bims-bac4me 2024-10-27 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2024–10–27
37 papers selected by
Chun-Chi Chang, Universitäts Spital Zürich

The Staphylococcus aureus-antagonizing human nasal commensal Staphylococcus lugdunensis depends on siderophore piracy.
Air-Pollution-Mediated Microbial Dysbiosis in Health and Disease: Lung-Gut Axis and Beyond.
Impact of cooperative or competitive dynamics between the yeast Saccharomyces cerevisiae and lactobacilli on the immune response of the host.
Macrophages and autophagy: partners in crime.
IL-1β-induced epithelial cell and fibroblast transdifferentiation promotes neutrophil recruitment in chronic rhinosinusitis with nasal polyps.
Interaction between intestinal mycobiota and microbiota shapes lung inflammation.
Leukocyte kinetics and bacterial clearance during S. pneumoniae pneumonia and contributions of ICAM-1.
Cultivating complexity: Advancements in establishing in vitro models for the mucus-adhering gut microbiota.
Airway macrophage glycolysis controls lung homeostasis and responses to aeroallergen.
Epidermal Stem Cells: Interplay with the Skin Microenvironment During Wound Healing.
Macrophage variants in laboratory research: most are well done, but some are RAW.
Microbiota activation and regulation of adaptive immunity.
[Current progress on trained immunity-based vaccines].
The protective effect and immunomodulatory ability of orally administrated Lacticaseibacillus rhamnosus GG against Mycoplasma pneumoniae infection in BALB/c mice.
Molecular Evolution and Pathogenicity of Methicillin-Resistant Staphylococcus aureus.
CENCAT enables immunometabolic profiling by measuring protein synthesis via bioorthogonal noncanonical amino acid tagging.
Fpa (YlaN) is an iron(II) binding protein that functions to relieve Fur-mediated repression of gene expression in Staphylococcus aureus.
MicrobiomeNet: exploring microbial associations and metabolic profiles for mechanistic insights.
Effects of hyperglycemia on airway epithelial barrier function in WT and CF 16HBE cells.
Unravelling monocyte functions: from the guardians of health to the regulators of disease.
Inflammasome activation links enteric Salmonella Typhimurium infection to a rapid, cytokine-dependent increase in intestinal mucin release.
Cellular Mechanisms of Lung Injury: Current Perspectives.
Bacterial extracellular vesicles as intranasal postbiotics: Detailed characterization and interaction with airway cells.
Differential Nasal Recolonization and Microbial Profiles in Chronic Rhinosinusitis With Nasal Polyps Patients After Endoscopic Sinus Surgery or Dupilumab Treatment: A Prospective Observational Study.
Understanding the role of innate immune training in prevention of respiratory infections.
Knowledge mapping of trained immunity/innate immune memory: Insights from two decades of studies.
Muropeptides and muropeptide transporters impact on host immune response.
Examining the healthy human microbiome concept.
Interleukin-26 expression in tuberculosis disease and its regulatory effect in macrophage polarization and intracellular elimination of Mycobacterium tuberculosis.
Mitochondrial Damage in Sepsis.
Gut microbiota-derived acetic acids promoted sepsis-induced acute respiratory distress syndrome by delaying neutrophil apoptosis through FABP4.
Autophagy and autophagic cell death in sepsis: friend or foe?
Regional specialization within the mammalian respiratory immune system.
The important role of ferroptosis in inflammatory bowel disease.
Extracellular vesicles from the dead: the final message.
Quorum sensing and antibiotic resistance in polymicrobial infections.
Unveiling ferroptosis: a new frontier in skin disease research.

Microbiome. 2024 Oct 22. 12(1): 213

The Staphylococcus aureus-antagonizing human nasal commensal Staphylococcus lugdunensis depends on siderophore piracy.

Ralf Rosenstein, Benjamin O Torres Salazar, Claudia Sauer, Simon Heilbronner, Bernhard Krismer, Andreas Peschel.

   BACKGROUND: Bacterial pathogens such as Staphylococcus aureus colonize body surfaces of part of the human population, which represents a critical risk factor for skin disorders and invasive infections. However, such pathogens do not belong to the human core microbiomes. Beneficial commensal bacteria can often prevent the invasion and persistence of such pathogens by using molecular strategies that are only superficially understood. We recently reported that the commensal bacterium Staphylococcus lugdunensis produces the novel antibiotic lugdunin, which eradicates S. aureus from the nasal microbiomes of hospitalized patients. However, it has remained unclear if S. lugdunensis may affect S. aureus carriage in the general population and which external factors might promote S. lugdunensis carriage to enhance its S. aureus-eliminating capacity.
RESULTS: We could cultivate S. lugdunensis from the noses of 6.3% of healthy human volunteers. In addition, S. lugdunensis DNA could be identified in metagenomes of many culture-negative nasal samples indicating that cultivation success depends on a specific bacterial threshold density. Healthy S. lugdunensis carriers had a 5.2-fold lower propensity to be colonized by S. aureus indicating that lugdunin can eliminate S. aureus also in healthy humans. S. lugdunensis-positive microbiomes were dominated by either Staphylococcus epidermidis, Corynebacterium species, or Dolosigranulum pigrum. These and further bacterial commensals, whose abundance was positively associated with S. lugdunensis, promoted S. lugdunensis growth in co-culture. Such mutualistic interactions depended on the production of iron-scavenging siderophores by supportive commensals and on the capacity of S. lugdunensis to import siderophores. Video Abstract CONCLUSIONS: These findings underscore the importance of microbiome homeostasis for eliminating pathogen colonization. Elucidating mechanisms that drive microbiome interactions will become crucial for microbiome-precision editing approaches.

Keywords:   Staphylococcus aureus ; Bacteriocin; Inter-species competition; Iron limitation; Nasal commensals; Nasal microbiome; Nutritional immunity; Siderophore

DOI:  https://doi.org/10.1186/s40168-024-01913-x
J Xenobiot. 2024 Oct 21. 14(4): 1595-1612

Air-Pollution-Mediated Microbial Dysbiosis in Health and Disease: Lung-Gut Axis and Beyond.

Md Habibul Hasan Mazumder, Salik Hussain.

  Growing evidence suggests physiological and pathological functions of lung and gut microbiomes in various pathologies. Epidemiological and experimental data associate air pollution exposure with host microbial dysbiosis in the lungs and gut. Air pollution through increased reactive oxygen species generation, the disruption of epithelial barrier integrity, and systemic inflammation modulates microbial imbalance. Microbiome balance is crucial in regulating inflammation and metabolic pathways to maintain health. Microbiome dysbiosis is proposed as a potential mechanism for the air-pollution-induced modulation of pulmonary and systemic disorders. Microbiome-based therapeutic approaches are increasingly gaining attention and could have added value in promoting lung health. This review summarizes and discusses air-pollution-mediated microbiome alterations in the lungs and gut in humans and mice and elaborates on their role in health and disease. We discuss and summarize the current literature, highlight important mechanisms that lead to microbial dysbiosis, and elaborate on pathways that potentially link lung and lung microbiomes in the context of environmental exposures. Finally, we discuss the lung-liver-gut axis and its potential pathophysiological implications in air-pollution-mediated pathologies through microbial dysbiosis.

Keywords:  air pollution; gastrointestinal microbiome; lung–gut–liver axis; microbiome dysbiosis; respiratory microbiome

DOI:  https://doi.org/10.3390/jox14040086
Front Immunol. 2024 ;15 1399842

Impact of cooperative or competitive dynamics between the yeast Saccharomyces cerevisiae and lactobacilli on the immune response of the host.

