic bronchopulmonary aspergillosis. Resident alveolar macrophages and recruited neutrophils are important first lines of defence for clearance of Af in the lung. However, their contribution to the inflammatory phenotype in CF during Af infection is not well understood. Here, utilising CFTR deficient mice we describe a hyperinflammatory phenotype in both acute and allergic murine models of pulmonary aspergillosis. We show that during aspergillosis, CFTR deficiency leads to increased alveolar macrophage death and persistent inflammation of the airways in CF, accompanied by impaired fungal control. Utilising CFTR deficient murine cells and primary human CF cells we show that at a cellular level there is increased activation of NFκB and NFAT in response to Af which, as in in vivo models, is associated with increased cell death and reduced fungal control. Taken together, these studies indicate that CFTR deficiency promotes increased activation of inflammatory pathways, the induction of macrophage cell death and reduced fungal control contributing to the hyper-inflammatory of pulmonary aspergillosis phenotypes in CF.

DOI: https://doi.org/10.1371/journal.ppat.1012784
Front Immunol. 2024 ;15 1495853

Lipid metabolism in myeloid cell function and chronic inflammatory diseases.

Ayaka Ito, Takayoshi Suganami.

  Immune cells adapt their metabolism in response to their differentiation and activation status to meet the energy demands for an appropriate immune response. Recent studies have elucidated that during immune cell metabolic reprogramming, lipid metabolism, including lipid uptake, de novo lipid synthesis and fatty acid oxidation, undergoes significant alteration, resulting in dynamic changes in the quantity and quality of intracellular lipids. Given that lipids serve as an energy source and structural components of cellular membranes, they have important implications for physiological function. Myeloid cells, which are essential in bridging innate and adaptive immunity, are sensitive to these changes. Dysregulation of lipid metabolism in myeloid cells can result in immune dysfunction, chronic inflammation and impaired resolution of inflammation. Understanding the mechanism by which lipids regulate immune cell function might provide novel therapeutic insights into chronic inflammatory diseases, including metabolic diseases, autoimmune diseases and cancer. (143 words).

Keywords:  autoimmunity; cancer; immunometabolism; lipid metabolism; metabolic disease

DOI:  https://doi.org/10.3389/fimmu.2024.1495853
Clin Perinatol. 2025 Mar;pii: S0095-5108(24)00110-6. [Epub ahead of print]52(1): 147-166

Role of the Microbiome in Neonatal Infection: Pathogenesis and Implications for Management.

Carolyn McGann, Riley Phyu, Kyle Bittinger, Sagori Mukhopadhyay.

  The human microbiome refers to the collective genome of microorganisms, including bacteria, fungi, and viruses residing on human body surfaces that are in contact with the environment. Together these communities protect against invasive infections. Conversely, when disrupted, the microbiome can be the source of pathogens causing invasive infection. Interventions to manipulate it via probiotics, antibiotics, and fecal transplantation are available. The risk benefit of these interventions remains unclear. In this review, the authors discuss evidence linking the gut microbiome to neonatal sepsis and also discuss the challenges for translating this knowledge into better clinical care.

Keywords:  Bacteremia; Bacterial meningitis; Colonization; Microbiome; Neonate; Preterm; Sepsis

DOI:  https://doi.org/10.1016/j.clp.2024.10.010
Methods Mol Biol. 2025 ;2890 237-252

Nasal Mucociliary Epithelial Cell Culture Models for Studying Viral Infections.

Giuseppe Balistreri.

  Respiratory nasal or lung epithelial cells serve as a valuable in vitro model for studying respiratory viral infections due to their physiological relevance and ability to recapitulate key aspects of the nasal or lung mucosa. In this chapter, we discuss the use of primary nasal epithelial cell cultures in studying viral infections, including their advantages, production methods, quality control, and identifiable disadvantages. Different methods for quantifying infection are presented with a special emphasis on how to adapt automated imaging methods and image analysis tools to the pseudostratified nasal epithelial cell models where cells are grown at the air-liquid interphase.

Keywords:  Air–liquid interphase models; Automated imaging; Nasal epithelial cells; Organotypic cultures; Respiratory viruses

DOI:  https://doi.org/10.1007/978-1-0716-4326-6_13
J Vis Exp. 2025 Jan 17.

Development and Assessment of Intracellular Infection Models for Staphylococcus aureus.

