bims-bac4me Biomed News
on Microbiome and trained immunity
Issue of 2023–12–17
forty-nine papers selected by
Chun-Chi Chang, Universitäts Spital Zürich
  1. Airway environment drives the selection of quorum sensing mutants and promote Staphylococcus aureus chronic lifestyle.
  2. Antiviral innate immune memory in alveolar macrophages following SARS-CoV-2 infection.
  3. Role of solute carrier transporters in regulating dendritic cell maturation and function.
  4. Diesel Exhaust Particles Induce Polarization-State Dependent Functional and Transcriptional Changes in Human Monocyte-Derived Macrophages.
  5. COVID-19 and trained immunity: the inflammatory burden of long covid.
  6. mSphere of Influence: How host genetics impact microbial pathogenesis and treatment of infectious disease.
  7. The preprogrammed anti-inflammatory phenotypes of CD11chigh macrophages by Streptococcus pneumoniae aminopeptidase N safeguard from allergic asthma.
  8. Tracheal epithelial cell-exosome-derived MiR-21-5p inhibits alveolar macrophage pyroptosis to resist pulmonary bacterial infection through PIK3CD-autophagy pathway.
  9. Microinjection of β-glucan Into Larval Zebrafish (Danio rerio) for the Assessment of a Trained-Like Immunity Phenotype.
  10. Decoding immunogenic cell death from a dendritic cell perspective.
  11. Tissue-resident memory T cells exhibit phenotypically and functionally heterogeneous in human physiological and pathological nasal mucosa.
  12. BCG vaccination impacts the epigenetic landscape of progenitor cells in human bone marrow.
  13. A chromatin-regulated biphasic circuit coordinates IL-1β-mediated inflammation.
  14. GehB Inactivates Lipoproteins to Delay the Healing of Acute Wounds Infected with Staphylococcus aureus.
  15. Host Transcriptional Regulatory Genes and Microbiome Networks Crosstalk through Immune Receptors Establishing Normal and Tumor Multiomics Metafirm of the Oral-Gut-Lung Axis.
  16. Environmental bisphenol A exposure triggers trained immunity-related pathways in monocytes.
  17. This group of bizarre gut microbes is unexpectedly complex.
  18. Medicine Targeting Epithelial-Mesenchymal Transition to Treat Airway Remodeling and Pulmonary Fibrosis Progression.
  19. The noncanonical inflammasome in health and disease.
  20. Serine metabolism in macrophage polarization.
  21. Nucleic acid sensing promotes inflammatory monocyte migration through biased coagulation factor VIIa signaling.
  22. Elucidating granulocytic myeloid-derived suppressor cell heterogeneity during Staphylococcus aureus biofilm infection.
  23. Commensal bacteria promote type I interferon signaling to maintain immune tolerance in mice.
  24. Microbiome diversity protects against pathogens by nutrient blocking.
  25. The world's largest proteins? These mega-molecules turn bacteria into predators.
  26. Very Rapid Improvement in Extended Nitric Oxide Parameters Is Associated With Clinical and Functional Improvement in Patients With Chronic Rhinosinusitis With Nasal Polyps Treated With Dupilumab.
  27. Staphylococcal superantigen-like protein 10 enhances the amyloidogenic biofilm formation in Staphylococcus aureus.
  28. Editorial: Respiratory microbiome in health and disease.
  29. Beyond antiviral: Interferon induced by bacteria maintains tolerance in the gut.
  30. Bacille-Calmette-Guerin modulates human macrophage and dendritic cell response to SARS-CoV-2 S-glycoprotein.
  31. Heterogeneity in lung macrophage control of Mycobacterium tuberculosis is determined by T cells.
  32. ovadExploring alternative strategies for Staphylococcus aureus Nasal decolonization: Insights from Preclinical Studies.
  33. Toolbox of Characterized Genetic Parts for Staphylococcus aureus.
  34. Alpha-defensins inhibit ERK/STAT3 signaling during monocyte-macrophage differentiation and impede macrophage function.
  35. Staphylococcus aureus functional amyloids catalyze degradation of β-lactam antibiotics.
  36. The nuclear receptor Nurr1 is preferentially expressed in human pro-inflammatory macrophages and limits their inflammatory profile.
  37. Efficient material-induced activation of monocyte-derived dendritic cells releasing surface molecules, matrix metalloproteinases, and growth factors needed for regenerative tissue remodeling.
  38. Differential in vivo labeling with barcoded antibodies allows for simultaneous transcriptomic profiling of airway, lung tissue and intravascular immune cells.
  39. Lacticaseibacillus rhamnosus CRL1505 Peptidoglycan Modulates the Inflammation-Coagulation Response Triggered by Poly(I:C) in the Respiratory Tract.
  40. The fight against antimicrobial resistance.
  41. A healthy mouth helps to maintain balanced metabolic profiles.
  42. Epigenetic memory in 3D.
  43. Harnessing bioengineered myeloid progenitors for precision immunotherapies.
  44. Corrigendum: Role of histamine-mediated macrophage differentiation in clearance of metastatic bacterial infection.
  45. Defining solute carrier transporter signatures of murine immune cell subsets.
  46. A deep lung cell atlas reveals cytokine-mediated lineage switching of a rare cell progenitor of the human airway epithelium.
  47. Nicotinic acetylcholine receptor signaling maintains epithelial barrier integrity.
  48. Lung dendritic-cell metabolism underlies susceptibility to viral infection in diabetes.
  49. SMYD3 activates the TCA cycle to promote M1-M2 conversion in macrophages.
  1. Nat Commun. 2023 Dec 08. 14(1): 8135
    Airway environment drives the selection of quorum sensing mutants and promote Staphylococcus aureus chronic lifestyle.
    Xiongqi Ding, Catherine Robbe-Masselot, Xiali Fu, Renaud Léonard, Benjamin Marsac, Charlene J G Dauriat, Agathe Lepissier, Héloïse Rytter, Elodie Ramond, Marion Dupuis, Daniel Euphrasie, Iharilalao Dubail, Cécile Schimmich, Xiaoquan Qin, Jessica Parraga, Maria Leite-de-Moraes, Agnes Ferroni, Benoit Chassaing, Isabelle Sermet-Gaudelus, Alain Charbit, Mathieu Coureuil, Anne Jamet.
      Staphylococcus aureus is a predominant cause of chronic lung infections. While the airway environment is rich in highly sialylated mucins, the interaction of S. aureus with sialic acid is poorly characterized. Using S. aureus USA300 as well as clinical isolates, we demonstrate that quorum-sensing dysfunction, a hallmark of S. aureus adaptation, correlates with a greater ability to consume free sialic acid, providing a growth advantage in an air-liquid interface model and in vivo. Furthermore, RNA-seq experiment reveals that free sialic acid triggers transcriptional reprogramming promoting S. aureus chronic lifestyle. To support the clinical relevance of our results, we show the co-occurrence of S. aureus, sialidase-producing microbiota and free sialic acid in the airway of patients with cystic fibrosis. Our findings suggest a dual role for sialic acid in S. aureus airway infection, triggering virulence reprogramming and driving S. aureus adaptive strategies through the selection of quorum-sensing dysfunctional strains.
    DOI:  https://doi.org/10.1038/s41467-023-43863-2
  2. bioRxiv. 2023 Nov 27. pii: 2023.11.24.568354. [Epub ahead of print]
    Antiviral innate immune memory in alveolar macrophages following SARS-CoV-2 infection.
    Alexander Lercher, Jin-Gyu Cheong, Chenyang Jiang, Hans-Heinrich Hoffmann, Alison W Ashbrook, Yue S Yin, Corrine Quirk, Emma J DeGrace, Luis Chiriboga, Brad R Rosenberg, Steven Z Josefowicz, Charles M Rice.
      Pathogen encounter results in long-lasting epigenetic imprinting that shapes diseases caused by heterologous pathogens. The breadth of this innate immune memory is of particular interest in the context of respiratory pathogens with increased pandemic potential and wide-ranging impact on global health. Here, we investigated epigenetic imprinting across cell lineages in a disease relevant murine model of SARS-CoV-2 recovery. Past SARS-CoV-2 infection resulted in increased chromatin accessibility of type I interferon (IFN-I) related transcription factors in airway-resident macrophages. Mechanistically, establishment of this innate immune memory required viral pattern recognition and canonical IFN-I signaling and augmented secondary antiviral responses. Past SARS-CoV-2 infection ameliorated disease caused by the heterologous respiratory pathogen influenza A virus. Insights into innate immune memory and how it affects subsequent infections with heterologous pathogens to influence disease pathology could facilitate the development of broadly effective therapeutic strategies.
    DOI:  https://doi.org/10.1101/2023.11.24.568354
  3. Eur J Immunol. 2023 Dec 11. e2350385
    Role of solute carrier transporters in regulating dendritic cell maturation and function.
    Lin Shao, Mengxin Yang, Tao Sun, Haotang Xia, Dan Du, Xun Li, Zuliang Jie.
      Dendritic cells (DCs) are specialized antigen-presenting cells (APCs) that initiate and regulate innate and adaptive immune responses. Solute carrier (SLC) transporters mediate diverse physiological functions and maintain cellular metabolite homeostasis. Recent studies have highlighted the significance of SLCs in immune processes. Notably, upon activation, immune cells undergo rapid and robust metabolic reprogramming, largely dependent on SLCs to modulate diverse immunological responses. In this review, we explore the central roles of SLC proteins and their transported substrates in shaping DC functions. We provide a comprehensive overview of recent studies on amino acid transporters, metal ion transporters, and glucose transporters, emphasizing their essential contributions to DC homeostasis under varying pathological conditions. Finally, we propose potential strategies for targeting SLCs in DCs to bolster immunotherapy for a spectrum of human diseases. This article is protected by copyright. All rights reserved.
    Keywords:  Dendritic cells; Immune regulation; Immunotherapy; Solute carrier transporters
    DOI:  https://doi.org/10.1002/eji.202350385
  4. Am J Physiol Lung Cell Mol Physiol. 2023 Dec 12.
    Diesel Exhaust Particles Induce Polarization-State Dependent Functional and Transcriptional Changes in Human Monocyte-Derived Macrophages.
    Timothy Robert Smyth, Ilona Jaspers.
