bims-bac4me Biomed News
on Microbiome and trained immunity
Issue of 2024‒08‒18
38 papers selected by
Chun-Chi Chang, University Hospital Zurich
  1. Type I interferon governs immunometabolic checkpoints that coordinate inflammation during Staphylococcal infection.
  2. Exposure to bacterial PAMPs before RSV infection exacerbates innate inflammation and disease via IL-1α and TNF-α.
  3. RSV enhances Staphylococcus aureus bacterial growth in the lung.
  4. Broad-spectrum antibiotics disrupt homeostatic efferocytosis.
  5. The microbiome-derived antibacterial lugdunin acts as a cation ionophore in synergy with host peptides.
  6. A path forward for Staphylococcus aureus vaccine development.
  7. Commensal microbe regulation of skin cells in disease.
  8. The Role of the Gut and Airway Microbiota in Chronic Rhinosinusitis with Nasal Polyps: A Systematic Review.
  9. Staphylococcus aureus adapts to exploit collagen-derived proline during chronic infection.
  10. A lentiviral toolkit to monitor airway epithelial cell differentiation using bioluminescence.
  11. Transitions in lung microbiota landscape associate with distinct patterns of pneumonia progression.
  12. Resistance of Pseudomonas aeruginosa and Staphylococcus aureus to the airway epithelium oxidative response assessed by a cell-free in vitro assay.
  13. Protective innate immunity against Pneumocystis does not require Stat6-dependent macrophage polarization.
  14. Interleukin-1α inhibits transforming growth factor-β1 and β2-induced extracellular matrix production, remodeling and signaling in human lung fibroblasts: Master regulator in lung mucosal repair.
  15. Trained immunity suppression determines kidney allograft survival.
  16. Macrophage polarization and its impact on idiopathic pulmonary fibrosis.
  17. Deep skin fibroblast-mediated macrophage recruitment supports acute wound healing.
  18. Induction of trained immunity in broiler chickens following delivery of oligodeoxynucleotide containing CpG motifs to protect against Escherichia coli septicemia.
  19. Five ways science is tackling the antibiotic resistance crisis.
  20. Interleukin-1 receptor-associated kinase 4 (IRAK4) is a critical regulator of inflammatory signalling through toll-like receptors 4 and 7/8 in murine and human lungs.
  21. Recreating chronic respiratory infections in vitro using physiologically relevant models.
  22. Airway Epithelium-derived CXCL14 Promotes Eosinophil Accumulation in Allergic Airway Inflammation.
  23. ACOD1 mediates Staphylococcus aureus-induced inflammatory response via the TLR4/NF-κB signaling pathway.
  24. Competitive dynamics and balance between Streptococcus mutans and commensal streptococci in oral microecology.
  25. Synergistic action of antimicrobial peptides and antibiotics: current understanding and future directions.
  26. Microbiome modification for personalized treatment of dysbiotic diseases.
  27. Relationship between Respiratory Microbiome and Systemic Inflammatory Markers in COPD: A Pilot Study.
  28. Insights into the recognition of hypermucoviscous Klebsiella pneumoniae clinical isolates by innate immune lectins of the Siglec and galectin families.
  29. Perfused In Vitro Intestine Tissue Model to Evaluate the Role of Stromal and Immune Cells in Epithelial Response to Inflammatory Cues and Drug Therapies.
  30. Intracellular pH differentially regulates transcription of metabolic and signaling pathways in normal epithelial cells.
  31. Pharmacologic Inhibition of Ferroptosis Attenuates Experimental Abdominal Aortic Aneurysm Formation.
  32. Targeting Macrophage Phenotypes and Metabolism as Novel Therapeutic Approaches in Atherosclerosis and Related Cardiovascular Diseases.
  33. Nasal Microbiome in Granulomatosis with Polyangiitis Compared to Chronic Rhinosinusitis.
  34. Itaconate suppresses house dust mite-induced allergic airways disease and Th2 cell differentiation.
  35. SARS-CoV2 infection in whole lung primarily targets macrophages that display subset-specific responses.
  36. Exploring strain-level diversity in the gut microbiome through mucin particle adhesion.
  37. Airway bacterial microbiome signatures correlate with occupational pneumoconiosis progression.
  38. In vitro assessment of the immunomodulatory effects of probiotic Bacillus strains on chicken PBMCs.
  1. Cell Rep. 2024 Aug 09. pii: S2211-1247(24)00957-4. [Epub ahead of print]43(8): 114607
    Type I interferon governs immunometabolic checkpoints that coordinate inflammation during Staphylococcal infection.
    Mack B Reynolds, Benjamin Klein, Michael J McFadden, Norah K Judge, Hannah E Navarrete, Britton C Michmerhuizen, Dominik Awad, Tracey L Schultz, Paul W Harms, Li Zhang, Teresa R O'Meara, Jonathan Z Sexton, Costas A Lyssiotis, J Michelle Kahlenberg, Mary X O'Riordan.
      Macrophage metabolic plasticity is central to inflammatory programming, yet mechanisms of coordinating metabolic and inflammatory programs during infection are poorly defined. Here, we show that type I interferon (IFN) temporally guides metabolic control of inflammation during methicillin-resistant Staphylococcus aureus (MRSA) infection. We find that staggered Toll-like receptor and type I IFN signaling in macrophages permit a transient energetic state of combined oxidative phosphorylation (OXPHOS) and aerobic glycolysis followed by inducible nitric oxide synthase (iNOS)-mediated OXPHOS disruption. This disruption promotes type I IFN, suppressing other pro-inflammatory cytokines, notably interleukin-1β. Upon infection, iNOS expression peaks at 24 h, followed by lactate-driven Nos2 repression via histone lactylation. Type I IFN pre-conditioning prolongs infection-induced iNOS expression, amplifying type I IFN. Cutaneous MRSA infection in mice constitutively expressing epidermal type I IFN results in elevated iNOS levels, impaired wound healing, vasculopathy, and lung infection. Thus, kinetically regulated type I IFN signaling coordinates immunometabolic checkpoints that control infection-induced inflammation.
    Keywords:  CP: Immunology; CP: Metabolism; Staphylococcus aureus; epigenetics; immunometabolism; inflammation; innate immunity; interferon; lactate; macrophage; nitric oxide; respiratory complex
    DOI:  https://doi.org/10.1016/j.celrep.2024.114607
  2. Mucosal Immunol. 2024 Aug 08. pii: S1933-0219(24)00083-7. [Epub ahead of print]
    Exposure to bacterial PAMPs before RSV infection exacerbates innate inflammation and disease via IL-1α and TNF-α.
    Amber R Owen, Ana Farias, Anne-Marie Levins, Ziyin Wang, Sophie L Higham, Matthias Mack, John S Tregoning, Cecilia Johansson.
      Respiratory syncytial virus (RSV) can cause severe lower respiratory tract infections. Understanding why some individuals get more serious disease may help with diagnosis and treatment. One possible risk factor underlying severe disease is bacterial exposure before RSV infection. Bacterial exposure has been associated with increased respiratory viral-induced disease severity but the mechanism remains unknown. Respiratory bacterial infections or exposure to their pathogen associated molecular patterns (PAMPs) trigger innate immune inflammation, characterised by neutrophil and inflammatory monocyte recruitment and the production of inflammatory cytokines. We hypothesise that these changes to the lung environment alter the immune response and disease severity during subsequent RSV infection. To test this, we intranasally exposed mice to LPS, LTA or Acinetobacter baumannii (an airway bacterial pathogen) before RSV infection and observed an early induction of disease, measured by weight loss, at days 1-3 after infection. This exacerbated weight loss was not driven by neutrophils or inflammatory monocytes were not responsible for driving this exacerbated weight loss. Instead, exacerbated disease was associated with increased IL-1α and TNF-α, which orchestrated the recruitment of innate immune cells into the lung. This study shows that exposure to bacterial PAMPs prior to RSV infection increases the expression of IL-1α and TNF-α, which dysregulate the immune response resulting in exacerbated disease.
    Keywords:  Bacteria; Innate immunity; Pro-inflammatory cytokines; Respiratory infections; Virus infections
    DOI:  https://doi.org/10.1016/j.mucimm.2024.08.002
  3. Infect Immun. 2024 Aug 16. e0030424
    RSV enhances Staphylococcus aureus bacterial growth in the lung.
    Helen E Rich, Simran Bhutia, Francina Gonzales de Los Santos, Gabrielle P Entrup, Helen I Warheit-Niemi, Stephen J Gurczynski, Monica Bame, Michael T Douglas, Susan B Morris, Rachel L Zemans, Nicholas W Lukacs, Bethany B Moore.