Chengwen Zhang, Chuanfei Xu, Fumei Luo, Yu Zuo, Ping Luo, Ping Cheng, Weijun Zhang, Si Sun, Hao Zeng, Quanming Zou.

S. aureus can invade and persist within host cells, including immune cells, which allows it to evade immune detection and clearance. This intracellular persistence contributes to chronic and recurrent infections, complicating treatment and prolonging the disease. Consequently, there is a critical need for an intracellular infection model to better understand, prevent, and treat infections caused by S. aureus. This study indicated that antibiotics effectively eliminated extracellular bacteria but could not eradicate those that had entered the cells. Thus, a stable intracellular infection in vitro was established by RAW264.7 infected with S. aureus and co-culturing them with antibiotics. Subsequently, an intracellular infection model in mice was established by injecting peritoneal macrophages containing the intracellular infection. Vancomycin effectively cleared bacterial loads in mice challenged with planktonic S. aureus; however, it was ineffective against mice infected with equal or lower levels of intracellular bacteria within the peritoneal macrophages. This indicates that the intracellular infection model of S. aureus was successfully established, offering potential insights for the prevention and treatment of intracellular infections.

DOI: https://doi.org/10.3791/67834
Sci Rep. 2025 Feb 04. 15(1): 4242

The impaired response of nasal epithelial cells to microplastic stimulation in asthma and COPD.

Magdalena Paplińska-Goryca, Paulina Misiukiewicz-Stępień, Monika Wróbel, Katarzyna Mycroft-Rzeszotarska, Dorota Adamska, Julia Rachowka, Milena Królikowska, Krzysztof Goryca, Rafał Krenke.

  Microplastic particles from the air are inhaled and accumulate in the lungs, potentially causing immunological reactions and airway tissue injury. This study aimed to evaluate the biological effects of polyamide fibres on nasal epithelium co-cultivated with macrophages in control, asthma, and COPD groups. Nasal epithelial cells alone or in co-culture with monocyte-derived macrophages were exposed to polyamide fibres for 48 h. We identified 8 differentially expressed genes (DEGs) in controls, 309 DEGs in asthma (including ANKRD36C, BCL2L15, FCGBP, and IL-19), and 22 DEGs in COPD (e.g., BCL2L15, IL-19, CAPN14, PGBD5, PTPRH), particularly in epithelial/moMφ co-cultures. Microplastic exposure induced inflammatory cytokine secretion only for IL-8 production in controls (epithelial/ moMφs co-culture) and asthmatic (monoculture) epithelial cells in contrast to PM2.5, which was a strong inflammatory inducer. Gene Ontology analysis revealed that microplastic exposure affected sterol and cholesterol biosynthesis, secondary alcohol metabolism, and acetyl-CoA metabolism in asthma, and cell motility, chemokine signaling, leukocyte migration, and chemotaxis in COPD. Microplastic stimulation altered the response of airway epithelial cells in obstructive lung diseases differently than in controls, linking to Th2 inflammation, stress response modulation, and carcinogenesis. Asthmatic and COPD epithelial cells are more susceptible to damage from microplastic fibre exposure.

Keywords:  Asthma; COPD; Epithelium; Microplastic; Pollution

DOI:  https://doi.org/10.1038/s41598-025-87242-x
Microbiol Spectr. 2025 Feb 04. e0119624

Regulation of IL-10 production in dendritic cells is controlled by the co-activation of TLR2 and Mincle by Lactiplantibacillus plantarum OLL2712.

Ryuhei Sakabe, Kazumasa Onishi, Junko Mochizuki, Takayuki Toshimitsu, Tomoyuki Shimazu, Shigenobu Kishino, Jun Ogawa, Sho Yamasaki, Toshihiro Sashihara.

