bims-bac4me Biomed News
on Microbiome and trained immunity
Issue of 2023–10–01
sixty-five papers selected by
Chun-Chi Chang, Universitäts Spital Zürich
  1. Antiviral epithelial-macrophage crosstalk permits secondary bacterial infections.
  2. New Insights in Immunometabolism in Neonatal Monocytes and Macrophages in Health and Disease.
  3. Sputum from People with Cystic Fibrosis Reduces the Killing of Methicillin-Resistant Staphylococcus aureus by Neutrophils and Diminishes Phagosomal Production of Reactive Oxygen Species.
  4. The gut ecosystem and immune tolerance.
  5. The gasdermins: a pore-forming protein family expressed in the epidermis.
  6. Interaction among inflammasome, PANoptosise, and innate immune cells in infection of influenza virus: Updated review.
  7. Transcriptional profiling and genetic analysis of a cystic fibrosis airway-relevant model shows asymmetric responses to growth in a polymicrobial community.
  8. The Interaction between the Host Genome, Epigenome, and the Gut-Skin Axis Microbiome in Atopic Dermatitis.
  9. Lung Microbiome as a Treatable Trait in Chronic Respiratory Disorders.
  10. Cystic fibrosis autoantibody signatures associate with Staphylococcus aureus lung infection or cystic fibrosis-related diabetes.
  11. A computational method to dissect colonization resistance of the gut microbiota against pathogens.
  12. Latest Review Papers in Molecular Microbiology.
  13. MDA5 Enhances Invasive Candida albicans Infection by Regulating Macrophage Apoptosis and Phagocytosis/Killing Functions.
  14. Recent advances in understanding the role of the skin microbiome in the treatment of atopic dermatitis.
  15. Coordination of cross-talk between metabolism and epigenetic regulation by the SIN3 complex.
  16. Protective versus Pathogenic Type I Interferon Responses during Virus Infections.
  17. Potential impact of trained innate immunity on the pathophysiology of metabolic dysfunction-associated fatty liver disease.
  18. Biodiversity of Skin Microbiota as an Important Biomarker for Wound Healing.
  19. The mechanisms and factors that induce trained immunity in arthropods and mollusks.
  20. Molecular commensalism-how to investigate underappreciated health-associated polymicrobial communities.
  21. Impact of breastfeeding and other early-life factors on the development of the oral microbiome.
  22. Differentiation of Bone Marrow Monocytes into Alveolar Macrophages-like Cells through Co-culture with Lung Epithelial Cells and Group 2 Innate Lymphoid Cells.
  23. Skin microbiota secretomes modulate cutaneous innate immunity against Borrelia burgdorferi s.s.
  24. Mycobacterium tuberculosis infection drives differential responses in the bone marrow hematopoietic stem and progenitor cells.
  25. The chemorepellent, SLIT2, bolsters innate immunity against Staphylococcus aureus.
  26. Unraveling the Role of Epithelial Cells in the Development of Chronic Rhinosinusitis.
  27. Plasma membrane abundance dictates phagocytic capacity and functional crosstalk in myeloid cells.
  28. SifA SUMOylation governs Salmonella Typhimurium intracellular survival via modulation of lysosomal function.
  29. Butyrate protects against MRSA pneumonia via regulating gut-lung microbiota and alveolar macrophage M2 polarization.
  30. M2a macrophages facilitate resolution of chemically-induced colitis in TLR4-SNP mice.
  31. The immunometabolic reprogramming of microglia in Alzheimer's disease.
  32. Exploring Longitudinal Gut Microbiome towards Metabolic Functional Changes Associated in Atopic Dermatitis in Early Childhood.
  33. A way to wipe a cell's memory.
  34. Tea Tree Essential Oil Kills Escherichia coli and Staphylococcus epidermidis Persisters.
  35. Mitochondrial PGAM5-Drp1 signaling regulates the metabolic reprogramming of macrophages and regulates the induction of inflammatory responses.
  36. The effect of Staphylococcus aureus on innate and adaptive immunity and potential immunotherapy for S. aureus-induced osteomyelitis.
  37. Dynamic atlas of immune cells reveals multiple functional features of macrophages associated with progression of pulmonary fibrosis.