      Patients coinfected with respiratory syncytial virus (RSV) and bacteria have longer hospital stays, higher risk of intensive care unit admission, and worse outcomes. We describe a model of RSV line 19F/methicillin-resistant Staphylococcus aureus (MRSA) USA300 coinfection that does not impair viral clearance, but prior RSV infection enhances USA300 MRSA bacterial growth in the lung. The increased bacterial burden post-RSV correlates with reduced accumulation of neutrophils and impaired bacterial killing by alveolar macrophages. Surprisingly, reduced neutrophil accumulation is likely not explained by reductions in phagocyte-recruiting chemokines or alterations in proinflammatory cytokine production compared with mice infected with S. aureus alone. Neutrophils from RSV-infected mice retain their ability to migrate toward chemokine signals, and neutrophils from the RSV-infected lung are better able to phagocytize and kill S. aureus ex vivo on a per cell basis. In contrast, while alveolar macrophages could ingest USA300 post-RSV, intracellular bacterial killing was impaired. The RSV/S. aureus coinfected lung promotes a state of overactivation in neutrophils, demonstrated by increased production of reactive oxygen species (ROS) that can drive formation of neutrophil extracellular traps (NETs), resulting in cell death. Mice with RSV/S. aureus coinfection had increased extracellular DNA and protein in bronchoalveolar lavage fluid and histological evidence confirmed NETosis in vivo. Taken together, these data highlight that prior RSV infection can prime the overactivation of neutrophils leading to cell death that impairs neutrophil accumulation in the lung. Additionally, alveolar macrophage killing of bacteria is impaired post-RSV. Together, these defects enhance USA300 MRSA bacterial growth in the lung post-RSV.
    Keywords:  MRSA; alveolar macrophage; lung; neutrophil; respiratory syncitial virus
    DOI:  https://doi.org/10.1128/iai.00304-24
  4. Nat Metab. 2024 Aug 09.
    Broad-spectrum antibiotics disrupt homeostatic efferocytosis.
    Pedro H V Saavedra, Alissa J Trzeciak, Allie Lipshutz, Andrew W Daman, Anya J O'Neal, Zong-Lin Liu, Zhaoquan Wang, Jesús E Romero-Pichardo, Waleska Saitz Rojas, Giulia Zago, Marcel R M van den Brink, Steven Z Josefowicz, Christopher D Lucas, Christopher J Anderson, Alexander Y Rudensky, Justin S A Perry.
      The clearance of apoptotic cells, termed efferocytosis, is essential for tissue homeostasis and prevention of autoimmunity1. Although past studies have elucidated local molecular signals that regulate homeostatic efferocytosis in a tissue2,3, whether signals arising distally also regulate homeostatic efferocytosis remains elusive. Here, we show that large peritoneal macrophage (LPM) display impairs efferocytosis in broad-spectrum antibiotics (ABX)-treated, vancomycin-treated and germ-free mice in vivo, all of which have a depleted gut microbiota. Mechanistically, the microbiota-derived short-chain fatty acid butyrate directly boosts efferocytosis efficiency and capacity in mouse and human macrophages, and rescues ABX-induced LPM efferocytosis defects in vivo. Bulk messenger RNA sequencing of butyrate-treated macrophages in vitro and single-cell messenger RNA sequencing of LPMs isolated from ABX-treated and butyrate-rescued mice reveals regulation of efferocytosis-supportive transcriptional programmes. Specifically, we find that the efferocytosis receptor T cell immunoglobulin and mucin domain containing 4 (TIM-4, Timd4) is downregulated in LPMs of ABX-treated mice but rescued by oral butyrate. We show that TIM-4 is required for the butyrate-induced enhancement of LPM efferocytosis capacity and that LPM efferocytosis is impaired beyond withdrawal of ABX. ABX-treated mice exhibit significantly worse disease in a mouse model of lupus. Our results demonstrate that homeostatic efferocytosis relies on distal metabolic signals and suggest that defective homeostatic efferocytosis may explain the link between ABX use and inflammatory disease4-7.
    DOI:  https://doi.org/10.1038/s42255-024-01107-7
  5. mBio. 2024 Aug 12. e0057824
    The microbiome-derived antibacterial lugdunin acts as a cation ionophore in synergy with host peptides.
    Anne Berscheid, Jan Straetener, Nadine A Schilling, Dominik Ruppelt, Martin C Konnerth, Birgit Schittek, Bernhard Krismer, Andreas Peschel, Claudia Steinem, Stephanie Grond, Heike Brötz-Oesterhelt.
      Lugdunin is a microbiome-derived antibacterial agent with good activity against Gram-positive pathogens in vitro and in animal models of nose colonization and skin infection. We have previously shown that lugdunin depletes bacterial energy resources by dissipating the membrane potential of Staphylococcus aureus. Here, we explored the mechanism of action of lugdunin in more detail and show that lugdunin quickly depolarizes cytoplasmic membranes of different bacterial species and acidifies the cytoplasm of S. aureus within minutes due to protonophore activity. Varying the salt species and concentrations in buffers revealed that not only protons are transported, and we demonstrate the binding of the monovalent cations K+, Na+, and Li+ to lugdunin. By comparing known ionophores with various ion transport mechanisms, we conclude that the ion selectivity of lugdunin largely resembles that of 15-mer linear peptide gramicidin A. Direct interference with the main bacterial metabolic pathways including DNA, RNA, protein, and cell wall biosyntheses can be excluded. The previously observed synergism of lugdunin with dermcidin-derived peptides such as DCD-1 in killing S. aureus is mechanistically based on potentiated membrane depolarization. We also found that lugdunin was active against certain eukaryotic cells, however strongly depending on the cell line and growth conditions. While adherent lung epithelial cell lines were almost unaffected, more sensitive cells showed dissipation of the mitochondrial membrane potential. Lugdunin seems specifically adapted to its natural environment in the respiratory tract. The ionophore mechanism is refractory to resistance development and benefits from synergy with host-derived antimicrobial peptides.IMPORTANCE: The vast majority of antimicrobial peptides produced by members of the microbiome target the bacterial cell envelope by many different mechanisms. These compounds and their producers have evolved side-by-side with their host and were constantly challenged by the host's immune system. These molecules are optimized to be well tolerated at their physiological site of production, and their modes of action have proven efficient in vivo. Imbalancing the cellular ion homeostasis is a prominent mechanism among antibacterial natural products. For instance, over 120 naturally occurring polyether ionophores are known to date, and antimicrobial peptides with ionophore activity have also been detected in microbiomes. In this study, we elucidated the mechanism underlying the membrane potential-dissipating activity of the thiazolidine-containing cycloheptapeptide lugdunin, the first member of the fibupeptides discovered in a commensal bacterium from the human nose, which is a promising future probiotic candidate that is not prone to resistance development.
    Keywords:  Staphylococcus aureus; antibacterial agent; bacteriocin; dermcidin; mechanism of action; membrane potential; microbiome interaction; natural product; synergism
    DOI:  https://doi.org/10.1128/mbio.00578-24
  6. J Exp Med. 2024 Oct 07. pii: e20240002. [Epub ahead of print]221(10):
    A path forward for Staphylococcus aureus vaccine development.
    Stephanie A Fritz, Juliane Bubeck Wardenburg.
      The pursuit of a vaccine to quell Staphylococcus aureus disease has been unfruitful. In this Viewpoint, we explore the biological linkage between microbial niche acquisition and host immunity as a basis to guide future vaccine efforts.
    DOI:  https://doi.org/10.1084/jem.20240002
  7. Cell Host Microbe. 2024 Aug 14. pii: S1931-3128(24)00279-8. [Epub ahead of print]32(8): 1264-1279
    Commensal microbe regulation of skin cells in disease.
    Yuyang Gan, Jiarui Zhang, Fangfang Qi, Zhiqi Hu, Evan Sweren, Sashank K Reddy, Lu Chen, Xinyi Feng, Elizabeth A Grice, Luis A Garza, Gaofeng Wang.
      Human skin is the host to various commensal microbes that constitute a substantial microbial community. The reciprocal communication between these microbial inhabitants and host cells upholds both the morphological and functional attributes of the skin layers, contributing indispensably to microenvironmental and tissue homeostasis. Thus, disruption of the skin barrier or imbalances in the microbial communities can exert profound effects on the behavior of host cells. This influence, mediated by the microbes themselves or their metabolites, manifests in diverse outcomes. In this review, we examine existing knowledge to provide insight into the nuanced behavior exhibited by the microbiota on skin cells in health and disease states. These interactions provide insight into potential cellular targets for future microbiota-based therapies to prevent and treat skin disease.
    DOI:  https://doi.org/10.1016/j.chom.2024.07.020
  8. Int J Mol Sci. 2024 Jul 27. pii: 8223. [Epub ahead of print]25(15):
    The Role of the Gut and Airway Microbiota in Chronic Rhinosinusitis with Nasal Polyps: A Systematic Review.
    Manuel Gómez-García, Emma Moreno-Jimenez, Natalia Morgado, Asunción García-Sánchez, María Gil-Melcón, Jacqueline Pérez-Pazos, Miguel Estravís, María Isidoro-García, Ignacio Dávila, Catalina Sanz.
      In recent years, there has been growing interest in understanding the potential role of microbiota dysbiosis or alterations in the composition and function of human microbiota in the development of chronic rhinosinusitis with nasal polyposis (CRSwNP). This systematic review evaluated the literature on CRSwNP and host microbiota for the last ten years, including mainly nasal bacteria, viruses, and fungi, following the PRISMA guidelines and using the major scientific publication databases. Seventy original papers, mainly from Asia and Europe, met the inclusion criteria, providing a comprehensive overview of the microbiota composition in CRSwNP patients and its implications for inflammatory processes in nasal polyps. This review also explores the potential impact of microbiota-modulating therapies for the CRSwNP treatment. Despite variability in study populations and methodologies, findings suggest that fluctuations in specific taxa abundance and reduced bacterial diversity can be accepted as critical factors influencing the onset or severity of CRSwNP. These microbiota alterations appear to be implicated in triggering cell-mediated immune responses, cytokine cascade changes, and defects in the epithelial barrier. Although further human studies are required, microbiota-modulating strategies could become integral to future combined CRSwNP treatments, complementing current therapies that mainly target inflammatory mediators and potentially improving patient outcomes.