  We showed that Lactiplantibacillus plantarum OLL2712 (OLL2712) strongly induces interleukin (IL)-10 production in immune cells. Although beneficial effects of this strain have been observed in both mice and humans, the mechanisms underlying IL-10 induction remain unclear. In this study, we found that OLL2712 co-activates two pattern recognition receptors, leading to IL-10 production in the mouse-derived thermosensitive dendritic cell line, tsDC. We first revealed the involvement of the Toll-like receptor (TLR)2-Myeloid differentiation primary response gene (MYD) 88 pathway in OLL2712-induced IL-10 production in tsDCs. However, stimulation with the TLR2 agonist alone was insufficient to induce IL-10 production. Consequently, we explored additional signaling pathways and found that the phosphorylation of spleen tyrosine kinase (Syk) was important in response to OLL2712, which was not triggered by a TLR2 agonist alone. Notably, the activation of Syk was found to depend on macrophage-inducible C-type lectin receptor (Mincle), one of the C-type lectin receptors. However, the surface-expressed Mincle is not responsible for the IL-10 production by OLL2712. Instead, it depends on the incorporation of OLL2712 into tsDCs, suggesting that Mincle recognizes incorporated OLL2712 intracellularly. In summary, OLL2712 is initially recognized by TLR2, which subsequently induces the expression of Mincle to recognize incorporated OLL2712, ultimately inducing IL-10 production.IMPORTANCEThe objective of this study is to elucidate the mechanism by which Lactiplantibacillus plantarum OLL2712 (OLL2712), previously identified by our research group as a potent stimulator of interleukin-10 production in immune cells, exerts its immunomodulatory effects. Our findings indicate that OLL2712 acts in synergy with two pattern-recognition receptors: Toll-like receptor 2 and Macrophage inducible C-type lectin receptor (Mincle). Additionally, we observed that OLL2712 needs to be internalized intracellularly to be recognized by Mincle. These findings represent the first insights into the detailed mechanism underlying the anti-inflammatory effects of OLL2712.

Keywords:  Toll-like receptor 2; anti-inflammation; interleukin-10; lactic acid bacteria; macrophage inducible C-type lectin receptor; phagocytosis

DOI:  https://doi.org/10.1128/spectrum.01196-24
Virulence. 2025 Dec;16(1): 2459336

Bacterial metabolism in the host and its association with virulence.

Amrita Bhagwat, Tiyasa Haldar, Poonam Kanojiya, Sunil D Saroj.

  The host restricted pathogens are competently dependent on their respective host for nutritional requirements. The bacterial metabolic pathways are surprisingly varied and remarkably flexible that in turn help them to successfully overcome competition and colonise their host. The metabolic adaptation plays pivotal role in bacterial pathogenesis. The understanding of host-pathogen metabolic crosstalk needs to be prioritized to decipher host-pathogen interactions. The review focuses on various aspects of host pathogen interactions that majorly involves adaptation of bacterial metabolism to counteract immune mechanisms by rectifying metabolic cues that provides pathogen the idea of different anatomical sites and the local physiology of the host. The key set of metabolites that are recognized as centre of competition between host and its pathogens are also briefly discussed. The factors that control the timely expression of virulence of bacterial pathogens is poorly understood. The perspective presented herein will facilitate us with a broader view of molecular mechanisms that modulates the expression of virulence factors in bacterial pathogens. The knowledge of crosslinked metabolic pathways of bacteria and their host will serve to develop novel potential therapeutics.

Keywords:  Intracellular pathogen; commensal; competition; immune-metabolites; metabolic-cross talk; metabolism

DOI:  https://doi.org/10.1080/21505594.2025.2459336
J Clin Invest. 2025 Feb 03. pii: e174910. [Epub ahead of print]135(3):

Lactobacillus rhamnosus GG induces STING-dependent IL-10 in intestinal monocytes and alleviates inflammatory colitis in mice.

Wei Si, Xin Zhao, Ruitong Li, Yaopeng Li, Cui Ma, Xiaohan Zhao, Jason Bugno, Yuchang Qin, Junmin Zhang, Hongwei Liu, Liangliang Wang.

  Preclinical and clinical observations indicate that the probiotic Lactobacillus rhamnosus GG (LGG) can modulate colonic inflammation. However, the underlying mechanisms have not been explored in depth. Here, we demonstrate that oral administration of live LGG alleviated inflammatory colitis by increasing IL-10 expression in intestinal Ly6C+ monocytes. Mechanistically, LGG induced IL-10 production via the stimulator of IFN genes (STING)/TBK1/NF-κB (RELA) signaling pathway in intestinal Ly6C+ monocytes, enhancing their immune-suppressive function. Elevated IL-10 subsequently activated IL-10 signaling in Ly6C+ monocytes, resulting in an IL-10-based autocrine regulatory loop and inhibition of proinflammatory cytokine production. Furthermore, LGG shifted the gut microbial community and its metabolic functions, leading to intestinal immune responses against colitis. Fecal microbiota transplantation from LGG-colonized mice alleviated immune checkpoint blockade-associated colitis. Our findings highlight the importance of STING signaling in IL-10-dependent antiinflammatory immunity and establish an empirical basis for developing oral administration of live LGG as an efficient and safe therapeutic strategy against inflammatory colitis.