      Macrophage populations exist on a spectrum between the pro-inflammatory M1 and the pro-resolution M2 states and have demonstrated the ability to reprogram between them following exposure to opposing polarization stimuli. Particulate matter (PM) has been repeatedly linked to worsening morbidity and mortality following respiratory infections and has been demonstrated to modify macrophage function and polarization. The purpose of this study was to determine whether diesel exhaust particles (DEP), a key component of airborne PM, would demonstrate polarization-state dependent effects on human monocyte-derived macrophages (hMDMs) and whether DEP would modify macrophage reprogramming. CD14+CD16- monocytes were isolated from the blood of healthy human volunteers and differentiated into macrophages using macrophage colony-stimulating factor (M-CSF). Resulting macrophages were left unpolarized or polarized into the pro-resolution M2 state before being exposed to DEP, M1-polarizing conditions (IFN-γ and LPS), or both and tested for phagocytic function, secretory profile, gene expression patterns, and bioenergetic properties. Contrary to previous reports, we observed a mixed M1/M2 phenotype in reprogrammed M2 cells when considering the broader range of functional readouts. In addition, we determined that DEP exposure dampens phagocytic function in all polarization states while modifying bioenergetic properties in M1 macrophages preferentially. Together, these data suggest DEP exposure of reprogrammed M2 macrophages results in a highly inflammatory, highly energetic subpopulation of macrophages which may contribute to the poor health outcomes following PM exposure during respiratory infections.
    Keywords:  Macrophage Reprogramming; Macrophages; PCA analysis; Particulate Matter
    DOI:  https://doi.org/10.1152/ajplung.00085.2023
  5. Front Immunol. 2023 ;14 1294959
    COVID-19 and trained immunity: the inflammatory burden of long covid.
    Jienan Gu, Qianhui Liu, Jiale Zhang, Shijie Xu.
      Severe COVID-19 elicits excessive inflammation mediated by innate immune cells like monocytes. Recent evidence reveals extensive epigenetic changes in monocytes during recovery from severe COVID-19, including increased chromatin accessibility at genes related to cytokine production and leukocyte activation. These changes likely originate from the reprogramming of upstream hematopoietic stem and progenitor cells (HSPCs) and represent "trained immunity". HSPC-to-monocyte transmission of epigenetic memory may explain the persistence of these monocyte alterations despite their short lifespan. IL-6 appears pivotal for imprinting durable epigenetic modifications in monocytes during acute infection, with IL-1β potentially playing a contributory role. The poised inflammatory phenotype of monocytes post-COVID-19 may drive chronic inflammation and tissue damage, contributing to post-acute sequelae of COVID-19 symptoms. COVID-19 could also exacerbate inflammation-related diseases, such multisystem inflammatory syndromes, by altering innate immune tendencies via hematopoietic epigenetic reprogramming. Further clinical investigations quantifying inflammatory mediators and mapping epigenetic changes in HSPCs/monocytes of recovering patients are warranted. Research should also examine whether COVID-19 elicits transgenerational inheritance of epigenetic alterations. Elucidating mechanisms underlying COVID-19-induced monocyte reprogramming and developing interventions targeting key inflammatory regulators like IL-6 may mitigate the sustained inflammatory burden imposed by the aberrant trained immunity post-COVID-19.
    Keywords:  chronic inflammation; hematopoietic stem and progenitor cells; innate immune; interleukin-1β; interleukin-6; monocytes; post-acute sequelae of COVID-19 symptoms
    DOI:  https://doi.org/10.3389/fimmu.2023.1294959
  6. mSphere. 2023 Dec 14. e0062923
    mSphere of Influence: How host genetics impact microbial pathogenesis and treatment of infectious disease.
    Emily E Rosowski.
      Emily Rosowski works in the field of host-pathogen interactions, studying how host innate immune mechanisms control pathogens. In this mSphere of Influence article, she reflects on how "Host genotype-specific therapies can optimize the inflammatory response to mycobacterial infections" by D. M. Tobin, F. J. Roca, S. F. Oh, R. McFarland, et al. (Cell 148:434-446, 2012, https://doi.org/10.1016/j.cell.2011.12.023) made an impact on her by investigating how differences in host genetics can affect modes of microbial pathogenesis and inform treatments for infectious disease.
    Keywords:  Aspergillus; Mycobacterium; host-pathogen interactions; zebrafish
    DOI:  https://doi.org/10.1128/msphere.00629-23
  7. J Transl Med. 2023 Dec 11. 21(1): 898
    The preprogrammed anti-inflammatory phenotypes of CD11chigh macrophages by Streptococcus pneumoniae aminopeptidase N safeguard from allergic asthma.
    Shifei Yao, Danlin Weng, Yan Wang, Yanyu Zhang, Qi Huang, Kaifeng Wu, Honghui Li, Xuemei Zhang, Yibing Yin, Wenchun Xu.
       BACKGROUND: Early microbial exposure is associate with protective allergic asthma. We have previously demonstrated that Streptococcus pneumoniae aminopeptidase N (PepN), one of the pneumococcal components, inhibits ovalbumin (OVA) -induced airway inflammation in murine models of allergic asthma, but the underlying mechanism was incompletely determined.
    METHODS: BALB/c mice were pretreated with the PepN protein and exposed intranasally to HDM allergen. The anti-inflammatory mechanisms were investigated using depletion and adoptive transfer experiments as well as transcriptome analysis and isolated lung CD11chigh macrophages.
    RESULTS: We found pretreatment of mice with PepN promoted the proliferation of lung-resident F4/80+CD11chigh macrophages in situ but also mobilized bone marrow monocytes to infiltrate lung tissue that were then transformed into CD11high macrophages. PepN pre-programmed the macrophages during maturation to an anti-inflammatory phenotype by shaping the metabolic preference for oxidative phosphorylation (OXPHOS) and also inhibited the inflammatory response of macrophages by activating AMP-activated protein kinase. Furthermore, PepN treated macrophages also exhibited high-level costimulatory signaling molecules which directed the differentiation into Treg.
    CONCLUSION: Our results demonstrated that the expansion of CD11chigh macrophages in lungs and the OXPHOS metabolic bias of macrophages are associated with reduced allergic airway inflammation after PepN exposure, which paves the way for its application in preventing allergic asthma.
    Keywords:  Allergic asthma; Hygiene hypothesis; Macrophage; Oxidation phosphorylation; Streptococcus pneumoniae aminopeptidase N
    DOI:  https://doi.org/10.1186/s12967-023-04768-2
  8. Life Sci. 2023 Dec 12. pii: S0024-3205(23)00975-X. [Epub ahead of print]336 122340
    Tracheal epithelial cell-exosome-derived MiR-21-5p inhibits alveolar macrophage pyroptosis to resist pulmonary bacterial infection through PIK3CD-autophagy pathway.
    Jun Wang, Lin Gan, Fengyang Li, Qin Li, Tong Wu, Zengshuai Wu, Peiru Chen, Brendon P Scicluna, Xin Feng, Jingmin Gu, Wenyu Han, Na Li, Liancheng Lei.
       AIMS: Structural cells play an important role in regulating immune cells during infection. Our aim was to determine whether structural porcine tracheal epithelial cells (PTECs) can regulate alveolar macrophages (AMs) to prevent bacterial pneumonia, explore the underlying mechanism(s) and therapeutic target.
    MATERIALS AND METHODS: Actinobacillus pleuropneumoniae (APP) was used as the model strain for infection studies. Small RNA sequencing was used to identify differentially abundant exosome-derived miRNAs. The role of PTECs exosome-derived miR-21-5p in regulating AMs autophagy, pyroptosis, reactive oxygen species (ROS) was determined using RT-qPCR, western-blotting, flow cytometry, immunohistochemistry. Luciferase reporter assays were conducted to identify potential binding targets of miR-21-5p. The universality of miR-21-5p action on resistance to bacterial pulmonary infection was demonstrated using Klebsiella pneumoniae or Staphylococcus aureus in vitro and in vivo infection models.
    KEY FINDINGS: MiR-21-5p was enriched in PETCs-derived exosomes, which protected AMs against pulmonary bacterial infection. Mechanistically, miR-21-5p targeted PIK3CD, to promote autophagy of AMs, which reduced the pyroptosis induced by APP infection via inhibiting the over-production of ROS, which in turn suppressed the over-expression of pro-inflammatory cytokines, and increased bacterial clearance. Importantly, the protective effect and mechanism of miR-21-5p were universal as they also occurred upon challenge with Klebsiella pneumoniae and Staphylococcus aureus.
    SIGNIFICANCE: Our data reveals miR-21-5p can promote pulmonary resistance to bacterial infection by inhibiting pyroptosis of alveolar macrophages through the PIK3CD-autophagy-ROS pathway, suggesting PIK3CD may be a potential therapeutic target for bacterial pneumonia.
    Keywords:  Autophagy; Bacterial pneumonia; Exosomes; PIK3CD; Pyroptosis; miRNA-21-5p
    DOI:  https://doi.org/10.1016/j.lfs.2023.122340
  9. Bio Protoc. 2023 Dec 05. 13(23): e4888
    Microinjection of β-glucan Into Larval Zebrafish (Danio rerio) for the Assessment of a Trained-Like Immunity Phenotype.
    Hannah Darroch, Jonathan W Astin, Christopher J Hall.
      The innate immune system can remember previous inflammatory insults, enabling long-term heightened responsiveness to secondary immune challenges in a process termed "trained immunity." Trained innate immune cells undergo metabolic and epigenetic remodelling and, upon a secondary challenge, provide enhanced protection with therapeutic potential. Trained immunity has largely been studied in innate immune cells in vitro or following ex vivo re-stimulation where the primary insult is typically injected into a mouse, adult zebrafish, or human. While highly informative, there is an opportunity to investigate trained immunity entirely in vivo within an unperturbed, intact whole organism. The exclusively innate immune response of larval zebrafish offers an attractive system to model trained immunity. Larval zebrafish have a functional innate immune system by 2 days post fertilisation (dpf) and are amenable to high-resolution, high-throughput analysis. This, combined with their optical transparency, conserved antibacterial responses, and availability of transgenic reporter lines, makes them an attractive alternative model to study trained immunity in vivo. We have devised a protocol where β-glucan (one of the most widely used experimental triggers of trained immunity) is systemically delivered into larval zebrafish using microinjection to stimulate a trained-like phenotype. Following stimulation, larvae are assessed for changes in gene expression, which indicate the stimulatory effect of β-glucan. This protocol describes a robust delivery method of one of the gold standard stimulators of trained immunity into a model organism that is highly amenable to several non-invasive downstream analyses. Key features • This protocol outlines the delivery of one of the most common experimental stimulators of trained immunity into larval zebrafish. • The protocol enables the assessment of a trained-like phenotype in vivo. • This protocol can be applied to transgenic or mutant zebrafish lines to investigate cells or genes of interest in response to β-glucan stimulation.