    Keywords:  chronic rhinosinusitis with nasal polyps; functional modulation of the microbiota; human microbiota; immune system; respiratory diseases
    DOI:  https://doi.org/10.3390/ijms25158223
  9. Nat Microbiol. 2024 Aug 12.
    Staphylococcus aureus adapts to exploit collagen-derived proline during chronic infection.
    Andreacarola Urso, Ian R Monk, Ying-Tsun Cheng, Camilla Predella, Tania Wong Fok Lung, Erin M Theiller, Jack Boylan, Sofya Perelman, Swikrity U Baskota, Ahmed M Moustafa, Gaurav Lohia, Ian A Lewis, Benjamin P Howden, Timothy P Stinear, Nicolino V Dorrello, Victor Torres, Alice S Prince.
      Staphylococcus aureus is a pulmonary pathogen associated with substantial human morbidity and mortality. As vaccines targeting virulence determinants have failed to be protective in humans, other factors are likely involved in pathogenesis. Here we analysed transcriptomic responses of human clinical isolates of S. aureus from initial and chronic infections. We observed upregulated collagenase and proline transporter gene expression in chronic infection isolates. Metabolomics of bronchiolar lavage fluid and fibroblast infection, growth assays and analysis of bacterial mutant strains showed that airway fibroblasts produce collagen during S. aureus infection. Host-adapted bacteria upregulate collagenase, which degrades collagen and releases proline. S. aureus then imports proline, which fuels oxidative metabolism via the tricarboxylic acid cycle. Proline metabolism provides host-adapted S. aureus with a metabolic benefit enabling out-competition of non-adapted strains. These data suggest that clinical settings characterized by airway repair processes and fibrosis provide a milieu that promotes S. aureus adaptation and supports infection.
    DOI:  https://doi.org/10.1038/s41564-024-01769-9
  10. Am J Physiol Lung Cell Mol Physiol. 2024 Aug 13.
    A lentiviral toolkit to monitor airway epithelial cell differentiation using bioluminescence.
    Jessica C Orr, Asma Laali, Pascal F Durrenberger, Kyren A Lazarus, Marie-Belle El Mdawar, Sam M Janes, Robert E Hynds.
      Basal cells are adult stem cells in the airway epithelium and regenerate differentiated cell populations, including the mucosecretory and ciliated cells that enact mucociliary clearance. Human basal cells can proliferate and produce differentiated epithelium in vitro. However, studies of airway epithelial differentiation mostly rely on immunohistochemical or immunofluorescence-based staining approaches, meaning that a dynamic approach is lacking, and quantitative data is limited. Here, we use a lentiviral reporter gene approach to transduce primary human basal cells with bioluminescence reporter constructs to monitor airway epithelial differentiation longitudinally. We generated three constructs driven by promoter sequences from the TP63, MUC5AC and FOXJ1 genes to quantitatively assess basal cell, mucosecretory cell and ciliated cell abundance, respectively. We validated these constructs by tracking differentiation of basal cells in air-liquid interface and organoid ('bronchosphere') cultures. Transduced cells also responded appropriately to stimulation with interleukin 13 (IL-13; to increase mucosecretory differentiation and mucus production) and IL-6 (to increase ciliated cell differentiation). These constructs represent a new tool for monitoring airway epithelial cell differentiation in primary epithelial and/or induced pluripotent stem cell (iPSC) cell cultures.
    Keywords:  airway epithelium; basal cells; lentiviral transduction; multiciliated cells; primary cell culture
    DOI:  https://doi.org/10.1152/ajplung.00047.2024
  11. medRxiv. 2024 Aug 06. pii: 2024.08.02.24311426. [Epub ahead of print]
    Transitions in lung microbiota landscape associate with distinct patterns of pneumonia progression.
    NU SCRIPT Study Investigators
      Pneumonia and other lower respiratory tract infections are the leading contributors to global mortality of any communicable disease [1]. During normal pulmonary homeostasis, competing microbial immigration and elimination produce a transient microbiome with distinct microbial states [2-4]. Disruption of underlying ecological forces, like aspiration rate and immune tone, are hypothesized to drive microbiome dysbiosis and pneumonia progression [5-7]. However, the precise microbiome transitions that accompany clinical outcomes in severe pneumonia are unknown. Here, we leverage our unique systematic and serial bronchoscopic sampling to combine quantitative PCR and culture for bacterial biomass with 16S rRNA gene amplicon, shotgun metagenomic, and transcriptomic sequencing in patients with suspected pneumonia to distill microbial signatures of clinical outcome. These data support the presence of four distinct microbiota states-oral-like, skin-like, Staphylococcus -predominant, and mixed-each differentially associated with pneumonia subtype and responses to pneumonia therapy. Infection-specific dysbiosis, quantified relative to non-pneumonia patients, associates with bacterial biomass and elevated oral-associated microbiota. Time series analysis suggests that microbiome shifts from baseline are greater with successful pneumonia therapy, following distinct trajectories dependent on the pneumonia subtype. In summary, our results highlight the dynamic nature of the lung microbiome as it progresses through community assemblages that parallel patient prognosis. Application of a microbial ecology framework to study lower respiratory tract infections enables contextualization of the microbiome composition and gene content within clinical phenotypes. Further unveiling the ecological dynamics of the lung microbial ecosystem provides critical insights for future work toward improving pneumonia therapy.
    DOI:  https://doi.org/10.1101/2024.08.02.24311426
  12. PLoS One. 2024 ;19(8): e0306259
    Resistance of Pseudomonas aeruginosa and Staphylococcus aureus to the airway epithelium oxidative response assessed by a cell-free in vitro assay.
    Maïwenn Petithomme-Nanrocki, Nathan Nicolau-Guillaumet, Nicolas Borie, Arnaud Haudrechy, Jean-Hugues Renault, Sophie Moussalih, Anaëlle Muggeo, Thomas Guillard.
      The antibacterial oxidative response, which relies on the production of hydrogen peroxide (H2O2) and hypothiocyanite (OSCN-), is a major line of defense protecting the human airway epithelium (HAE) from lesions when infected. The in vitro studies of the oxidative responses are performed mainly by one-shot H2O2 exposure that does not recapitulate the complex H2O2/LPO/SCN- system releasing the reactive oxygen species in airway secretions. A cell-free in vitro assay mimicking this system has been described but was not fully characterized. Here, we comprehensively characterized the hourly H2O2/OSCN- concentrations produced within this in vitro assay and assessed the resistance of Pseudomonas aeruginosa and Staphylococcus aureus clinical strains to the HAE oxidative response. We found that H2O2/OSCN- were steadily produced from 7h and up to 25h, but OSCN- was detoxified in 15 minutes by bacteria upon exposure. Preliminary tests on PA14 showed survival rates at 1-hour post-exposure (hpe) to H2O2 of roughly 50% for 105 and 107 colony-forming unit (CFU)/mL inocula, while 102 and 104 CFU/mL inocula were cleared after one hpe. Thirteen clinical strains were then exposed, highlighting that conversely to P. aeruginosa, S. aureus showed resistance to oxidative stress independently of its antibiotic resistance phenotype. Our results demonstrated how this in vitro assay can be helpful in assessing whether pathogens can resist the antibacterial oxidative HAE response. We anticipate these findings as a starting point for more sophisticated in vitro models that could serve as high-throughput screening for molecules targeting the bacterial antioxidant response.
    DOI:  https://doi.org/10.1371/journal.pone.0306259
  13. Infect Immun. 2024 Aug 16. e0022224
    Protective innate immunity against Pneumocystis does not require Stat6-dependent macrophage polarization.
    T Mousso, S J Pollock, P C Inzerillo, F Gigliotti, T W Wright.
      Pneumocystis species are respiratory fungal pathogens that cause life-threatening opportunistic infections in immunocompromised hosts. Pneumocystis typically evade pulmonary innate immunity but are efficiently eradicated by a functional adaptive immune response. FVB/NJ mice are unique in that they display protective alveolar macrophage-dependent innate immunity against Pneumocystis, and remain resistant to infection even in the absence of CD4+ T lymphocyte function. FVB/NJ alveolar macrophages (AMs) were found to display an M2-biased phenotype at baseline, which was potentiated after stimulation with Pneumocystis, suggesting that macrophage polarization may dictate the outcome of the Pneumocystis-macrophage interaction. To determine whether Stat6, a key global regulator of M2 polarization, was required for FVB/NJ innate immunity, FVB Stat6-/- mice were generated. FVB Stat6-deficient AMs were markedly impaired in their ability to polarize to an M2 phenotype when stimulated with Th2 cytokines. However, FVB Stat6-/- mice remained highly resistant to infection, indicating that Stat6 signaling is dispensable for innate FVB/NJ resistance. Despite the loss of Stat6 signaling, primary AMs from FVB Stat6-/- mice maintained baseline expression of M2 markers, and also strongly upregulated M2-associated genes following direct stimulation with Pneumocystis. Additional FVB/NJ knockout strains were generated, but only FVB MerTK-/- mice showed a marginally increased susceptibility to Pneumocystis infection. Together, these findings demonstrate that effective FVB/NJ innate immunity against Pneumocystis does not require Stat6 signaling and suggest that alternative pathways regulate M2 bias and macrophage-mediated innate resistance in FVB/NJ mice.