Keywords:  Immunology; Inflammation; Inflammatory bowel disease; Innate immunity; Monocytes

DOI:  https://doi.org/10.1172/JCI174910
FEMS Microbiol Lett. 2025 Jan 31. pii: fnaf011. [Epub ahead of print]

Metabolic analysis of the Mode-of-Action (MoA) and Mode-of-Resistance (MoR) of fusidic acid against S.aureus.

Dan Luo, Juanjuan Ma, Weile Xie, Zhe Wang.

  Understanding bacterial responses to antibiotics is essential for identifying resistance mechanisms and developing novel therapies. This study evaluated the resistance of Staphylococcus aureus (S. aureus) to fusidic acid (FD) in 100 patients with skin and soft tissue infections (SSTIs), revealing susceptibility to FD despite resistance to other antibiotics. Through adaptive laboratory evolution, we developed a highly FD-resistant strain, E10, and identified three gene mutations (fusA, BPENGOFF-00211, and rplF) using whole-genome sequencing. The fusA mutation was the primary contributor to resistance. Furthermore, the evolved fusA mutant strain (H457Y) displayed impaired coagulation function and reduced growth rates. We also analyzed the metabolomic profiles of ancestral ATCC 25923 and evolved E10 strains, both treated and untreated with FD, revealing that the fusA gene can independently induce metabolic reprogramming. These changes primarily impacted pathways involved in central carbon metabolism, nucleotide metabolism, and amino acid synthesis. This study highlights the complexity of FD resistance in S. aureus and offers insights into the metabolic pathways associated with antibiotic resistance.

Keywords:   staphylococcus aureus ; antibacterial mechanism; fusa; fusidic acid; metabolomic

DOI:  https://doi.org/10.1093/femsle/fnaf011
Nat Immunol. 2025 Feb 07.

Author Correction: β-Glucan reprograms neutrophils to promote disease tolerance against influenza A virus.

Nargis Khan, Kim A Tran, Raphael Chevre, Veronica Locher, Mathis Richter, Sarah Sun, Mina Sadeghi, Erwan Pernet, Andrea Herrero-Cervera, Alexandre Grant, Ahmed Saif, Jeffrey Downey, Eva Kaufmann, Shabaana Abdul Khader, Philippe Joubert, Luis B Barreiro, Bryan G Yipp, Oliver Soehnlein, Maziar Divangahi.

DOI: https://doi.org/10.1038/s41590-025-02099-6
Nature. 2025 Feb 06.

Engineered nose bacteria sneak drugs into the brain.

Heidi Ledford.



Keywords:  Brain; Medical research; Microbiology; Microbiome

DOI:  https://doi.org/10.1038/d41586-025-00375-x
Oxf Open Immunol. 2025 ;6(1): iqae015

Impact of cryopreservation on immune cell metabolism as measured by SCENITH.

Curtis Luscombe, Eben Jones, Michaela Gregorova, Nicholas Jones, Laura Rivino.

  The dynamic functioning of immune cells is regulated by cellular metabolic processes, and there is growing interest in the study of immunometabolic correlates of dysfunctional immune responses. SCENITH is a novel flow cytometry-based technique that allows for ex vivo metabolic profiling of immune cells within heterogeneous samples. Cryopreservation of clinical samples is frequently undertaken to facilitate high throughput processing and longitudinal analyses of immune responses, but is thought to lead to cellular metabolic dysfunction. We aimed to investigate the impact of cryopreservation on immune cell metabolism, harnessing SCENITH's unique ability to describe the divergent bioenergetic characteristics of distinct immune cell subsets. We demonstrate that upon activation, T cells are unable to sufficiently/readily undergo metabolic reprogramming. Additionally, we find that cryopreservation introduces a time-dependent metabolic artefact that favours glycolysis and impairs oxidative phosphorylation, suggesting that cryopreservation results in mitochondrial dysfunction. Despite this artefact, SCENITH was still able to reveal the distinct bioenergetic profiles of contrasting immune cells populations following cryopreservation. Whilst SCENITH can provide valuable information about immune cell metabolism even in cryopreserved samples, our findings have important implications for the design of future studies. Investigators should carefully consider how to process and store clinical samples to ensure that cryopreservation does not confound analyses, particularly where longitudinal sampling is required.