    Keywords:  Innate immunity response; Larval zebrafish; Microinjection; Trained immunity; β-glucan
    DOI:  https://doi.org/10.21769/BioProtoc.4888
  10. Immunol Rev. 2023 Dec 13.
    Decoding immunogenic cell death from a dendritic cell perspective.
    Sophie Janssens, Sofie Rennen, Patrizia Agostinis.
      Dendritic cells (DCs) are myeloid cells bridging the innate and adaptive immune system. By cross-presenting tumor-associated antigens (TAAs) liberated upon spontaneous or therapy-induced tumor cell death to T cells, DCs occupy a pivotal position in the cancer immunity cycle. Over the last decades, the mechanisms linking cancer cell death to DC maturation, have been the focus of intense research. Growing evidence supports the concept that the mere transfer of TAAs during the process of cell death is insufficient to drive immunogenic DC maturation unless this process is coupled with the release of immunomodulatory signals by dying cancer cells. Malignant cells succumbing to a regulated cell death variant called immunogenic cell death (ICD), foster a proficient interface with DCs, enabling their immunogenic maturation and engagement of adaptive immunity against cancer. This property relies on the ability of ICD to exhibit pathogen-mimicry hallmarks and orchestrate the emission of a spectrum of constitutively present or de novo-induced danger signals, collectively known as damage-associated molecular patterns (DAMPs). In this review, we discuss how DCs perceive and decode danger signals emanating from malignant cells undergoing ICD and provide an outlook of the major signaling and functional consequences of this interaction for DCs and antitumor immunity.
    Keywords:  antitumor immunity; damage-associated molecular patterns; dendritic cells; immunogenic cell death; inflammation
    DOI:  https://doi.org/10.1111/imr.13301
  11. Clin Immunol. 2023 Dec 06. pii: S1521-6616(23)00624-1. [Epub ahead of print]258 109860
    Tissue-resident memory T cells exhibit phenotypically and functionally heterogeneous in human physiological and pathological nasal mucosa.
    Sifei Yu, Kai Wang, Chen Cao, Beiying Zhang, Youmou Chen, Changyou Wu, Chunwei Li, Jun Tang, Wei Luo.
      Pathogens commonly enter mucosal barrier tissues and tissue-resident memory T cells (TRM) are essential for preventing mucosal lesions. However, the immunological properties of TRM cells in nasal mucosa are poorly known. In comparison with control tissues, decreasing CD103+ TRM cells were observed in Chronic rhinosinusitis with nasal polyps (CRSwNPs) and sinonasal inverted papilloma (SNIP), which presented high capability to produce effector cytokines. In CRSwNPs, we found that CD103+ TRM cells with higher cytokine and Granzyme B coexpressed high PD-1, CD103- TRM cells expressed higher IL-10. Homogenates isolated from CRSwNPs induced CD103 expression on peripheral T cells which could be inhibited by blocking TGF-β. The frequencies of CD103+ TRM cells in CRSwNPs were extremely negatively correlated with neutrophil infiltration. CD103+ TRM cells from Staphylococcus aureus positive CRSwNPs had a stronger response to SEB. Taken together, two phenotypically and functionally distinct subsets of TRM cells exist in nasal tissues and play critical roles in the progress of CRSwNPs and SNIPs.
    Keywords:  CD103; CRSwNPs; Cytokine; NIPs; Tissue-resident memory T cells
    DOI:  https://doi.org/10.1016/j.clim.2023.109860
  12. bioRxiv. 2023 Nov 28. pii: 2023.11.28.569076. [Epub ahead of print]
    BCG vaccination impacts the epigenetic landscape of progenitor cells in human bone marrow.
    Sarah J Sun, Raúl Aguirre-Gamboa, L Charlotte J de Bree, Joaquin Sanz, Anne Dumaine, Leo A B Joosten, Maziar Divangahi, Mihai G Netea, Luis B Barreiro.
      While the Bacille-Calmette-Guérin (BCG) vaccine is used to prevent tuberculosis, it also offers protection against a diverse range of non-mycobacterial infections. However, the underlying protective mechanisms in humans are not yet fully understood. Here, we surveyed at single-cell resolution the gene expression and chromatin landscape of human bone marrow, aspirated before and 90 days after BCG vaccination or placebo administration. We show that BCG vaccination significantly alters both the gene expression and epigenetic profiles of human hematopoietic stem and progenitor cells (HSPCs). Changes in gene expression occur primarily on the most uncommitted stem cells and are reflective of a persistent myeloid bias. In contrast, BCG-induced changes in chromatin accessibility are most prevalent within differentiated progenitor cells at sites influenced by Kruppel-like factor (KLF)/SP and EGR transcription factors (TFs). These TFs are also activated in the most uncommitted stem cells, indicating that activated TFs, which drive persistent changes in HSC gene expression, likely also drive chromatin dynamics appearing within downstream progenitor cells. This perspective contests the prevailing notion that epigenetic modifications linked to innate immune memory transfer directly from stem cells to their differentiated derivatives. Finally, we show that alterations in gene expression and chromatin accessibility in HSPCs due to BCG vaccination were highly correlated (r>0.8) with the IL-1β secretion capacity of paired PBMCs upon secondary immune challenge. Overall, our findings shed light on BCG vaccination's profound and lasting effects on HSPCs and its influence on innate immune responses.
    DOI:  https://doi.org/10.1101/2023.11.28.569076
  13. Nat Genet. 2023 Dec 13.
    A chromatin-regulated biphasic circuit coordinates IL-1β-mediated inflammation.
    Ezio T Fok, Simone J C F M Moorlag, Yutaka Negishi, Laszlo A Groh, Jéssica Cristina Dos Santos, Cathrin Gräwe, Valerie Villacorta Monge, Daphne D D Craenmehr, Mellanie van Roosmalen, David Pablo da Cunha Jolvino, Letícia Busato Migliorini, Ary Serpa Neto, Patricia Severino, Michiel Vermeulen, Leo A B Joosten, Mihai G Netea, Stephanie Fanucchi, Musa M Mhlanga.
      Inflammation is characterized by a biphasic cycle consisting initially of a proinflammatory phase that is subsequently resolved by anti-inflammatory processes. Interleukin-1β (IL-1β) is a master regulator of proinflammation and is encoded within the same topologically associating domain (TAD) as IL-37, which is an anti-inflammatory cytokine that opposes the function of IL-1β. Within this TAD, we identified a long noncoding RNA called AMANZI, which negatively regulates IL-1β expression and trained immunity through the induction of IL37 transcription. We found that the activation of IL37 occurs through the formation of a dynamic long-range chromatin contact that leads to the temporal delay of anti-inflammatory responses. The common variant rs16944 present in AMANZI augments this regulatory circuit, predisposing individuals to enhanced proinflammation or immunosuppression. Our work illuminates a chromatin-mediated biphasic circuit coordinating expression of IL-1β and IL-37, thereby regulating two functionally opposed states of inflammation from within a single TAD.
    DOI:  https://doi.org/10.1038/s41588-023-01598-2
  14. Curr Microbiol. 2023 Dec 08. 81(1): 36
    GehB Inactivates Lipoproteins to Delay the Healing of Acute Wounds Infected with Staphylococcus aureus.
    Kaiyu Wang, Xinyu Cai, Yifan Rao, Lu Liu, Zhen Hu, Huagang Peng, Yuting Wang, Yi Yang, Xiancai Rao, Kaiyu Nie, Weilong Shang.
      Staphylococcus aureus is one of the most prevalent bacteria found in acute wounds. S. aureus produces many virulence factors and extracellular enzymes that contribute to bacterial survival, dissemination, and pathogenicity. Lipase GehB is a glycerol ester hydrolase that hydrolyzes triglycerides to facilitate the evasion of S. aureus from host immune recognition. However, the role and mechanism of lipase GehB in skin acute wound healing after S. aureus infection remain unclear. In this study, we found that the gehB gene deletion mutant (USA300ΔgehB) stimulated significantly higher levels of pro-inflammatory cytokines in RAW264.7 and Toll-like receptor 2 (TLR2)-transfected HEK293 cells than the wild-type USA300 strain did. Recombinant GehB-His treated lipoprotein (Lpp) reduced stimulation of TLR2-dependent TNF-α production by RAW264.7 macrophages. GehB delayed the skin acute wound healing in BALB/c mice infected with S. aureus, while wound healing was similar in C57BL/6 TLR2-/- mice infected with either wild-type USA300 or USA300ΔgehB. In BALB/c mice, we also observed more bacterial survival, less leukocyte recruitment, lower IL-8 production, and adipocyte differentiation in USA300-infected skin acute wound tissues than those in USA300ΔgehB-challenged ones. Our data indicated that GehB inactivates lipoproteins to shield S. aureus from innate immune killing, resulting in delayed the healing of skin acute wounds infected with S. aureus.
    DOI:  https://doi.org/10.1007/s00284-023-03550-3
  15. Int J Mol Sci. 2023 Nov 23. pii: 16638. [Epub ahead of print]24(23):
    Host Transcriptional Regulatory Genes and Microbiome Networks Crosstalk through Immune Receptors Establishing Normal and Tumor Multiomics Metafirm of the Oral-Gut-Lung Axis.
    Beatriz Andrea Otálora-Otálora, Juan Javier López-Rivera, Claudia Aristizábal-Guzmán, Mario Arturo Isaza-Ruget, Carlos Arturo Álvarez-Moreno.
      The microbiome has shown a correlation with the diet and lifestyle of each population in health and disease, the ability to communicate at the cellular level with the host through innate and adaptative immune receptors, and therefore an important role in modulating inflammatory process related to the establishment and progression of cancer. The oral cavity is one of the most important interaction windows between the human body and the environment, allowing the entry of an important number of microorganisms and their passage across the gastrointestinal tract and lungs. In this review, the contribution of the microbiome network to the establishment of systemic diseases like cancer is analyzed through their synergistic interactions and bidirectional crosstalk in the oral-gut-lung axis as well as its communication with the host cells. Moreover, the impact of the characteristic microbiota of each population in the formation of the multiomics molecular metafirm of the oral-gut-lung axis is also analyzed through state-of-the-art sequencing techniques, which allow a global study of the molecular processes involved of the flow of the microbiota environmental signals through cancer-related cells and its relationship with the establishment of the transcription factor network responsible for the control of regulatory processes involved with tumorigenesis.