Stefano Nenciarini, Damariz Rivero, Alessia Ciccione, Roberta Amoriello, Benedetta Cerasuolo, Marco Pallecchi, Gian Luca Bartolucci, Clara Ballerini, Duccio Cavalieri.

  Fungi and bacteria can be found coexisting in a wide variety of environments. The combination of their physical and molecular interactions can result in a broad range of outcomes for each partner, from competition to cooperative relationships. Most of these interactions can also be found in the human gastrointestinal tract. The gut microbiota is essential for humans, helping the assimilation of food components as well as the prevention of pathogen invasions through host immune system modulation and the production of beneficial metabolites such as short-chain fatty acids (SCFAs). Several factors, including changes in diet habits due to the progressive Westernization of the lifestyle, are linked to the onset of dysbiosis statuses that impair the correct balance of the gut environment. It is therefore crucial to explore the interactions between commensal and diet-derived microorganisms and their influence on host health. Investigating these interactions through co-cultures between human- and fermented food-derived lactobacilli and yeasts led us to understand how the strains' growth yield and their metabolic products rely on the nature and concentration of the species involved, producing either cooperative or competitive dynamics. Moreover, single cultures of yeasts and lactobacilli proved to be ideal candidates for developing immune-enhancing products, given their ability to induce trained immunity in blood-derived human monocytes in vitro. Conversely, co-cultures as well as mixtures of yeasts and lactobacilli have been shown to induce an anti-inflammatory response on the same immune cells in terms of cytokine profiles and activation surface markers, opening new possibilities in the design of probiotic and dietary therapies.

Keywords:  Saccharomyces cerevisiae; fermented food; host immune system modulation; lactobacilli; microbial ecology; short-chain fatty acids; trained immunity; yeasts

DOI:  https://doi.org/10.3389/fimmu.2024.1399842
FEBS J. 2024 Oct 22.

Macrophages and autophagy: partners in crime.

Alessandra Vitaliti, Alessio Reggio, Alessandro Palma.

  Macrophages and autophagy are intricately linked, both playing vital roles in maintaining homeostasis and responding to disease. Macrophages, known for their 'eating' function, rely on a sophisticated digestion system to process a variety of targets, from apoptotic cells to pathogens. The connection between macrophages and autophagy is established early in their development, influencing both differentiation and mature functions. Autophagy regulates essential immune functions, such as inflammation control, pathogen clearance, and antigen presentation, linking innate and adaptive immunity. Moreover, it modulates cytokine production, ensuring a balanced inflammatory response that prevents excessive tissue damage. Autophagy also plays a critical role in macrophage polarization, influencing their shift between pro-inflammatory and anti-inflammatory states. This review explores the role of autophagy in macrophages, emphasizing its impact across various tissues and pathological conditions, and detailing the cellular and molecular mechanisms by which autophagy shapes macrophage function.

Keywords:  autophagy; immunity; lysosome; macrophages; phagocytes

DOI:  https://doi.org/10.1111/febs.17305
Nat Commun. 2024 Oct 22. 15(1): 9101

IL-1β-induced epithelial cell and fibroblast transdifferentiation promotes neutrophil recruitment in chronic rhinosinusitis with nasal polyps.

Xinyu Xie, Pin Wang, Min Jin, Yue Wang, Lijie Qi, Changhua Wu, Shu Guo, Changqing Li, Xiaojun Zhang, Ye Yuan, Xinyi Ma, Fangying Liu, Weiyuan Liu, Heng Liu, Chen Duan, Ping Ye, Xuezhong Li, Larry Borish, Wei Zhao, Xin Feng.

Neutrophilic inflammation contributes to multiple chronic inflammatory airway diseases, including asthma and chronic rhinosinusitis with nasal polyps (CRSwNP), and is associated with an unfavorable prognosis. Here, using single-cell RNA sequencing (scRNA-seq) to profile human nasal mucosa obtained from the inferior turbinates, middle turbinates, and nasal polyps of CRSwNP patients, we identify two IL-1 signaling-induced cell subsets-LY6D+ club cells and IDO1+ fibroblasts-that promote neutrophil recruitment by respectively releasing S100A8/A9 and CXCL1/2/3/5/6/8 into inflammatory regions. IL-1β, a pro-inflammatory cytokine involved in IL-1 signaling, induces the transdifferentiation of LY6D+ club cells and IDO1+ fibroblasts from primary epithelial cells and fibroblasts, respectively. In an LPS-induced neutrophilic CRSwNP mouse model, blocking IL-1β activity with a receptor antagonist significantly reduces the numbers of LY6D+ club cells and IDO1+ fibroblasts and mitigates nasal inflammation. This study implicates the function of two cell subsets in neutrophil recruitment and demonstrates an IL-1-based intervention for mitigating neutrophilic inflammation in CRSwNP.

DOI: https://doi.org/10.1038/s41467-024-53307-0
Imeta. 2024 Oct;3(5): e241

Interaction between intestinal mycobiota and microbiota shapes lung inflammation.

Youxia Wang, Fang He, Bingnan Liu, Xiaoyan Wu, Ziyi Han, Xuefei Wang, Yuexia Liao, Jielin Duan, Wenkai Ren.

  Gut microbiota is an intricate microbial community containing bacteria, fungi, viruses, archaea, and protozoa, and each of them contributes to diverse aspects of host health. Nevertheless, the influence of interaction among gut microbiota on host health remains uncovered. Here, we showed that the interaction between intestinal fungi and bacteria shaped lung inflammation during infection. Specifically, antifungal drug-induced dysbiosis of gut mycobiota enhanced lung inflammation during infection. Dysbiosis of gut mycobiota led to gut Escherichia coli (E. coli) overgrowth and translocation to the lung during infection, which induced lung accumulation of the CD45+F4/80+Ly6G-Ly6C-CD11b+CD11c+ macrophages. Clearance of macrophages or deletion of TLR4 (Toll-like receptor 4, recognition of LPS) rather than Dectin-1 (recognition of beta-1,3/1,6 glucans on fungi) blocked the antifungal drug-induced aggravation of lung inflammation during infection. These findings suggest that the interaction between intestinal mycobiota and commensal bacteria affects host health through the gut-lung axis, offering a potential therapeutic target for ameliorating lung inflammation during infection.

Keywords:  intestinal microbiota; intestinal mycrobiota; lung inflammation; macrophages

DOI:  https://doi.org/10.1002/imt2.241
Am J Physiol Lung Cell Mol Physiol. 2024 Oct 22.

Leukocyte kinetics and bacterial clearance during S. pneumoniae pneumonia and contributions of ICAM-1.

Matthew K McPeek, John C Gomez, Jessica R Martin, Marie Anne Iannone, Hong Dang, Claire M Doerschuk.

  Streptococcus pneumoniae is a leading cause of community-acquired pneumonia. Intercellular adhesion molecule-1 (ICAM-1) is an adhesion molecule that is highly expressed on the pulmonary capillary endothelium, alveolar epithelium and other cell types within the lung. ICAM-1 plays important roles in leukocyte adhesion, migration, and motility. To determine the contributions of ICAM-1 to bacterial clearance and leukocyte kinetics during pneumonia, mice were inoculated with S. pneumoniae and evaluated 1, 4 and 7 days later. Our results show that Icam1-/-mice have a greater number of viable bacteria within the lung at each time point. The impaired clearance observed in Icam1-/- mice was not due to an impediment in leukocyte recruitment. In fact, Icam1-/- mice had a greater number of neutrophils and recruited inflammatory macrophages in the lung tissue and the alveoli/airways on day 7. In contrast, fewer alveolar macrophages were present in the BAL of Icam1-/-mice. The loss of body weight and the concentrations of inflammatory mediators in the BAL were also significantly greater in Icam1-/- mice. Mechanistic studies to understand the defect in clearance show that neutrophils and macrophage subpopulations had no defect in phagocytosis or acidification of phagosomes. RNA sequencing reveals many differences in gene expression, but no suggestion of a defect in phagocytosis or killing. Thus, that ICAM-1 is necessary for the clearance of S. pneumoniae and for the resolution of pneumonia, but is not required for the recruitment of neutrophils or inflammatory macrophages into the pneumonic lung parenchyma or the alveoli/airways during S. pneumoniae-induced pneumonia.

