bims-bac4me Biomed News
on Microbiome and trained immunity
Issue of 2023–07–16
forty-nine papers selected by
Chun-Chi Chang, Universitäts Spital Zürich
  1. Macrophages Orchestrate Airway Inflammation, Remodeling, and Resolution in Asthma.
  2. Turning foes into permissive hosts: manipulation of macrophage polarization by intracellular bacteria.
  3. Defining the metabolic signatures associated with human macrophage polarisation.
  4. Human metapneumovirus driven IFN-β production antagonizes macrophage transcriptional induction of IL1-β in response to bacterial pathogens.
  5. Pyroptosis in defense against intracellular bacteria.
  6. TLR2 is non-redundant in the population and subpopulation responses to Mycobacterium tuberculosis in macrophages and in vivo.
  7. Tapping lipid droplets: A rich fat diet of intracellular bacterial pathogens.
  8. Immunotherapies for the prevention and treatment of Staphylococcus aureus infections: updates and challenges.
  9. Lactiplantibacillus plantarum LOC1 Isolated from Fresh Tea Leaves Modulates Macrophage Response to TLR4 Activation.
  10. How Do Microorganisms Influence the Development of Endometriosis? Participation of Genital, Intestinal and Oral Microbiota in Metabolic Regulation and Immunopathogenesis of Endometriosis.
  11. α-Aminobutyric Acid Constrains Macrophage-Associated Inflammatory Diseases through Metabolic Reprogramming and Epigenetic Modification.
  12. Imbalance of gut microbiota is involved in the development of chronic obstructive pulmonary disease: A review.
  13. Role of innate immunity and systemic inflammation in cystic fibrosis disease progression.
  14. Prevalence and antibiotic resistance of Staphylococcus aureus associated with a college-aged cohort: life-style factors that contribute to nasal carriage.
  15. Biochemical and molecular inducers and modulators of M2 macrophage polarization in clinical perspective.
  16. Contribution of Circulating Host and Microbial Tryptophan Metabolites Toward Ah Receptor Activation.
  17. Proline is increased in allergic asthma and promotes airway remodeling.
  18. Short-term mucosal disruption enables colibactin-producing E. coli to cause long-term perturbation of colonic homeostasis.
  19. The microbial code and cancer immunotherapy outcome.
  20. Ubiquitination and cell-autonomous immunity.
  21. Pre-existing T Cell Memory to Novel Pathogens.
  22. Type-I interferons promote innate immune tolerance in macrophages exposed to Mycobacterium ulcerans vesicles.
  23. Gut Immunobiosis and Biomodulators.
  24. The HDAC10 instructs macrophage M2 program via deacetylation of STAT3 and promotes allergic airway inflammation.
  25. Isolation and Culture of Bone Marrow-Derived Macrophages from Mice.
  26. EPs® 7630 Stimulates Tissue Repair Mechanisms and Modifies Tight Junction Protein Expression in Human Airway Epithelial Cells.
  27. γ-Secretase fanning the fire of innate immunity.
  28. When the allergy alarm bells toll: The role of Toll-like receptors in allergic diseases and treatment.
  29. Inflammatory and tolerogenic myeloid cells determine outcome following human allergen challenge.
  30. A novel in vitro model to study prolonged Pseudomonas aeruginosa infection in the cystic fibrosis bronchial epithelium.
  31. Shotgun metagenomic sequencing on skin microbiome indicates dysbiosis exists prior to the onset of atopic dermatitis.
  32. Impact of air pollution on respiratory microbiome: A narrative review.
  33. Pyroptosis and the cellular consequences of gasdermin pores.
  34. The Global Burden of Community-Acquired Pneumonia in Adults, Encompassing Invasive Pneumococcal Disease and the Prevalence of Its Associated Cardiovascular Events, with a Focus on Pneumolysin and Macrolide Antibiotics in Pathogenesis and Therapy.
  35. NMDA receptor activation induces damage of alveolar type II cells and lung fibrogenesis through ferroptosis.
  36. Limosilactobacillus fermentum CECT5716: Clinical Potential of a Probiotic Strain Isolated from Human Milk.
  37. Bacterium detected by gram stain and drug sensitivity in Chinese children with acute sinusitis.
  38. Th2-dependent disappearance and phenotypic conversion of mouse alveolar macrophages.
  39. A novel reporter mouse line for studying alveolar macrophages.
  40. Multi-arming ourselves against drug-resistant bacteria.
  41. Random forest and live single-cell metabolomics reveal metabolic profiles of human macrophages upon polarization.
  42. Iron acquisition by a commensal bacterium modifies host nutritional immunity during Salmonella infection.
  43. Comprehensive Genomic Characterization of Staphylococcus aureus Isolated from Atopic Dermatitis Patients in Japan: Correlations with Disease Severity, Eruption Type, and Anatomical Site.
  44. Impact of the pentose phosphate pathway on metabolism and pathogenesis of Staphylococcus aureus.
  45. Novel evidence on sepsis-inducing pathogens: from laboratory to bedside.
  46. Truncated oxidized phospholipids exacerbate endothelial dysfunction and lung injury caused by bacterial pathogens.
  47. Fucose promotes intestinal stem cell-mediated intestinal epithelial development through promoting Akkermansia-related propanoate metabolism.
  48. Microbiome Engineering Using Probiotic Yeast: Saccharomyces boulardii and the Secreted Human Lysozyme Lead to Changes in the Gut Microbiome and Metabolome of Mice.
  49. Nanoscaled Discovery of a Shunt Rifamycin from Salinispora arenicola Using a Three-Color GFP-Tagged Staphylococcus aureus Macrophage Infection Assay.
  1. Int J Mol Sci. 2023 Jun 21. pii: 10451. [Epub ahead of print]24(13):
    Macrophages Orchestrate Airway Inflammation, Remodeling, and Resolution in Asthma.
    Rodney D Britt, Anushka Ruwanpathirana, Maria L Ford, Brandon W Lewis.
      Asthma is a heterogenous chronic inflammatory lung disease with endotypes that manifest different immune system profiles, severity, and responses to current therapies. Regardless of endotype, asthma features increased immune cell infiltration, inflammatory cytokine release, and airway remodeling. Lung macrophages are also heterogenous in that there are separate subsets and, depending on the environment, different effector functions. Lung macrophages are important in recruitment of immune cells such as eosinophils, neutrophils, and monocytes that enhance allergic inflammation and initiate T helper cell responses. Persistent lung remodeling including mucus hypersecretion, increased airway smooth muscle mass, and airway fibrosis contributes to progressive lung function decline that is insensitive to current asthma treatments. Macrophages secrete inflammatory mediators that induce airway inflammation and remodeling. Additionally, lung macrophages are instrumental in protecting against pathogens and play a critical role in resolution of inflammation and return to homeostasis. This review summarizes current literature detailing the roles and existing knowledge gaps for macrophages as key inflammatory orchestrators in asthma pathogenesis. We also raise the idea that modulating inflammatory responses in lung macrophages is important for alleviating asthma.
    Keywords:  asthma; inflammation; macrophages; remodeling
    DOI:  https://doi.org/10.3390/ijms241310451
  2. Curr Opin Immunol. 2023 Jul 10. pii: S0952-7915(23)00086-9. [Epub ahead of print]84 102367
    Turning foes into permissive hosts: manipulation of macrophage polarization by intracellular bacteria.
    Trung Hm Pham, Denise M Monack.
      Macrophages function as tissue-immune sentinels and mediate key antimicrobial responses against bacterial pathogens. Yet, they can also act as a cellular niche for intracellular bacteria, such as Salmonella enterica, to persist in infected tissues. Macrophages exhibit heterogeneous activation or polarization, states that are linked to differential antibacterial responses and bacteria permissiveness. Remarkably, recent studies demonstrate that Salmonella and other intracellular bacteria inject virulence effectors into the cellular cytoplasm to skew the macrophage polarization state and reprogram these immune cells into a permissive niche. Here, we review mechanisms of macrophage reprogramming by Salmonella and highlight manipulation of macrophage polarization as a shared bacterial pathogenesis strategy. In addition, we discuss how the interplay of bacterial effector mechanisms, microenvironmental signals, and ontogeny may shape macrophage cell states and functions. Finally, we propose ideas of how further research will advance our understanding of macrophage functional diversity and immunobiology.
    DOI:  https://doi.org/10.1016/j.coi.2023.102367
  3. Biochem Soc Trans. 2023 Jul 14. pii: BST20220504. [Epub ahead of print]
    Defining the metabolic signatures associated with human macrophage polarisation.
    Adrián Povo-Retana, Rodrigo Landauro-Vera, Marco Fariñas, Sergio Sánchez-García, Carlota Alvarez-Lucena, Silvia Marin, Marta Cascante, Lisardo Boscá.
      Macrophages are essential components of the innate immune system that play both homeostatic roles in healthy organs, and host defence functions against pathogens after tissue injury. To accomplish their physiological role, macrophages display different profiles of gene expression, immune function, and metabolic phenotypes that allow these cells to participate in different steps of the inflammatory reaction, from the initiation to the resolution phase. In addition, significant differences exist in the phenotype of macrophages depending on the tissue in which they are present and on the mammalian species. From a metabolic point of view, macrophages are essentially glycolytic cells; however, their metabolic fluxes are dependent on the functional polarisation of these cells. This metabolic and cellular plasticity offers the possibility to interfere with the activity of macrophages to avoid harmful effects due to persistent activation or the release of molecules that delay tissue recovery after injury.
    Keywords:  cell homeostasis; fibrosis; immunometabolism; inflammation; macrophages; monocytes
    DOI:  https://doi.org/10.1042/BST20220504
  4. Front Immunol. 2023 ;14 1173605
    Human metapneumovirus driven IFN-β production antagonizes macrophage transcriptional induction of IL1-β in response to bacterial pathogens.
    Simon Loevenich, Nicola P Montaldo, Arthur Wickenhagen, Tatyana Sherstova, Barbara van Loon, Victor Boyartchuk, Marit W Anthonsen.
      Human metapneumovirus (HMPV) is a pneumovirus that may cause severe respiratory disease in humans. HMPV infection has been found to increase susceptibility to bacterial superinfections leading to increased morbidity and mortality. The molecular mechanisms underlying HMPV-mediated increase in bacterial susceptibility are poorly understood and largely understudied. Type I interferons (IFNs), while critical for antiviral defenses, may often have detrimental effects by skewing the host immune response and cytokine output of immune cells. It is currently unknown if HMPV skews the inflammatory response in human macrophages triggered by bacterial stimuli. Here we report that HMPV pre-infection impacts production of specific cytokines. HMPV strongly suppresses IL-1β transcription in response to LPS or heat-killed Pseudomonas aeruginosa and Streptococcus pneumonia, while enhancing mRNA levels of IL-6, TNF-α and IFN-β. We demonstrate that in human macrophages the HMPV-mediated suppression of IL-1β transcription requires TANK-binding kinase 1 (TBK1) and signaling via the IFN-β-IFNAR axis. Interestingly, our results show that HMPV pre-infection did not impair the LPS-stimulated activation of NF-κB and HIF-1α, transcription factors that stimulate IL-1β mRNA synthesis in human cells. Furthermore, we determined that sequential HMPV-LPS treatment resulted in accumulation of the repressive epigenetic mark H3K27me3 at the IL1B promoter. Thus, for the first time we present data revealing the molecular mechanisms by which HMPV shapes the cytokine output of human macrophages exposed to bacterial pathogens/LPS, which appears to be dependent on epigenetic reprogramming at the IL1B promoter leading to reduced synthesis of IL-1β. These results may improve current understanding of the role of type I IFNs in respiratory disease mediated not only by HMPV, but also by other respiratory viruses that are associated with superinfections.