    Keywords:  adaptive and innate immune receptors; cancer; epigenomics; genomics; host–microbiome crosstalk; oral-gut-lung axis; transcriptional regulatory network (TRN); transcriptomics
    DOI:  https://doi.org/10.3390/ijms242316638
  16. Front Immunol. 2023 ;14 1270391
    Environmental bisphenol A exposure triggers trained immunity-related pathways in monocytes.
    Marcello Dallio, Lorenzo Ventriglia, Mario Romeo, Flavia Scognamiglio, Nadia Diano, Martina Moggio, Marina Cipullo, Annachiara Coppola, Athanasios Ziogas, Mihai G Netea, Alessandro Federico.
       Introduction: Trained Immunity represents a novel revolutionary concept of the immunological response involving innate immune cells. Bisphenol A is a well-known endocrine disrupter, widely disseminated worldwide and accumulated in the human body. Due to the increased interest regarding the effects of plastic-derived compounds on the immune system, our purpose was to explore whether BPA was able to induce trained immunity in human primary monocytes in vitro using low environmental concentrations.
    Materials and methods: We extracted BPA from the serum of 10 healthy individuals through a liquid-liquid extraction followed by a solid phase extraction and measured the concentration using an HPLC system coupled to a triple quadrupole mass spectrometer. In parallel, monocytes were isolated from whole blood and acutely stimulated or trained with BPA at three different concentrations (1 nM, 10 nM, 20 nM). Pro- and anti-inflammatory cytokines (IL-1β, TNF-α, IL-6, and IL-10) production were assessed after 24 hours of acute stimulation and after Lipopolysaccharide (LPS) rechallenge. A comprehensive overview of the metabolic changes after BPA acute stimulation and trained immunity induction was assessed through extracellular lactate measurements, Seahorse XFb metabolic flux analysis and ROS production.
    Results: Monocytes primed with BPA showed increased pro- and anti-inflammatory cytokine responses upon restimulation, sustained by the modulation of the immunometabolic circuits. Moreover, we proved the non-toxic effect of BPA at each experimental concentration by performing an MTT assay. Additionally, correlation analysis were performed between pro- and anti-inflammatory cytokines production after LPS acute stimulation or BPA-mediated trained immunity and BPA serum concentrations showing a significant association between TNF-α and BPA circulating levels.
    Discussion: Overall, this study pointed out for the first time the immunological effects of an environmental chemical and plastic-derived compound in the induction of trained immunity in a healthy cohort.
    Keywords:  bisphenol A; endocrine-disrupting compounds; inflammation; innate response; trained immunity
    DOI:  https://doi.org/10.3389/fimmu.2023.1270391
  17. Nature. 2023 Dec 13.
    This group of bizarre gut microbes is unexpectedly complex.
    McKenzie Prillaman.
      
    Keywords:  Microbiology; Microbiome
    DOI:  https://doi.org/10.1038/d41586-023-03990-8
  18. Can Respir J. 2023 ;2023 3291957
    Medicine Targeting Epithelial-Mesenchymal Transition to Treat Airway Remodeling and Pulmonary Fibrosis Progression.
    Hongjuan He, Xiaoyan Ji, Lihua Cao, Zhenzhen Wang, Xiaoyu Wang, Xiu-Min Li, Mingsan Miao.
      Objective. Dysregulation of epithelial-mesenchymal transition (EMT) in the airway epithelium is associated with airway remodeling and the progression of pulmonary fibrosis. Many treatments have been shown to inhibit airway remodeling and pulmonary fibrosis progression in asthma and chronic obstructive pulmonary disease (COPD) by regulating EMT and have few side effects. This review aimed to describe the development of airway remodeling through the EMT pathway, as well as the potential therapeutic targets in these pathways. Furthermore, this study aimed to review the current research on drugs to treat airway remodeling and their effects on the EMT pathway. Findings. The dysregulation of EMT was associated with airway remodeling in various respiratory diseases. The cytokines released during inflammation may induce EMT and subsequent airway remodeling. Various drugs, including herbal formulations, specific herbal compounds, cytokines, amino acid or protein inhibitors, microRNAs, and vitamins, may suppress airway remodeling by inhibiting EMT-related pathways.
    DOI:  https://doi.org/10.1155/2023/3291957
  19. Infect Med (Beijing). 2022 Sep;1(3): 208-216
    The noncanonical inflammasome in health and disease.
    Jason Cahoon, Duomeng Yang, Penghua Wang.
      Innate immune signaling plays a significant role in the rapid cellular responses against foreign entities. An inflammasome is a large cytosolic polymer of a pattern recognition receptor with/without an adaptor protein, formed in response to these entities. Canonically, an inflammasome can recruit and lead to auto-activation of caspase-1, subsequent maturation and secretion of inflammatory cytokines, and pyroptosis. One particular inflammasome, the noncanonical inflammasome, is formed by caspase-4 or -5 (mouse caspase-11) upon binding of lipopolysaccharide and is essential for controlling gram-negative bacterial infection. However, prolonged hyper-activation of the non-canonical inflammasome has been implicated in the pathogenesis of inflammatory diseases and endotoxemia sepsis. This review will summarize the recent advances on the noncanonical inflammasome, its mechanism of activation, key cellular regulators and role in health and disease.
    Keywords:  Caspase; Inflammasome; Inflammatory; Non-canonical; Pyroptosis
    DOI:  https://doi.org/10.1016/j.imj.2022.09.001
  20. Inflamm Res. 2023 Dec 09.
    Serine metabolism in macrophage polarization.
    Xinqiong Huang, Xue Yang, Li Xiang, Yuping Chen.
       OBJECTIVE: Emerging studies have revealed that macrophages possess different dependences on the uptake, synthesis, and metabolism of serine for their activation and functionalization, necessitating our insight into how serine availability and utilization impact macrophage activation and inflammatory responses.
    METHODS: This article summarizes the reports published domestically and internationally about the serine uptake, synthesis, and metabolic flux by the macrophages polarizing with distinct stimuli and under different pathologic conditions, and particularly analyzes how altered serine metabolism rewires the metabolic behaviors of polarizing macrophages and their genetic and epigenetic reprogramming.
    RESULTS: Macrophages dynamically change serine metabolism to orchestrate their anabolism, redox balance, mitochondrial function, epigenetics, and post-translation modification, and thus match the distinct needs for both classical and alternative activation.
    CONCLUSION: Serine metabolism coordinates multiple metabolic pathways to tailor macrophage polarization and their responses to different pathogenic attacks and thus holds the potential as therapeutic target for types of acute and chronic inflammatory diseases.
    Keywords:  Inflammation; Innate immunity; Macrophage polarization; Serine metabolism
    DOI:  https://doi.org/10.1007/s00011-023-01815-y
  21. Blood. 2023 Dec 14. pii: blood.2023021149. [Epub ahead of print]
    Nucleic acid sensing promotes inflammatory monocyte migration through biased coagulation factor VIIa signaling.
    Hortensia Zelaya, Kristin Grunz, Thanh Son Nguyen, Anxhela Habibi, Claudius Leon Witzler, Sabine Reyda, Irene Gonzalez-Menendez, Leticia Quintanilla-Martinez, Markus Bosmann, Hartmut Weiler, Wolfram Ruf.
      Protease activated receptors (PARs) are cleaved by coagulation proteases and thereby connect hemostasis with innate immune responses. Signaling of the tissue factor (TF) complex with FVIIa via PAR2 stimulates extracellular signal-regulated kinase (ERK) activation and cancer cell migration, but functions of cell autonomous TF-FVIIa signaling in immune cells are unknown. Here we show that myeloid cell expression of FVII but not of FX is crucial for inflammatory cell recruitment to the alveolar space after challenge with the double stranded viral RNA mimic Poly(I:C). In line with these data, genetically modified mice completely resistant to PAR2 cleavage but not FXa-resistant PAR2 mutant mice are protected from lung inflammation. Poly(I:C) stimulated migration of monocytes/macrophages is dependent on ERK activation and mitochondrial antiviral signaling (MAVS), but independent of toll-like receptor (TLR) 3. Monocyte/ macrophage synthesized FVIIa cleaving PAR2 is required for integrin αMβ2-dependent migration on fibrinogen, but not for integrin β1-dependent migration on fibronectin. To further dissect the downstream signaling pathway, we generated PAR2S365/T368A mutant mice deficient in β-arrestin recruitment and ERK scaffolding. This mutation reduces cytosolic, but not nuclear ERK phosphorylation by Poly(I:C) stimulation and prevents macrophage migration on fibrinogen, but not fibronectin following stimulation with Poly(I:C) or CpG-B, a single stranded DNA TLR9 agonist. In addition, PAR2S365/T368A mutant mice display markedly reduced immune cell recruitment to the alveolar space after Poly(I:C) challenge. These results identify TF-FVIIa-PAR2-β-arrestin biased signaling as a driver for lung infiltration in response to viral nucleic acids and suggest potential therapeutic interventions specifically targeting TF-VIIa signaling in thrombo-inflammation.
    DOI:  https://doi.org/10.1182/blood.2023021149
  22. J Leukoc Biol. 2023 Dec 14. pii: qiad158. [Epub ahead of print]
    Elucidating granulocytic myeloid-derived suppressor cell heterogeneity during Staphylococcus aureus biofilm infection.
    Blake P Bertrand, Cortney E Heim, Scott A Koepsell, Tammy Kielian.