Keywords:  Bacterial clearance; ICAM-1; Leukocytes; Pneumonia; S. pneumoniae

DOI:  https://doi.org/10.1152/ajplung.00039.2024
Microb Biotechnol. 2024 10;17(10): e70036

Cultivating complexity: Advancements in establishing in vitro models for the mucus-adhering gut microbiota.

Marco Calvigioni, Diletta Mazzantini, Francesco Celandroni, Giovanni Vozzi, Emilia Ghelardi.

A healthy mucus is essential for maintaining intestinal homeostasis and overall well-being. In recent years, extensive research focused on understanding the intricate interactions between mucus and the gut microbiota. Mucus-adhering bacteria play crucial roles in preserving barrier integrity, epithelial permeability and mucus architecture, as well as in the colonization resistance against pathogens. Unravelling the significance of these microorganisms in human health and disease is challenging, primarily because most of the studies on the human gut microbiota rely on faecal samples, which do not fully represent the microecological complexity found in the intestinal mucosa. This review discusses novel strategies to specifically target and evaluate the mucosal microbiota, such as culturomics applied to mucosal biopsies or brushings, intestinal organoids and artificial in vitro models incorporating mucus.

DOI: https://doi.org/10.1111/1751-7915.70036
Mucosal Immunol. 2024 Oct 18. pii: S1933-0219(24)00105-3. [Epub ahead of print]

Airway macrophage glycolysis controls lung homeostasis and responses to aeroallergen.

Gesa J Albers, Christina Michalaki, Patricia P Ogger, Amy F Lloyd, Benjamin Causton, Simone A Walker, Anna Caldwell, John M Halket, Linda V Sinclair, Sarah H Forde, Cormac McCarthy, Timothy S C Hinks, Clare M Lloyd, Adam J Byrne.

The lungs represent a dynamic microenvironment where airway macrophages (AMs) are the major lung-resident macrophages. AMs dictate the balance between tissue homeostasis and immune activation and thus have contradictory functions by maintaining tolerance and tissue homeostasis, as well as initiating strong inflammatory responses. Emerging evidence has highlighted the connection between macrophage function and cellular metabolism. However, the functional importance of these processes in tissue-resident specialized macrophage populations such as those found in the airways, remain poorly elucidated. Here, we reveal that glycolysis is a fundamental pathway in AMs which regulates both lung homeostasis and responses to inhaled allergen. Using macrophage specific targeting in vivo, and multi-omics approaches, we determined that glycolytic activity in AMs is necessary to restrain type 2 (T2) immunity during homeostasis. Exposure to a range of common aeroallergens, including house dust mite (HDM), drove AM-glycolysis and furthermore, AM-specific inhibition of glycolysis altered inflammation in the airways and HDM-driven airway metabolic adaptations in vivo. Additionally, allergen sensitised asthmatics had profound metabolic changes in the airways, compared to non-sensitised asthmatic controls. Finally, we found that allergen driven AM-glycolysis in mice was TLR2 dependent. Thus, our findings demonstrate a direct relationship between glycolysis in AMs, AM-mediated homeostatic processes, and T2 immune responses in the lungs. These data suggest that glycolysis is essential for the plasticity of AMs. Depending on the immunological context, AM-glycolysis is required to exert homeostatic activity but once activated by allergen, AM-glycolysis influences inflammatory responses. Thus, precise modulation of glycolytic activity in AMs is essential for preserving lung homeostasis and regulating airway inflammation.

DOI: https://doi.org/10.1016/j.mucimm.2024.10.002
Mol Cells. 2024 Oct 21. pii: S1016-8478(24)00163-8. [Epub ahead of print] 100138

Epidermal Stem Cells: Interplay with the Skin Microenvironment During Wound Healing.

Yun Ha Hur.

  Skin undergoes everyday turnover while often challenged by injuries. The wound healing process in the skin is a dynamic sequence of events that involves various cell types and signaling pathways. Epidermal stem cells (EpdSCs), the tissue-resident stem cells in the skin tissue, are in the center of this complicated process due to their special ability to self-renew and differentiate. During this process, EpdSCs interact actively with the tissue microenvironment, which is essential for proper re-epithelialization and skin barrier restoration. This review describes the intricate interplays between EpdSCs and various components of their surroundings, including ECM/fibroblasts, vasculature/endothelial cells, and immune cells, as well as their roles in tissue repair.

Keywords:  epidermal stem cells (EpdSCs); re-epithelialization; tissue microenvironment; tissue repair; wound healing

DOI:  https://doi.org/10.1016/j.mocell.2024.100138
Front Cell Infect Microbiol. 2024 ;14 1457323

Macrophage variants in laboratory research: most are well done, but some are RAW.

Marc Herb, Valentin Schatz, Karina Hadrian, Deniz Hos, Bohdan Holoborodko, Jonathan Jantsch, Natascha Brigo.

  Macrophages play a pivotal role in the innate immune response. While their most characteristic function is phagocytosis, it is important not to solely characterize macrophages by this activity. Their crucial roles in body development, homeostasis, repair, and immune responses against pathogens necessitate a broader understanding. Macrophages exhibit remarkable plasticity, allowing them to modify their functional characteristics in response to the tissue microenvironment (tissue type, presence of pathogens or inflammation, and specific signals from neighboring cells) swiftly. While there is no single defined "macrophage" entity, there is a diverse array of macrophage types because macrophage ontogeny involves the differentiation of progenitor cells into tissue-resident macrophages, as well as the recruitment and differentiation of circulating monocytes in response to tissue-specific cues. In addition, macrophages continuously sense and respond to environmental cues and tissue conditions, adjusting their functional and metabolic states accordingly. Consequently, it is of paramount importance to comprehend the heterogeneous origins and functions of macrophages employed in in vitro studies, as each available in vitro macrophage model is associated with specific sets of strengths and limitations. This review centers its attention on a comprehensive comparison between immortalized mouse macrophage cell lines and primary mouse macrophages. It provides a detailed analysis of the strengths and weaknesses inherent in these in vitro models. Finally, it explores the subtle distinctions between diverse macrophage cell lines, offering insights into numerous factors beyond the model type that can profoundly influence macrophage function.

Keywords:  immunity; macrophage polarization (MP); macrophage types; macrophage-like cell lines; primary macrophages

DOI:  https://doi.org/10.3389/fcimb.2024.1457323
Front Immunol. 2024 ;15 1429436

Microbiota activation and regulation of adaptive immunity.

Mozhdeh Heidari, Saman Maleki Vareki, Ramin Yaghobi, Mohammad Hossein Karimi.