    Keywords:  IFN-β; IL-1β; airway bacteria; co-infection; human metapneumovirus; inflammasome; proinflammatory cytokines
    DOI:  https://doi.org/10.3389/fimmu.2023.1173605
  5. Semin Immunol. 2023 Jul 08. pii: S1044-5323(23)00096-9. [Epub ahead of print]69 101805
    Pyroptosis in defense against intracellular bacteria.
    Lupeng Li, Mary S Dickinson, Jörn Coers, Edward A Miao.
      Pathogenic microbes invade the human body and trigger a host immune response to defend against the infection. In response, host-adapted pathogens employ numerous virulence strategies to overcome host defense mechanisms. As a result, the interaction between the host and pathogen is a dynamic process that shapes the evolution of the host's immune response. Among the immune responses against intracellular bacteria, pyroptosis, a lytic form of cell death, is a crucial mechanism that eliminates replicative niches for intracellular pathogens and modulates the immune system by releasing danger signals. This review focuses on the role of pyroptosis in combating intracellular bacterial infection. We examine the cell type specific roles of pyroptosis in neutrophils and intestinal epithelial cells. We discuss the regulatory mechanisms of pyroptosis, including its modulation by autophagy and interferon-inducible GTPases. Furthermore, we highlight that while host-adapted pathogens can often subvert pyroptosis, environmental microbes are effectively eliminated by pyroptosis.
    Keywords:  Autophagy; Environmental pathogen; Guanylate-binding protein; Host-adapted pathogen; Intracellular bacteria; Pyroptosis
    DOI:  https://doi.org/10.1016/j.smim.2023.101805
  6. mSystems. 2023 Jul 13. e0005223
    TLR2 is non-redundant in the population and subpopulation responses to Mycobacterium tuberculosis in macrophages and in vivo.
    Charul Jani, Sydney L Solomon, Joshua M Peters, Stephanie C Pringle, Amelia E Hinman, Julie Boucau, Bryan D Bryson, Amy K Barczak.
      Tuberculosis (TB), caused by the pathogenic bacterium Mycobacterium tuberculosis (Mtb), is a global health threat. Targeting host pathways that modulate protective or harmful components of inflammation has been proposed as a therapeutic strategy that could aid sterilization or mitigate TB-associated permanent tissue damage. In purified form, many Mtb components can activate innate immune pathways. However, knowledge of the pathways that contribute most to the observed response to live Mtb is incomplete, limiting the possibility of precise intervention. We took a systematic, unbiased approach to define the pathways that drive the earliest immune response to Mtb. Using a macrophage model of infection, we compared the bulk transcriptional response to infection with the response to a panel of Mtb-derived putative innate immune ligands. We identified two axes of response: an NF-kB-dependent response similarly elicited by all Mtb pathogen-associated molecular patterns (PAMPs) and a type I interferon axis unique to cells infected with live Mtb. Consistent with growing literature data pointing to TLR2 as a dominant Mtb-associated PAMP, the TLR2 ligand PIM6 most closely approximated the NF-kB-dependent response to the intact bacterium. Quantitatively, the macrophage response to Mtb was slower and weaker than the response to purified PIM6. On a subpopulation level, the TLR2-dependent response was heterogeneously induced, with only a subset of infected cells expressing key inflammatory genes known to contribute to the control of infection. Despite potential redundancies in Mtb ligand/innate immune receptor interactions during in vivo infection, loss of the TLR2/PIM6 interaction impacted the cellular composition of both the innate and adaptive compartments. IMPORTANCE Tuberculosis (TB) is a leading cause of death globally. Drug resistance is outpacing new antibiotic discovery, and even after successful treatment, individuals are often left with permanent lung damage from the negative consequences of inflammation. Targeting host inflammatory pathways has been proposed as an approach that could either improve sterilization or improve post-treatment lung health. However, our understanding of the inflammatory pathways triggered by Mycobacterium tuberculosis (Mtb) in infected cells and lungs is incomplete, in part because of the complex array of potential molecular interactions between bacterium and host. Here, we take an unbiased approach to identify the pathways most central to the host response to Mtb. We examine how individual pathways are triggered differently by purified Mtb products or infection with the live bacterium and consider how these pathways inform the emergence of subpopulation responses in cell culture and in infected mice. Understanding how individual interactions and immune pathways contribute to inflammation in TB opens the door to the possibility of developing precise therapeutic interventions.
    Keywords:  Mycobacterium tuberculosis; TLR2; innate immunity; macrophage; mycobacteria; single-cell RNAseq; tuberculosis
    DOI:  https://doi.org/10.1128/msystems.00052-23
  7. Mol Microbiol. 2023 Jul 10.
    Tapping lipid droplets: A rich fat diet of intracellular bacterial pathogens.
    Dario Hüsler, Pia Stauffer, Hubert Hilbi.
      Lipid droplets (LDs) are dynamic and versatile organelles present in most eukaryotic cells. LDs consist of a hydrophobic core of neutral lipids, a phospholipid monolayer coat, and a variety of associated proteins. LDs are formed at the endoplasmic reticulum and have diverse roles in lipid storage, energy metabolism, membrane trafficking, and cellular signaling. In addition to their physiological cellular functions, LDs have been implicated in the pathogenesis of several diseases, including metabolic disorders, cancer, and infections. A number of intracellular bacterial pathogens modulate and/or interact with LDs during host cell infection. Members of the genera Mycobacterium, Legionella, Coxiella, Chlamydia, and Salmonella exploit LDs as a source of intracellular nutrients and membrane components to establish their distinct intracellular replicative niches. In this review, we focus on the biogenesis, interactions, and functions of LDs, as well as on their role in lipid metabolism of intracellular bacterial pathogens.
    Keywords:   Chlamydia ; Dictyostelium discoideum ; Legionella ; Mycobacterium ; Salmonella ; Legionnaires' disease; amoeba; bacterial pathogenesis; fatty acid transport; host-pathogen interaction; inclusion; intracellular pathogens; lipid droplet; pathogen vacuole
    DOI:  https://doi.org/10.1111/mmi.15120
  8. Pathog Dis. 2023 Jul 08. pii: ftad016. [Epub ahead of print]
    Immunotherapies for the prevention and treatment of Staphylococcus aureus infections: updates and challenges.
    Chung Pooi Yin.
      Staphylococcus aureus is the leading cause of hospital-acquired infections and can cause a wide range of diseases from mild skin infections to invasive diseases including deep surgical site infections, life-threatening bacteremia, and sepsis. This pathogen remains a challenge to manage due to its ability to rapidly develop resistance to antibiotic treatment and to form biofilms. Despite the current infection control measures which involve mainly antibiotics, the burden of infection remains high. The 'omics' approaches have not led to the discovery of novel antibacterials at a pace sufficient to cope with the emergence of multidrug-resistant and biofilm-forming S. aureus, Hence, new strategies for anti-infective therapies need to be explored urgently. One promising strategy is harnessing the immune response to enhance the protective antimicrobial immunity in the host. This review discusses the potential of monoclonal antibodies and vaccines as alternatives to treat and manage infections caused by planktonic and biofilms of S. aureus.
    Keywords:  immunotherapy; monoclonal antibodies; multi-drug resistant Staphylococcus aureus; vaccines
    DOI:  https://doi.org/10.1093/femspd/ftad016
  9. Foods. 2022 Oct 18. pii: 3257. [Epub ahead of print]11(20):
    Lactiplantibacillus plantarum LOC1 Isolated from Fresh Tea Leaves Modulates Macrophage Response to TLR4 Activation.
    Masahiko Suzuki, Leonardo Albarracin, Yuji Tsujikawa, Kohtaro Fukuyama, Iwao Sakane, Julio Villena, Haruki Kitazawa.
      Previously, we demonstrated that Lactiplantibacillus plantarum LOC1, originally isolated from fresh tea leaves, was able to improve epithelial barrier integrity in in vitro models, suggesting that this strain is an interesting probiotic candidate. In this work, we aimed to continue characterizing the potential probiotic properties of the LOC1 strain, focusing on its immunomodulatory properties in the context of innate immunity triggered by Toll-like receptor 4 (TLR4) activation. These studies were complemented by comparative and functional genomics analysis to characterize the bacterial genes involved in the immunomodulatory capacity. We carried out a transcriptomic study to evaluate the effect of L. plantarum LOC1 on the response of murine macrophages (RAW264.7 cells) to the activation of TLR4. We demonstrated that L. plantarum LOC1 exerts a modulatory effect on lipopolysaccharide (LPS)-induced inflammation, resulting in a differential regulation of immune factor expression in macrophages. The LOC1 strain markedly reduced the LPS-induced expression of some inflammatory cytokines (IL-1β, IL-12, and CSF2) and chemokines (CCL17, CCL28, CXCL3, CXCL13, CXCL1, and CX3CL1), while it significantly increased the expression of other cytokines (TNF-α, IL-6, IL-18, IFN-β, IFN-γ, and CSF3), chemokines (IL-15 and CXCL9), and activation markers (H2-k1, H2-M3, CD80, and CD86) in RAW macrophages. Our results show that L. plantarum LOC1 would enhance the intrinsic functions of macrophages, promoting their protective effects mediated by the stimulation of the Th1 response without affecting the regulatory mechanisms that help control inflammation. In addition, we sequenced the LOC1 genome and performed a genomic characterization. Genomic comparative analysis with the well-known immunomodulatory strains WCSF1 and CRL1506 demonstrated that L. plantarum LOC1 possess a set of adhesion factors and genes involved in the biosynthesis of teichoic acids and lipoproteins that could be involved in its immunomodulatory capacity. The results of this work can contribute to the development of immune-related functional foods containing L. plantarum LOC1.
    Keywords:  LOC1; Lactiplantibacillus plantarum; TLR4; genomics; immunobiotic; macrophages; tea leaves
    DOI:  https://doi.org/10.3390/foods11203257
  10. Int J Mol Sci. 2023 Jun 30. pii: 10920. [Epub ahead of print]24(13):
    How Do Microorganisms Influence the Development of Endometriosis? Participation of Genital, Intestinal and Oral Microbiota in Metabolic Regulation and Immunopathogenesis of Endometriosis.
    Anna Sobstyl, Aleksandra Chałupnik, Paulina Mertowska, Ewelina Grywalska.