  38. Bleach baths enhance skin barrier, reduce itch but do not normalize skin dysbiosis in atopic dermatitis.
  39. Lysosomal control of dendritic cell function.
  40. A simplified bacterial community found within the epidermis than at the epidermal surface of atopic dermatitis patients and healthy controls.
  41. SHIP1 and its role for innate immune regulation - novel targets for immunotherapy.
  42. Oral Microbiota: The Influences and Interactions of Saliva, IgA, and Dietary Factors in Health and Disease.
  43. Omentin-1 induces mechanically activated fibroblasts lipogenic differentiation through pkm2/yap/pparγ pathway to promote lung fibrosis resolution.
  44. Interplay of Chemokines Receptors, Toll-like Receptors, and Host Immunological Pathways.
  45. Bifidobacteria shape antimicrobial T-helper cell responses during infancy and adulthood.
  46. Small Heterodimer Partner Modulates Macrophage Differentiation during Innate Immune Response through the Regulation of Peroxisome Proliferator Activated Receptor Gamma, Mitogen-Activated Protein Kinase, and Nuclear Factor Kappa B Pathways.
  47. The role of the glycome in symbiotic host-microbe interactions.
  48. Pivotal role of tissue-resident memory lymphocytes in the control of mucosal infections: can mucosal vaccination induce protective tissue-resident memory T and B cells?
  49. Epithelial alarmins: a new target to treat chronic respiratory diseases.
  50. Systematic analysis of drug combinations against Gram-positive bacteria.
  51. Clinical rel mutations in Staphylococcus aureus prime pathogen expansion under nutrient stress.
  52. Metabolic signature for a dysbiotic microbiome in the female genital tract: A systematic review and meta-analysis.
  53. The Contribution of Antimicrobial Peptides to Immune Cell Function: A Review of Recent Advances.
  54. Gut microbiota-derived autoinducer-2 regulates lung inflammation through the gut-lung axis.
  55. OMIP-096: A 24-color flow cytometry panel to identify and characterize CD4+ and CD8+ tissue-resident T cells in human skin, intestinal, and type II mucosal tissue.
  56. BCG mediated protection of the lung against experimental SARS-CoV-2 infection.
  57. Metabolic inputs in the probiotic bacterium Lacticaseibacillus rhamnosus contribute to cell-wall remodeling and increased fitness.
  58. The Formation of Non-Specific Immunological Memory Phenotype in Human Monocyte-Like THP-1 and U-937 Cell Lines.
  59. Probiotics Modulate Host Immune Response and Interact with the Gut Microbiota: Shaping Their Composition and Mediating Antibiotic Resistance.
  60. Functional and structural analyses reveal that a dual domain sialidase protects bacteria from complement killing through desialylation of complement factors.
  61. A Review of the Epigenetic Clock: Emerging Biomarkers for Asthma and Allergic Disease.
  62. Beneficial Effects of Lactobacilli Species on Intestinal Homeostasis in Low-Grade Inflammation and Stress Rodent Models and Their Implication in the Modulation of the Adhesive Junctional Complex.
  63. Immune predisposition drives susceptibility to pneumococcal pneumonia after mild influenza A virus infection in mice.
  64. The World's First Acne Dysbiosis-like Model of Human 3D Ex Vivo Sebaceous Gland Colonized with Cutibacterium acnes and Staphylococcus epidermidis.
  65. Fucoxanthin Ameliorates Sepsis via Modulating Microbiota by Targeting IRF3 Activation.
  1. mBio. 2023 Sep 29. e0086323
    Antiviral epithelial-macrophage crosstalk permits secondary bacterial infections.
    Sidney Lane, Tristan L A White, Erin E Walsh, Richard T Cattley, Rachel Cumberland, William F Hawse, Greg M Delgoffe, Stephen F Badylak, Jennifer M Bomberger.