      Myeloid-derived suppressor cells (MDSCs) are pathologically activated immature myeloid cells with immunosuppressive activity that expand during chronic inflammation, such as cancer and prosthetic joint infection (PJI). MDSCs can be broadly separated into two populations based on surface marker expression and function, namely monocytic MDSCs (M-MDSCs) and granulocytic MDSCs (G-MDSCs). G-MDSCs are the most abundant leukocyte infiltrate during PJI; however, how this population is maintained in vivo and cellular heterogeneity is currently unknown. In this study, we identified a previously unknown population of Ly6G + Ly6C + F4/80 + MHCII+ MDSCs during PJI that displayed immunosuppressive properties ex vivo. We leveraged F4/80 and MHCII expression by these cells for further characterization using cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq), which revealed a distinct transcriptomic signature of this population. F4/80 + MHCII+ MDSCs displayed gene signatures resembling G-MDSCs, neutrophils, and monocytes, but had significantly increased expression of pathways involved in cytokine response/production, inflammatory cell death, and mononuclear cell differentiation. To determine whether F4/80 + MHCII+ MDSCs represented an alternate phenotypic state of G-MDSCs, Ly6G + Ly6C + F4/80-MHCII- G-MDSCs from CD45.1 mice were adoptively transferred into CD45.2 recipients using a mouse model of PJI. A small percentage of transferred G-MDSCs acquired F4/80 and MHCII expression in vivo, suggesting some degree of plasticity in this population. Collectively, these results demonstrate a previously unappreciated phenotype of F4/80 + MHCII+ MDSCs during PJI, revealing that a granulocytic-to-monocytic transition can occur during biofilm infection.
    Keywords:   S. aureus ; CITE-seq; G-MDSC; transcriptomics
    DOI:  https://doi.org/10.1093/jleuko/qiad158
  23. J Exp Med. 2024 Jan 01. pii: e20230063. [Epub ahead of print]221(1):
    Commensal bacteria promote type I interferon signaling to maintain immune tolerance in mice.
    Adriana Vasquez Ayala, Chia-Yun Hsu, Renee E Oles, Kazuhiko Matsuo, Luke R Loomis, Ekaterina Buzun, Marvic Carrillo Terrazas, Romana R Gerner, Hsueh-Han Lu, Sohee Kim, Ziyue Zhang, Jong Hwee Park, Paul Rivaud, Matt Thomson, Li-Fan Lu, Booki Min, Hiutung Chu.
      Type I interferons (IFNs) exert a broad range of biological effects important in coordinating immune responses, which have classically been studied in the context of pathogen clearance. Yet, whether immunomodulatory bacteria operate through IFN pathways to support intestinal immune tolerance remains elusive. Here, we reveal that the commensal bacterium, Bacteroides fragilis, utilizes canonical antiviral pathways to modulate intestinal dendritic cells (DCs) and regulatory T cell (Treg) responses. Specifically, IFN signaling is required for commensal-induced tolerance as IFNAR1-deficient DCs display blunted IL-10 and IL-27 production in response to B. fragilis. We further establish that IFN-driven IL-27 in DCs is critical in shaping the ensuing Foxp3+ Treg via IL-27Rα signaling. Consistent with these findings, single-cell RNA sequencing of gut Tregs demonstrated that colonization with B. fragilis promotes a distinct IFN gene signature in Foxp3+ Tregs during intestinal inflammation. Altogether, our findings demonstrate a critical role of commensal-mediated immune tolerance via tonic type I IFN signaling.
    DOI:  https://doi.org/10.1084/jem.20230063
  24. Science. 2023 Dec 15. 382(6676): eadj3502
    Microbiome diversity protects against pathogens by nutrient blocking.
    Frances Spragge, Erik Bakkeren, Martin T Jahn, Elizete B N Araujo, Claire F Pearson, Xuedan Wang, Louise Pankhurst, Olivier Cunrath, Kevin R Foster.
      The human gut microbiome plays an important role in resisting colonization of the host by pathogens, but we lack the ability to predict which communities will be protective. We studied how human gut bacteria influence colonization of two major bacterial pathogens, both in vitro and in gnotobiotic mice. Whereas single species alone had negligible effects, colonization resistance greatly increased with community diversity. Moreover, this community-level resistance rested critically upon certain species being present. We explained these ecological patterns through the collective ability of resistant communities to consume nutrients that overlap with those used by the pathogen. Furthermore, we applied our findings to successfully predict communities that resist a novel target strain. Our work provides a reason why microbiome diversity is beneficial and suggests a route for the rational design of pathogen-resistant communities.
    DOI:  https://doi.org/10.1126/science.adj3502
  25. Nature. 2023 Dec 08.
    The world's largest proteins? These mega-molecules turn bacteria into predators.
    Ewen Callaway.
      
    Keywords:  Culture; Evolution; Microbiology
    DOI:  https://doi.org/10.1038/d41586-023-03937-z
  26. J Investig Allergol Clin Immunol. 2023 Dec;33(6): 457-463
    Very Rapid Improvement in Extended Nitric Oxide Parameters Is Associated With Clinical and Functional Improvement in Patients With Chronic Rhinosinusitis With Nasal Polyps Treated With Dupilumab.
    G Paoletti, M Casini, L Malvezzi, F Pirola, E Russo, E Nappi, G Q Muci, C Montagna, M R Messina, S Ferri, F Racca, D Lamacchia, G Cataldo, F Puggioni, A De Virgilio, F Ferreli, G Mercante, G Spriano, G W Canonica, E Heffler.
       BACKGROUND AND OBJECTIVE: Dupilumab, an anti-IL-4 receptor a monoclonal antibody, was recently approved for the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) and moderate-to-severe asthma. Onset of its clinical effects is rapid. CRSwNP is characterized by extended type 2 inflammatory involvement that can be assessed using extended nitric oxide analysis. We investigated whether dupilumab was associated with a rapid improvement in extended nitric oxide parameters, lung function, and clinical outcomes in patients with CRSwNP.
    METHODS: Consecutive patients with CRSwNP and an indication for dupilumab were evaluated for extended nitric oxide analysis (exhaled, FeNO; bronchial, JawNO; alveolar, CalvNO; nasal, nNO) and lung function 15 and 30 days after initiation of treatment and for clinical outcomes (nasal polyps score [NPS], quality of life questionnaires, visual analog scale [VAS] for the main symptoms, and the Asthma Control Test [ACT]) 30 days after initiation of treatment.
    RESULTS: We enrolled 33 patients. All extended nitric oxide and lung function parameters improved significantly after 15 days of treatment, remaining stable at 30 days. Scores on the NPS, VAS for the main RSwNP symptoms, quality of life questionnaires, and the ACT improved significantly 30 days after initiation of treatment.
    CONCLUSION: Dupilumab is associated with very rapid improvement in type 2 inflammation in all airway areas. This is associated with improved lung function and clinical parameters in patients with CRSwNP.
    Keywords:  Asthma; Biologics; Breath analysis; Chronic rhinosinusitis; Dupilumab; Lung function; Nasal polyps; Nitric oxide
    DOI:  https://doi.org/10.18176/jiaci.0851
  27. BMC Microbiol. 2023 Dec 07. 23(1): 390
    Staphylococcal superantigen-like protein 10 enhances the amyloidogenic biofilm formation in Staphylococcus aureus.
    Shakilur Rahman, Amit Kumar Das.
      Staphylococcus aureus is a highly infectious pathogen that represents a significant burden on the current healthcare system. Bacterial attachment to medical implants and host tissue, and the establishment of a mature biofilm, play an important role in chronic diseases such as endocarditis, osteomyelitis and wound infections. These biofilms decrease bacterial susceptibility to antibiotics and immune defences, making the infections challenging to treatment. S. aureus produces numerous exotoxins that contribute to the pathogenesis of the bacteria. In this study, we have identified a novel function of staphylococcal superantigen-like protein 10 (SSL10) in enhancing the formation of staphylococcal biofilms. Biofilm biomass is significantly increased when SSL10 is added exogenously to bacterial cultures, whereas SSL2 and SSL12 are found to be less active. Exogenously added SSL10 mask the surface charge of the bacterial cells and lowers their zeta potential, leading to the aggregation of the cells. Moreover, the biofilm formation by SSL10 is governed by amyloid aggregation, as evident from spectroscopic and microscopic studies. These findings thereby give the first overview of the SSL-mediated amyloid-based biofilm formation and further drive the future research in identifying potential molecules for developing new antibacterial therapies against Staphylococcus aureus.
    Keywords:  Aggregation; Amyloid; Biofilm; SSL; Staphylococcal superantigen-like protein
    DOI:  https://doi.org/10.1186/s12866-023-03134-y
  28. Front Cell Infect Microbiol. 2023 ;13 1335337
    Editorial: Respiratory microbiome in health and disease.
    Yimin Zhuang, Tao Ding, Jiangchao Zhao, Jianmin Chai.
      
    Keywords:  health; microbe-host interaction; microbe-microbe interaction; respiratory disease; respiratory microbiome; respiratory tracts
    DOI:  https://doi.org/10.3389/fcimb.2023.1335337
  29. J Exp Med. 2024 Jan 01. pii: e20232011. [Epub ahead of print]221(1):
    Beyond antiviral: Interferon induced by bacteria maintains tolerance in the gut.
    Yi Yang, Ken Cadwell.
      Type I interferons are best known for their antiviral role. Here, Ayala et al. (https://doi.org/10.1084/jem.20230063) reveal that commensal bacteria elicit tonic type I interferons to prime dendritic cells and induce regulatory T cells that maintain a tolerogenic intestinal milieu.
    DOI:  https://doi.org/10.1084/jem.20232011
  30. Infect Med (Beijing). 2023 Sep;2(3): 241-245
    Bacille-Calmette-Guerin modulates human macrophage and dendritic cell response to SARS-CoV-2 S-glycoprotein.
    Regina C Ambe, Shubhang Bhalla, Alejandra Alvarado, Jose Barragan, Jorge Cervantes.
       Background: Given that epidemiological evidence suggests a potential protective role for Bacille-Calmette-Guerin against COVID-19, we aimed to explore whether pre-exposure of human monocyte-derived macrophages and dendritic cells to BCG could modulate their response to SARS-CoV-2 S-glycoprotein.
    Methods: Dual THP-1 cells containing 2 reporter plasmids for transcription factors NF-κB, and IRF were differentiated into macrophages over 3 days using phorbol 12-myristate 13-acetate, or into dendritic cells over 6 days using commercial monocyte-dencritic cell differentiation media and matured with recombinant tumor necrosis factor-α. Cells were exposed to BCG for 24 h and then stimulated with SARS-CoV-2 S-glycoprotein for 24 hours.
    Results: Pre-exposure of human macrophages and DCs to BCG increased IRF and NF-kb activation in response to the SARS-CoV-2 S-glycoprotein.
    Conclusions: Our results showed that pre-exposure of both types of cells to BCG exhibited an increase in inflammatory transcription factors upon stimulation with S-glycoprotein. BCG-induced trained immunity may be an important tool for reducing susceptibility to SARS-CoV-2 infection and severity of COVID-19. Our findings help in the design of future BCG-based therapeutic approaches in the treatment of diseases caused by viral infections.