      Microorganisms inhabiting the human body play an extremely key role in its proper functioning, as well as in the development of the immune system, which, by maintaining the immune balance, allows you to enjoy health. Dysbiosis of the intestinal microbiota, or in the oral cavity or reproductive tract, understood as a change in the number and diversity of all microorganisms inhabiting them, may correlate with the development of many diseases, including endometriosis, as researchers have emphasized. Endometriosis is an inflammatory, estrogen-dependent gynecological condition defined by the growth of endometrial cells outside the uterine cavity. Deregulation of immune homeostasis resulting from microbiological disorders may generate chronic inflammation, thus creating an environment conducive to the increased adhesion and angiogenesis involved in the development of endometriosis. In addition, research in recent years has implicated bacterial contamination and immune activation, reduced gastrointestinal function by cytokines, altered estrogen metabolism and signaling, and abnormal progenitor and stem cell homeostasis, in the pathogenesis of endometriosis. The aim of this review was to present the influence of intestinal, oral and genital microbiota dysbiosis in the metabolic regulation and immunopathogenesis of endometriosis.
    Keywords:  Lactobacillus spp.; dysbiosis; endometriosis; estrobolome; estrogen; immune dysregulation; inflammation; intestinal microflora; metabolome; microbiota; uterine microflora; vaginal microbiome
    DOI:  https://doi.org/10.3390/ijms241310920
  11. Int J Mol Sci. 2023 Jun 21. pii: 10444. [Epub ahead of print]24(13):
    α-Aminobutyric Acid Constrains Macrophage-Associated Inflammatory Diseases through Metabolic Reprogramming and Epigenetic Modification.
    Fei Li, Yuting Xia, Shijie Yuan, Xiaorong Xie, Lin Li, Yuan Luo, Qiuyang Du, Yuqi Yuan, Ran He.
      Metabolites play critical roles in macrophage polarization and in their function in response to infection and inflammation. α-aminobutyric acid (AABA), a non-proteinogenic amino acid which can be generated from methionine, threonine, serine, and glycine, has not been studied extensively in relation to macrophage polarization and function. In this study, we aimed to investigate the immunomodulatory function of AABA in regulating M1 macrophage polarization and function in vitro and in vivo. We stimulated bone-marrow-derived macrophages with lipopolysaccharide (LPS) to generate M1 macrophages. Subsequently, we induced sepsis and colitis in mice, followed by treatment with AABA. We then analyzed the samples using ELISA, real-time PCR, Western blotting, flow cytometry, and histopathological analysis to evaluate cytokine secretion, inflammatory gene expression, macrophage activation, disease progression, and inflammation severity. Additionally, metabolomic and chromatin immunoprecipitation-qPCR were conducted to investigate the function of AABA on metabolic reprogramming and epigenetic modifications of M1 macrophages. Our results revealed that AABA inhibited M1 macrophage polarization and function, which led to prolonged survival in septic mice and reduced disease severity in colitis mice. Mechanically, AABA promoted oxidative phosphorylation (OXPHOS) and glutamine and arginine metabolism while inhibiting glycolysis. Moreover, AABA could increase the occupancy of trimethylation of histone H3K27 at the promoter regions of M1 macrophage-associated inflammatory genes, which contributed to the inhibition of M1 macrophage polarization. These findings suggest that AABA may have therapeutic potential for inflammatory diseases by regulating macrophage polarization and function through metabolic and epigenetic pathways.
    Keywords:  EZH2; H3K27me3; inflammation; macrophage; metabolic reprogramming; α-aminobutyric acid
    DOI:  https://doi.org/10.3390/ijms241310444
  12. Biomed Pharmacother. 2023 Jul 08. pii: S0753-3322(23)00941-1. [Epub ahead of print]165 115150
    Imbalance of gut microbiota is involved in the development of chronic obstructive pulmonary disease: A review.
    Wei Song, Yuanyi Yue, Qiang Zhang.
      Chronic obstructive pulmonary disease (COPD) is a common chronic disease characterized by chronic airway inflammation and remodeling, which seriously endangers human health. Recent developments in genomics and metabolomics have revealed the roles of the gut microbiota and its metabolites in COPD. Dysbiosis of the gut microbiota directly increases gut permeability, thereby promoting the translocation of pathological bacteria. The gut microbiota and associated metabolites may influence the development and progression of COPD by modulating immunity and inflammation. Furthermore, the systemic hypoxia and oxidative stress that occur in COPD may also be involved in intestinal dysfunction. The cross-talk between the gut and lungs is known as the gut-lung axis; however, an overview of its mechanism is lacking. This review highlights the critical and complex interplay of gut microbiota and immune responses in the gut-lung axis, further explores possible links between the gut and lungs, and summarizes new interventions through diet, probiotics, vitamins, and fecal microbiota transplantation, which are critical to COPD.
    Keywords:  Chronic obstructive pulmonary disease; Cross-talk; Dysbiosis; Gut microbiota; Gut–lung axis; Probiotics
    DOI:  https://doi.org/10.1016/j.biopha.2023.115150
  13. Heliyon. 2023 Jul;9(7): e17553
    Role of innate immunity and systemic inflammation in cystic fibrosis disease progression.
    Anand Kumar Purushothaman, Everette Jacob Remington Nelson.
      Pathophysiological manifestations of cystic fibrosis (CF) result from a functional defect in the cystic fibrosis transmembrane conductance regulator (CFTR) paving way for mucus obstruction and pathogen colonization. The role of CFTR in modulating immune cell function and vascular integrity, irrespective of mucus thickening, in determining the host cell response to pathogens/allergens and causing systemic inflammation is least appreciated. Since CFTR plays a key role in the conductance of anions like Cl-, loss of CFTR function could affect various basic cellular processes, such as cellular homeostasis, lysosome acidification, and redox balance. CFTR aids in endotoxin tolerance by regulating Toll-like receptor-mediated signaling resulting in uncontrolled activation of innate immune cells. Although leukocytes of CF patients are hyperactivated, they exhibit compromised phagosome activity thus favouring the orchestration of sepsis from defective pathogen clearance. This review will emphasize the importance of innate immunity and systemic inflammatory response in the development of CF and other CFTR-associated pathologies.
    Keywords:  Cystic fibrosis; Innate immunity; NETosis; PRR-Mediated signaling; Systemic inflammation; T1/T2 immune cell ratio
    DOI:  https://doi.org/10.1016/j.heliyon.2023.e17553
  14. Front Cell Infect Microbiol. 2023 ;13 1195758
    Prevalence and antibiotic resistance of Staphylococcus aureus associated with a college-aged cohort: life-style factors that contribute to nasal carriage.
    Sean T Congdon, John A Guaglione, Omario M A Ricketts, Kyle V Murphy, Megan G Anderson, Darby A Trowbridge, Yousuf Al-Abduladheem, Annabelle M Phillips, Allison M Beausoleil, Alexus J Stanley, Timothy J Becker, Adam C Silver.
      Staphylococcus aureus is an opportunistic human pathogen that can frequently be found at various body locations, such as the upper respiratory tract, nostrils, skin, and perineum. S. aureus is responsible for causing a variety of conditions, which range from minor skin infections and food poisoning to life-threatening sepsis and endocarditis. Furthermore, S. aureus has developed resistance to numerous antimicrobial agents, which has made treatment of S. aureus infections difficult. In the present study, we examined lifestyle factors that could increase the likelihood of S. aureus carriage, the overall prevalence of S. aureus, as well as assessed the antibiotic resistance profiles of the S. aureus isolates among a population of college students. Five hundred nasal samples were collected and analyzed via selective growth media, coagulase and protein A testing, as well as polymerase chain reaction and DNA sequencing. One hundred four out of the 500 samples collected (21%) were identified as containing S. aureus. The S. aureus isolates were resistant to penicillin (74%), azithromycin (34%), cefoxitin (5%), ciprofloxacin (5%), tetracycline (4%), and trimethoprim (1%), but sensitive to gentamicin and rifampin. Lastly, we identified several lifestyle factors (i.e., pet exposure, time spent at the university recreational facility, musical instrument usage, and tobacco usage) positively correlated with S. aureus nasal colonization.
    Keywords:  Staphylococcus aureus; antibiotic resistance; life-style factors; methicillin-resistant Staphylococcus aureus (MRSA); nasal carriage Stapylococcus aureus.; prevalence
    DOI:  https://doi.org/10.3389/fcimb.2023.1195758
  15. Int Immunopharmacol. 2023 Jul 07. pii: S1567-5769(23)00909-8. [Epub ahead of print]122 110583
    Biochemical and molecular inducers and modulators of M2 macrophage polarization in clinical perspective.
    Kiseleva Viktoriia, Vishnyakova Polina, Elchaninov Andrey, Fatkhudinov Timur, Sukhikh Gennady.
      Macrophages as innate immune cells with great plasticity are of great interest for cell therapy. There are two main macrophage populations - pro- and anti-inflammatory cells also known as M1 and M2. High potential in cancer research contributed to the in-depth study of the molecular processes leading to the polarization of macrophages into the M1 phenotype, and much less attention has been paid to anti-inflammatory M2 macrophages, which can be successfully used in cell therapy of inflammatory diseases. This review describes ontogenesis of macrophages, main functions of pro- and and-inflammatory cells and four M2 subpopulations characterized by different functionalities. Data on agents (cytokines, microRNAs, drugs, plant extracts) that may induce M2 polarization through the changes in microenvironment, metabolism, and efferocytosis are summarized. Finally, recent attempts at stable macrophage polarization using genetic modifications are described. This review may be helpful for researchers concerned with the problem of M2 macrophage polarization and potential use of these anti-inflammatory cells for the purposes of regenerative medicine.
    Keywords:  Anti-inflammatory phenotype; Cytokines; Efferocytosis; Inflammation; M2 macrophages; Macrophage polarization
    DOI:  https://doi.org/10.1016/j.intimp.2023.110583
  16. Int J Tryptophan Res. 2023 ;16 11786469231182510
    Contribution of Circulating Host and Microbial Tryptophan Metabolites Toward Ah Receptor Activation.
    Ethan W Morgan, Fangcong Dong, Andrew J Annalora, Iain A Murray, Trenton Wolfe, Reece Erickson, Krishne Gowda, Shantu G Amin, Kristina S Petersen, Penny M Kris-Etherton, Craig B Marcus, Seth T Walk, Andrew D Patterson, Gary H Perdew.
      The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor that plays an integral role in homeostatic maintenance by regulating cellular functions such as cellular differentiation, metabolism, barrier function, and immune response. An important but poorly understood class of AHR activators are compounds derived from host and bacterial metabolism of tryptophan. The commensal bacteria of the gut microbiome are major producers of tryptophan metabolites known to activate the AHR, while the host also produces AHR activators through tryptophan metabolism. We used targeted mass spectrometry-based metabolite profiling to determine the presence and metabolic source of these metabolites in the sera of conventional mice, germ-free mice, and humans. Surprisingly, sera concentrations of many tryptophan metabolites are comparable between germ-free and conventional mice. Therefore, many major AHR-activating tryptophan metabolites in mouse sera are produced by the host, despite their presence in feces and mouse cecal contents. Here we present an investigation of AHR activation using a complex mixture of tryptophan metabolites to examine the biological relevance of circulating tryptophan metabolites. AHR activation is rarely studied in the context of a mixture at relevant concentrations, as we present here. The AHR activation potentials of individual and pooled metabolites were explored using cell-based assays, while ligand binding competition assays and ligand docking simulations were used to assess the detected metabolites as AHR agonists. The physiological and biomedical relevance of the identified metabolites was investigated in the context of a cell-based model for rheumatoid arthritis. We present data that reframe AHR biology to include the presence of a mixture of ubiquitous tryptophan metabolites, improving our understanding of homeostatic AHR activity and models of AHR-linked diseases.