  In the mucosa, T cells and B cells of the immune system are essential for maintaining immune homeostasis by suppressing reactions to harmless antigens and upholding the integrity of intestinal mucosal barrier functions. Host immunity and homeostasis are regulated by metabolites produced by the gut microbiota, which has developed through the long-term coevolution of the host and the gut biome. This is achieved by the immunological system's tolerance for symbiote microbiota, and its ability to generate a proinflammatory response against invasive organisms. The imbalance of the intestinal immune system with commensal organisms is causing a disturbance in the homeostasis of the gut microbiome. The lack of balance results in microbiota dysbiosis, the weakened integrity of the gut barrier, and the development of inflammatory immune reactions toward symbiotic organisms. Researchers may uncover potential therapeutic targets for preventing or regulating inflammatory diseases by understanding the interactions between adaptive immunity and the microbiota. This discussion will explore the connection between adaptive immunity and microbiota.

Keywords:  B cells; T cells; adaptive Immunity; microbiota; regulatory T cells

DOI:  https://doi.org/10.3389/fimmu.2024.1429436
Zhonghua Yu Fang Yi Xue Za Zhi. 2024 Oct 06. 58(10): 1598-1603

[Current progress on trained immunity-based vaccines].

C Y Xiang, N Wang, Y Shi.

Trained immunity-based vaccines (TIbV) is an emerging vaccine strategy in the field of vaccine research, referring to vaccines designed based on the principles of trained immunity (TI). TI involves the enhanced immune response of innate immune cells upon re-stimulation after being trained. TIbV, built on the concept of TI, aims to enhance resistance to various infectious pathogens by training the host's innate immune system to acquire natural immune memory. This approach is designed to bolster immunity against a wide range of infectious agents, including those not covered by conventional vaccines. This article reviews the concepts, mechanisms, application areas, and future prospects of TIbV, intending to offer a new perspective for vaccine development and design.

DOI: https://doi.org/10.3760/cma.j.cn112150-20231121-00360
PLoS One. 2024 ;19(10): e0312318

The protective effect and immunomodulatory ability of orally administrated Lacticaseibacillus rhamnosus GG against Mycoplasma pneumoniae infection in BALB/c mice.

Huanbing Long, Guiting He, Jiarong He, Ting Feng Du, Pengxiao Feng, Cuiming Zhu.

Mycoplasma pneumoniae represents one of the significant etiologies of community-acquired pneumonia in pediatric patients. However, clinical treatment of M. pneumoniae infection in children has encountered challenges due to the escalating resistance to quinolones. Numerous studies have highlighted the potential of probiotic lactobacillus administration in boosting immune responses to bacterial and viral respiratory infections. In this study, the protective efficacy of pre-oral administration of Lacticaseibacillus rhamnosus GG (LGG), Limosilactobacillus reuteri F275, Lactiplantibacillus plantarum NCIMB 8826, L. plantarum S1 or L. plantarum S2 was evaluated in the BALB/c mice model; it was observed that among these five strains of lactobacillus, the supplementation of LGG exhibited the most significant protective effect against M. pneumoniae infection. Moreover, when administered orally, both live LGG and heat-inactivated LGG have demonstrated efficacy in reducing the burden of M. pneumoniae in the lungs and alleviating pulmonary inflammation. Oral supplementation with LGG resulted in the inhibition of neutrophil recruitment into the lungs and increased recruitment of alveolar macrophages in M. pneumoniae-infected mice. Additionally, LGG supplementation led to increased production of IL-10 and secretory IgA (sIgA), while suppressing the levels of IL-1β, IL-6, IL-17A, and TNF-α in the lungs of mice infected with M. pneumoniae. The data suggests that supplementation with LGG can modulate immune responses, decrease pathogen load, and alleviate inflammatory injury in the lungs of M. pneumoniae-infected mice.

DOI: https://doi.org/10.1371/journal.pone.0312318
Antibiotics (Basel). 2024 Oct 10. pii: 953. [Epub ahead of print]13(10):

Molecular Evolution and Pathogenicity of Methicillin-Resistant Staphylococcus aureus.

Kunyan Zhang.

Staphylococcus aureus is a Gram-positive and coagulase-positive pathogen, belonging to the Staphylococcaceae family [...].

DOI: https://doi.org/10.3390/antibiotics13100953
Cell Rep Methods. 2024 Oct 21. pii: S2667-2375(24)00266-2. [Epub ahead of print]4(10): 100883

CENCAT enables immunometabolic profiling by measuring protein synthesis via bioorthogonal noncanonical amino acid tagging.

Frank Vrieling, Hendrik J P van der Zande, Britta Naus, Lisa Smeehuijzen, Julia I P van Heck, Bob J Ignacio, Kimberly M Bonger, Jan Van den Bossche, Sander Kersten, Rinke Stienstra.

  Cellular energy metabolism significantly contributes to immune cell function. To further advance immunometabolic research, novel methods to study the metabolism of immune cells in complex samples are required. Here, we introduce CENCAT (cellular energetics through noncanonical amino acid tagging). This technique utilizes click labeling of alkyne-bearing noncanonical amino acids to measure protein synthesis inhibition as a proxy for metabolic activity. CENCAT successfully reproduced known metabolic signatures of lipopolysaccharide (LPS)/interferon (IFN)γ and interleukin (IL)-4 activation in human primary macrophages. Application of CENCAT in peripheral blood mononuclear cells revealed diverse metabolic rewiring upon stimulation with different activators. Finally, CENCAT was used to analyze the cellular metabolism of murine tissue-resident immune cells from various organs. Tissue-specific clustering was observed based on metabolic profiles, likely driven by microenvironmental priming. In conclusion, CENCAT offers valuable insights into immune cell metabolic responses, presenting a powerful platform for studying cellular metabolism in complex samples and tissues in both humans and mice.

Keywords:  CP: Immunology; CP: Metabolism; OXPHOS; SCENITH; energy metabolism; glycolysis; immunometabolism

DOI:  https://doi.org/10.1016/j.crmeth.2024.100883
mBio. 2024 Oct 23. e0231024

Fpa (YlaN) is an iron(II) binding protein that functions to relieve Fur-mediated repression of gene expression in Staphylococcus aureus.

Jeffrey M Boyd, Kylie Ryan Kaler, Karla Esquilín-Lebrón, Ashley Pall, Courtney J Campbell, Mary E Foley, Gustavo Rios-Delgado, Emilee M Mustor, Timothy G Stephens, Hannah Bovermann, Todd M Greco, Ileana M Cristea, Valerie J Carabetta, William N Beavers, Debashish Bhattacharya, Eric P Skaar, Lindsey N Shaw, Timothy L Stemmler.

  Iron (Fe) is a trace nutrient required by nearly all organisms. As a result of the demand for Fe and the toxicity of non-chelated cytosolic ionic Fe, regulatory systems have evolved to tightly balance Fe acquisition and usage while limiting overload. In most bacteria, including the mammalian pathogen Staphylococcus aureus, the ferric uptake regulator (Fur) is the primary transcriptional regulator controlling the transcription of genes that code for Fe uptake and utilization proteins. Fpa (formerly YlaN) was demonstrated to be essential in Bacillus subtilis unless excess Fe is added to the growth medium, suggesting a role in Fe homeostasis. Here, we demonstrate that Fpa is essential in S. aureus upon Fe deprivation. Null fur alleles bypassed the essentiality of Fpa. The absence of Fpa abolished the derepression of Fur-regulated genes during Fe limitation. Bioinformatic analyses suggest that fpa was recruited to Gram-positive bacteria and, once acquired, was maintained in the genome as it co-evolved with Fur. Consistent with a role for Fpa in alleviating Fur-dependent repression, Fpa and Fur interacted in vivo, and Fpa decreased the DNA-binding ability of Fur in vitro. Fpa bound Fe(II) in vitro using oxygen or nitrogen ligands with an association constant that is consistent with a physiological role in Fe homeostasis. These findings have led to a model wherein Fpa is an Fe(II) binding protein that influences Fur-dependent regulation through direct interaction.IMPORTANCEIron (Fe) is an essential nutrient for nearly all organisms. If Fe homeostasis is not maintained, Fe may accumulate in the cytosol, which can be toxic. Questions remain about how cells efficiently balance Fe uptake and usage to prevent overload. Iron uptake and proper metalation of proteins are essential processes in the mammalian bacterial pathogen Staphylococcus aureus. Understanding the gene products involved in the genetic regulation of Fe uptake and usage and the physiological adaptations that S. aureus uses to survive in Fe-depleted conditions provides insight into pathogenesis. Herein, we demonstrate that the DNA-binding activity of the ferric uptake regulator transcriptional repressor is alleviated under Fe limitation, but uniquely, in S. aureus, alleviation requires the presence of Fpa.