    Keywords:  Pneumocystis; fungal pathogen; innate immunity
    DOI:  https://doi.org/10.1128/iai.00222-24
  14. Matrix Biol. 2024 Sep;pii: S0945-053X(24)00091-X. [Epub ahead of print]132 47-58
    Interleukin-1α inhibits transforming growth factor-β1 and β2-induced extracellular matrix production, remodeling and signaling in human lung fibroblasts: Master regulator in lung mucosal repair.
    Kauna Usman, May Fouadi, Kingsley Okechukwu Nwozor, Fatemeh Aminazadeh, Parameswaran Nair, Honglin Luo, Don D Sin, Emmanuel Twumasi Osei, Tillie-Louise Hackett.
      BACKGROUND: Lung fibroblasts play a central role in maintaining lung homeostasis and facilitating repair through the synthesis and organization of the extracellular matrix (ECM). This study investigated the cross-talk between interleukin-1 alpha (IL-1α) and transforming growth factor-β (TGF-β) signaling, two key regulators in tissue repair and fibrosis, in the context of lung fibroblast repair in the healthy lung.RESULTS: Stimulation of lung fibroblasts with TGF-β1 and TGF-β2 induced collagen-I and fibronectin protein expression (p < 0.05), a response inhibited with co-treatment with IL-1α (p < 0.05). Additionally, TGF-β1 and TGF-β2 induced myofibroblast differentiation, and collagen-I gel contraction, which were both suppressed by IL-1α (p < 0.05). In contrast, interleukin (IL)-6, IL-8 and thymic stromal lymphopoietin induced by IL-1α, were unaffected by TGF-β1 or TGF-β2. Mechanistically, IL-1α administration led to the suppression of TGF-β1 and TGF-β2 signaling, through downregulation of mRNA and protein for TGF-β receptor II and the downstream adaptor protein TRAF6, but not through miR-146a that is known to be induced by IL-1α.
    DISCUSSION: IL-1α acts as a master regulator, modulating TGF-β1 and TGF-β2-induced ECM production, remodeling, and myofibroblast differentiation in human lung fibroblasts, playing a vital role in balancing tissue repair versus fibrosis. Further research is required to understand the dysregulated cross-talk between IL-1α and TGF-β signaling in chronic lung diseases and the exploration of therapeutic opportunities.
    METHODS: Primary human lung fibroblasts (PHLF) were treated with media control, or 1 ng/ml IL-1α with or without 50 ng/ml TGF-β1 or TGF-β2 for 1, 6 and 72 h. Cell lysates were assessed for the expression of ECM proteins and signaling molecules by western blot, miRNA by qPCR, mRNA by RNA sequencing and cell supernatants for cytokine production by ELISA. PHLFs were also seeded in non-tethered collagen-I gels to measure contraction, and myofibroblast differentiation using confocal microscopy.
    Keywords:  Extracellular matrix; Interleukin-1 alpha; Lung fibroblasts; Lung repair; Transforming growth factor-β
    DOI:  https://doi.org/10.1016/j.matbio.2024.06.007
  15. Am J Transplant. 2024 Aug 13. pii: S1600-6135(24)00492-1. [Epub ahead of print]
    Trained immunity suppression determines kidney allograft survival.
    Inge Jonkman, Maaike M E Jacobs, Yutaka Negishi, Cansu Yanginlar, Joost H A Martens, Marijke Baltissen, Michiel Vermeulen, Martijn W F van den Hoogen, Marije Baas, Johan van der Vlag, Zahi A Fayad, Abraham J P Teunissen, Joren C Madsen, Jordi Ochando, Leo A B Joosten, Mihai G Netea, Willem J M Mulder, Musa M Mhlanga, Luuk B Hilbrands, Nils Rother, Raphaël Duivenvoorden.
      The innate immune system plays an essential role in regulating the immune responses to kidney transplantation, but the mechanisms through which innate immune cells influence long-term graft survival are unclear. The current study highlights the vital role of trained immunity in kidney allograft survival. Trained immunity describes the epigenetic and metabolic changes that innate immune cells undergo following an initial stimulus, allowing them have a stronger inflammatory response to subsequent stimuli. We stimulated healthy peripheral blood mononuclear cells (PBMCs) with pre- and post-transplantation serum of kidney transplant patients, and immunosuppressive drugs in an in vitro trained immunity assay and measured tumor necrosis factor (TNF) and interleukin-6 (IL-6) cytokine levels in the supernatant as a readout for trained immunity. We show that the serum of kidney transplant recipients collected one week after transplantation can suppress trained immunity. Importantly, we found that kidney transplant recipients whose serum most strongly suppressed trained immunity, rarely experienced graft loss. This suppressive effect of post-transplant serum is likely mediated, by previously unreported effects of immunosuppressive drugs. Our findings provide mechanistic insights into the role of innate immunity in kidney allograft survival, uncovering trained immunity as a potential therapeutic target for improving graft survival.
    Keywords:  Trained immunity; graft survival; innate immunity; kidney transplantation
    DOI:  https://doi.org/10.1016/j.ajt.2024.08.006
  16. Front Immunol. 2024 ;15 1444964
    Macrophage polarization and its impact on idiopathic pulmonary fibrosis.
    Zhouling Ge, Yong Chen, Leikai Ma, Fangjun Hu, Lubin Xie.
      Idiopathic pulmonary fibrosis (IPF) is a lung disease that worsens over time, causing fibrosis in the lungs and ultimately resulting in respiratory failure and a high risk of death. Macrophages play a crucial role in the immune system, showing flexibility by transforming into either pro-inflammatory (M1) or anti-inflammatory (M2) macrophages when exposed to different stimuli, ultimately impacting the development of IPF. Recent research has indicated that the polarization of macrophages is crucial in the onset and progression of IPF. M1 macrophages secrete inflammatory cytokines and agents causing early lung damage and fibrosis, while M2 macrophages support tissue healing and fibrosis by releasing anti-inflammatory cytokines. Developing novel treatments for IPF relies on a thorough comprehension of the processes involved in macrophage polarization in IPF. The review outlines the regulation of macrophage polarization and its impact on the development of IPF, with the goal of investigating the possible therapeutic benefits of macrophage polarization in the advancement of IPF.
    Keywords:  M1 macrophages; M2 macrophages; fibrosis; idiopathic pulmonary fibrosis; inflammation; macrophage polarization
    DOI:  https://doi.org/10.3389/fimmu.2024.1444964
  17. bioRxiv. 2024 Aug 10. pii: 2024.08.09.607357. [Epub ahead of print]
    Deep skin fibroblast-mediated macrophage recruitment supports acute wound healing.
    Veronica M Amuso, MaryEllen R Haas, Paula O Cooper, Ranojoy Chatterjee, Sana Hafiz, Shatha Salameh, Chiraag Gohel, Miguel F Mazumder, Violet Josephson, Khatereh Khorsandi, Anelia Horvath, Ali Rahnavard, Brett A Shook.
      Epithelial and immune cells have long been appreciated for their contribution to the early immune response after injury; however, much less is known about the role of mesenchymal cells. Using single nuclei RNA-sequencing, we defined changes in gene expression associated with inflammation at 1-day post-wounding (dpw) in mouse skin. Compared to keratinocytes and myeloid cells, we detected enriched expression of pro-inflammatory genes in fibroblasts associated with deeper layers of the skin. In particular, SCA1+ fibroblasts were enriched for numerous chemokines, including CCL2, CCL7, and IL33 compared to SCA1-fibroblasts. Genetic deletion of Ccl2 in fibroblasts resulted in fewer wound bed macrophages and monocytes during injury-induced inflammation with reduced revascularization and re-epithelialization during the proliferation phase of healing. These findings highlight the important contribution of deep skin fibroblast-derived factors to injury-induced inflammation and the impact of immune cell dysregulation on subsequent tissue repair.
    DOI:  https://doi.org/10.1101/2024.08.09.607357
  18. Sci Rep. 2024 08 14. 14(1): 18882
    Induction of trained immunity in broiler chickens following delivery of oligodeoxynucleotide containing CpG motifs to protect against Escherichia coli septicemia.
    Iresha Subhasinghe, Khawaja Ashfaque Ahmed, Lisanework E Ayalew, Hemlata Gautam, Shelly Popowich, Ayumi Matsuyama-Kato, Betty Chow-Lockerbie, Suresh K Tikoo, Philip Griebel, Susantha Gomis.
      Oligodeoxynucleotides containing CpG motifs (CpG-ODN) can promote antimicrobial immunity in chickens by enriching immune compartments and activating immune cells. Innate memory, or trained immunity, has been demonstrated in humans and mice, featuring the absence of specificity to the initial stimulus and subsequently cross-protection against pathogens. We hypothesize that CpG-ODN can induce trained immunity in chickens. We delivered single or multiple administrations of CpG-ODN to birds and mitochondrial oxidative phosphorylation (OXPHOS) and glycolysis of peripheral blood mononuclear cells were quantified using Seahorse XFp. Next, chickens were administered with CpG-ODN twice at 1 and 4 day of age and challenged with Escherichia coli at 27 days of age. The CpG-ODN administered groups had significantly higher mitochondrial OXPHOS until 21 days of age while cellular glycolysis gradually declined by 14 days of age. The group administered with CpG-ODN twice at 1 and 4 days of age had significantly higher survival, lower clinical score and bacterial load following challenge with E. coli at 27 d of age. This study demonstrated the induction of trained immunity in broiler chickens following administration of CpG-ODN twice during the first 4 days of age to protect birds against E. coli septicemia at 27 days of age.