    Keywords:  Aryl hydrocarbon receptor; homeostasis; indole; kynurenine pathway; metabolomics; microbiome; tryptophan metabolism
    DOI:  https://doi.org/10.1177/11786469231182510
  17. JCI Insight. 2023 Jul 11. pii: e167395. [Epub ahead of print]
    Proline is increased in allergic asthma and promotes airway remodeling.
    Tingting Xu, Zhenzhen Wu, Qi Yuan, Xijie Zhang, Yanan Liu, Chaojie Wu, Meijuan Song, Jingjing Wu, Jingxian Jiang, Zhengxia Wang, Zhongqi Chen, Mingshun Zhang, Mao Huang, Ningfei Ji.
      Proline and its synthesis enzyme pyrroline-5-carboxylate reductase 1 (PYCR1) are implicated in epithelial-mesenchymal transition (EMT), yet how proline and PYCR1 function in allergic asthmatic airway remodeling via EMT has not yet been addressed. In the present study, increased levels of plasma proline and PYCR1 were observed in asthmatic patients. Similarly, proline and PYCR1 in lung tissues were higher in a murine allergic asthma model induced by house dust mites (HDMs). Pycr1 knockout (KO) decreased proline in lung tissues, with reduced airway remodeling and EMT. Mechanistically, loss of Pycr1 restrained HDM-induced EMT by modulating mitochondrial fission, metabolic reprogramming, and the AKT/mTOR1 and WNT3a/β-catenin signaling pathways in airway epithelial cells. Therapeutic inhibition of PYCR1 in wild-type mice disrupted HDM-induced airway inflammation and remodeling. Deprivation of exogeneous proline partially relieved HDM-induced airway remodeling to some extent. Collectively, this study illuminates that proline and PYCR1 involved with airway remodeling in allergic asthma could be viable targets for asthma treatment.
    Keywords:  Amino acid metabolism; Asthma; Metabolism; Pulmonology
    DOI:  https://doi.org/10.1172/jci.insight.167395
  18. Gut Microbes. 2023 Jan-Dec;15(1):15(1): 2233689
    Short-term mucosal disruption enables colibactin-producing E. coli to cause long-term perturbation of colonic homeostasis.
    Christine Harnack, Hilmar Berger, Lichao Liu, Hans-Joachim Mollenkopf, Till Strowig, Michael Sigal.
      Colibactin, a bacterial genotoxin produced by E. coli strains harboring the pks genomic island, induces cytopathic effects, such as DNA breaks, cell cycle arrest, and apoptosis. Patients with inflammatory bowel diseases, such as ulcerative colitis, display changes in their microbiota with the expansion of E. coli. Whether and how colibactin affects the integrity of the colonic mucosa and whether pks+ E. coli contributes to the pathogenesis of colitis is not clear. Using a gnotobiotic mouse model, we show that under homeostatic conditions, pks+ E. coli do not directly interact with the epithelium or affect colonic integrity. However, upon short-term chemical disruption of mucosal integrity, pks+ E. coli gain direct access to the epithelium, causing epithelial injury and chronic colitis, while mice colonized with an isogenic ΔclbR mutant incapable of producing colibactin show a rapid recovery. pks+ E. coli colonized mice are unable to reestablish a functional barrier. In turn, pks+ E. coli remains in direct contact with the epithelium, perpetuating the process and triggering chronic mucosal inflammation that morphologically and transcriptionally resembles human ulcerative colitis. This state is characterized by impaired epithelial differentiation and high proliferative activity, which is associated with high levels of stromal R-spondin 3. Genetic overexpression of R-spondin 3 in colon myofibroblasts is sufficient to mimic barrier disruption and expansion of E. coli. Together, our data reveal that pks+ E. coli are pathobionts that promote severe injury and initiate a proinflammatory trajectory upon contact with the colonic epithelium, resulting in a chronic impairment of tissue integrity.
    Keywords:  E. coli; Inflammtory bowel diseases; colibactin; colitis; microbiota; mucosal barrier; regeneration; stem cells
    DOI:  https://doi.org/10.1080/19490976.2023.2233689
  19. Cell Host Microbe. 2023 Jul 12. pii: S1931-3128(23)00255-X. [Epub ahead of print]31(7): 1081-1083
    The microbial code and cancer immunotherapy outcome.
    Yan Yan.
      The contribution of the gut microbiome to immune responsiveness is largely unknown. In a recent Nature Medicine article, Stein-Thoeringer et al. assess the microbiome configuration before cancer immunotherapy and determine the impact of antibiotic-masked microbial features on therapy's effectiveness. This provides a framework for identifying microbial signatures to inform clinical strategies.
    DOI:  https://doi.org/10.1016/j.chom.2023.06.004
  20. Curr Opin Immunol. 2023 Jul 12. pii: S0952-7915(23)00087-0. [Epub ahead of print]84 102368
    Ubiquitination and cell-autonomous immunity.
    João Mello-Vieira, Tobias Bopp, Ivan Dikic.
      Cell-autonomous immunity is the first line of defense by which cells recognize and contribute to eliminating invasive pathogens. It is composed of immune signaling networks that sense microbial pathogens, promote pathogen restriction, and stimulate their elimination, including host cell death. Ubiquitination is a pivotal orchestrator of these pathways, by changing the activity of signal transducers and effector proteins in an efficient way. In this review, we will focus on how ubiquitin connects the pathways that sense pathogens to the cellular responses to invaders and shed light on how ubiquitination impacts the microenvironment around the infected cell, stimulating the appropriate immune response. Finally, we discuss therapeutic options directed at favoring cell-autonomous immune responses to infection.
    DOI:  https://doi.org/10.1016/j.coi.2023.102368
  21. Immunohorizons. 2023 Jul 01. 7(7): 543-553
    Pre-existing T Cell Memory to Novel Pathogens.
    Sumbul Afroz, Laurent Bartolo, Laura F Su.
      Immunological experiences lead to the development of specific T and B cell memory, which readies the host for a later pathogen rechallenge. Currently, immunological memory is best understood as a linear process whereby memory responses are generated by and directed against the same pathogen. However, numerous studies have identified memory cells that target pathogens in unexposed individuals. How "pre-existing memory" forms and impacts the outcome of infection remains unclear. In this review, we discuss differences in the composition of baseline T cell repertoire in mice and humans, factors that influence pre-existing immune states, and recent literature on their functional significance. We summarize current knowledge on the roles of pre-existing T cells in homeostasis and perturbation and their impacts on health and disease.
    DOI:  https://doi.org/10.4049/immunohorizons.2200003
  22. PLoS Pathog. 2023 Jul 10. 19(7): e1011479
    Type-I interferons promote innate immune tolerance in macrophages exposed to Mycobacterium ulcerans vesicles.
    Quentin Bernard, Maïssa Goumeidane, Emmanuel Chaumond, Marie Robbe-Saule, Yan Boucaud, Lucille Esnault, Anne Croué, Jerome Jullien, Laurent Marsollier, Estelle Marion.
      Buruli ulcer is a chronic infectious disease caused by Mycobacterium ulcerans. The pathogen persistence in host skin is associated with the development of ulcerative and necrotic lesions leading to permanent disabilities in most patients. However, few of diagnosed cases are thought to resolve through an unknown self-healing process. Using in vitro and in vivo mouse models and M. ulcerans purified vesicles and mycolactone, we showed that the development of an innate immune tolerance was only specific to macrophages from mice able to heal spontaneously. This tolerance mechanism depends on a type I interferon response and can be induced by interferon beta. A type I interferon signature was further detected during in vivo infection in mice as well as in skin samples from patients under antibiotics regiment. Our results indicate that type I interferon-related genes expressed in macrophages may promote tolerance and healing during infection with skin damaging pathogen.
    DOI:  https://doi.org/10.1371/journal.ppat.1011479
  23. Nutrients. 2023 Apr 28. pii: 2114. [Epub ahead of print]15(9):
    Gut Immunobiosis and Biomodulators.
    Vito Leonardo Miniello, Andrea Miniello, Laura Ficele, Aleksandra Skublewska-D'Elia, Vanessa Nadia Dargenio, Fernanda Cristofori, Ruggiero Francavilla.
      The human gastrointestinal (GI) tract hosts complex and dynamic populations of microorganisms (gut microbiota) in advantageous symbiosis with the host organism through sophisticated molecular cross-talk. The balance and diversification within microbial communities (eubiosis) are crucial for the immune and metabolic homeostasis of the host, as well as for inhibiting pathogen penetration. In contrast, compositional dysregulation of the microbiota (dysbiosis) is blamed for the determinism of numerous diseases. Although further advances in the so-called 'omics' disciplines are needed, dietary manipulation of the gut microbial ecosystem through biomodulators (prebiotics, probiotics, symbionts, and postbiotics) represents an intriguing target to stabilize and/or restore eubiosis. Recently, new approaches have been developed for the production of infant formulas supplemented with prebiotics (human milk oligosaccharides [HMOs], galacto-oligosaccharides [GOS], fructo-oligosaccharides [FOS]), probiotics, and postbiotics to obtain formulas that are nutritionally and biologically equivalent to human milk (closer to the reference).
    Keywords:  biomodulators; dysbiosis; eubiosis; food allergy; gut microbiota; infant formulas; prebiotics; probiotics
    DOI:  https://doi.org/10.3390/nu15092114
  24. Theranostics. 2023 ;13(11): 3568-3581
    The HDAC10 instructs macrophage M2 program via deacetylation of STAT3 and promotes allergic airway inflammation.
    Yu Zhong, Tong Huang, Jiewen Huang, Jingyun Quan, Guomei Su, Zhilin Xiong, Yingying Lv, Shihai Li, Xianwen Lai, Yuanyuan Xiang, Qu Wang, Lianxiang Luo, Xiao Gao, Yiming Shao, Jing Tang, Tianwen Lai.
      Background: Perturbation of macrophage homeostasis is one of the key mechanisms of airway inflammation in asthma. However, the exact mechanisms remain poorly understood. Objectives: We sought to examine the role of histone deacetylase (HDAC) 10 as an epigenetic regulator that governs macrophage M2 program and promotes airway inflammation in asthma, and to elucidate the underlying mechanisms. Methods: Peripheral blood and airway biopsies were obtained from healthy individuals and asthmatic patients. Asthma was induced by exposure to allergen in mice with myeloid-specific deletion of Hdac10 (Hdac10fl/fl-LysMCre) mice. HDAC10 inhibitor Salvianolic acid B (SAB), STAT3 selective agonist Colivelin, and the specific PI3K/Akt activator 1,3-Dicaffeoylquinic acid (DA) were also used in asthmatic mice. For cell studies, THP1 cells, primary mouse bone marrow derived macrophage (BMDMs) were used and related signaling pathways was investigated. Results: HDAC10 expression was highly expressed by macrophages and promoted M2 macrophage activation and airway inflammation in asthmatic patients and mice. Hdac10fl/fl-LysMCre mice were protected from airway inflammation in experimental asthma model. Hdac10 deficiency significantly attenuated STAT3 expression and decreased M2 macrophage polarization following allergen exposure. Mechanistically, HDAC10 directly binds STAT3 for deacetylation in macrophages, by which it promotes STAT3 expression and activates the macrophage M2 program. Importantly, we identified SAB as a HDAC10 inhibitor that had protective effects against airway inflammation in mice. Conclusions: Our results revealed that HDAC10-STAT3 interaction governs macrophage polarization to promote airway inflammation in asthma, implicating HDAC10 as a therapeutic target.