Keywords:  Fpa; Fur; Staphylococcus aureus; YlaN; iron; sulfur

DOI:  https://doi.org/10.1128/mbio.02310-24
Nucleic Acids Res. 2024 Oct 23. pii: gkae944. [Epub ahead of print]

MicrobiomeNet: exploring microbial associations and metabolic profiles for mechanistic insights.

Yao Lu, Fiona Hui, Guangyan Zhou, Jianguo Xia.

The growing volumes of microbiome studies over the past decade have revealed a wide repertoire of microbial associations under diverse conditions. Microbes produce small molecules to interact with each other as well as to modulate their environments. Their metabolic profiles hold the key to understanding these association patterns for translational applications. Based on this concept, we developed MicrobiomeNet, a comprehensive database that integrates microbial associations with their metabolic profiles for mechanistic insights. It currently contains a total of ∼5.8 million known microbial associations, coupled with >12 400 genome-scale metabolic models (GEMs) covering ∼6000 microbial species. Users can intuitively explore microbial associations and compare their corresponding metabolic profiles. Our case studies show that MicrobiomeNet can provide mechanistic insights that are consistent with the literature. MicrobiomeNet is freely available at https://www.microbiomenet.com/.

DOI: https://doi.org/10.1093/nar/gkae944
Sci Rep. 2024 10 23. 14(1): 25095

Effects of hyperglycemia on airway epithelial barrier function in WT and CF 16HBE cells.

Analia J Vazquez Cegla, Kymry T Jones, Guiying Cui, Kirsten A Cottrill, Michael Koval, Nael A McCarty.

Cystic fibrosis related diabetes (CFRD), the main co-morbidity in cystic fibrosis (CF), is associated with higher rates of lung function decline. We hypothesize that airway epithelial barrier function is impaired in CF and is further exacerbated under hyperglycemia, worsening pulmonary outcomes. Using 16HBE cells, we studied the effects of hyperglycemia in airway epithelial barrier function. Results show increased paracellular dye flux in CF cells in response to insulin under hyperglycemia. Gene expression experiments identified claudin-4 (CLDN4) as a key tight junction protein dysregulated in CF cells. CLDN4 protein localization by confocal microscopy showed that CLDN4 was tightly localized at tight junctions in WT cells, which did not change under hyperglycemia. ln contrast, CLDN4 was less well-localized in CF cells at normal glucose and localization was worsened under hyperglycemia. Treatment with highly effective modulator compounds (ETI) reversed this trend, and CFTR rescue was not affected by insulin or hyperglycemia. Bulk RNA sequencing showed differences in transcriptional responses in CF compared to WT cells under normal or high glucose, highlighting promising targets for future investigation. One of these targets is protein tyrosine phosphatase receptor type G (PTPRG), which has been previously found to play a role in defective Akt signaling and insulin resistance.

DOI: https://doi.org/10.1038/s41598-024-76526-3
Discov Immunol. 2024 ;3(1): kyae014

Unravelling monocyte functions: from the guardians of health to the regulators of disease.

Alexander Mildner, Ki-Wook Kim, Simon Yona.

  Monocytes are a key component of the innate immune system. They undergo intricate developmental processes within the bone marrow, leading to diverse monocyte subsets in the circulation. In a state of healthy homeostasis, monocytes are continuously released into the bloodstream, destined to repopulate specific tissue-resident macrophage pools where they fulfil tissue-specific functions. However, under pathological conditions monocytes adopt various phenotypes to resolve inflammation and return to a healthy physiological state. This review explores the nuanced developmental pathways and functional roles that monocytes perform, shedding light on their significance in both physiological and pathological contexts.

Keywords:  cancer; haematopoiesis and metabolic disease; inflammation; macrophages; monocytes

DOI:  https://doi.org/10.1093/discim/kyae014
Gut Microbes. 2024 Jan-Dec;16(1):16(1): 2413372

Inflammasome activation links enteric Salmonella Typhimurium infection to a rapid, cytokine-dependent increase in intestinal mucin release.

Xiao Han, Joannie M Allaire, Shauna M Crowley, Jocelyn J Chan, Kelly Lau, Conghao Zhang, Simon A Hirota, Kirk Bergstrom, Leigh A Knodler, Bruce A Vallance.

  The host restricts Salmonella enterica serovar Typhimurium infection of the gut via inflammasome-dependent sloughing of infected epithelial cells. Here we determined that concurrent caspase 1/11-dependent release of the goblet cell-derived mucin, Muc2, into the intestinal lumen also controls Salmonella burdens in infected mice. The increased release of mucins from goblet cells in the cecum and nearby proximal colon, and the subsequent thickening of the protective mucus barrier layer in the distal colon, were all dependent on the cytokines interleukin (IL)-18 and IL-22, as deficiencies in either cytokine resulted in reduced mucin secretion. Supplementation of IL-18 into IL-22 deficient mice restored mucin secretion, indicating that IL-22 acted upstream of IL-18 secretion during infection. In contrast, IL-18 and IL-22 independent signaling through Nlrp6 underlies only a modest, infection-induced increase in mucin secretion from goblet cells in the distal colon. These findings reveal that inflammasome signaling orchestrates multiple levels of protection centered on the intestinal epithelium, including pyroptosis and expulsion of infected enterocytes, as well as the release of mucins by goblet cells in the cecum and along the length of the colon. Our studies underscore the pivotal, multi-faceted role of inflammasome signaling in promoting host defense at the intestinal mucosal surface.

Keywords:  IL-22; Salmonella; enteric infection; goblet cell; inflammasome; mucus

DOI:  https://doi.org/10.1080/19490976.2024.2413372
Clin Chest Med. 2024 Dec;pii: S0272-5231(24)00066-2. [Epub ahead of print]45(4): 821-833

Cellular Mechanisms of Lung Injury: Current Perspectives.

Jamie E Meegan, Alicia N Rizzo, Eric P Schmidt, Julie A Bastarache.

  The alveolar-capillary barrier includes microvascular endothelial and alveolar epithelial cells and their matrices, and its disruption is a critical driver of lung injury during development of acute respiratory distress syndrome. In this review, we provide an overview of the structure and function of the alveolar-capillary barrier during health and highlight several important signaling mechanisms that underlie endothelial and epithelial injury during critical illness, emphasizing areas with potential for development of therapeutic strategies targeting alveolar-capillary leak. We also emphasize the importance of biomarker and preclinical studies in developing novel therapies and highlight important areas warranting future investigation.

Keywords:  Alveolar epithelial type 1cells; Alveolar epithelial type 2cells; Alveolar epithelium; Glycocalyx; Lung microvascular endothelium; Permeability

DOI:  https://doi.org/10.1016/j.ccm.2024.08.004
J Extracell Vesicles. 2024 Oct;13(10): e70004

Bacterial extracellular vesicles as intranasal postbiotics: Detailed characterization and interaction with airway cells.