    Keywords:  BCG; Dendritic cell; Macrophage; SARS-CoV-2
    DOI:  https://doi.org/10.1016/j.imj.2023.08.004
  31. bioRxiv. 2023 Dec 01. pii: 2023.11.29.569283. [Epub ahead of print]
    Heterogeneity in lung macrophage control of Mycobacterium tuberculosis is determined by T cells.
    Rocky Lai, Travis Williams, Tasfia Rakib, Jinhee Lee, Samuel M Behar.
      Following Mycobacterium tuberculosis infection, alveolar macrophages are initially infected but ineffectively restrict bacterial replication. The distribution of M. tuberculosis among different cell types in the lung changes with the onset of T cell immunity when the dominant infected cellular niche shifts from alveolar to monocyte-derived macrophages (MDM). We hypothesize that changes in bacterial distribution among different cell types is driven by differences in T cell recognition of infected cells and their subsequent activation of antimicrobial effector mechanisms. We show that CD4 and CD8 T cells efficiently eliminate M. tuberculosis infection in alveolar macrophages, but they have less impact on suppressing infection in MDM, which may be a bacterial niche. Importantly, CD4 T cell responses enhance MDM recruitment to the lung. Thus, the outcome of infection depends on the interaction between the T cell subset and the infected cell; both contribute to the resolution and persistence of the infection.
    DOI:  https://doi.org/10.1101/2023.11.29.569283
  32. Lett Appl Microbiol. 2023 Dec 08. pii: ovad137. [Epub ahead of print]
    ovadExploring alternative strategies for Staphylococcus aureus Nasal decolonization: Insights from Preclinical Studies.
    Jayalakshmi Jayakumar, Vivek Vinod, Lalitha Biswas, Anil Kumar V, Raja Biswas.
      Nasal decolonization of Staphylococcus aureus with the antibiotic mupirocin is a common clinical practice before complex surgical procedures, to prevent hospital acquired infections. However, widespread use of mupirocin has led to the development of resistant S. aureus strains and there is a limited scope for developing new antibiotics for S. aureus nasal decolonization. It is therefore necessary to develop alternative and non-antibiotic nasal decolonization methods. In this review, we broadly discussed the effectiveness of different non-antibiotic antimicrobial agents that are currently not in clinical practice, but are experimentally proved to be efficacious in promoting S. aureus nasal decolonization. These include lytic bacteriophages, bacteriolytic enzymes, tea tree oil, apple vinegar and antimicrobial peptides. We have also discussed the possibility of using photodynamic therapy for S. aureus nasal decolonization. This article highlights the importance of further large scale clinical studies for selecting the most suitable and alternative nasal decolonizing agent.
    Keywords:   Staphylococcus aureus ; antimicrobial peptides; bacteriophages; infection; nasal decolonization
    DOI:  https://doi.org/10.1093/lambio/ovad137
  33. ACS Synth Biol. 2023 Dec 08.
    Toolbox of Characterized Genetic Parts for Staphylococcus aureus.
    Stephen N Rondthaler, Biprodev Sarker, Nathaniel Howitz, Ishita Shah, Lauren B Andrews.
      Staphylococcus aureus is an important clinical bacterium prevalent in human-associated microbiomes and the cause of many diseases. However, S. aureus has been intractable to synthetic biology approaches due to limited characterized genetic parts for this nonmodel Gram-positive bacterium. Moreover, genetic manipulation of S. aureus has relied on cumbersome and inefficient cloning strategies. Here, we report the first standardized genetic parts toolbox for S. aureus, which includes characterized promoters, ribosome binding sites, terminators, and plasmid replicons from a variety of bacteria for precise control of gene expression. We established a standard relative expression unit (REU) for S. aureus using a plasmid reference and characterized genetic parts in standardized REUs using S. aureus ATCC 12600. We constructed promoter and terminator part plasmids that are compatible with an efficient Type IIS DNA assembly strategy to effectively build multipart DNA constructs. A library of 24 constitutive promoters was built and characterized in S. aureus, which showed a 380-fold activity range. This promoter library was also assayed in Bacillus subtilis (122-fold activity range) to demonstrate the transferability of the constitutive promoters between these Gram-positive bacteria. By applying an iterative design-build-test-learn cycle, we demonstrated the use of our toolbox for the rational design and engineering of a tetracycline sensor in S. aureus using the PXyl-TetO aTc-inducible promoter that achieved 25.8-fold induction. This toolbox greatly expands the growing number of genetic parts for Gram-positive bacteria and will allow researchers to leverage synthetic biology approaches to study and engineer cellular processes in S. aureus.
    Keywords:  Gram-positive bacteria; biological parts; characterized genetic elements; genetic standards; genetic toolbox
    DOI:  https://doi.org/10.1021/acssynbio.3c00325
  34. Respir Res. 2023 Dec 11. 24(1): 309
    Alpha-defensins inhibit ERK/STAT3 signaling during monocyte-macrophage differentiation and impede macrophage function.
    Jungnam Lee, Naweed Mohammad, Yuanqing Lu, Regina Oshins, Alek Aranyos, Mark Brantly.
      Alpha-1-antitrypsin deficiency (AATD) is a genetic disorder associated with a 5-tenfold decrease in lung levels of alpha-1-antitrypsin (AAT) and an increased risk for obstructive lung disease. α-defensins are cationic broad-spectrum cytotoxic and pro-inflammatory peptides found in the azurophilic granules of neutrophils. The concentration of α-defensins is less than 30 nM in the bronchoalveolar lavage fluid of healthy controls but is up to 6 μM in AATD individuals with significant lung function impairment. Alveolar macrophages are generally classified into pro-inflammatory (M1) or anti-inflammatory (M2) subsets that play distinct roles in the initiation and resolution of inflammation. Therefore, monocyte-macrophage differentiation should be tightly controlled to maintain lung integrity. In this study, we determined the effect of α-defensins on monocyte-macrophage differentiation and identified the molecular mechanism of this effect. The results of this study demonstrate that 2.5 μM of α-defensins inhibit the phosphorylation of ERK1/2 and STAT3 and suppress the expression of M2 macrophage markers, CD163 and CD206. In addition, a scratch assay shows that the high concentration of α-defensins inhibits cell movement by ~ 50%, and the phagocytosis assay using flow cytometry shows that α-defensins significantly reduce the bacterial phagocytosis rate of monocyte-derived macrophages (MDMs). To examine whether exogenous AAT is able to alleviate the inhibitory effect of α-defensins on macrophage function, we incubated MDMs with AAT prior to α-defensin treatment and demonstrate that AAT improves the migratory ability and phagocytic ability of MDMs compared with MDMs incubated only with α-defensins. Taken together, this study suggests that a high concentration of α-defensins inhibits the activation of ERK/STAT3 signaling, negatively regulates the expression of M2 macrophage markers, and impairs innate immune function of macrophages.
    Keywords:  AAT deficiency (AATD); Alpha-1-antitrysin (AAT); CD163; CD206; ERK1/2; STAT3; α-defensin
    DOI:  https://doi.org/10.1186/s12931-023-02605-0
  35. Nat Commun. 2023 Dec 11. 14(1): 8198
    Staphylococcus aureus functional amyloids catalyze degradation of β-lactam antibiotics.
    Elad Arad, Kasper B Pedersen, Orit Malka, Sisira Mambram Kunnath, Nimrod Golan, Polina Aibinder, Birgit Schiøtt, Hanna Rapaport, Meytal Landau, Raz Jelinek.
      Antibiotic resistance of bacteria is considered one of the most alarming developments in modern medicine. While varied pathways for bacteria acquiring antibiotic resistance have been identified, there still are open questions concerning the mechanisms underlying resistance. Here, we show that alpha phenol-soluble modulins (PSMαs), functional bacterial amyloids secreted by Staphylococcus aureus, catalyze hydrolysis of β-lactams, a prominent class of antibiotic compounds. Specifically, we show that PSMα2 and, particularly, PSMα3 catalyze hydrolysis of the amide-like bond of the four membered β-lactam ring of nitrocefin, an antibiotic β-lactam surrogate. Examination of the catalytic activities of several PSMα3 variants allowed mapping of the active sites on the amyloid fibrils' surface, specifically underscoring the key roles of the cross-α fibril organization, and the combined electrostatic and nucleophilic functions of the lysine arrays. Molecular dynamics simulations further illuminate the structural features of β-lactam association upon the fibril surface. Complementary experimental data underscore the generality of the functional amyloid-mediated catalytic phenomenon, demonstrating hydrolysis of clinically employed β-lactams by PSMα3 fibrils, and illustrating antibiotic degradation in actual S. aureus biofilms and live bacteria environments. Overall, this study unveils functional amyloids as catalytic agents inducing degradation of β-lactam antibiotics, underlying possible antibiotic resistance mechanisms associated with bacterial biofilms.
    DOI:  https://doi.org/10.1038/s41467-023-43624-1
  36. Int Immunol. 2023 Dec 08. pii: dxad048. [Epub ahead of print]
    The nuclear receptor Nurr1 is preferentially expressed in human pro-inflammatory macrophages and limits their inflammatory profile.
    Miguel A Solís-Barbosa, Eduardo Santana, José R Muñoz-Torres, Norma C Segovia-Gamboa, Eduardo Patiño-Martínez, Marco A Meraz-Ríos, Rafael Samaniego, Paloma Sánchez-Mateos, Carmen Sánchez-Torres.
      Nurr1 is a member of the orphan nuclear receptor family NR4A that modulates inflammation in several cell lineages, both positively and negatively. Macrophages are key regulators of inflammatory responses, yet information about the role of Nurr1 in human macrophages is scarce. Here we examined Nurr1 expression and activity in steady state and activated human macrophages. Pro- and anti-inflammatory macrophages were generated in vitro by culture of blood monocytes with GM-CSF and M-CSF, respectively. Nurr1 expression was predominant in macrophages with pro-inflammatory phenotype. Nurr1 activation with the agonists C-DIM12 or IP7e did not globally modify the polarization status of pro-inflammatory macrophages, but they decreased their production of TNF, IL-1β, IL-6, IL-8, IL-12 p40, CCL2, IFN-β, and reactive oxygen species, with variable potencies. Conversely, Nurr1 deficient macrophages increased the expression of transcripts encoding inflammatory mediators, particularly that of IL6, IFNB1, and CCL2. Mechanistically, endogenous Nurr1 interacted with NF-κB p65 in basal conditions and upon LPS activation. C-DIM12 stabilized those complexes in cells exposed to LPS and concurrently decreased NF-κB transcriptional activity and p65 nuclear translocation. Expression of high levels of Nurr1 was associated with a subset of dermal macrophages that display enhanced levels of TNF and lower expression of the anti-inflammatory marker CD163L1 in skin lesions from patients with bullous pemphigoid, a chronic inflammatory autoimmune blistering disorder. These results suggest that Nurr1 expression is linked with the pro-inflammatory phenotype of human macrophages, both in vivo and in vitro, where it may constitute a brake to attenuate the synthesis of inflammatory mediators.