Keywords:  Immunometabolism; SCENITH; T cell activation; aerobic glycolysis; cryopreservation; immune cell metabolism; oxidative phosphorylation; protein translation

DOI:  https://doi.org/10.1093/oxfimm/iqae015
Nature. 2025 Feb 05.

RUNX2 promotes fibrosis via an alveolar-to-pathological fibroblast transition.

Yinshan Fang, Sanny S W Chung, Le Xu, Chenyi Xue, Xue Liu, Dianhua Jiang, Rongbo Li, Yohei Korogi, Ke Yuan, Anjali Saqi, Hanina Hibshoosh, Yuefeng Huang, Chyuan-Sheng Lin, Tatsuya Tsukui, Dean Sheppard, Xin Sun, Jianwen Que.

A hallmark of pulmonary fibrosis is the aberrant activation of lung fibroblasts into pathological fibroblasts that produce excessive extracellular matrix1-3. Thus, the identification of key regulators that promote the generation of pathological fibroblasts can inform the development of effective countermeasures against disease progression. Here we use two mouse models of pulmonary fibrosis to show that LEPR+ fibroblasts that arise during alveologenesis include SCUBE2+ alveolar fibroblasts as a major constituent. These alveolar fibroblasts in turn contribute substantially to CTHRC1+POSTN+ pathological fibroblasts. Genetic ablation of POSTN+ pathological fibroblasts attenuates fibrosis. Comprehensive analyses of scRNA-seq and scATAC-seq data reveal that RUNX2 is a key regulator of the expression of fibrotic genes. Consistently, conditional deletion of Runx2 with LeprcreERT2 or Scube2creERT2 reduces the generation of pathological fibroblasts, extracellular matrix deposition and pulmonary fibrosis. Therefore, LEPR+ cells that include SCUBE2+ alveolar fibroblasts are a key source of pathological fibroblasts, and targeting Runx2 provides a potential treatment option for pulmonary fibrosis.

DOI: https://doi.org/10.1038/s41586-024-08542-2
Zhonghua Jie He He Hu Xi Za Zhi. 2025 Feb 12. 48(2): 123-129

[Preliminary study on the role of siglec-9 expression in peripheral blood of acute respiratory distress syndrome patients].

X G Liu, Z H Lu, Y C Cai, Z Yang, X W Sun, J Zhu, X Su.

Objective: Sialic acid-binding immunoglobulin-like lectin (siglec)-9 is a type Ⅰ transmembrane protein that plays an important role in intrinsic immunity. In this study, we examined the siglec-9 expression levels in mononuclear macrophages, neutrophils and plasma from peripheral blood of acute respiratory distress syndrome (ARDS) patients and investigated its clinical value. Methods: Peripheral blood was obtained from ARDS patients (n=54) admitted to the Department of Respiratory and Critical Care Medicine, Nanjing Jinling Hospital and the Second People's Hospital of Wuhu, Anhui Province, China, from July 2021 to October 2022. Healthy volunteers (n=50) from the physical examination center and hospitalized patients (n=47) with lung infection were included as control groups. The expression of cellular and plasma siglec-9 was detected by flow cytometry and ELISA separately. Results: Compared with lung infection group and healthy control group, the expression of monocytes and plasma siglec-9 in ARDS group increased significantly. But there was no significant difference in the expression of monocytes and plasma siglec-9 between lung infection group and healthy control group. The level of plasma siglec-9 was significantly higher in moderate-severe ARDS patients than that in mild patients (P<0.05). Multivariable logistic regression analysis showed that IL-6, LDH and plasma siglec-9 were independent risk factors of ARDS, while plasma siglec-9, IL-6 and APACHE Ⅱ were independent risk factors of moderate-severe ARDS. Conclusion: The expression of siglec-9 in the plasma of ARDS patients is positively correlated with the severity of ARDS, which has a certain value in the assessment of ARDS.