Agnieszka Razim, Agnieszka Zabłocka, Anna Schmid, Michael Thaler, Viktor Černý, Tamara Weinmayer, Bradley Whitehead, Anke Martens, Magdalena Skalska, Mattia Morandi, Katy Schmidt, Magdalena E Wysmołek, Akos Végvári, Dagmar Srutkova, Martin Schwarzer, Lukas Neuninger, Peter Nejsum, Jiri Hrdý, Johan Palmfeldt, Marco Brucale, Francesco Valle, Sabina Górska, Lukas Wisgrill, Aleksandra Inic-Kanada, Ursula Wiedermann, Irma Schabussova.

  Escherichia coli A0 34/86 (EcO83) is a probiotic strain used in newborns to prevent nosocomial infections and diarrhoea. This bacterium stimulates both pro- and anti-inflammatory cytokine production and its intranasal administration reduces allergic airway inflammation in mice. Despite its benefits, there are concerns about the use of live probiotic bacteria due to potential systemic infections and gene transfer. Extracellular vesicles (EVs) derived from EcO83 (EcO83-EVs) might offer a safer alternative to live bacteria. This study characterizes EcO83-EVs and investigates their interaction with host cells, highlighting their potential as postbiotic therapeutics. EcO83-EVs were isolated, purified, and characterised following the Minimal Information of Studies of Extracellular Vesicles (MISEV) guidelines. Ex vivo studies conducted in human nasal epithelial cells showed that EcO83-EVs increased the expression of proteins linked to oxidative stress and inflammation, indicating an effective interaction between EVs and the host cells. Further in vivo studies in mice demonstrated that EcO83-EVs interact with nasal-associated lymphoid tissue, are internalised by airway macrophages, and stimulate neutrophil recruitment in the lung. Mechanistically, EcO83-EVs activate the NF-κΒ signalling pathway, resulting in the nitric oxide production. EcO83-EVs demonstrate significant potential as a postbiotic alternative to live bacteria, offering a safer option for therapeutic applications. Further research is required to explore their clinical use, particularly in mucosal vaccination and targeted immunotherapy strategies.

Keywords:  EVs; Ec083; NF‐κΒ signalling; bacterial extracellular vesicles; macrophage; nitric oxide; postbiotics; probiotic

DOI:  https://doi.org/10.1002/jev2.70004
Clin Otolaryngol. 2024 Oct 23.

Differential Nasal Recolonization and Microbial Profiles in Chronic Rhinosinusitis With Nasal Polyps Patients After Endoscopic Sinus Surgery or Dupilumab Treatment: A Prospective Observational Study.

Antonino Maniaci, Gaia Vertillo Aluisio, Stefania Stefani, Salvatore Cocuzza, Jerome Rene Lechien, Thomas Radulesco, Justin Michel, Maria Santagati, Ignazio La Mantia.

   INTRODUCTION: The role of microbial profiles in Chronic Rhinosinusitis with Nasal Polyps (CRSwNP) pathogenesis is increasingly recognised, with microbial imbalances perpetuating inflammation. We performed this study to associate the different nasal microbiological profile changes with the response to surgical or monoclonal treatment.
METHODS: This prospective observational study evaluated changes in the nasal microbial profiles of 44 patients (22 dupilumab, 22 surgery) over 6 months. Clinical assessments were performed at baseline and follow-ups, including Sino-Nasal Outcome Test-22 (SNOT-22) scores and Sniffin Sticks-Identification (SS-I) olfactory testing. Microbial profiling of nasal swabs was carried out by microbial culture and subsequent molecular identification by Polymerase chain reaction (PCR) and sequencing.
RESULTS: Baseline characteristics of 44 patients (22 dupilumab, 22 surgery) enrolled in this study were similar between groups. In the dupilumab group, Staphylococcus epidermidis prevalence rose from 37.03% to 59.25%, while Pseudomonas aeruginosa was eradicated. Moreover, dupilumab stabilised Staphylococcus aureus at 63.64%, while its prevalence increased in the surgery group (from 22.72% to 50%). When bacterial groups were associated with clinical scores, P. aeruginosa carriers had worse SNOT-22 (21.00 ± 1.41) and SS-I (5.50 ± 0.71) scores. Instead, S. epidermidis-colonised patients exhibited significantly lower mean SNOT-22 (15.39 ± 8.54) and greater SS-I scores (8.39 ± 3.77). The best outcomes were found in the subgroup of S. epidermidis carriers undergoing the dupilumab treatment.
CONCLUSION: The two treatments modulated the microbial profiles differently, and, most importantly, clinical responses might depend on the association between treatment and the dominant bacterial species colonising the nasal cavity. Further investigation into microbial-restorative strategies could enhance outcomes for better treatment of CRS.

Keywords:   Pseudomonas aeruginosa ; Staphylococcus aureus ; CRSwNP; Dupilumab; nasal microbiome

DOI:  https://doi.org/10.1111/coa.14246
Pediatr Pulmonol. 2024 Oct 22.

Understanding the role of innate immune training in prevention of respiratory infections.

Peter D Sly.



Keywords:  child; immune maturation; infant; maternal gut mcrobiome; microbial exposure

DOI:  https://doi.org/10.1002/ppul.27278
Hum Vaccin Immunother. 2024 Dec 31. 20(1): 2415823

Knowledge mapping of trained immunity/innate immune memory: Insights from two decades of studies.

Jiacheng He, Hongxia Cui, Guoqian Jiang, Lijun Fang, Jianlei Hao.

  This study employs knowledge mapping and bibliometric techniques to analyze the research landscape of trained immunity over the past 20 years and to identify current research hotspots and future development directions. The literature related to trained immunity was searched from the Web of Science Core Collection database, spanning 2004 to 2023. VOSViewer, CiteSpace and Bibliometrix were used for the knowledge mapping analysis. The foremost research institutions are Radboud University Nijmegen, University of Bonn, and Harvard University. Professor Netea MG of Radboud University Nijmegen has published the greatest number of articles. The current research focus encompasses immune memory, nonspecific effects, epigenetics, metabolic reprogramming, BCG vaccine, and the development of trained immunity-based vaccines. It is likely that research on trained immunity-based vaccines will become a major focus in the development of new vaccines in the future. It would be advantageous to observe a greater number of prospective clinical studies with robust evidence.

Keywords:  Bibliometrix; CiteSpace; Trained immunity; Vosviewer; innate immune memories; visual analysis

DOI:  https://doi.org/10.1080/21645515.2024.2415823
Gut Microbes. 2024 Jan-Dec;16(1):16(1): 2418412

Muropeptides and muropeptide transporters impact on host immune response.

Maria Lucia Orsini Delgado, Joao Gamelas Magalhaes, Rachel Morra, Antonietta Cultrone.

  In bacteria, the cell envelope is the key element surrounding and protecting the bacterial content from mechanical or osmotic damages. It allows the selective interchanges of solutes, ions, cellular debris, and drugs between the cellular compartments and the external environment, thanks to the presence of transmembrane proteins called transporters. The major component of the cell envelope is the peptidoglycan, consisting of long linear glycan strands cross-linked by short peptide stems. During cell growth or under stress conditions, peptidoglycan fragments, the muropeptides, are released by bacteria and recognized by the host Pattern Recognition Receptor, promoting the activation of their innate defense mechanisms. The review sums up the salient aspects of microbiota-host interaction with a focus on the NOD-dependent immune response to bacterial peptidoglycan and on the accountability of muropeptide transporters in the crosstalk with the host and in antibiotic resistance. Furthermore, it retraces the discoveries and applications of microorganisms-derived components such as vaccines or vaccine adjuvants.