    Keywords:  HDAC10; STAT3; airway inflammation; asthma; macrophage.
    DOI:  https://doi.org/10.7150/thno.82535
  25. J Vis Exp. 2023 06 23.
    Isolation and Culture of Bone Marrow-Derived Macrophages from Mice.
    Ricardo Gonçalves, Gabriela Kaliff Teófilo Murta, Izabela Aparecida de Souza, David M Mosser.
      Macrophages have important effector functions in homeostasis and inflammation. These cells are present in every tissue in the body and have the important ability to change their profile according to the stimuli present in the microenvironment. Cytokines can profoundly affect macrophage physiology, especially IFN-γ and interleukin 4, generating M1 and M2 types respectively. Because of the versatility of these cells, the production of a population of bone marrow-derived macrophages can be a basic step in many experimental models of cell biology. The aim of this protocol is to help researchers in the isolation and culture of macrophages derived from bone marrow progenitors. Bone marrow progenitors from pathogen-free C57BL/6 mice are transformed into macrophages upon exposure to macrophage colony-stimulating factor (M-CSF) that, in this protocol, is obtained from the supernatant of the murine fibroblast lineage L-929. After incubation, mature macrophages are available for use from the 7th to the 10th day. A single animal can be the source of approximately 2 x 107 macrophages. Therefore, it is an ideal protocol for obtaining large amounts of primary macrophages using basic methods of cell culture.
    DOI:  https://doi.org/10.3791/64566
  26. Int J Mol Sci. 2023 Jul 07. pii: 11230. [Epub ahead of print]24(13):
    EPs® 7630 Stimulates Tissue Repair Mechanisms and Modifies Tight Junction Protein Expression in Human Airway Epithelial Cells.
    Lei Fang, Liang Zhou, Žarko Kulić, Martin D Lehner, Michael Tamm, Michael Roth.
      Airway epithelium repair after infection consists of wound repair, re-synthesis of the extracellular matrix (ECM), and tight junction proteins. In humans, EPs® 7630 obtained from Pelargonium sidoides roots reduces the severity and duration of acute respiratory tract infections. The effect of EPs® 7630 on tissue repair of rhinovirus-16 (RV-16) infected and control human airway epithelial cells was assessed for: (i) epithelial cell proliferation by manual cell counts, (ii) epithelial wound repair by "scratch assay", (iii) ECM composition by Western-blotting and cell-based ELISA, and (iv) epithelial tight junction proteins by Western-blotting. EPs® 7630 stimulated cell proliferation through cAMP, CREB, and p38 MAPK. EPs® 7630 significantly improved wound repair. Pro-inflammatory collagen type-I expression was reduced by EPs® 7630, while fibronectin was increased. Virus-binding tight junction proteins desmoglein2, desmocollin2, ZO-1, claudin1, and claudin4 were downregulated by EPs® 7630. The RV16-induced shift of the ECM towards the pro-inflammatory type was prevented by EPs® 7630. Most of the effects of EPs® 7630 on tissue repair and regeneration were sensitive to inhibition of cAMP-induced signaling. The data suggest that EPs® 7630-dependent modification of epithelial cell metabolism and function might underlie the faster recovery time from viral infections, as reported by others in clinical studies.
    Keywords:  EPs® 7630; acute respiratory tract infection; airway epithelium repair; epithelial tight junction proteins; intracellular signaling
    DOI:  https://doi.org/10.3390/ijms241311230
  27. Biochem Soc Trans. 2023 Jul 14. pii: BST20221445. [Epub ahead of print]
    γ-Secretase fanning the fire of innate immunity.
    Chenge Liu, Cyrus Nikain, Yue-Ming Li.
      Innate immunity is the first line of defense against pathogens, alerting the individual cell and surrounding area to respond to this potential invasion. γ-secretase is a transmembrane protease complex that plays an intricate role in nearly every stage of this innate immune response. Through regulation of pattern recognition receptors (PRR) such as TREM2 and RAGE γ-secretase can modulate pathogen recognition. γ-secretase can act on cytokine receptors such as IFNαR2 and CSF1R to dampen their signaling capacity. While γ-secretase-mediated regulated intramembrane proteolysis (RIP) can further moderate innate immune responses through downstream signaling pathways. Furthermore, γ-secretase has also been shown to be regulated by the innate immune system through cytokine signaling and γ-secretase modulatory proteins such as IFITM3 and Hif-1α. This review article gives an overview of how γ-secretase is implicated in innate immunity and the maintenance of its responses through potentially positive and negative feedback loops.
    Keywords:  Hif1a; IFITM3; cytokine signaling; inflammation; innate immunity; regulated intramembrane proteolysis
    DOI:  https://doi.org/10.1042/BST20221445
  28. Front Mol Biosci. 2023 ;10 1204025
    When the allergy alarm bells toll: The role of Toll-like receptors in allergic diseases and treatment.
    Mario Wenger, Sophie Grosse-Kathoefer, Amin Kraiem, Erica Pelamatti, Natalia Nunes, Lisa Pointner, Lorenz Aglas.
      Toll-like receptors of the human immune system are specialized pathogen detectors able to link innate and adaptive immune responses. TLR ligands include among others bacteria-, mycoplasma- or virus-derived compounds such as lipids, lipo- and glycoproteins and nucleic acids. Not only are genetic variations in TLR-related genes associated with the pathogenesis of allergic diseases, including asthma and allergic rhinitis, their expression also differs between allergic and non-allergic individuals. Due to a complex interplay of genes, environmental factors, and allergen sources the interpretation of TLRs involved in immunoglobulin E-mediated diseases remains challenging. Therefore, it is imperative to dissect the role of TLRs in allergies. In this review, we discuss i) the expression of TLRs in organs and cell types involved in the allergic immune response, ii) their involvement in modulating allergy-associated or -protective immune responses, and iii) how differential activation of TLRs by environmental factors, such as microbial, viral or air pollutant exposure, results in allergy development. However, we focus on iv) allergen sources interacting with TLRs, and v) how targeting TLRs could be employed in novel therapeutic strategies. Understanding the contributions of TLRs to allergy development allow the identification of knowledge gaps, provide guidance for ongoing research efforts, and built the foundation for future exploitation of TLRs in vaccine design.
    Keywords:  LPS; TLR; Toll-like receptors; allergic rhinitis; allergic sensitization; allergy; microbiome; treatment
    DOI:  https://doi.org/10.3389/fmolb.2023.1204025
  29. J Exp Med. 2023 09 04. pii: e20221111. [Epub ahead of print]220(9):
    Inflammatory and tolerogenic myeloid cells determine outcome following human allergen challenge.
    Astrid L Voskamp, Tamar Tak, Maarten L Gerdes, Roberta Menafra, Ellen Duijster, Szymon M Kielbasa, Tom Groot Kormelink, Koen A Stam, Oscar R J van Hengel, Nicolette W de Jong, Rudi W Hendriks, Susan L Kloet, Maria Yazdanbakhsh, Esther C de Jong, Roy Gerth van Wijk, Hermelijn H Smits.
      Innate mononuclear phagocytic system (MPS) cells preserve mucosal immune homeostasis. We investigated their role at nasal mucosa following allergen challenge with house dust mite. We combined single-cell proteome and transcriptome profiling on nasal immune cells from nasal biopsies cells from 30 allergic rhinitis and 27 non-allergic subjects before and after repeated nasal allergen challenge. Biopsies of patients showed infiltrating inflammatory HLA-DRhi/CD14+ and CD16+ monocytes and proallergic transcriptional changes in resident CD1C+/CD1A+ conventional dendritic cells (cDC)2 following challenge. In contrast, non-allergic individuals displayed distinct innate MPS responses to allergen challenge: predominant infiltration of myeloid-derived suppressor cells (MDSC: HLA-DRlow/CD14+ monocytes) and cDC2 expressing inhibitory/tolerogenic transcripts. These divergent patterns were confirmed in ex vivo stimulated MPS nasal biopsy cells. Thus, we identified not only MPS cell clusters involved in airway allergic inflammation but also highlight novel roles for non-inflammatory innate MPS responses by MDSC to allergens in non-allergic individuals. Future therapies should address MDSC activity as treatment for inflammatory airway diseases.
    DOI:  https://doi.org/10.1084/jem.20221111
  30. PLoS One. 2023 ;18(7): e0288002
    A novel in vitro model to study prolonged Pseudomonas aeruginosa infection in the cystic fibrosis bronchial epithelium.
    Meghan J Hirsch, Emily M Hughes, Molly M Easter, Seth E Bollenbecker, Patrick H Howze Iv, Susan E Birket, Jarrod W Barnes, Megan R Kiedrowski, Stefanie Krick.
      Pseudomonas aeruginosa (PA) is known to chronically infect airways of people with cystic fibrosis (CF) by early adulthood. PA infections can lead to increased airway inflammation and lung tissue damage, ultimately contributing to decreased lung function and quality of life. Existing models of PA infection in vitro commonly utilize 1-6-hour time courses. However, these relatively early time points may not encompass downstream airway cell signaling in response to the chronic PA infections observed in people with cystic fibrosis. To fill this gap in knowledge, the aim of this study was to establish an in vitro model that allows for PA infection of CF bronchial epithelial cells, cultured at the air liquid interface, for 24 hours. Our model shows with an inoculum of 2 x 102 CFUs of PA for 24 hours pro-inflammatory markers such as interleukin 6 and interleukin 8 are upregulated with little decrease in CF bronchial epithelial cell survival or monolayer confluency. Additionally, immunoblotting for phosphorylated phospholipase C gamma, a well-known downstream protein of fibroblast growth factor receptor signaling, showed significantly elevated levels after 24 hours with PA infection that were not seen at earlier timepoints. Finally, inhibition of phospholipase C shows significant downregulation of interleukin 8. Our data suggest that this newly developed in vitro "prolonged PA infection model" recapitulates the elevated inflammatory markers observed in CF, without compromising cell survival. This extended period of PA growth on CF bronchial epithelial cells will have impact on further studies of cell signaling and microbiological studies that were not possible in previous models using shorter PA exposures.
    DOI:  https://doi.org/10.1371/journal.pone.0288002
  31. Allergy. 2023 Jul 08.
    Shotgun metagenomic sequencing on skin microbiome indicates dysbiosis exists prior to the onset of atopic dermatitis.
    Prem Prashant Chaudhary, Ian A Myles, Jordan Zeldin, Shareef Dabdoub, Varsha Deopujari, Rajiv Baveja, Robin Baker, Sarah Bengtson, Ashleigh Sutton, Shira Levy, Suchitra K Hourigan.