    Keywords:  Broiler chicken; Cellular glycolysis; CpG-ODN; Innate immune memory; Mitochondrial OXPHOS; Trained immunity
    DOI:  https://doi.org/10.1038/s41598-024-69781-x
  19. Nature. 2024 Aug;632(8025): 494-496
    Five ways science is tackling the antibiotic resistance crisis.
    Amber Dance.
      
    Keywords:  Antibiotics; Biotechnology; Drug discovery; Microbiology
    DOI:  https://doi.org/10.1038/d41586-024-02601-4
  20. Br J Pharmacol. 2024 Aug 13.
    Interleukin-1 receptor-associated kinase 4 (IRAK4) is a critical regulator of inflammatory signalling through toll-like receptors 4 and 7/8 in murine and human lungs.
    Ian Sayers, Dhruma Thakker, Charlotte Billington, Stefan Kreideweiss, Marc A Grundl, Thierry Bouyssou, Sven Thamm, Sebastian Kreuz, Ian P Hall.
      BACKGROUND AND PURPOSE: Toll-like receptors 4 (TLR4) and TLR7/TLR8 play an important role in mediating the inflammatory effects of bacterial and viral pathogens. Interleukin-1 receptor-associated kinase 4 (IRAK4) is an important regulator of signalling by toll-like receptor (TLR) and hence is a potential therapeutic target in diseases characterized by increased lung inflammatory signalling.EXPERIMENTAL APPROACH: We used an established murine model of acute lung inflammation, and studied human lung tissue ex vivo, to investigate the effects of inhibiting IRAK4 on lung inflammatory pathways.
    KEY RESULTS: We show that TLR4 stimulation produces an inflammatory response characterized by neutrophil influx and tumour necrosis factor-α (TNF-α) production in murine lungs and that these responses are markedly reduced in IRAK4 kinase-dead mice. In addition, we characterize a novel selective IRAK4 inhibitor, BI1543673, and show that this compound can reduce lipopolysaccharide (LPS)-induced airway inflammation in wild-type mice. Additionally, BI1543673 reduced inflammatory responses to both TLR4 and TLR7/8 stimulation in human lung tissue studied ex vivo.
    CONCLUSION AND IMPLICATIONS: These data demonstrate a key role for IRAK4 signalling in lung inflammation and suggest that IRAK4 inhibition has potential utility to treat lung diseases characterized by inflammatory responses driven through TLR4 and TLR7/8.
    Keywords:  IRAK4; chronic obstructive pulmonary disease; exacerbations; interstitial lung disease; lung inflammation; toll‐ like receptors
    DOI:  https://doi.org/10.1111/bph.16509
  21. Eur Respir Rev. 2024 Jul;pii: 240062. [Epub ahead of print]33(173):
    Recreating chronic respiratory infections in vitro using physiologically relevant models.
    Lucia Grassi, Aurélie Crabbé.
      Despite the need for effective treatments against chronic respiratory infections (often caused by pathogenic biofilms), only a few new antimicrobials have been introduced to the market in recent decades. Although different factors impede the successful advancement of antimicrobial candidates from the bench to the clinic, a major driver is the use of poorly predictive model systems in preclinical research. To bridge this translational gap, significant efforts have been made to develop physiologically relevant models capable of recapitulating the key aspects of the airway microenvironment that are known to influence infection dynamics and antimicrobial activity in vivo In this review, we provide an overview of state-of-the-art cell culture platforms and ex vivo models that have been used to model chronic (biofilm-associated) airway infections, including air-liquid interfaces, three-dimensional cultures obtained with rotating-wall vessel bioreactors, lung-on-a-chips and ex vivo pig lungs. Our focus is on highlighting the advantages of these infection models over standard (abiotic) biofilm methods by describing studies that have benefited from these platforms to investigate chronic bacterial infections and explore novel antibiofilm strategies. Furthermore, we discuss the challenges that still need to be overcome to ensure the widespread application of in vivo-like infection models in antimicrobial drug development, suggesting possible directions for future research. Bearing in mind that no single model is able to faithfully capture the full complexity of the (infected) airways, we emphasise the importance of informed model selection in order to generate clinically relevant experimental data.
    DOI:  https://doi.org/10.1183/16000617.0062-2024
  22. Am J Respir Cell Mol Biol. 2024 Aug 14.
    Airway Epithelium-derived CXCL14 Promotes Eosinophil Accumulation in Allergic Airway Inflammation.
    Takunori Ogawa, Yohei Maki, Shusaku Takahashi, Takeshi Ono, Kimiya Sato, Akihiko Kawana, Yoshifumi Kimizuka.
      C-X-C motif chemokine ligand 14 (CXCL14) is expressed in the airway epithelial cells of patients with asthma. However, the mechanisms of CXCL14 secretion and its effects on asthma pathogenesis remain unclear. Here, we investigated the role of CXCL14 in allergic airway inflammation and its effects on eosinophil infiltration. Our findings showed that Alternaria alternata, a major environmental allergen, stimulated CXCL14 secretion from airway epithelial cells via reactive oxygen species (ROS) generated in mitochondrial oxidative phosphorylation (OXPHOS) complexes, especially in OXPHOS complex II. In vivo, in a mouse model of allergic airway inflammation, intranasal administration of anti-CXCL14 antibody suppressed eosinophil and dendritic cell infiltration into the airways and goblet cell hyperplasia. In vitro, in human eosinophil-like cells, CXCL14 promoted cell migration through C-X-C chemokine receptor type 4 (CXCR4) binding. Eosinophil CXCR4 expression was upregulated by Alternaria stimulation via ROS production. These findings suggest that the crosstalk between Alternaria-stimulated airway epithelial CXCL14 secretion and eosinophil CXCR4 upregulation plays an important role in eosinophil infiltration into the lungs during allergic airway inflammation. In summary, this study demonstrates that CXCL14 could be a therapeutic target for allergic airway inflammation.
    Keywords:  CXCL14; CXCR4; asthma; reactive oxygen species
    DOI:  https://doi.org/10.1165/rcmb.2024-0142OC
  23. Int Immunopharmacol. 2024 Aug 11. pii: S1567-5769(24)01445-0. [Epub ahead of print]140 112924
    ACOD1 mediates Staphylococcus aureus-induced inflammatory response via the TLR4/NF-κB signaling pathway.
    Fan Dai, Xuyang Zhang, Guilan Ma, Wu Li.
      Staphylococcus aureus (SA) is a common Gram-positive bacterium that activates inflammatory cells, expressing various cytokines and inducing an inflammatory response. Recent research revealed aconitate decarboxylase 1 (ACOD1) as a regulator of the immune response through various metabolic pathways, playing a dual role in the inflammatory response. However, the mechanism by which ACOD1 participates in the regulation of SA-induced inflammatory responses in macrophages remains unknown. Therefore, this study aims to investigate the function and underlying regulatory mechanisms of ACOD1 in SA-induced inflammatory response. This study reveals that SA induced a macrophage inflammatory response and upregulated ACOD1 expression. ACOD1 knockdown significantly inhibited SA-induced macrophage inflammatory response, attenuated SA-induced nuclear envelope wrinkling, and plasma membrane rupture, and suppressed the TLR4/NF-κB signaling pathway. Furthermore, ACOD1 knockdown reduced the inflammatory response and alleviated lung tissue injury and cellular damage, leading to decreased bacterial loads in the lungs of SA-infected mice. Collectively, these findings demonstrate that SA induces an inflammatory response in macrophages and increases ACOD1 expression. ACOD1 enhances SA-induced inflammatory responses via the TLR4/NF-κB signaling pathway. Our findings highlight the significant role of ACOD1 in mediating the inflammatory response in SA-infected macrophages and elucidate its molecular mechanism in regulating the SA-induced inflammatory response.
    Keywords:  ACOD1; C57BL/6J mice; Inflammatory response; Macrophage; Staphylococcus aureus
    DOI:  https://doi.org/10.1016/j.intimp.2024.112924
  24. Crit Rev Microbiol. 2024 Aug 12. 1-12
    Competitive dynamics and balance between Streptococcus mutans and commensal streptococci in oral microecology.
    Dingwei Ye, Yaqi Liu, Jing Li, Jing Zhou, Jingwei Cao, Yumeng Wu, Xinyue Wang, Yuwen Fang, Xingchen Ye, Jing Zou, Qizhao Ma.
      Dental caries, as a biofilm-related disease, is closely linked to dysbiosis in microbial ecology within dental biofilms. Beyond its impact on oral health, bacteria within the oral cavity pose systemic health risks by potentially entering the bloodstream, thereby increasing susceptibility to bacterial endocarditis, among other related diseases. Streptococcus mutans, a principal cariogenic bacterium, possesses virulence factors crucial to the pathogenesis of dental caries. Its ability to adhere to tooth surfaces, produce glucans for biofilm formation, and metabolize sugars into lactic acid contributes to enamel demineralization and the initiation of carious lesions. Its aciduricity and ability to produce bacteriocins enable a competitive advantage, allowing it to thrive in acidic environments and dominate in changing oral microenvironments. In contrast, commensal streptococci, such as Streptococcus sanguinis, Streptococcus gordonii, and Streptococcus salivarius, act as primary colonizers and compete with S. mutans for adherence sites and nutrients during biofilm formation. This competition involves the production of alkali, peroxides, and antibacterial substances, thereby inhibiting S. mutans growth and maintaining microbial balance. This dynamic interaction influences the balance of oral microbiota, with disruptions leading to shifts in microbial composition that are marked by rapid increases in S. mutans abundance, contributing to the onset of dental caries. Thus, understanding the dynamic interactions between commensal and pathogenic bacteria in oral microecology is important for developing effective strategies to promote oral health and prevent dental caries. This review highlights the roles and competitive interactions of commensal bacteria and S. mutans in oral microecology, emphasizing the importance of maintaining oral microbial balance for health, and discusses the pathological implications of perturbations in this balance.