Keywords:  Muropeptides; antibiotic resistance; innate response; microbiota; transporter

DOI:  https://doi.org/10.1080/19490976.2024.2418412
Nat Rev Microbiol. 2024 Oct 23.

Examining the healthy human microbiome concept.

Human Microbiome Action Consortium

Human microbiomes are essential to health throughout the lifespan and are increasingly recognized and studied for their roles in metabolic, immunological and neurological processes. Although the full complexity of these microbial communities is not fully understood, their clinical and industrial exploitation is well advanced and expanding, needing greater oversight guided by a consensus from the research community. One of the most controversial issues in microbiome research is the definition of a 'healthy' human microbiome. This concept is complicated by the microbial variability over different spatial and temporal scales along with the challenge of applying a unified definition to the spectrum of healthy microbiome configurations. In this Perspective, we examine the progress made and the key gaps that remain to be addressed to fully harness the benefits of the human microbiome. We propose a road map to expand our knowledge of the microbiome-health relationship, incorporating epidemiological approaches informed by the unique ecological characteristics of these communities.

DOI: https://doi.org/10.1038/s41579-024-01107-0
Front Cell Infect Microbiol. 2024 ;14 1455819

Interleukin-26 expression in tuberculosis disease and its regulatory effect in macrophage polarization and intracellular elimination of Mycobacterium tuberculosis.

Kaisong Huang, Haijin Zhou, Mei Chen, Rui Chen, Xiaoping Wang, Qi Chen, Zhiyun Shi, Yanfang Liang, Luxin Yu, Ping Ouyang, Li Li, Dan Jiang, Guangxian Xu.

  Tuberculosis(TB), an infectious disease caused by Mycobacterium tuberculosis (Mtb) infections, remains the leading cause of mortality from a single infectious agent globally. The progression of tuberculosis disease is contingent upon the complex interplay between the host's immune system and the pathogen Mtb. Interleukin-26 (IL-26), the most recently identified cytokine belonging to the IL-10 family, exhibits both extracellular antimicrobial properties and pro-inflammatory functions. However, the precise role of IL-26 in the host immune defense against Mtb infections and intracellular killing remains largely unexplored. In this study, we observed significantly elevated IL-26 mRNA expression in peripheral blood mononuclear cells of active-TB patients compared to healthy individuals. Conversely, circulating IL-26 levels in the plasma of adult TB patients were markedly lower than those of healthy cohorts. We purified recombinant IL-26 from an E. coli expression system using the Ni-NTA resin. Upon stimulations with the recombinant IL-26, human THP1 cells exhibited rapid morphological changes characterized by increased irregular spindle shape and formation of granular structures. Treating THP1 cells with IL-26 can also lead to heightened expressions of CD80, TNF-α, and iNOS but not CD206 and Arg1 in these cells, indicating an M1 macrophage differentiation phenotype. Furthermore, our investigations revealed a dose-dependent escalation of reactive oxygen species production, decreased mitochondrial membrane potential, and enhanced autophagy flux activity in THP1 macrophages following IL-26 treatment. Moreover, our results demonstrated that IL-26 contributed to the elimination of intracellular Mycobacterium tuberculosis via orchestrated ROS production. In conclusion, our findings elucidated the role of IL-26 in the development of tuberculosis and its contributions to intracellular bacilli killing by macrophages through the induction of M1-polarization and ROS production. These insights may have significant implications for understanding the pathogenesis of tuberculosis and developing novel therapeutic strategies.

Keywords:  M1 macrophages; Mycobacterium tuberculosis; ROS; Tuberculosis; interleukin-26

DOI:  https://doi.org/10.3389/fcimb.2024.1455819
Juntendo Iji Zasshi. 2024 ;70(4): 269-272

Mitochondrial Damage in Sepsis.

Ricard Ferrer, Toshiaki Iba.

  Mitochondria not only generate adenosine triphosphate (ATP) and act as the powerhouse of the cell but also contribute to host defense by producing reactive oxygen species. Therefore, mitochondrial damage in sepsis directly results in a shortage of energy currency and dysregulation of the immune system. Other than those, mitochondrial damage results in the release of highly dangerous mitochondrial DNA, facilitating acidosis by modulating the metabolism and inducing programmed cell death, thereby facilitating disease progression in sepsis. Various forms of cell death are induced by mitochondrial damage. Aponecrosis is a secondary conversion from apoptosis to necrosis. Although apoptosis is initially intended, it cannot be completed due to ATP depletion from mitochondrial damage, ultimately leading to inflammatory necrosis. Besides such accidental cell death, programmed inflammation-inducing cell deaths such as necroptosis, ferroptosis, and pyroptosis are induced by mitochondrial damage in sepsis. Based on these findings, the regulation of mitochondrial damage holds promise for the development of new therapeutic approaches for sepsis.

Keywords:  mitochondria; organ dysfunction; oxidative stress; programmed cell death; sepsis

DOI:  https://doi.org/10.14789/jmj.JMJ24-0016-P
Cell Mol Life Sci. 2024 Oct 25. 81(1): 438

Gut microbiota-derived acetic acids promoted sepsis-induced acute respiratory distress syndrome by delaying neutrophil apoptosis through FABP4.

Weixia Xuan, Xu Wu, Longcheng Zheng, Huayun Jia, Xiaoju Zhang, Xulong Zhang, Bin Cao.

  In patients with sepsis, neutrophil apoptosis tends to be inversely proportional to the severity of sepsis, but its mechanism is not yet clear. This study aimed to explore the mechanism of fatty acid binding protein 4 (FABP4) regulating neutrophil apoptosis through combined analysis of gut microbiota and short-chain fatty acids (SCFAs) metabolism. First, neutrophils from bronchoalveolar lavage fluid (BALF) of patients with sepsis-induced acute respiratory distress syndrome (ARDS) were purified and isolated RNA was applied for sequencing. Then, the cecal ligation and puncture (CLP) method was applied to induce the mouse sepsis model. After intervention with differential SCFAs sodium acetate, neutrophil apoptosis and FABP4 expression were further analyzed. Then, FABP4 inhibitor BMS309403 was used to treat neutrophils. We found CLP group had increased lung injury score, lung tissue wet/dry ratio, lung vascular permeability, and inflammatory factors IL-1β, TNF-α, IL-6, IFN-γ, and CCL3 levels in both bronchoalveolar lavage fluid and lung tissue. Additionally, FABP4 was lower in neutrophils of ARDS patients and mice. Meanwhile, CLP-induced dysbiosis of gut microbiota and changes in SCFAs levels were observed. Further verification showed that acetic acids reduced neutrophil apoptosis and FABP4 expression via FFAR2. Besides, FABP4 affected neutrophil apoptosis through endoplasmic reticulum (ER) stress, and neutrophil depletion alleviated the promotion of ARDS development by BMS309403. Moreover, FABP4 in neutrophils regulated the injury of RLE-6TN through inflammatory factors. In conclusion, FABP4 affected by gut microbiota-derived SCFAs delayed neutrophil apoptosis through ER stress, leading to increased inflammatory factors mediating lung epithelial cell damage.

Keywords:  ARDS; FABP4; Gut microbiota; Neutrophils; Short-chain fatty acids

DOI:  https://doi.org/10.1007/s00018-024-05474-y
J Intensive Care. 2024 Oct 25. 12(1): 41

Autophagy and autophagic cell death in sepsis: friend or foe?

Toshiaki Iba, Julie Helms, Cheryl L Maier, Ricard Ferrer, Jerrold H Levy.