       BACKGROUND: While the microbiome is increasingly seen as a targetable contributor to atopic dermatitis (AD), questions remain as to whether the dysbiosis is secondary to diseased skin or if it predates symptom onset. Previous work has evaluated how the skin microbiome changes with age and established the influence of factors like delivery mode and breastfeeding on global microbiome diversity. However, these studies were unable to identify taxa which predict subsequent AD.
    METHODS: Skin swab samples were collected from the first week of life for 72 children in the neonatal intensive care unit (NICU) at a single site hospital. Participants were followed for 3 years to determine their health status. We applied shotgun metagenomic sequencing to assess the microbiome differences between 31 children who went on to develop AD and 41 controls.
    RESULTS: We identified that subsequent development of AD was associated with differential abundance of several bacterial and fungal taxa as well as several metabolic pathways, each of which have been previously associated with active AD.
    CONCLUSIONS: Our work provides evidence of reproducibility for the previously reported dysbiotic signatures predating AD onset while also expanding prior findings through the first use of metagenomic assessment prior to AD onset. While extrapolation of our findings beyond the pre-term, NICU cohort is limited, our findings add to the evidence that the dysbiosis associated with AD pre-dates disease onset rather than reflect a secondary consequence of skin inflammation.
    Keywords:   Malassezia ; Staphylococcus ; atopic dermatitis; dysbiosis; eczema; microbiome
    DOI:  https://doi.org/10.1111/all.15806
  32. Intensive Crit Care Nurs. 2023 Feb;pii: S0964-3397(22)00139-2. [Epub ahead of print]74 103336
    Impact of air pollution on respiratory microbiome: A narrative review.
    Tarsila Vieceli, Sofia Tejada, Raquel Martinez-Reviejo, Tomas Pumarola, Jacques Schrenzel, Grant W Waterer, Jordi Rello.
       BACKGROUND: Respiratory microbiome composition depends on an intricate balance between host characteristics, diet, and environmental factors. Some studies indicate a bidirectional relationship between respiratory microbiota and disease. Air pollution is consistently associated with increased respiratory morbidity and mortality in different populations and across different ages. The aim of this review was to report a summary of the evidence regarding the impact of air pollution on the upper and lower respiratory tract microbiome.
    METHODS: A literature search from interaction between air pollution and respiratory microbiome was performed (2010-2022).
    RESULTS: Sixteen studies demonstrated changes in microbiome with both environmental and household air pollution. Increasing levels of air pollutants are associated with lower relative abundance of Corynebacterium and increasing levels of pathogen colonization, such as Haemophilus influenzae, Moraxella catarrhalis, Streptococcus pneumoniae and Pseudomonas aeruginosa and Acinetobacter baumannii, altering the incidence and clinical course of respiratory infections. This ultimately leads to an excess of morbidity and mortality due to antimicrobial resistance.
    CONCLUSION: Changes of air pollution on the respiratory microbiome may influence respiratory infections in critical care. Use of probiotics may restore the diversity of baseline microbiome, preventing infections by resistant organisms in the critical care setting. Using protective equipment decreased the effect of air pollutants on increasing potentially pathogenic microorganisms.
    Keywords:  Air contamination; Ambient air; Climate change; Healthcare; Microbiome; Pneumonia; Prevention; Public health; Quality of life; Respiratory infections
    DOI:  https://doi.org/10.1016/j.iccn.2022.103336
  33. Semin Immunol. 2023 Jul 10. pii: S1044-5323(23)00094-5. [Epub ahead of print]69 101803
    Pyroptosis and the cellular consequences of gasdermin pores.
    Hanna C Huston, Marisa J Anderson, Susan L Fink.
      The family of gasdermin proteins plays a key role in the host response against external and internal pathogenic signals by mediating the form of inflammatory regulated cell death known as pyroptosis. One of the most well-studied gasdermins within innate immunity is gasdermin D, which is cleaved, oligomerizes, and forms plasma membrane pores. Gasdermin D pores lead to a number of downstream cellular consequences including plasma membrane rupture, or cell lysis. In this review, we describe mechanisms of activation for each of the gasdermins, their cell type specificity and some disease associations. We then discuss downstream consequences of gasdermin pore formation, including cellular mechanisms of membrane repair. Finally, we present some important next steps to better understand pyroptosis and the cellular consequences of gasdermin pore formation.
    Keywords:  Gasdermin; Inflammasome; Inflammation; Pyroptosis; Regulated cell death
    DOI:  https://doi.org/10.1016/j.smim.2023.101803
  34. Int J Mol Sci. 2023 Jul 03. pii: 11038. [Epub ahead of print]24(13):
    The Global Burden of Community-Acquired Pneumonia in Adults, Encompassing Invasive Pneumococcal Disease and the Prevalence of Its Associated Cardiovascular Events, with a Focus on Pneumolysin and Macrolide Antibiotics in Pathogenesis and Therapy.
    Ronald Anderson, Charles Feldman.
      Despite innovative advances in anti-infective therapies and vaccine development technologies, community-acquired pneumonia (CAP) remains the most persistent cause of infection-related mortality globally. Confronting the ongoing threat posed by Streptococcus pneumoniae (the pneumococcus), the most common bacterial cause of CAP, particularly to the non-immune elderly, remains challenging due to the propensity of the elderly to develop invasive pneumococcal disease (IPD), together with the predilection of the pathogen for the heart. The resultant development of often fatal cardiovascular events (CVEs), particularly during the first seven days of acute infection, is now recognized as a relatively common complication of IPD. The current review represents an update on the prevalence and types of CVEs associated with acute bacterial CAP, particularly IPD. In addition, it is focused on recent insights into the involvement of the pneumococcal pore-forming toxin, pneumolysin (Ply), in subverting host immune defenses, particularly the protective functions of the alveolar macrophage during early-stage disease. This, in turn, enables extra-pulmonary dissemination of the pathogen, leading to cardiac invasion, cardiotoxicity and myocardial dysfunction. The review concludes with an overview of the current status of macrolide antibiotics in the treatment of bacterial CAP in general, as well as severe pneumococcal CAP, including a consideration of the mechanisms by which these agents inhibit the production of Ply by macrolide-resistant strains of the pathogen.
    Keywords:  Streptococcus pneumoniae; cardiovascular events; community-acquired pneumonia; dendritic cells; macrolides; macrophages; mannose receptor C-type1; platelets; pneumolysin; pro-inflammatory cytokines
    DOI:  https://doi.org/10.3390/ijms241311038
  35. Biochim Biophys Acta Mol Cell Res. 2023 Jul 12. pii: S0167-4889(23)00107-6. [Epub ahead of print] 119535
    NMDA receptor activation induces damage of alveolar type II cells and lung fibrogenesis through ferroptosis.
    Hai-Peng Cheng, Dan-Dan Feng, Xiao-Hong Li, Li-Hua Gao, Yu-Jia Qiu, Xing-Yue Liang, Yan Zhou, Pu Huang, Min Shao, Yun-Na Zhang, Yan-Fen Chang, Jia-Feng Fu, Yan-Hong Huang, Wei Liu, Si-Yuan Tang, Chen Li, Zi-Qiang Luo.
      Ferroptosis, a newly discovered type of regulated cell death, has been implicated in numerous human diseases. Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal interstitial lung disease with poor prognosis and limited treatment options. Emerging evidence has linked ferroptosis and glutamate-determined cell fate which is considered a new light on the etiology of pulmonary fibrosis. Here, we observed that N-methyl d-aspartate receptor (NMDAR) activation promoted cell damage and iron deposition in MLE-12 cells in a dose-, time-, and receptor-dependent manner. This mediated substantial Ca2+ influx, upregulated the expression levels of nNOS and IRP1, and affected intracellular iron homeostasis by regulating the expression of iron transport-related proteins (i.e., TFR1, DMT1, and FPN). Excessive iron load promoted the continuous accumulation of total intracellular and mitochondrial reactive oxygen species, which ultimately led to ferroptosis. NMDAR inhibition reduced lung injury and pulmonary fibrosis in bleomycin-induced mice. Bleomycin stimulation upregulated the expression of NMDAR1, nNOS, and IRP1 in mouse lung tissues, which ultimately led to iron deposition via regulation of the expression of various iron metabolism-related genes. NMDAR activation initiated the pulmonary fibrosis process by inducing iron deposition in lung tissues and ferroptosis of alveolar type II cells. Our data suggest that NMDAR activation regulates the expression of iron metabolism-related genes by promoting calcium influx, increasing nNOS and IRP1 expression, and increasing iron deposition by affecting cellular iron homeostasis, ultimately leading to mitochondrial damage, mitochondrial dysfunction, and ferroptosis. NMDAR activation-induced ferroptosis of alveolar type II cells might be a key event to the initiation of pulmonary fibrosis.
    Keywords:  Alveolar type II cells; Ferroptosis; N-Methyl-d-aspartate (NMDA) receptors; Pulmonary fibrosis
    DOI:  https://doi.org/10.1016/j.bbamcr.2023.119535
  36. Nutrients. 2023 May 06. pii: 2207. [Epub ahead of print]15(9):
    Limosilactobacillus fermentum CECT5716: Clinical Potential of a Probiotic Strain Isolated from Human Milk.
    Metehan Ozen, Hugues Piloquet, Monika Schaubeck.
      Breastfeeding provides the ideal nutrition for infants. Human milk contains a plethora of functional ingredients which foster the development of the immune system. The human milk microbiota predominantly contributes to this protective effect. This is mediated by various mechanisms, such as an antimicrobial effect, pathogen exclusion and barrier integrity, beneficial effects on the gastrointestinal microbiota, vitamin synthesis, immunity enhancement, secreted probiotic factors, and postbiotic mechanisms. Therefore, human milk is a good source for isolating probiotics for infants who cannot be exclusively breastfed. One such probiotic which was isolated from human milk is Limosilactobacillus fermentum CECT5716. In this review, we give an overview of available interventional studies using Limosilactobacillus fermentum CECT5716 and summarise preclinical trials in several animal models of different pathologies, which have given first insights into its mechanisms of action. We present several randomised clinical studies, which have been conducted to investigate the clinical efficacy of the Limosilactobacillus fermentum CECT5716 strain in supporting the host's health.
    Keywords:  Lactobacillus fermentum CECT5716; Limosilactobacillus fermentum CECT5716; diarrhoea; human milk; infant formula; infant microbiota; probiotic; respiratory tract infections
    DOI:  https://doi.org/10.3390/nu15092207
  37. BMC Pediatr. 2023 Jul 11. 23(1): 350
    Bacterium detected by gram stain and drug sensitivity in Chinese children with acute sinusitis.
    Yan Li, Yinhui Zeng, Haiqing Xiao, Wenlong Liu.
       BACKGROUND: Acute rhinosinusitis (ARS) is one of the common diseases of upper respiratory tract infection in children. Bacterial infection is a significant aggravating factor in pediatric ARS. In this research, our goal was to detected the bacterial flora and antibiotic sensitivity of ARS in Chinese children.
    METHODS: We recruited 133 children with ARS between January 2020 and January 2022 from our hospital. Sinus secretion were collected and cultured for Gram stain as well as antimicrobial susceptibility tests.