DOI: https://doi.org/10.3760/cma.j.cn112147-20240620-00350
bioRxiv. 2025 Jan 24. pii: 2025.01.24.634694. [Epub ahead of print]

Path of differentiation defines human macrophage identity.

Katie Frenis, Brianna Badalamenti, Ohanez Mamigonian, Chen Weng, Dahai Wang, Sara Fierstein, Parker Côté, Hesper Khong, Hojun Li, Edroaldo Lummertz da Rocha, Vijay G Sankaran, R Grant Rowe.

Macrophages play central roles in immunity, wound healing, and homeostasis - a functional diversity that is underpinned by varying developmental origins. The impact of ontogeny on properties of human macrophages is inadequately understood. We demonstrate that definitive human fetal liver (HFL) hematopoietic stem cells (HSCs) possess two divergent paths of macrophage specification that lead to distinct identities. The monocyte-dependent pathway exists in both prenatal and postnatal hematopoiesis and generates macrophages with adult-like responses properties. We now uncover a fetal-specific pathway of expedited differentiation that generates tissue resident-like macrophages (TRMs) that retain HSC-like self-renewal programs governed by the aryl hydrocarbon receptor (AHR). We show that AHR antagonism promotes TRM expansion and mitigates inflammation in models of atopic dermatitis (AD). Overall, we directly connect path of differentiation with functional properties of macrophages and identify an approach to promote selective expansion of TRMs with direct relevance to inflammation and diseases of macrophage dysfunction.

DOI: https://doi.org/10.1101/2025.01.24.634694
J Infect Dis. 2025 Feb 06. pii: jiaf051. [Epub ahead of print]

Is systemic dissemination of BCG following neonatal vaccination required for protection against M. tuberculosis?

Tobias R Kollmann, Nelly Amenyogbe, Frederik Schaltz-Buchholzer, Ole Bæk, James Campbell, David J Lynn, Anita J Campbell, Peter Aaby, Christine Stabell Benn, Mihai G Netea, Maziar Divangahi.

  Tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb) and is the leading cause of death. Bacillus Calmette-Guérin (BCG) is the only licensed TB vaccine. Preclinical studies have shown that in adults intravenous administration of BCG improves protection against TB. We hypothesize that intradermal administration of BCG to the human newborn leads to low grade BCG bacteraemia and that this systemic dissemination improves protection against Mtb infection. This hypothesis is based on supporting observations including animal and human studies. It is a testable hypothesis and offers to deliver immediately actionable insight to advance the global efforts against TB.

Keywords:  Adult; BCG; Bacteraemia; Neonate; TB; Vaccine

DOI:  https://doi.org/10.1093/infdis/jiaf051
Front Med (Lausanne). 2025 ;12 1388814

MHC class II of different non-professional antigen-presenting cells mediate multiple effects of crosstalk with CD4+T cells in lung diseases.

Ming-Yan Wang, Yu Qiao, Shan-Jie Wei, Zhao-Liang Su, Hong-Yan Lu.

  The respiratory system is continuously exposed to the outside world, making it vulnerable to airborne particles and harmful pathogens like bacteria and viruses that can enter through breathing. Antigen presenting cells (APCs) have a vital function in the innate immune response as they present antigens to T cells and initiate the response of adaptive immune cells. Professional APCs engulf foreign microorganisms and display their peptides to T lymphocytes using MHC molecules. MHC II on their cell surface and potentially present antigen to CD4+T cells. Furthermore, various other types of cells have similar function that can also serve as APCs by expressing MHC II, thus impacting the progression of lung diseases, such as alveolar epithelial cells (AECs), endothelial cells (ECs), fibroblasts, innate lymphoid cells (ILCs), eosinophils, interstitial cells, mast cells, etc. express MHC II and present antigen. The non-professional APCs type and the extra signals it provides have a direct impact on CD4+T cell programming and downstream effector mechanisms. Here, we summarize the existing research on the expression of MHC II on non-professional APCs in different lung diseases and its influence on CD4+T differentiation types and disease outcomes, in order to further clarify the role of MHC II of different non-professional APCs in lung diseases, such as asthma, chronic obstructive pulmonary disease (COPD), etc.

Keywords:  T cells; alveolar epithelial cells; antigen-presenting cells; lung disease; major histocompatibility complex

DOI:  https://doi.org/10.3389/fmed.2025.1388814
Front Endocrinol (Lausanne). 2024 ;15 1484829

NOD1: a metabolic modulator.