      Extracellular vesicles (EVs) are produced by most known cell types as a form of intercellular communication to influence the physiological function of neighboring cells. During respiratory viral-bacterial coinfection, the preceding antiviral response can lead to an impaired antibacterial response, driven by miscommunication between cells responding to viruses and cells responding to bacteria. Previous studies have shown that antiviral signaling can influence EV cargo and promote antiviral defense in the recipient cell; however, how antiviral EVs may influence host defense against coinfecting microorganisms, specifically bacteria, is not known. Herein, we demonstrated that EVs released from the respiratory epithelium during antiviral signaling alter macrophage inflammatory signaling, induce anti-inflammatory metabolic reprogramming, and impair antibacterial activity against Staphylococcus aureus, a common coinfecting bacterial pathogen. Further proteomic analysis revealed that antiviral EVs are preferentially loaded with pyruvate kinase M2 (PKM2), a metabolic enzyme with immunomodulatory effects, and treatment with antiviral EVs leads to increased PKM2 in macrophages. Moreover, we showed that antiviral EV-treated macrophages displayed enhanced oxidative phosphorylation, a metabolic profile consistent with impaired S. aureus clearance, and that this metabolic state is phenocopied in macrophages treated with a PKM2 activator. Taken together, our findings identify EVs as a component of the epithelial antiviral response that contributes to impaired bacterial clearance through epithelial-macrophage crosstalk and suggest a role for EVs in driving disease progression during respiratory coinfection. IMPORTANCE Miscommunication of antiviral and antibacterial immune signals drives worsened morbidity and mortality during respiratory viral-bacterial coinfections. Extracellular vesicles (EVs) are a form of intercellular communication with broad implications during infection, and here we show that epithelium-derived EVs released during the antiviral response impair the antibacterial activity of macrophages, an innate immune cell crucial for bacterial control in the airway. Macrophages exposed to antiviral EVs display reduced clearance of Staphylococcus aureus as well as altered inflammatory signaling and anti-inflammatory metabolic reprogramming, thus revealing EVs as a source of dysregulated epithelium-macrophage crosstalk during coinfection. As effective epithelium-macrophage communication is critical in mounting an appropriate immune response, this novel observation of epithelium-macrophage crosstalk shaping macrophage metabolism and antimicrobial function provides exciting new insight and improves our understanding of immune dysfunction during respiratory coinfections.
    Keywords:  antiviral signaling; extracellular vesicles; host-pathogen interactions; macrophage; respiratory epithelium
    DOI:  https://doi.org/10.1128/mbio.00863-23
  2. Int J Mol Sci. 2023 Sep 16. pii: 14173. [Epub ahead of print]24(18):
    New Insights in Immunometabolism in Neonatal Monocytes and Macrophages in Health and Disease.
    Renske de Jong, Klaus Tenbrock, Kim Ohl.
      It is well established that the neonatal immune system is different from the adult immune system. A major task of the neonatal immune system is to bridge the achievement of tolerance towards harmless antigens and commensal bacteria while providing protection against pathogens. This is highly important because neonates are immunologically challenged directly after birth by a rigorous change from a semi-allogeneic sterile environment into a world rich with microbes. A so called disease tolerogenic state is typical for neonates and is anticipated to prevent immunopathological damage potentially at the cost of uncontrolled pathogen proliferation. As a consequence, neonates are more susceptible than adults to life-threatening infections. At the basis of a well-functioning immune response, both for adults and neonates, innate immune cells such as monocytes and monocyte-derived macrophages play an essential role. A well-responsive monocyte will alter its cellular metabolism to subsequently induce certain immune effector function, a process which is called immunometabolism. Immunometabolism has received extensive attention in the last decade; however, it has not been broadly studied in neonates. This review focuses on carbohydrate metabolism in monocytes and macrophages in neonates. We will exhibit pathways involving glycolysis, the tricarboxylic acid (TCA) cycle and oxidative phosphorylation and their role in shaping neonates' immune systems to a favorable tolerogenic state. More insight into these pathways will elucidate potential treatments targets in life-threatening conditions including neonatal sepsis or expose potential targets which can be used to induce tolerance in conditions where tolerance is harmfully impaired such as in autoimmune diseases.
    Keywords:  bacterial; commensals; neonatal infection; neonatal tolerance
    DOI:  https://doi.org/10.3390/ijms241814173
  3. Pathogens. 2023 Sep 09. pii: 1148. [Epub ahead of print]12(9):
    Sputum from People with Cystic Fibrosis Reduces the Killing of Methicillin-Resistant Staphylococcus aureus by Neutrophils and Diminishes Phagosomal Production of Reactive Oxygen Species.
    Kayla M Fantone, Joanna B Goldberg, Arlene A Stecenko, Balázs Rada.