    Keywords:  Nurr1 agonists; inflammatory response; macrophage polarization
    DOI:  https://doi.org/10.1093/intimm/dxad048
  37. Mater Today Bio. 2023 Dec;23 100869
    Efficient material-induced activation of monocyte-derived dendritic cells releasing surface molecules, matrix metalloproteinases, and growth factors needed for regenerative tissue remodeling.
    Daniel David Stöbener, Andrea Cosimi, Marie Weinhart, Matthias Peiser.
      New experimental approaches for tissue repair have recently been proposed and include the application of natural or synthetic biomaterials and immune cells. Herein, fully synthetic poly(glycidyl ether) (PGE) copolymer coatings are evaluated as bioinstructive materials for the in vitro culture and intrinsic activation of human immune cells. Immature monocyte-derived dendritic cells (moDCs) are exposed to PGE brush and gel coatings of varying copolymer composition, wettability, and deformability immobilized on polystyrene culture dishes. Compared to moDCs cultured on standard tissue culture-treated polystyrene, activation marker levels on the cell surface are strongly enhanced on PGE substrates. Thereby, moDCs undergo a distinct morphological change and reach levels of activation comparable to those achieved by toll-like receptor (TLR) ligand liposaccharide (LPS), specifically for the expression of costimulatory molecules CD86 and CD40 as well as human leukocyte antigen (HLA)-DR. In addition, PGE coatings induce a significantly enhanced level of programmed cell death ligands 1 and 2 (PD-L1/-L2) on the moDC surface, two molecules crucially involved in maintaining immune tolerance. In addition, an increased release of matrix metalloproteinases MMP-1 and MMP-7, as well as transforming growth factor (TGF)-β1 and epidermal growth factor (EGF) was observed in moDCs cultured on PGE substrates. As fully synthetic biomaterials, PGE coatings demonstrate intrinsic functional competence in instructing immature human moDCs for phenotypic activation in vitro, accompanied by the secretion of bioactive molecules, which are known to be crucial for tissue regeneration. Hence, PGE coatings hold strong potential for immune-modulating implant coatings, while PGE-activated moDCs are promising candidates for future clinical cell-based immunoengineering therapies.
    Keywords:  Ex vivo dendritic cell priming; Functional surface coatings; Immunoengineering; Poly(glycidyl ether) copolymers; Regenerative medicine
    DOI:  https://doi.org/10.1016/j.mtbio.2023.100869
  38. Front Immunol. 2023 ;14 1227175
    Differential in vivo labeling with barcoded antibodies allows for simultaneous transcriptomic profiling of airway, lung tissue and intravascular immune cells.
    Barbara C Mindt, John Kim, Troy Warren, Yang Song, Antonio DiGiandomenico.
      Single-cell RNA sequencing (scRNA-seq) is the state-of-the-art approach to study transcriptomic signatures in individual cells in respiratory health and disease. However, classical scRNA-seq approaches provide no spatial information and are performed using either bronchoalveolar lavage fluid (BAL) or lung single cell suspensions to assess transcript levels in airway and tissue immune cells, respectively. Herein we describe a simple method to simultaneously characterize transcriptomic features of airway, lung parenchymal and intravascular immune cells based on differential in vivo labeling with barcoded antibodies. In addition to gaining basic spatial information, this approach allows for direct comparison of cells within different anatomical compartments. Furthermore, this method provides a time- and cost-effective alternative to classical scRNA-seq where lung and BAL samples are processed individually, reducing animal and reagent use. We demonstrate the feasibility of this approach in a preclinical mouse model of bacterial lung infection comparing airway, parenchymal and vasculature neutrophils early after infection.
    Keywords:  bacterial lung infection; in vivo antibody labeling; neutrophils; respiratory disease; scRNA-seq; spatial transcriptomics
    DOI:  https://doi.org/10.3389/fimmu.2023.1227175
  39. Int J Mol Sci. 2023 Nov 29. pii: 16907. [Epub ahead of print]24(23):
    Lacticaseibacillus rhamnosus CRL1505 Peptidoglycan Modulates the Inflammation-Coagulation Response Triggered by Poly(I:C) in the Respiratory Tract.
    Hortensia Zelaya, Luciano Arellano-Arriagada, Kohtaro Fukuyama, Kaho Matsumoto, Gabriela Marranzino, Fu Namai, Susana Salva, Susana Alvarez, Graciela Agüero, Haruki Kitazawa, Julio Villena.
      Lacticaseibacillus rhamnosus CRL1505 beneficially modulates the inflammation-coagulation response during respiratory viral infections. This study evaluated the capacity of the peptidoglycan obtained from the CRL1505 strain (PG-Lr1505) to modulate the immuno-coagulative response triggered by the viral pathogen-associated molecular pattern poly(I:C) in the respiratory tract. Adult BALB/c mice were nasally treated with PG-Lr1505 for two days. Treated and untreated control mice were then nasally challenged with poly(I:C). Mice received three doses of poly(I:C) with a 24 h rest period between each administration. The immuno-coagulative response was studied after the last administration of poly(I:C). The challenge with poly(I:C) significantly increased blood and respiratory pro-inflammatory mediators, decreased prothrombin activity (PT), and increased von Willebrand factor (vWF) levels in plasma. Furthermore, tissue factor (TF), tissue factor pathway inhibitor (TFPI), and thrombomodulin (TM) expressions were increased in the lungs. PG-Lr1505-treated mice showed significant modulation of hemostatic parameters in plasma (PT in %, Control = 71.3 ± 3.8, PG-Lr1505 = 94.0 ± 4.0, p < 0.01) and lungs. Moreover, PG-Lr1505-treated mice demonstrated reduced TF in F4/80 cells from lungs, higher pro-inflammatory mediators, and increased IL-10 compared to poly(I:C) control mice (IL-10 in pg/mL, Control = 379.1 ± 12.1, PG-Lr1505 = 483.9 ± 11.3, p < 0.0001). These changes induced by PG-Lr1505 correlated with a significant reduction in lung tissue damage. Complementary in vitro studies using Raw 264.7 cells confirmed the beneficial effect of PG-Lr1505 on poly(I:C)-induced inflammation, since increased IL-10 expression, as well as reduced damage, production of inflammatory mediators, and hemostatic parameter expressions were observed. In addition, protease-activated receptor-1 (PAR1) activation in lungs and Raw 264.7 cells was observed after TLR3 stimulation, which was differentially modulated by PG-Lr1505. The peptidoglycan from L. rhamnosus CRL1505 is able to regulate inflammation, the procoagulant state, and PAR1 activation in mice and macrophages in the context of the activation of TLR3 signaling pathways, contributing to a beneficial modulation of inflammation-hemostasis crosstalk.
    Keywords:  Lacticaseibacillus rhamnosus CRL1505 peptidoglycan; TLR3; coagulation; inflammation
    DOI:  https://doi.org/10.3390/ijms242316907
  40. Nature. 2023 Dec;624(7991): S30-S32
    The fight against antimicrobial resistance.
    Bianca Nogrady.
      
    Keywords:  Antibiotics; Developing world; Vaccines
    DOI:  https://doi.org/10.1038/d41586-023-03912-8
  41. Br Dent J. 2023 Dec;235(11): 851
    A healthy mouth helps to maintain balanced metabolic profiles.
      
    DOI:  https://doi.org/10.1038/s41415-023-6650-7
  42. Nat Genet. 2023 Dec;55(12): 2019
    Epigenetic memory in 3D.
    Chiara Anania.
      
    DOI:  https://doi.org/10.1038/s41588-023-01615-4
  43. NPJ Regen Med. 2023 Dec 12. 8(1): 66
    Harnessing bioengineered myeloid progenitors for precision immunotherapies.
    Willem Buys, Elias T Zambidis.
      Granulocytes and macrophages are the frontline defenders of the innate immune system. These myeloid cells play a crucial role in not only eliminating pathogens and tumor cells, but also regulating adaptive immune responses. In neonatal sepsis and post-chemotherapy agranulocytosis, the absence of these cells leaves the host highly vulnerable to infections. Beyond replacement to prevent or control neutropenic sepsis, engineered myeloid cells may offer distinct opportunities for cell therapies. For example, the mobility and specific homing capacities of neutrophils to sites of inflammation could be exploited to deliver biocidal agents, or anti-inflammatory healing signals during sepsis, autoimmunity, and organ transplantation. Additionally, myeloid cells can be engineered to express chimeric antigen receptors (CAR), carry chemotherapeutics, or enhance lymphoid tumor killing. However, traditional methods of cell isolation are incapable of providing sufficient cell numbers of these short-lived cells; their propensity for premature activation further complicates their cell engineering. Here, we review current and future biotherapeutic innovations that employ engineered multipotent myeloid progenitors derived from either self-renewing human induced pluripotent stem cells (hiPSC) or primary CD34+ hematopoietic stem-progenitors. We provide a roadmap for solving the challenges of sourcing, cost, and production of engineered myeloid cell therapies.
    DOI:  https://doi.org/10.1038/s41536-023-00343-x
  44. Front Immunol. 2023 ;14 1341818
    Corrigendum: Role of histamine-mediated macrophage differentiation in clearance of metastatic bacterial infection.
    Kwang H Kim, Donghwan Park, Soo Young Cho, Yejin Cho, Buhyun Lee, Haengdueng Jeong, Yura Lee, Yourim Lee, Ki Taek Nam.
      [This corrects the article DOI: 10.3389/fimmu.2023.1290191.].
    Keywords:  bacterial infection; histamine; macrophage differentiation; peritoneal cells; single-cell RNA sequencing
    DOI:  https://doi.org/10.3389/fimmu.2023.1341818
  45. Front Immunol. 2023 ;14 1276196
    Defining solute carrier transporter signatures of murine immune cell subsets.