Ruobing Tang, Chunguang Xie, Xiyu Zhang.

  Nucleotide-binding oligomerization domain 1 (NOD1) is an intracellular pattern recognition receptor that detects injury signals and initiates inflammatory responses and host defense. Furthermore, NOD1 serves as a metabolic mediator by influencing the metabolism of various tissues, including adipose tissue, liver, cardiovascular tissue, pancreatic β cells, adrenal glands, and bones through diverse mechanisms. It has been discovered that activated NOD1 is associated with the pathological mechanisms of certain metabolic diseases. This review presents a comprehensive summary of the impact of NOD1 on tissue-specific metabolism.

Keywords:  NOD1; endocrine; immunity; inflammation; metabolism

DOI:  https://doi.org/10.3389/fendo.2024.1484829
Cytokine. 2025 Mar;pii: S1043-4666(25)00018-3. [Epub ahead of print]187 156871

Effect of Saccharomyces cerevisiae β-glucan on the T helper cytokine profile.

Patricia Vuscan, Rutger J Röring, Brenda Kischkel, Maria Tintoré, Jordi Cuñé, Carlos de Lecea, Leo A B Joosten, Mihai G Netea.

  ABBi16 is a high-complexity blend of β-1,3/1,6-glucans from Saccharomyces cerevisiae with strong immunomodulatory activities, that have been recently shown to support anti-tumoral immune responses through the induction of trained immunity. Whether ABBi16 also modulates the balance between the various T helper (Th) lymphocyte responses is not known. Here, we show that ABBi16 induces Th1 responses, as indicated by stimulation of IFNγ and TNF production by human peripheral blood mononuclear cells (PBMCs). Moreover, the elevated secretion of IL-10 and IL-22 suggests a potential regulatory response of the Th1/Th2/Th17 balance. Co-stimulating PBMCs with ABBi16 alongside Bacille Calmette-Guerin (BCG), IL-1beta + IL-23, and IL-12 + IL-18 cytokine combinations further enhanced Th1 polarization and IL-22 induction, hinting at an additive effect of β-glucan on both Th1 and regulatory Th17 immune responses. ABBi16 did not induce IL-17 production, the prototype pro-inflammatory product of Th17 responses, suggesting that it can be safely used as an oral supplement in patients with autoimmune conditions. These results highlight the potential of ABBi16 to regulate the Th1/Th2/Th17 balance toward antimicrobial and regulatory effects.

Keywords:  Autoimmune diseases; Interleukin-17; Interleukin-5; Type 17 T helper cells (Th17); Type 1 T helper cells (Th1); Type 2 T helper cells (Th2); β-glucan

DOI:  https://doi.org/10.1016/j.cyto.2025.156871
Mol Med. 2025 Feb 04. 31(1): 40

Plasma-derived extracellular vesicles prime alveolar macrophages for autophagy and ferroptosis in sepsis-induced acute lung injury.

Rongzong Ye, Yating Wei, Jingwen Li, Yu Zhong, Xiukai Chen, Chaoqian Li.

  Sepsis-induced acute respiratory distress syndrome (ARDS) is a severe complication of sepsis and the leading cause of mortality. Although the role of alveolar macrophages (AMs) in stabilizing pulmonary homeostasis is well established, the effects of circulating extracellular vesicles (EVs) on AMs remain largely unknown. In this study, an investigation was conducted to map the miRNA and protein expression profiles of EVs derived from septic plasma. Notably, EV-based panels (miR-122-5p, miR-125b-5p, miR-223-3p, OLFM4, and LCN2) have been found to be associated with the severity or prognosis of sepsis, with promising AUC values. Moreover, the levels of LCN2, miR-122-5p, and miR-223-3p were identified as independent predictors of septic ARDS. The in vitro coculture results revealed that the effects of LPS-EVs from the plasma of sepsis-induced acute lung injury (ALI), which carry pro-inflammatory EVs, were partly mediated by miR-223-3p, as evidenced by the promotion of inflammation, autophagy and ferroptosis in AMs. Mechanistically, the upregulation of miR-223-3p in LPS-EVs triggers autophagy and ferroptosis in AMs by activating Hippo signaling via the targeting of MEF2C. In vivo, the inhibition of miR-223-3p effectively mitigated LPS-EV-induced inflammation and AM death in the lungs, as well as histological lesions. Overall, miR-223-3p in LPS-EVs contributes to sepsis-induced ALI by priming AMs for autophagy and ferroptosis through the MEF2C/Hippo signaling pathway. These findings suggest a novel mechanism of plasma-AM interaction in sepsis-induced ALI, offering a plausible strategy for assessing septic progression and treating lung injury.