    RESULTS: Moraxella catarrhalis, Staphylococcus aureus, Haemophilus influenzae, Streptococcus pneumoniae and Pseudomonas aeruginosa were detected in order in children with ARS, of which 25% were negative for bacterial culture and 10% were positive for two strains. Amoxicillin and clavulanate potassium were useful for Haemophilus influenzae, Streptococcus pneumoniae and Moraxella catarrhalis. Quinolones are useful for Staphylococcus aureus, Haemophilus influenzae, Streptococcus pneumoniae and Pseudomonas aeruginosa.
    CONCLUSIONS: This research updates the proportion of ARS bacterial infection in children in southern China and the antibiotic sensitivity.
    Keywords:  ARS; Antibiotic sensitivity; Bacteriology; Children
    DOI:  https://doi.org/10.1186/s12887-023-04178-9
  38. Eur J Immunol. 2023 Jul 15. e2350475
    Th2-dependent disappearance and phenotypic conversion of mouse alveolar macrophages.
    Axel Dietschmann, Andreas Ruhl, Peter J Murray, Claudia Günther, Christoph Becker, Padraic Fallon, David Voehringer.
      Alveolar macrophages (alvMs) play an important role for maintenance of lung function by constant removal of cellular debris in the alveolar space. They further contribute to defense against microbial or viral infections and limit tissue damage during acute lung injury. AlvMs arise from embryonic progenitor cells, seed the alveoli before birth and have life-long self-renewing capacity. However, recruited monocytes may also help to restore the alvM population after depletion caused e.g. by toxins or influenza virus infection. At present, the population dynamics and cellular plasticity of alvMs during allergic lung inflammation is poorly defined. To address this point, we used a mouse model of Aspergillus fumigatus-induced allergic lung inflammation and observed that Th2-derived IL-4 and IL-13 caused almost complete disappearance of alvMs. This effect required STAT6 expression in alvMs and also occurred in various other settings of type 2 immunity-mediated lung inflammation or administration of IL-4 complexes to the lung. In addition, Th2 cells promoted conversion of alvMs to alternatively activated macrophages (AAMs) and multinucleated giant cells (MGCs). Given the well-established role of alvMs for maintenance of lung function, this process may have implications for resolution of inflammation and tissue homeostasis in allergic asthma. This article is protected by copyright. All rights reserved.
    Keywords:  Aspergillus; STAT6; allergic asthma; alternatively activated macrophages; alveolar macrophages; multinucleated giant cells
    DOI:  https://doi.org/10.1002/eji.202350475
  39. Sci China Life Sci. 2023 Jul 06.
    A novel reporter mouse line for studying alveolar macrophages.
    Xiaoyun Zhao, Liang Li, Hongxiang Sun, Xiaoli Jiang, Wenjuan Bai, Ningbo Wu, Jing Wang, Bing Su.
      Alveolar macrophages (AMs) are self-maintained immune cells that play vital roles in lung homeostasis and immunity. Although reporter mice and culture systems have been established for studying macrophages, an accurate and specific reporter line for alveolar macrophage study is still not available. Here we reported a novel Rspo1-tdTomato gene reporter mouse line that could specifically label mouse AMs in a cell-intrinsic manner. Using this reporter system, we visualized the dynamics of alveolar macrophages intravitally under steady state and characterized the alveolar macrophage differentiation under in vitro condition. By performing ATAC-seq, we found that insertion of the tdTomato cassette in the Rspo1 locus increased the accessibility of a PPARE motif within the Rspo1 locus and revealed a potential regulation by key transcription factor PPAR-γ for alveolar macrophage differentiation in vitro and in vivo. Consistently, perturbation of PPAR-γ by its agonist rosiglitazone or inhibitor GW9662 resulted in corresponding alteration of tdTomato expression in alveolar macrophages together with the transcription of PPAR-γ downstream target genes. Furthermore, global transcriptomic analyses of AMs from the wild type mice and the Rspo1-tdTomato mice showed comparable gene expression profiles, especially those AM-specific genes, confirming that the insertion of the tdTomato cassette in the Rspo1 locus does not impact the cell identity and biological function of AMs under normal condition. Taken together, our study provides an alternative tool for in vivo and in vitro labeling of alveolar macrophages with high specificity which could also be utilized as an indicator of PPAR-γ activity for future development of PPAR-γ specific targeting drugs.
    Keywords:  ATAC-seq; PPAR-γ; R-spondin 1; alveolar macrophage; gene reporter mice
    DOI:  https://doi.org/10.1007/s11427-022-2325-1
  40. Cell Host Microbe. 2023 Jul 12. pii: S1931-3128(23)00262-7. [Epub ahead of print]31(7): 1075-1076
    Multi-arming ourselves against drug-resistant bacteria.
    Jessia Raherisoanjato, Matthew T Henke.
      New classes of antibiotics are desperately needed in our fight against antibiotic-resistant bacterial infections. Jia et al. publish a new "multi-armed" antibiotic scaffold that effectively treats methicillin-resistant Staphylococcus aureus infections in mice. These compounds are structurally unlike pre-clinical or approved antibiotics, and they may hit an "irresistible" target.
    DOI:  https://doi.org/10.1016/j.chom.2023.06.011
  41. Biotechnol Bioeng. 2023 Jul 10.
    Random forest and live single-cell metabolomics reveal metabolic profiles of human macrophages upon polarization.
    Huaqi Tang, Ahmed Ali, Eman Abdelazem, Tom H M Ottenhoff, Ron M A Heeren, Alireza Mashaghi.
      Human macrophages are innate immune cells with diverse, functionally distinct phenotypes, namely, pro-inflammatory M1 and anti-inflammatory M2 macrophages. Both are involved in multiple physiological and pathological processes, including would healing, infection, and cancer. However, the metabolic differences between these phenotypes are largely unexplored at single-cell resolution. To address this knowledge gap, an untargeted live single-cell mass spectrometry-based metabolomic profiling coupled with a machine-learning data analysis approach was developed to investigate the metabolic profile of each phenotype at the single-cell level. Results show that M1 and M2 macrophages have distinct metabolic profiles, with differential levels of fatty acyls, glycerophospholipids, and sterol lipids, which are important components of plasma membrane and involved in multiple biological processes. Furthermore, we could discern several putatively annotated molecules that contribute to inflammatory response of macrophages. The combination of random forest and live single-cell metabolomics provided an in-depth profile of the metabolome of primary human M1 and M2 macrophages at the single-cell level for the first time, which will pave the way for future studies targeting the differentiation of other immune cells.
    Keywords:  human macrophages; phenotype classification; random forest; single-cell metabolomics
    DOI:  https://doi.org/10.1002/bit.28494
  42. bioRxiv. 2023 Jun 26. pii: 2023.06.25.546471. [Epub ahead of print]
    Iron acquisition by a commensal bacterium modifies host nutritional immunity during Salmonella infection.
    Luisella Spiga, Ryan T Fansler, Yasiru R Perera, Nicolas G Shealy, Matthew J Munneke, Teresa P Torres, Holly E David, Andrew Lemoff, Xinchun Ran, Katrina L Richardson, Nicholas Pudlo, Eric C Martens, Zhongyue J Yang, Eric P Skaar, Mariana X Byndloss, Walter J Chazin, Wenhan Zhu.
      During intestinal inflammation, host nutritional immunity starves microbes of essential micronutrients such as iron. Pathogens scavenge iron using siderophores, which is counteracted by the host using lipocalin-2, a protein that sequesters iron-laden siderophores, including enterobactin. Although the host and pathogens compete for iron in the presence of gut commensal bacteria, the roles of commensals in nutritional immunity involving iron remain unexplored. Here, we report that the gut commensal Bacteroides thetaiotaomicron acquires iron in the inflamed gut by utilizing siderophores produced by other bacteria including Salmonella, via a secreted siderophore-binding lipoprotein termed XusB. Notably, XusB-bound siderophores are less accessible to host sequestration by lipocalin-2 but can be "re-acquired" by Salmonella , allowing the pathogen to evade nutritional immunity. As the host and pathogen have been the focus of studies of nutritional immunity, this work adds commensal iron metabolism as a previously unrecognized mechanism modulating the interactions between pathogen and host nutritional immunity.
    DOI:  https://doi.org/10.1101/2023.06.25.546471
  43. Microbiol Spectr. 2023 Jul 11. e0523922
    Comprehensive Genomic Characterization of Staphylococcus aureus Isolated from Atopic Dermatitis Patients in Japan: Correlations with Disease Severity, Eruption Type, and Anatomical Site.
    Shoko Obata, Junzo Hisatsune, Hiroshi Kawasaki, Ayano Fukushima-Nomura, Tamotsu Ebihara, Chika Arai, Kanako Masuda, Shoko Kutsuno, Yasuhisa Iwao, Motoyuki Sugai, Masayuki Amagai, Keiji Tanese.
      Atopic dermatitis (AD) shows frequent recurrence. Staphylococcus aureus is the primary microbial component in AD and is associated with disease activity. However, traditional typing methods have failed to characterize virulent AD isolates at the clone level. We conducted a comprehensive genomic characterization of S. aureus strains isolated from the skin of AD patients and healthy donors, comparing the whole-genome sequences of the 261 isolates with anatomical and lesional (AD-A)/nonlesional (AD-NL)/healthy sites, eruption types, clinical scores, virulence, and antimicrobial resistance gene repertoires in Japan. Sequence type (ST) diversity was lost with worsening disease activity; ST188 was the most frequently detected ST in AD-A and had the strongest correlation with AD according to the culture rate and proportion with worsening disease activity. ST188 and ST20 isolates inhabited all skin conditions, with significantly higher proportions in AD skin than in healthy skin. ST8, ST15, and ST5 proportions were equivalent for all skin conditions; ST30 was detected only in healthy skin; and ST12 was detected only in AD skin. ST97 detected in AD-A and healthy skin was clearly branched into two subclades, designated ST97A and ST97H. A comparison of two genomes led to the discovery that only ST97A possessed the complete trp operon, enabling bacterial survival without exogenous tryptophan (Trp) on AD skin, where the Trp level was significantly reduced. Primary STs showing an AD skin inhabitation trend (ST188, ST97A, ST20, and ST12) were all trp operon positive. The predominant clones (ST188 and ST97) possessed almost no enterotoxin genes, no mecA gene, and few other antimicrobial resistance genes, different from the trend observed in Europe/North America. IMPORTANCE While Staphylococcus aureus is a member of the normal human skin flora, its strong association with the onset of atopic dermatitis (AD) has been suggested. However, previous studies failed to assign specific clones relevant to disease activities. Enterotoxins produced by S. aureus have been suggested to aggravate and exacerbate the inflammation of AD skin, but their role remains ambiguous. We conducted a nuanced comprehensive characterization of isolates from AD patients and healthy donors, comparing the whole-genome sequences of the isolates with anatomical and lesional/nonlesional/healthy sites, eruption types, clinical scores, virulence, and antimicrobial resistance gene repertoires in Japan. We demonstrate that specific clones are associated with disease severity and clinical manifestations, and the dominant clones are devoid of enterotoxin genes and antimicrobial resistance genes. These findings undermine the established notion of the pathophysiological function of S. aureus associated with AD and introduce a new concept of S. aureus colonization in AD.