    Keywords:  Streptococcus mutans; commensal streptococci; dental caries; oral microecology
    DOI:  https://doi.org/10.1080/1040841X.2024.2389386
  25. Front Microbiol. 2024 ;15 1390765
    Synergistic action of antimicrobial peptides and antibiotics: current understanding and future directions.
    Sattar Taheri-Araghi.
      Antibiotic resistance is a growing global problem that requires innovative therapeutic approaches and strategies for administering antibiotics. One promising approach is combination therapy, in which two or more drugs are combined to combat an infection. Along this line, the combination of antimicrobial peptides (AMPs) with conventional antibiotics has gained attention mainly due to the complementary mechanisms of action of AMPs and conventional antibiotics. In this article, we review both in vitro and in vivo studies that explore the synergy between AMPs and antibiotics. We highlight several mechanisms through which synergy is observed in in vitro experiments, including increasing membrane permeability, disrupting biofilms, directly potentiating antibiotic efficacy, and inhibiting resistance development. Moreover, in vivo studies reveal additional mechanisms such as enhanced/modulated immune responses, reduced inflammation, and improved tissue regeneration. Together, the current literature demonstrates that AMP-antibiotic combinations can substantially enhance efficacy of antibiotic therapies, including therapies against resistant bacteria, which represents a valuable enhancement to current antimicrobial strategies.
    Keywords:  antibiotic synergy; antimicrobial peptides; antimicrobial resistance; combination therapy; drug combination
    DOI:  https://doi.org/10.3389/fmicb.2024.1390765
  26. Cell Host Microbe. 2024 Aug 14. pii: S1931-3128(24)00282-8. [Epub ahead of print]32(8): 1219-1224
    Microbiome modification for personalized treatment of dysbiotic diseases.
    R Balfour Sartor.
      Fecal microbial transplantation (FMT) for inflammatory diseases or refractory immune checkpoint inhibitor therapy is less effective than for preventing recurrent Clostridioides difficile infection. This commentary outlines strategies to use biomarkers of successful FMT to guide newer approaches to restore microbial homeostasis in individuals with dysbiosis-mediated inflammation.
    DOI:  https://doi.org/10.1016/j.chom.2024.07.023
  27. Int J Mol Sci. 2024 Aug 02. pii: 8467. [Epub ahead of print]25(15):
    Relationship between Respiratory Microbiome and Systemic Inflammatory Markers in COPD: A Pilot Study.
    Carme Casadevall, Sara Quero, Laura Millares, Rosa Faner, Borja G Cosío, Germán Peces-Barba, Ady Castro-Acosta, Concepción Montón, Alexandre Palou, Sergi Pascual-Guardia, Alvar Agustí, Joaquim Gea, Eduard Monsó, On Behalf Of The Biomepoc Group.
      The respiratory microbiome may influence the development and progression of COPD by modulating local immune and inflammatory events. We aimed to investigate whether relative changes in respiratory bacterial abundance are also associated with systemic inflammation, and explore their relationship with the main clinical COPD phenotypes. Multiplex analysis of inflammatory markers and transcript eosinophil-related markers were analyzed on peripheral blood in a cohort of stable COPD patients (n = 72). Respiratory microbiome composition was analyzed by 16S rRNA microbial sequencing on spontaneous sputum. Spearman correlations were applied to test the relationship between the microbiome composition and systemic inflammation. The concentration of the plasma IL-8 showed an inverted correlation with the relative abundance of 17 bacterial genera in the whole COPD cohort. COPD patients categorized as eosinophilic showed positive relationships with blood eosinophil markers and inversely correlated with the degree of airway obstruction and the number of exacerbations during the previous year. COPD patients categorized as frequent exacerbators were enriched with the bacterial genera Pseudomonas which, in turn, was positively associated with the severity of airflow limitation and the prior year's exacerbation history. The associative relationships of the sputum microbiome with the severity of the disease emphasize the relevance of the interaction between the respiratory microbiota and systemic inflammation.
    Keywords:  COPD; eosinophils; frequent exacerbators; respiratory microbiome; systemic inflammation
    DOI:  https://doi.org/10.3390/ijms25158467
  28. Front Immunol. 2024 ;15 1436039
    Insights into the recognition of hypermucoviscous Klebsiella pneumoniae clinical isolates by innate immune lectins of the Siglec and galectin families.
    María Asunción Campanero-Rhodes, Sara Martí, Noelia Hernández-Ortiz, Meritxell Cubero, June Ereño-Orbea, Ana Ardá, Jesús Jiménez-Barbero, Carmen Ardanuy, Dolores Solís.
      Klebsiella pneumoniae is an opportunistic bacterium that frequently colonizes the nasopharynx and gastrointestinal tract and can also cause severe infections when invading other tissues, particularly in immunocompromised individuals. Moreover, K. pneumoniae variants exhibiting a hypermucoviscous (HMV) phenotype are usually associated with hypervirulent strains that can produce invasive infections even in immunocompetent individuals. Major carbohydrate structures displayed on the K. pneumoniae surface are the polysaccharide capsule and the lipopolysaccharide, which presents an O-polysaccharide chain in its outermost part. Various capsular and O-chain structures have been described. Of note, production of a thick capsule is frequently observed in HMV variants. Here we examined the surface sugar epitopes of a collection of HMV and non-HMV K. pneumoniae clinical isolates and their recognition by several Siglecs and galectins, two lectin families of the innate immune system, using bacteria microarrays as main tool. No significant differences among isolates in sialic acid content or recognition by Siglecs were observed. In contrast, analysis of the binding of model lectins with diverse carbohydrate-binding specificities revealed striking differences in the recognition by galactose- and mannose-specific lectins, which correlated with the binding or lack of binding of galectins and pointed to the O-chain as the plausible ligand. Fluorescence microscopy and microarray analyses of galectin-9 binding to entire cells and outer membranes of two representative HMV isolates supported the bacteria microarray results. In addition, Western blot analysis of the binding of galectin-9 to outer membranes unveiled protein bands recognized by this galectin, and fingerprint analysis of these bands identified several proteins containing potential O-glycosylation sites, thus broadening the spectrum of possible galectin ligands on the K. pneumoniae surface. Moreover, Siglecs and galectins apparently target different structures on K. pneumoniae surfaces, thereby behaving as non-redundant complementary tools of the innate immune system.
    Keywords:  Klebsiella pneumoniae; Siglecs; bacterial cell surface carbohydrates; galectins; hypermucoviscosity; lectins
    DOI:  https://doi.org/10.3389/fimmu.2024.1436039
  29. ACS Appl Bio Mater. 2024 Aug 15.
    Perfused In Vitro Intestine Tissue Model to Evaluate the Role of Stromal and Immune Cells in Epithelial Response to Inflammatory Cues and Drug Therapies.
    Sara Rudolph, Terrence T Roh, Brooke Longo, Mina Shokoufandeh, Fatimah Mumuney, Anushka Chadha, Xiaoqin Wang, Gang Li, Xiuli Wang, Ying Chen, David Kaplan.
      We establish an in vitro perfusion intestinal tissue bioreactor system tailored to study drug responses related to inflammatory bowel disease (IBD). The system includes key components including multiple human intestinal cell types (colonoids, myofibroblasts, and macrophages), a three-dimensional (3D) intestinal architecture, and fluid flow. Inclusion of myofibroblasts resulted in increased secretion of cytokines such as glypican-1 (GCP-1), granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin 1-α (IL-1α), whereas inclusion of macrophages resulted in increased secretion of monocyte chemoattractant proteins (MCPs) demonstrating a significant role of both stromal and immune cell types in intestinal inflammation. The system is responsive to drug treatments, as reflected in the reduction of pro-inflammatory cytokine production in tissue in some treatment scenarios. While future studies are needed to evaluate more nuanced responses in an IBD context, the present study demonstrates the ability to establish a 3D intestinal model with multiple relevant cell types and flow that is responsive to both inflammatory cues and various drug treatment options.
    Keywords:  colonoids; cytokine profiling; drug testing; inflammatory bowel disease; organoids; perfused bioreactor
    DOI:  https://doi.org/10.1021/acsabm.4c00703
  30. J Biol Chem. 2024 Aug 09. pii: S0021-9258(24)02159-8. [Epub ahead of print] 107658
    Intracellular pH differentially regulates transcription of metabolic and signaling pathways in normal epithelial cells.
    Ricardo Romero-Moreno, Brandon J Czowski, Lindsey Harris, Jessamine F Kuehn, Katharine A White.