Keywords:  Alveolar macrophages; Autophagy; Extracellular vesicles; Ferroptosis; MicroRNAs; Sepsis-induced acute lung injury

DOI:  https://doi.org/10.1186/s10020-025-01111-x
Signal Transduct Target Ther. 2025 Feb 07. 10(1): 36

Mitochondrial heterogeneity: subpopulations with distinct metabolic activities.

Fabian den Brave, Swadha Mishra, Thomas Becker.

DOI: https://doi.org/10.1038/s41392-025-02130-0
J Theor Biol. 2025 Jan 30. pii: S0022-5193(25)00015-3. [Epub ahead of print]602-603 112049

A mathematical model of microglia glucose metabolism and lactylation with positive feedback.

Kamila Larripa, Anca Rǎdulescu.

  In this paper, we present and analyze a model for metabolism and lactylation in a single microglia. The model includes positive feedback from lactylation in the glycolytic pathway, and links metabolism and inflammation. Specific pathways include the transition of glucose to pyruvate to lactate in a microglia, as well as the gradient transport of glucose and lactate into and out of the cell. Additionally, the upregulation of certain pathways by either epigenetic modification or the inflammatory response are included. Bifurcation and sensitivity analyses demonstrate the importance of key parameters and pathways in the model, specifically the role of lactylation. Our model is validated by qualitatively reproducing recent in vitro experiments in which exogenous glucose and lactate are modified.

Keywords:  Bifurcation analysis; Differential equations; Feedback; Metabolism; Microglia

DOI:  https://doi.org/10.1016/j.jtbi.2025.112049
Br J Pharmacol. 2025 Jan 31.

Thiamine deficiency aggravates experimental colitis in mice by promoting glycolytic reprogramming in macrophages.

Xiaohua Pan, Zhengnan Ren, Wenjie Liang, Xiaoliang Dong, Jiahong Li, Lili Wang, Madhav Bhatia, Li-Long Pan, Jia Sun.

   BACKGROUND AND PURPOSE: Inflammatory bowel disease (IBD) is closely associated with immune dysfunction, where nutrient-mediated metabolic flux dictates immune cell fate and function. Thiamine is a central water-soluble vitamin involved in cellular energy metabolism, and its deficiency has been reported in IBD patients. However, whether thiamine deficiency is a cause or consequence of IBD pathogenesis remains unclear. The current study aimed to reveal the immunometabolic regulation of macrophages and underlying mechanism of thiamine deficiency in colitis development.
EXPERIMENTAL APPROACH: Thiamine deficiency was induced in C57BL/6 mice and bone marrow-derived macrophages (BMDMs), by administering a thiamine-deficient diet/medium together with pyrithiamine hydrobromide. The frequency of macrophage phenotypes and their intracellular metabolism were detected using flow cytometry and non-targeted metabolomics, respectively.
KEY RESULTS: Thiamine deficiency aggravated ulcerative colitis in mice and promoted the infiltration of proinflammatory M1 macrophages in colonic lamina propria. Our mechanistic study revealed that thiamine deficiency impaired pyruvate dehydrogenase (PDH) activity, thereby reprogramming cellular glucose metabolism to enhance glycolysis and lactic acid accumulation in M1 macrophages. Using a well-established PDH inhibitor (CPI-613) and lactic acid dehydrogenase inhibitor (galloflavin), we further demonstrated that PDH inhibition mimics, while lactate dehydrogenase inhibition partially rescues, thiamine deficiency-induced proinflammatory macrophage infiltration and experimental colitis in mice.
CONCLUSION AND IMPLICATIONS: Our study provides evidence linking thiamine deficiency with proinflammatory macrophage activation and colitis aggravation, suggesting that monitoring thiamine status and adjusting thiamine intake is necessary to protect against colitis.

Keywords:  glycolysis; macrophage; metabolic reprogramming; thiamine deficiency; ulcerative colitis

DOI:  https://doi.org/10.1111/bph.17435