    Keywords:  MLST; SCORAD; ST188; ST8; ST97; Staphylococcus aureus; atopic dermatitis; back; cubital fossa; glabella; multilocus sequence typing; phylogenetic analysis; volar forearm; whole-genome sequence
    DOI:  https://doi.org/10.1128/spectrum.05239-22
  44. PLoS Pathog. 2023 Jul 13. 19(7): e1011531
    Impact of the pentose phosphate pathway on metabolism and pathogenesis of Staphylococcus aureus.
    Jisun Kim, Gyu-Lee Kim, Javiera Norambuena, Jeffrey M Boyd, Dane Parker.
      Staphylococcus aureus is an important pathogen that leads to significant disease through multiple routes of infection. We recently published a transposon sequencing (Tn-seq) screen in a mouse acute pneumonia model and identified a hypothetical gene (SAUSA300_1902, pgl) with similarity to a lactonase of Escherichia coli involved in the pentose phosphate pathway (PPP) that was conditionally essential. Limited studies have investigated the role of the PPP in physiology and pathogenesis of S. aureus. We show here that mutation of pgl significantly impacts ATP levels and respiration. RNA-seq analysis of the pgl mutant and parent strains identified compensatory changes in gene expression for glucose and gluconate as well as reductions in the pyrimidine biosynthesis locus. These differences were also evident through unbiased metabolomics studies and 13C labeling experiments that showed mutation of pgl led to reductions in pyrimidine metabolism including decreases in ribose-5P, UMP and GMP. These nucleotide reductions impacted the amount of extracellular DNA in biofilms and reduced biofilm formation. Mutation also limited the capacity of the strain to resist oxidant damage induced by hydrogen peroxide and paraquat and subsequent intracellular survival inside macrophages. Changes in wall teichoic acid impacted susceptibility to hydrogen peroxide. We demonstrated the importance of these changes on virulence in three different models of infection, covering respiratory, skin and septicemia, demonstrating the need for proper PPP function in all models. This work demonstrates the multifaceted role metabolism can play in multiple aspects of S. aureus pathogenesis.
    DOI:  https://doi.org/10.1371/journal.ppat.1011531
  45. Front Microbiol. 2023 ;14 1198200
    Novel evidence on sepsis-inducing pathogens: from laboratory to bedside.
    Sebastian Gatica, Brandon Fuentes, Elizabeth Rivera-Asín, Paula Ramírez-Céspedes, Javiera Sepúlveda-Alfaro, Eduardo A Catalán, Susan M Bueno, Alexis M Kalergis, Felipe Simon, Claudia A Riedel, Felipe Melo-Gonzalez.
      Sepsis is a life-threatening condition and a significant cause of preventable morbidity and mortality globally. Among the leading causative agents of sepsis are bacterial pathogens Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, and Streptococcus pyogenes, along with fungal pathogens of the Candida species. Here, we focus on evidence from human studies but also include in vitro and in vivo cellular and molecular evidence, exploring how bacterial and fungal pathogens are associated with bloodstream infection and sepsis. This review presents a narrative update on pathogen epidemiology, virulence factors, host factors of susceptibility, mechanisms of immunomodulation, current therapies, antibiotic resistance, and opportunities for diagnosis, prognosis, and therapeutics, through the perspective of bloodstream infection and sepsis. A list of curated novel host and pathogen factors, diagnostic and prognostic markers, and potential therapeutical targets to tackle sepsis from the research laboratory is presented. Further, we discuss the complex nature of sepsis depending on the sepsis-inducing pathogen and host susceptibility, the more common strains associated with severe pathology and how these aspects may impact in the management of the clinical presentation of sepsis.
    Keywords:  diagnostics; immunology; inflammation; microorganisms; prognosis; sepsis; therapy
    DOI:  https://doi.org/10.3389/fmicb.2023.1198200
  46. Cell Signal. 2023 Jul 10. pii: S0898-6568(23)00218-8. [Epub ahead of print] 110804
    Truncated oxidized phospholipids exacerbate endothelial dysfunction and lung injury caused by bacterial pathogens.
    Pratap Karki, Chen-Ou Zhang, Kamoltip Promnares, Yue Li, Yunbo Ke, Anna A Birukova, Konstantin G Birukov.
      Oxidized phospholipids (OxPLs) are present at basal levels in circulation of healthy individuals, but a substantial increase and changes in composition of OxPLs may rapidly occur during microbial infections, sepsis, and trauma. Specifically, truncated oxidized phospholipids (Tr-OxPLs) exhibit detrimental effects on pulmonary endothelium, yet their role on modulation of lung injury caused by bacterial pathogens remains to be elucidated. This study investigated the effects of Tr-OxPL species: KOdiA-PC, POV-PC, PON-PC, PAz-PC, PGPC, and Lyso-PC on endothelial permeability and inflammatory responses to gram-positive bacterial particles. Results showed that all six tested Tr-OxPLs augmented endothelial barrier disruption caused by heat-killed Staphylococcus aureus (HKSA) as determined by VE-cadherin immunostaining and monitoring transendothelial electrical resistance. In parallel, even moderate elevation of Tr-OxPLs augmented HKSA-induced activation of NF-κB, secretion of IL-6 and IL-8, and protein expression of ICAM-1 and VCAM-1. In the mouse model of acute lung injury caused by intranasal injection of HKSA, intravenous Tr-OxPLs administration augmented HKSA-induced increase in BAL protein content and cell counts, tissue expression of TNFα, KC, IL1β, and CCL2, and promoted vascular leak monitored by lung infiltration of Evans Blue. These results suggest that elevated Tr-OxPLs act as critical risk factor worsening bacterial pathogen-induced endothelial dysfunction and lung injury.
    Keywords:  HKSA; Inflammation; Lung endothelium; Lung injury; Permeability; Truncated oxidized phospholipids
    DOI:  https://doi.org/10.1016/j.cellsig.2023.110804
  47. Gut Microbes. 2023 Jan-Dec;15(1):15(1): 2233149
    Fucose promotes intestinal stem cell-mediated intestinal epithelial development through promoting Akkermansia-related propanoate metabolism.
    Caihan Duan, Junhao Wu, Zhe Wang, Chen Tan, Lingzhi Hou, Wei Qian, Chaoqun Han, Xiaohua Hou.
      Intestinal stem cells (ISCs) are critical for the development and rapid turnover of intestinal epithelium. The regulatory effects of gut microbiota and their metabolites on ISCs stemness remain elusive. Fucose has been demonstrated to mediate host-microbe interactions in the intestine. However, the association between fucose, gut bacteria, and ISCs stemness remains unclear. To investigate the effects of fucose on ISCs-mediated intestinal epithelial cells (IECs) development, we administered fucose to 4-week-old mice for 4 weeks. ISCs stemness, IECs proliferation, and differentiation were examined. Variations in gut microbes and metabolism were detected using 16S rDNA sequencing and metabolomic analysis. Fucose was added to the bacterial culture medium to further study its effects on metabolism. Crypts were isolated from the mouse ileum for organoids culture in vitro to evaluate the effects of metabolites and the underlying mechanism. The results showed that fucose accelerated ISCs proliferation and secretory lineage differentiation in mice, whereas antibiotics eliminated these effects. The composition and functions of gut bacteria were altered by fucose treatment, while significant increases in Akkermansia and propanoate metabolism were noted. Propionic acid and propionate have been shown to promote organoid development. Fucose fermentation increases the production of propionic acid in Akkermansia muciniphila and enhances its ability to increase the stemness of ISCs. Moreover, ileal contents from fucose-treated mice promoted organoid development in a Gpr41/Gpr43-dependent manner. Fucose administration activates the Wnt signaling pathway in ISCs, and Wnt inhibitors suppress the effects of fucose. We conclude that fucose accelerates ISC-mediated intestinal epithelial development by promoting Akkermansia-related propanoate metabolism. These findings provide new insights into the promotion of gut homeostasis and the application potential of fucose as a prebiotic.
    Keywords:  Akkermansia muciniphila; Fucose; gut microbe; intestinal stem cell; propionic acid
    DOI:  https://doi.org/10.1080/19490976.2023.2233149
  48. Microbiol Spectr. 2023 Jul 12. e0078023
    Microbiome Engineering Using Probiotic Yeast: Saccharomyces boulardii and the Secreted Human Lysozyme Lead to Changes in the Gut Microbiome and Metabolome of Mice.
    Jungyeon Kim, Christine Atkinson, Michael J Miller, Kyoung Heon Kim, Yong-Su Jin.
      The probiotic yeast Saccharomyces boulardii has great potential for use as a chassis for microbiome engineering because of its high resistance to environmental stress, well-developed genetic tools, and the ability to secrete recombinant proteins in the intestine. As oral feeding of lysozyme has been reported to change the gut microbiome and fecal metabolites, we engineered S. boulardii to secrete human lysozyme, and investigated the changes in the microbiome and fecal metabolites in response to the administration of the engineered probiotic yeast into mice. Administration of S. boulardii changed the structure of the gut microbiome by promoting the growth of clostridia and increasing the diversity of strains. The human lysozyme secreted by S. boulardii in the intestine resulted in a unique gut microbiome structure through selective growth. In addition, the administration of probiotic yeast S. boulardii affected host energy metabolism and decreased blood urea and fructose levels, suggesting a mechanism of health benefits in mice. IMPORTANCE Our study identified changes in the microbiome by administering wild-type S. boulardii in mice to healthy mice based on long-read sequencing and demonstrated that a recombinant protein secreted by engineered S. boulardii in the intestine could change the microbiome. Our results provide valuable information for the development of therapeutics using engineered S. boulardii that changes the gut microbiome and host physiology.
    Keywords:  Saccharomyces boulardii; human lysozyme; metabolic engineering; metabolomics; microbiome; microbiome engineering
    DOI:  https://doi.org/10.1128/spectrum.00780-23
  49. ACS Infect Dis. 2023 Jul 11.
    Nanoscaled Discovery of a Shunt Rifamycin from Salinispora arenicola Using a Three-Color GFP-Tagged Staphylococcus aureus Macrophage Infection Assay.
    Nhan T Pham, Joana Alves, Fiona A Sargison, Reiko Cullum, Jan Wildenhain, William Fenical, Mark S Butler, David A Mead, Brendan M Duggan, J Ross Fitzgerald, James J La Clair, Manfred Auer.
      Antimicrobial resistance has emerged as a global public health threat, and development of novel therapeutics for treating infections caused by multi-drug resistant bacteria is urgent. Staphylococcus aureus is a major human and animal pathogen, responsible for high levels of morbidity and mortality worldwide. The intracellular survival of S. aureus in macrophages contributes to immune evasion, dissemination, and resilience to antibiotic treatment. Here, we present a confocal fluorescence imaging assay for monitoring macrophage infection by green fluorescent protein (GFP)-tagged S. aureus as a front-line tool to identify antibiotic leads. The assay was employed in combination with nanoscaled chemical analyses to facilitate the discovery of a new, active rifamycin analogue. Our findings indicate a promising new approach for the identification of antimicrobial compounds with macrophage intracellular activity. The antibiotic identified here may represent a useful addition to our armory in tackling the silent pandemic of antimicrobial resistance.
    Keywords:  Salinispora arenicola; Staphylococcus aureus; fluorescence imaging assay; macrophage; rifamycin
    DOI:  https://doi.org/10.1021/acsinfecdis.3c00049
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