      Intracellular pH (pHi) dynamics regulate normal cell function, and dysregulated pHi dynamics is an emerging hallmark of cancer (constitutively increased pHi) and neurodegeneration (constitutively decreased pHi). However, the molecular mechanisms by which pHi dynamics regulate cell biology are poorly understood. Here, we discovered that altering pHi in normal human breast epithelial cells triggers global transcriptional changes. We identified 176 genes differentially regulated by pHi, with pHi-dependent genes clustering in signaling and glycolytic pathways. Using various normal epithelial cell models, we showed pH-dependent Notch1 expression, with increased protein abundance at high pHi. This resulted in pH-dependent downstream signaling, with increased Notch1 signaling at high pHi. We also found that high pHi increased the expression of glycolytic enzymes and regulators of pyruvate fate, including lactate dehydrogenase and pyruvate dehydrogenase kinase. These transcriptional changes were sufficient to alter lactate production, with high pHi shifting these normal epithelial cells toward a glycolytic metabolism and increasing lactate production. Thus, pHi dynamics transcriptionally regulate signaling and metabolic pathways in normal epithelial cells. Our data reveal new molecular regulators of pHi-dependent biology and a role for increased pHi in driving the acquisition of cancer-associated signaling and metabolic changes in normal human epithelial cells.
    Keywords:  Intracellular pH; Notch1 signaling; glycolysis; lactate; metabolism; pyruvate
    DOI:  https://doi.org/10.1016/j.jbc.2024.107658
  31. bioRxiv. 2024 Jun 22. pii: 2024.06.18.599427. [Epub ahead of print]
    Pharmacologic Inhibition of Ferroptosis Attenuates Experimental Abdominal Aortic Aneurysm Formation.
    Jonathan R Krebs, Paolo Bellotti, Jeff Arni C Valisno, Gang Su, Shiven Sharma, Denny Joseph Manual Kollareth, Joseph B Hartman, Aravinthan Adithan, Michael Spinosa, Manasi Kamat, Timothy Garrett, Guoshuai Cai, Ashish K Sharma, Gilbert R Upchurch.
      The pathogenesis of abdominal aortic aneurysm (AAA) formation involves vascular inflammation, thrombosis formation and programmed cell death leading to aortic remodeling. Recent studies have suggested that ferroptosis, an excessive iron-mediated cell death, can regulate cardiovascular diseases, including AAAs. However, the role of ferroptosis in immune cells, like macrophages, and ferroptosis-related genes in AAA formation remains to be deciphered. Single cell-RNA sequencing of human aortic tissue from AAA patients demonstrates significant differences in ferroptosis-related genes compared to control aortic tissue. Using two established murine models of AAA and aortic rupture in C57BL/6 (WT) mice, we observed that treatment with liproxstatin-1, a specific ferroptosis inhibitor, significantly attenuated aortic diameter, pro-inflammatory cytokine production, immune cell infiltration (neutrophils and macrophages), increased smooth muscle cell α-actin expression and elastic fiber disruption compared to mice treated with inactivated elastase in both pre-treatment and treatment after a small AAA had already formed. Lipidomic analysis using mass spectrometry shows a significant increase in ceramides and a decrease in intact lipid species levels in murine tissue compared to controls in the chronic AAA model on day 28. Mechanistically, in vitro studies demonstrate that liproxstatin-1 treatment of macrophages mitigated the crosstalk with aortic smooth muscle cells (SMCs) by downregulating MMP2 secretion. Taken together, this study demonstrates that pharmacological inhibition by liproxstatin-1 mitigates macrophage-dependent ferroptosis contributing to inhibition of aortic inflammation and remodeling during AAA formation.
    DOI:  https://doi.org/10.1101/2024.06.18.599427
  32. Curr Atheroscler Rep. 2024 Aug 12.
    Targeting Macrophage Phenotypes and Metabolism as Novel Therapeutic Approaches in Atherosclerosis and Related Cardiovascular Diseases.
    Juan Wang, Qiang Wu, Xinyu Wang, Hongbin Liu, Mulei Chen, Li Xu, Ze Zhang, Kuibao Li, Weiming Li, Jiuchang Zhong.
      PURPOSE OF THE REVIEW: Macrophage accumulation and activation function as hallmarks of atherosclerosis and have complex and intricate dynamics throughout all components and stages of atherosclerotic plaques. In this review, we focus on the regulatory roles and underlying mechanisms of macrophage phenotypes and metabolism in atherosclerosis. We highlight the diverse range of macrophage phenotypes present in atherosclerosis and their potential roles in progression and regression of atherosclerotic plaque. Furthermore, we discuss the challenges and opportunities in developing therapeutic strategies for preventing and treating atherosclerotic cardiovascular disease.RECENT FINDINGS: Dysregulation of macrophage polarization between the proinflammatory M1 and anti-inflammatory M2 phenotypealters the immuno-inflammatory response during atherosclerosis progression, leading to plaque initiation, growth, and ultimately rupture. Altered metabolism of macrophage is a key feature for their function and the subsequent progression of atherosclerotic cardiovascular disease. The immunometabolism of macrophage has been implicated to macrophage activation and metabolic rewiring of macrophages within atherosclerotic lesions, thereby shifting altered macrophage immune-effector and tissue-reparative function. Targeting macrophage phenotypes and metabolism are potential therapeutic strategies in the prevention and treatment of atherosclerosis and atherosclerotic cardiovascular diseases. Understanding the precise function and metabolism of specific macrophage subsets and their contributions to the composition and growth of atherosclerotic plaques could reveal novel strategies to delay or halt development of atherosclerotic cardiovascular diseases and their associated pathophysiological consequences. Identifying biological stimuli capable of modulating macrophage phenotypes and metabolism may lead to the development of innovative therapeutic approaches for treating patients with atherosclerosis and coronary artery diseases.
    Keywords:  Atherosclerosis; Coronary artery diseases; Macrophage; Metabolism; Phenotype
    DOI:  https://doi.org/10.1007/s11883-024-01229-z
  33. Diagnostics (Basel). 2024 Aug 02. pii: 1673. [Epub ahead of print]14(15):
    Nasal Microbiome in Granulomatosis with Polyangiitis Compared to Chronic Rhinosinusitis.
    Eliza Brożek-Mądry, Zofia Burska, Katarzyna Życińska, Janusz Sierdziński.
      Rhinosinusitis in granulomatosis with polyangiitis (GPA) is categorised as a secondary, diffuse and inflammatory chronic rhinosinusitis (CRS). It is one of the conditions that impacts the nasal microbiota. This study aimed to compare the nasal microbiomes of patients with GPA, CRS and NSP. A total of 31 patients were included in the study (18 GPA, 6 CRS and 7 nasal septum perforation (NSP)). In all patients, SNOT 22, a nasal endoscopy (Lund-Kennedy scale) and a brush swab were performed. The metagenomic analysis was carried out based on the hypervariable V3-V4 region of the 16S rRNA gene. At the genus level, statistically significant differences were observed in two comparisons: the GPA/NSP and the GPA/CRS groups. In the GPA/NSP group, the differences were related to four genera (Actinomyces, Streptococcus, Methylobacterium-Methylorubrum, Paracoccus), while in the GPA/CRS group, they were related to six (Kocuria, Rothia, Cutibacterium, Streptococcus, Methylobacterium-Methylorubrum, Tepidimonas). Patients with GPA had lower diversity compared to CRS and NSP patients. There were no statistically significant differences found for the Staphylococcus family and Staphylococcus aureus between the three groups.
    Keywords:  chronic rhinosinusitis; granulomatosis with polyangiitis; microbiome; nasal septal perforation
    DOI:  https://doi.org/10.3390/diagnostics14151673
  34. Mucosal Immunol. 2024 Aug 13. pii: S1933-0219(24)00082-5. [Epub ahead of print]
    Itaconate suppresses house dust mite-induced allergic airways disease and Th2 cell differentiation.
    Yiran Li, Shilpi Singh, Haley A Breckenridge, Tracy X Cui, Thomas M Vigil, Jordan E Kreger, Jing Lei, Harrison K A Wong, Peter Sajjakulnukit, Xiaofeng Zhou, J Kelley Bentley, Costas A Lyssiotis, Richard M Mortensen, Marc B Hershenson.
      Itaconate was initially identified as an antimicrobial compound produced by myeloid cells. Beyond its antimicrobial role, itaconate may also serve as a crucial metabolic and immune modulator. We therefore examined the roles of aconitate decarboxylase 1 (Acod1) and itaconate in house dust mite (HDM)-sensitized and -challenged mice, a model of T helper 2 (Th2)-driven allergic airways disease. HDM treatment induced lung Acod1 mRNA expression and bronchoalveolar lavage (BAL) itaconate levels in wild-type C57BL/6 mice. Acod1 knockout mice (Acod1-KO) with negligible BAL itaconate showed heightened HDM-induced type 2 cytokine expression, increased serum IgE, and enhanced recruitment of Th2 cells in the lung, indicating a shift towards a more pronounced Th2 immune response. Acod1-KO mice also showed increased eosinophilic airway inflammation and hyperresponsiveness. Experiments in chimeric mice demonstrated that bone marrow from Acod1-KO mice is sufficient to increase type 2 cytokine expression in wild-type mice, and that restitution of bone marrow from wild type mice attenuates mRNA expression of Th2 cytokines in Acod1-KO mice. Specific deletion of Acod1 in lysozyme-secreting macrophages (LysM-cre+Acod1flox/flox) recapitulated the exaggerated phenotype observed in whole-body Acod1-KO mice. Adoptive transfer of Acod1-KO bone marrow-derived macrophages also increased lung mRNA expression of Th2 cytokines. In addition, treatment of Th2-polarized CD4 cells with itaconate impeded Th2 cell differentiation, as shown by reduced expression of Gata3 and decreased release of IL-5 and IL-13. Finally, public datasets of human samples show lower Acod1 expression in subjects with allergic asthma, consistent with a protective role of itaconate in asthma pathogenesis. Together, these data suggest that itaconate plays a protective, immunomodulatory role in limiting airway type 2 inflammation after allergen challenge by attenuating T cell responses.