    Tania Løve Aaes, Javier Burgoa Cardás, Kodi S Ravichandran.
      Solute carrier (SLC) transporters are membrane-bound proteins that facilitate nutrient transport, and the movement across cellular membranes of various substrates ranging from ions to amino acids, metabolites and drugs. Recently, SLCs have gained increased attention due to their functional linkage to innate immunological processes such as the clearance of dead cells and anti-microbial defense. Further, the druggable nature of these transporters provides unique opportunities for improving outcomes in different immunological diseases. Although the SLCs represent the largest group of transporters and are often identified as significant hits in omics data sets, their role in immunology has been insufficiently explored. This is partly due to the absence of tools that allow identification of SLC expression in particular immune cell types and enable their comparison before embarking on functional studies. In this study, we used publicly available RNA-Seq data sets to analyze the transcriptome in adaptive and innate immune cells, focusing on differentially and highly expressed SLCs. This revealed several new insights: first, we identify differentially expressed SLC transcripts in phagocytes (macrophages, dendritic cells, and neutrophils) compared to adaptive immune cells; second, we identify new potential immune cell markers based on SLC expression; and third, we provide user-friendly online tools for researchers to explore SLC genes of interest (and the rest of the genes as well), in three-way comparative dot plots among immune cells. We expect this work to facilitate SLC research and comparative transcriptomic studies across different immune cells.
    Keywords:  Triwise (R); inflammation; innate immunity; membrane transporter; phagocytes; solute carriers (SLCs); transcriptome (RNA-seq)
    DOI:  https://doi.org/10.3389/fimmu.2023.1276196
  46. bioRxiv. 2023 Nov 29. pii: 2023.11.28.569028. [Epub ahead of print]
    A deep lung cell atlas reveals cytokine-mediated lineage switching of a rare cell progenitor of the human airway epithelium.
    Avinash Waghray, Isha Monga, Brian Lin, Viral Shah, Michal Slyper, Bruno Giotti, Jiajie Xu, Julia Waldman, Danielle Dionne, Lan T Nguyen, Wendy Lou, Peiwen Cai, Eric Park, Christoph Muus, Jiawei Sun, Manalee V Surve, Lujia Cha Cha Yang, Orit Rozenblatt-Rosen, Toni M Dolerey, Srinivas Vinod Saladi, Alexander M Tsankov, Aviv Regev, Jayaraj Rajagopal.
      The human airway contains specialized rare epithelial cells whose roles in respiratory disease are not well understood. Ionocytes express the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), while chemosensory tuft cells express asthma-associated alarmins. However, surprisingly, exceedingly few mature tuft cells have been identified in human lung cell atlases despite the ready identification of rare ionocytes and neuroendocrine cells. To identify human rare cell progenitors and define their lineage relationship to mature tuft cells, we generated a deep lung cell atlas containing 311,748 single cell RNA-Seq (scRNA-seq) profiles from discrete anatomic sites along the large and small airways and lung lobes of explanted donor lungs that could not be used for organ transplantation. Of 154,222 airway epithelial cells, we identified 687 ionocytes (0.45%) that are present in similar proportions in both large and small airways, suggesting that they may contribute to both large and small airways pathologies in CF. In stark contrast, we recovered only 3 mature tuft cells (0.002%). Instead, we identified rare bipotent progenitor cells that can give rise to both ionocytes and tuft cells, which we termed tuft-ionocyte progenitor cells (TIP cells). Remarkably, the cycling fraction of these TIP cells was comparable to that of basal stem cells. We used scRNA-seq and scATAC-seq to predict transcription factors that mark this novel rare cell progenitor population and define intermediate states during TIP cell lineage transitions en route to the differentiation of mature ionocytes and tuft cells. The default lineage of TIP cell descendants is skewed towards ionocytes, explaining the paucity of mature tuft cells in the human airway. However, Type 2 and Type 17 cytokines, associated with asthma and CF, diverted the lineage of TIP cell descendants in vitro , resulting in the differentiation of mature tuft cells at the expense of ionocytes. Consistent with this model of mature tuft cell differentiation, we identify mature tuft cells in a patient who died from an asthma flare. Overall, our findings suggest that the immune signaling pathways active in asthma and CF may skew the composition of disease-relevant rare cells and illustrate how deep atlases are required for identifying physiologically-relevant scarce cell populations.
    DOI:  https://doi.org/10.1101/2023.11.28.569028
  47. Elife. 2023 Dec 08. pii: e86381. [Epub ahead of print]12
    Nicotinic acetylcholine receptor signaling maintains epithelial barrier integrity.
    Nadja S Katheder, Kristen C Browder, Diana Chang, Ann De Maziere, Pekka Kujala, Suzanne van Dijk, Judith Klumperman, Tzu-Chiao Lu, Hongjie Li, Zijuan Lai, Dewakar Sangaraju, Heinrich Jasper.
      Disruption of epithelial barriers is a common disease manifestation in chronic degenerative diseases of the airways, lung and intestine. Extensive human genetic studies have identified risk loci in such diseases, including in chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (IBD). The genes associated with these loci have not fully been determined, and functional characterization of such genes requires extensive studies in model organisms. Here, we report the results of a screen in Drosophila melanogaster that allowed for rapid identification, validation and prioritization of COPD risk genes that were selected based on risk loci identified in human genome-wide association studies (GWAS) studies. Using intestinal barrier dysfunction in flies as a readout, our results validate the impact of candidate gene perturbations on epithelial barrier function in 56% of the cases, resulting in a prioritized target gene list. We further report the functional characterization in flies of one family of these genes, encoding for nicotinic acetylcholine receptor subunits (nAchR). We find that nAchR signaling in enterocytes of the fly gut promotes epithelial barrier function and epithelial homeostasis by regulating the production of the peritrophic matrix. Our findings identify COPD associated genes critical for epithelial barrier maintenance, and provide insight into the role of epithelial nAchR signaling for homeostasis.
    Keywords:  D. melanogaster; genetics; genomics; immunology; inflammation
    DOI:  https://doi.org/10.7554/eLife.86381
  48. Nature. 2023 Dec 13.
    Lung dendritic-cell metabolism underlies susceptibility to viral infection in diabetes.
    Samuel Philip Nobs, Aleksandra A Kolodziejczyk, Lital Adler, Nir Horesh, Christine Botscharnikow, Ella Herzog, Gayatree Mohapatra, Sophia Hejndorf, Ryan-James Hodgetts, Igor Spivak, Lena Schorr, Leviel Fluhr, Denise Kviatcovsky, Anish Zacharia, Suzanne Njuki, Dinorah Barasch, Noa Stettner, Mally Dori-Bachash, Alon Harmelin, Alexander Brandis, Tevie Mehlman, Ayelet Erez, Yiming He, Sara Ferrini, Jens Puschhof, Hagit Shapiro, Manfred Kopf, Arieh Moussaieff, Suhaib K Abdeen, Eran Elinav.
      People with diabetes feature a life-risking susceptibility to respiratory viral infection, including influenza and SARS-CoV-2 (ref. 1), whose mechanism remains unknown. In acquired and genetic mouse models of diabetes, induced with an acute pulmonary viral infection, we demonstrate that hyperglycaemia leads to impaired costimulatory molecule expression, antigen transport and T cell priming in distinct lung dendritic cell (DC) subsets, driving a defective antiviral adaptive immune response, delayed viral clearance and enhanced mortality. Mechanistically, hyperglycaemia induces an altered metabolic DC circuitry characterized by increased glucose-to-acetyl-CoA shunting and downstream histone acetylation, leading to global chromatin alterations. These, in turn, drive impaired expression of key DC effectors including central antigen presentation-related genes. Either glucose-lowering treatment or pharmacological modulation of histone acetylation rescues DC function and antiviral immunity. Collectively, we highlight a hyperglycaemia-driven metabolic-immune axis orchestrating DC dysfunction during pulmonary viral infection and identify metabolic checkpoints that may be therapeutically exploited in mitigating exacerbated disease in infected diabetics.
    DOI:  https://doi.org/10.1038/s41586-023-06803-0
  49. Int Immunopharmacol. 2023 Dec 12. pii: S1567-5769(23)01656-9. [Epub ahead of print]127 111329
    SMYD3 activates the TCA cycle to promote M1-M2 conversion in macrophages.
    Wenqiang Zhu, Lina Liu, Jinjing Wu, Renzhuo Gao, Liying Fu, Xiaohong Yang, Yang Zou, Shuhua Zhang, Daya Luo.
       BACKGROUND: SMYD3 refers to a histone lysine methyltransferase from the SMYD family, which acts as a gene transcriptional regulator chiefly through catalysis of the histone subunit 3 at lysine 4 trimethylation (H3K4me3). Great progress has been made that epigenetic modification plays a pivotal role in regulating macrophage polarization. However, the effects of the histone lysine methyltransferase SMYD3 on macrophage polarization and phenotypic switching are unclear.
    RESULTS: We found that LPS/IFN-γ-stimulated macrophages gradually transformed from M1 to M2 in the late stage, and SMYD3 played a key role in this process. As demonstrated by RNA-seq assessment, SMYD3 prominently activated a metabolic pathway known as TCA cycle inside macrophages during M1-M2 conversion. Besides, by modifying H3K4me3 histone, the target genes regulated by SMYD3 were identified via the ChIP-seq assessment, including citrate synthase (CS), succinate dehydrogenase complex subunit C (SDHC) and pyruvate carboxylase (PC). SMYD3 activated the transcriptional activities of the metabolic enzymes CS, SDHC and PC through H3K4me3 by causing the aggregation of citrate, an intramacrophage metabolite, and the depletion of succinate. And additionally, it facilitated the generation of ROS, as well as the expressions of genes associated with mitochondrial respiratory chain complexes. This increased ROS production ultimately induced mitophagy, triggering the M1 to M2 phenotype switch in the macrophages.
    CONCLUSIONS: Our study provides a detailed intrinsic mechanism in the macrophage phenotypic transition process, in short, SMYD3 promotes the M1-M2 conversion of macrophages by activating the TCA cycle through the simultaneous regulation of the transcriptional activities of the metabolic enzymes CS, SDHC and PC.
    Keywords:  Histone modification; Macrophage phenotype conversion; Mitophagy; SMYD3; TCA cycle
    DOI:  https://doi.org/10.1016/j.intimp.2023.111329
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