  In sepsis, inflammation, and nutrient deficiencies endanger cellular homeostasis and survival. Autophagy is primarily a mechanism of cellular survival under fasting conditions. However, autophagy-dependent cell death, known as autophagic cell death, is proinflammatory and can exacerbate sepsis. Autophagy also regulates various types of non-inflammatory and inflammatory cell deaths. Non-inflammatory apoptosis tends to suppress inflammation, however, inflammatory necroptosis, pyroptosis, ferroptosis, and autophagic cell death lead to the release of inflammatory cytokines and damage-associated molecular patterns (DAMPs) and amplify inflammation. The selection of cell death mechanisms is complex and often involves a mixture of various styles. Similarly, protective autophagy and lethal autophagy may be triggered simultaneously in cells. How cells balance the regulatory mechanisms of these processes is an area of interest that is still under investigation. Therapies aimed at modulating autophagy are considered promising. Enhancing autophagy helps clear and recycle damaged organelles and reduce the burden of inflammatory processes while inhibiting excessive autophagy, which could prevent autophagic cell death. In this review, we introduce recent advances in research and the complex regulatory system of autophagy in sepsis.

Keywords:  Apoptosis; Autophagy; Mitochondria; Mitophagy; Necrosis; Sepsis

DOI:  https://doi.org/10.1186/s40560-024-00754-y
Trends Immunol. 2024 Oct 21. pii: S1471-4906(24)00219-9. [Epub ahead of print]

Regional specialization within the mammalian respiratory immune system.

David P Hoytema van Konijnenburg, Peter A Nigrovic, Ivan Zanoni.

  The respiratory tract is exposed to infection from inhaled pathogens, including viruses, bacteria, and fungi. So far, a comprehensive assessment that integrates common and distinct aspects of the immune response along different areas of the respiratory tract has been lacking. Here, we discuss key recent findings regarding anatomical, functional, and microbial factors driving regional immune adaptation in the mammalian respiratory system, how they differ between mice and humans, and the similarities and differences with the gastrointestinal tract. We demonstrate that, under evolutionary pressure, mammals evolved spatially organized immune defenses that vary between the upper and lower respiratory tract. Overall, we propose that the functional specialization of the immune response along the respiratory tract has fundamental implications for the management of infectious or inflammatory diseases.

Keywords:  airways; bacteria; fungi; immunity; tissue memory; virus

DOI:  https://doi.org/10.1016/j.it.2024.09.011
Front Med (Lausanne). 2024 ;11 1449037

The important role of ferroptosis in inflammatory bowel disease.

Hanhan Xie, Chun Cao, Dan Shu, Tong Liu, Tao Zhang.

  Ferroptosis is a type of regulated cell death that occurs due to the iron-dependent accumulation of lethal reactive oxygen species (ROS) from lipids. Ferroptosis is characterized by distinct morphological, biochemical, and genetic features that differentiate it from other regulated cell death (RCD) types, which include apoptosis, various necrosis types, and autophagy. Recent reports show that ferritin formation is correlated to many disorders, such as acute injury, infarction, inflammation, and cancer. Iron uptake disorders have also been associated with intestinal epithelial dysfunction, particularly inflammatory bowel disease (IBD). Studies of iron uptake disorders may provide new insights into the pathogenesis of IBD, thereby improving the efficacy of medical interventions. This review presents an overview of ferroptosis, elucidating its fundamental mechanisms and highlighting its significant involvement in IBD.

Keywords:  ROS; ferroptosis; inflammatory bowel disease; intestinal epithelial cells; mechanism

DOI:  https://doi.org/10.3389/fmed.2024.1449037
Trends Cell Biol. 2024 Oct 21. pii: S0962-8924(24)00205-8. [Epub ahead of print]

Extracellular vesicles from the dead: the final message.

Bo Shi, Thanh Kha Phan, Ivan K H Poon.

  Communication between dying and neighbouring cells is vital to ensure appropriate processes such as tissue repair or inflammation are initiated in response to cell death. As a mechanism to aid intercellular communication, cells undergoing apoptosis can release membrane-bound extracellular vesicles (EVs) called apoptotic-cell-derived EVs (ApoEVs) that can influence downstream processes through biomolecules within or on ApoEVs. ApoEVs are broadly categorised based on size as either large ApoEVs known as apoptotic bodies (ApoBDs) or small ApoEVs (s-ApoEVs). Notably, the mechanisms of ApoBD and s-ApoEV formation are different, and the functions of these two ApoEV subsets are distinct. This Review focuses on the biogenesis and functional properties of both ApoBDs and s-ApoEVs, particularly in the context of cell clearance, cell signalling and disease progression.

Keywords:  apoptosis; apoptotic bodies; apoptotic-cell-derived extracellular vesicles; cell clearance; cell-free therapeutics

DOI:  https://doi.org/10.1016/j.tcb.2024.09.005
Commun Integr Biol. 2024 ;17(1): 2415598

Quorum sensing and antibiotic resistance in polymicrobial infections.

Sunny Cui, Esther Kim.

  Quorum sensing (QS) is a critical bacterial communication system regulating behaviors like biofilm formation, virulence, and antibiotic resistance. This review highlights QS's role in polymicrobial infections, where bacterial species interactions enhance antibiotic resistance. We examine QS mechanisms, such as acyl-homoserine lactones (AHLs) in Gram-negative bacteria and autoinducing peptides (AIPs) in Gram-positive bacteria, and their impact on biofilm-associated antibiotic resistance. The challenges uniquely associated with polymicrobial infections, such as those found in cystic fibrosis lung infections, chronic wound infections, and medical device infections, are also summarized. Furthermore, we explore various laboratory models, including flow cells and dual-species culture models, used to study QS interactions in polymicrobial environments. The review also discusses promising quorum sensing inhibitors (QSIs), such as furanones and AHL analogs, which have demonstrated efficacy in reducing biofilm formation and virulence in laboratory and clinical studies. By addressing the interplay between QS and antibiotic resistance, this paper aims to advance therapeutic strategies that disrupt bacterial communication and improve antibiotic efficacy, ultimately mitigating the global challenge of antibiotic resistance in polymicrobial infections.

Keywords:  Bacteria communication; biofilm formation; biofilms; biological communication; polymicrobial infections; quorum inhibitors; quorum quenchers; quorum sensing; quorum sensing inhibitors; signal molecules

DOI:  https://doi.org/10.1080/19420889.2024.2415598
Front Immunol. 2024 ;15 1485523

Unveiling ferroptosis: a new frontier in skin disease research.

Ke Wang, Yumeng Lin, Dan Zhou, Peipei Li, Xiaoying Zhao, Zhongyu Han, Haoran Chen.

  Ferroptosis, a form of regulated cell death distinct from apoptosis, necrosis, and autophagy, is increasingly recognized for its role in skin disease pathology. Characterized by iron accumulation and lipid peroxidation, ferroptosis has been implicated in the progression of various skin conditions, including psoriasis, photosensitive dermatitis, and melanoma. This review provides an in-depth analysis of the molecular mechanisms underlying ferroptosis and compares its cellular effects with other forms of cell death in the context of skin health and disease. We systematically examine the role of ferroptosis in five specific skin diseases, including ichthyosis, psoriasis, polymorphous light eruption (PMLE), vitiligo, and melanoma, detailing its influence on disease pathogenesis and progression. Moreover, we explore the current clinical landscape of ferroptosis-targeted therapies, discussing their potential in managing and treating skin diseases. Our aim is to shed light on the therapeutic potential of modulating ferroptosis in skin disease research and practice.

Keywords:  ferroptosis; iron metabolism; melanoma; psoriasis; skin diseases

DOI:  https://doi.org/10.3389/fimmu.2024.1485523