    Keywords:  Aconitate decarboxylase 1; Allergen; Asthma; House dust mite; Itaconate; Macrophage
    DOI:  https://doi.org/10.1016/j.mucimm.2024.08.001
  35. Cell Mol Life Sci. 2024 Aug 15. 81(1): 351
    SARS-CoV2 infection in whole lung primarily targets macrophages that display subset-specific responses.
    Thien-Phong Vu Manh, Carla Gouin, Julien De Wolf, Luc Jouneau, Florentina Pascale, Claudia Bevilacqua, Meriadeg Ar Gouilh, Bruno Da Costa, Christophe Chevalier, Matthieu Glorion, Laurent Hannouche, Céline Urien, Jérôme Estephan, Antoine Magnan, Morgan Le Guen, Quentin Marquant, Delphyne Descamps, Marc Dalod, Isabelle Schwartz-Cornil, Edouard Sage.
      Deciphering the initial steps of SARS-CoV-2 infection, that influence COVID-19 outcomes, is challenging because animal models do not always reproduce human biological processes and in vitro systems do not recapitulate the histoarchitecture and cellular composition of respiratory tissues. To address this, we developed an innovative ex vivo model of whole human lung infection with SARS-CoV-2, leveraging a lung transplantation technique. Through single-cell RNA-seq, we identified that alveolar and monocyte-derived macrophages (AMs and MoMacs) were initial targets of the virus. Exposure of isolated lung AMs, MoMacs, classical monocytes and non-classical monocytes (ncMos) to SARS-CoV-2 variants revealed that while all subsets responded, MoMacs produced higher levels of inflammatory cytokines than AMs, and ncMos contributed the least. A Wuhan lineage appeared to be more potent than a D614G virus, in a dose-dependent manner. Amidst the ambiguity in the literature regarding the initial SARS-CoV-2 cell target, our study reveals that AMs and MoMacs are dominant primary entry points for the virus, and suggests that their responses may conduct subsequent injury, depending on their abundance, the viral strain and dose. Interfering on virus interaction with lung macrophages should be considered in prophylactic strategies.
    Keywords:  10X genomics; Azimuth software; Ex vivo lung perfusion; Viral nebulization
    DOI:  https://doi.org/10.1007/s00018-024-05322-z
  36. Appl Environ Microbiol. 2024 Aug 12. e0123524
    Exploring strain-level diversity in the gut microbiome through mucin particle adhesion.
    Keita Nishiyama, Ryuta Murakami, Masaki Nakahata, Binghui Zhou, Nanami Hashikura, Hiroki Kaneko, Fu Namai, Wakako Ikeda-Ohtsubo, Jin-Zhong Xiao, Haruki Kitazawa, Toshitaka Odamaki.
      Mucin glycoproteins are a significant source of carbon for the gut bacteria. Various gut microbial species possess diverse hydrolytic enzymes and catabolic pathways for breaking down mucin glycans, resulting in competition for the limited nutrients within the gut environment. Adherence to mucin glycans represents a crucial strategy used by gut microbes to access nutrient reservoirs. Understanding these properties is pivotal for comprehending the survival mechanisms of bacteria in the gastrointestinal tract. However, characterization of individual strains within the vast array of coexisting bacteria in the microbiome is challenging. To investigate this, we developed mucin-immobilized particles by immobilizing porcine gastric mucin (PGM) onto glass beads chemically modified with boronic acid. These PGM-immobilized particles were then anaerobically cultured with human fecal microbiota, and the bacteria adhering to PGM were isolated. Interestingly, the microbiome composition remained largely unchanged irrespective of PGM immobilization. Nonetheless, bacteria isolated from PGM-immobilized glass particles exhibited notably higher N-acetylgalactosaminidase activity compared to the control beads. Furthermore, Bacteroides strains isolated from PGM-immobilized glass particles displayed enhanced adhesive and metabolic properties to PGM. These findings underscore the utility of PGM particles in enriching and isolating specific microbes. Moreover, they highlight substantial differences in microbial properties at the strain level. We anticipate that PGM-immobilized particles will advance culture-based microbiome research, emphasizing the significance of strain-level characterization.IMPORTANCE: Metabolism of mucin glycans by gut bacteria represents a crucial strategy for accessing nutrient reservoirs. The efficacy of mucin glycan utilization among gut bacteria hinges on the metabolic capabilities of individual strains, necessitating meticulous strain-level characterization. In this investigation, we used glass beads chemically immobilized with mucins to selectively enrich bacteria from fecal fermentation cultures, based on their superior adhesion to and metabolism of mucin glycoproteins. These findings lend support to the hypothesis that the physical interactions between bacteria and mucin glycoprotein components directly correlate with their capacity to utilize mucins as nutrient sources. Furthermore, our study implies that physical proximity may significantly influence bacterial nutrient acquisition within the ecosystem, facilitating gut bacteria's access to carbohydrate components.
    Keywords:  adhesion; bacteroides; gut microbiome; metabolism; mucin; strain diversity
    DOI:  https://doi.org/10.1128/aem.01235-24
  37. Ecotoxicol Environ Saf. 2024 Aug 13. pii: S0147-6513(24)00951-5. [Epub ahead of print]284 116875
    Airway bacterial microbiome signatures correlate with occupational pneumoconiosis progression.
    Huimin Ma, Zheng Dong, Xu Zhang, Conghe Liu, Zhihao Liu, Xi Zhou, Jin He, Shuping Zhang.
      Recent evidence has pinpointed a key role of the microbiome in human respiratory health and disease. However, significant knowledge gaps still exist regarding the connection between bacterial communities and adverse effects caused by particulate matters (PMs). Here, we characterized the bacterial microbiome along different airway sites in occupational pneumoconiosis (OP) patients. The sequencing data revealed that OP patients exhibited distinct dysbiosis in the composition and function of the respiratory microbiota. To different extents, there was an overall increase in the colonization of microbiota, such as Streptococcus, implying a possible intrusion pathway provided by exogenous PMs. Compared to those of healthy subjects, unhealthy living habits (i.e., smoking) had a greater impact on microbiome changes in OP patients. Importantly, the associations between the bacterial community and disease indicators indicated that specific bacterial species, including Prevotella, Actinobacillus, and Leptotrichia, might be surrogate markers of OP disease progression. Collectively, our results highlighted the potential participation of the bacterial microbiota in the pathogenesis of respiratory diseases and helped in the discovery of microbiome-based diagnostics for PM-induced disorders.
    Keywords:  16S rRNA gene sequencing; Bacterial microbiome; Occupational pneumoconiosis; Particulate matters; Respiratory tract
    DOI:  https://doi.org/10.1016/j.ecoenv.2024.116875
  38. Front Immunol. 2024 ;15 1415009
    In vitro assessment of the immunomodulatory effects of probiotic Bacillus strains on chicken PBMCs.
    Filip Larsberg, Maximilian Sprechert, Deike Hesse, Clemens Falker-Gieske, Gunnar Loh, Gudrun A Brockmann, Susanne Kreuzer-Redmer.
      The beneficial effects of feeding probiotic Bacillus subtilis DSM 32315 (BS) and Bacillus velezensis CECT 5940 (BV) to chickens in vivo are well-documented, with potential immune modulation as a key mechanism. In this study, we investigated the direct interactions of chicken peripheral blood mononuclear cells (PBMCs) with BS or BV in vitro through whole transcriptome profiling and cytokine array analysis. Transcriptome profiling revealed 20 significantly differentially expressed genes (DEGs) in response to both Bacillus treatments, with twelve DEGs identified in BS-treated PBMCs and eight in BV-treated PBMCs. Pathway analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG) indicated significant regulation of immune-related pathways by both BS and BV. Notably, BS treatment upregulated genes associated with immune cell surface markers (CD4, CD25, CD28), anti-inflammatory cytokine interleukin-10 (IL-10), and C-C motif chemokine ligand 5 (CCL5), while downregulating the gene encoding pro-inflammatory IL-16. BV treatment similarly affected genes associated with immune cell surface markers, IL-16, and CCL5, with no impact on the gene encoding IL-10. Both treatments induced higher expression of the gene encoding the avian β-defensin 1 (AvBD1). The results of this in vitro study indicate an immunomodulatory effect of BS and BV in chicken PBMCs by regulating genes involved in anti-inflammatory, bacteriostatic, protective, and pro-inflammatory responses. Consequently, BS and BV may serve to augment the immune system's capacity to defend against infection by modulating immune responses and cytokine expression. Thus, the administration of these probiotics holds promise for reducing reliance on antimicrobials in farming practices.
    Keywords:  Bacillus spp.; antimicrobial resistance; broiler chicken; immune-modulating feed additives; probiotics
    DOI:  https://doi.org/10.3389/fimmu.2024.1415009
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