      Cystic fibrosis (CF) airway disease is characterized by chronic polymicrobial infections and an infiltration of neutrophils (PMNs). Staphylococcus aureus has been the most prevalent respiratory pathogen in CF. In particular, methicillin-resistant S. aureus (MRSA) represents a huge clinical burden in CF due to its association with lung disease and increased resistance to antibiotics. In CF, PMNs are unable to kill and clear MRSA. The reason for this remains largely unknown. Our study found that CF PMNs are as equally capable of killing MRSA as healthy PMNs. We show that the CF sputum, however, significantly impairs the ability of human PMNs to kill CF MRSA isolates. In the absence of CF sputum, PMNs kill MRSA via intracellular mechanisms mediated by phagocytosis, rather than extracellular mechanisms via NET formation. CF sputum does not affect the phagocytosis of MRSA via healthy or CF PMNs. Our results demonstrate that CF sputum exposure impairs phagosomal levels of reactive oxygen species (ROS) in MRSA-phagocytosing PMNs. While phagosomal co-localizations of MRSA with primary granule markers, myeloperoxidase and cathepsin D, were significantly reduced upon CF sputum exposure, that of a third azurophilic granule marker, neutrophil elastase, remained unaffected. This suggests that CF sputum does not compromise the fusion of primary granules with phagosomes but diminishes phagosomal ROS levels via another, likely more specific, mechanism. Overall, we identified the airway environment as an important factor that restricts neutrophils' oxidative microbicidal activities in CF against MRSA. These results deliver new details of the complex host-pathogen interactions present in the CF lung.
    Keywords:  MRSA; PMN; cystic fibrosis; phagocytosis; phagosome; respiratory burst; sputum
    DOI:  https://doi.org/10.3390/pathogens12091148
  4. J Autoimmun. 2023 Sep 23. pii: S0896-8411(23)00123-3. [Epub ahead of print] 103114
    The gut ecosystem and immune tolerance.
    Tihong Shao, Ronald Hsu, Desiree L Rafizadeh, Li Wang, Christopher L Bowlus, Narendra Kumar, Jayshree Mishra, Suraj Timilsina, William M Ridgway, M Eric Gershwin, Aftab A Ansari, Zongwen Shuai, Patrick S C Leung.
      The gastrointestinal tract is home to the largest microbial population in the human body. The gut microbiota plays significant roles in the development of the gut immune system and has a substantial impact on the maintenance of immune tolerance beginning in early life. These microbes interact with the immune system in a dynamic and interdependent manner. They generate immune signals by presenting a vast repertoire of antigenic determinants and microbial metabolites that influence the development, maturation and maintenance of immunological function and homeostasis. At the same time, both the innate and adaptive immune systems are involved in modulating a stable microbial ecosystem between the commensal and pathogenic microorganisms. Hence, the gut microbial population and the host immune system work together to maintain immune homeostasis synergistically. In susceptible hosts, disruption of such a harmonious state can greatly affect human health and lead to various auto-inflammatory and autoimmune disorders. In this review, we discuss our current understanding of the interactions between the gut microbiota and immunity with an emphasis on: a) important players of gut innate and adaptive immunity; b) the contribution of gut microbial metabolites; and c) the effect of disruption of innate and adaptive immunity as well as alteration of gut microbiome on the molecular mechanisms driving autoimmunity in various autoimmune diseases.
    Keywords:  Adaptive immunity; Autoimmune disease; Dysbiosis; Gut microbiota; Innate immunity; Microbial metabolites
    DOI:  https://doi.org/10.1016/j.jaut.2023.103114
  5. Front Immunol. 2023 ;14 1254150
    The gasdermins: a pore-forming protein family expressed in the epidermis.
    Marta Slaufova, Tugay Karakaya, Michela Di Filippo, Paulina Hennig, Hans-Dietmar Beer.
      Gasdermins comprise a family of pore-forming proteins, which play critical roles in (auto)inflammatory diseases and cancer. They are expressed as self-inhibited precursor proteins consisting of an aminoterminal cytotoxic effector domain (NT-GSDM) and a carboxyterminal inhibitor domain (GSDM-CT) separated by an unstructured linker region. Proteolytic processing in the linker region liberates NT-GSDM, which translocates to membranes, forms oligomers, and induces membrane permeabilization, which can disturb the cellular equilibrium that can lead to cell death. Gasdermin activation and pore formation are associated with inflammation, particularly when induced by the inflammatory protease caspase-1 upon inflammasome activation. These gasdermin pores allow the release of the pro-inflammatory cytokines interleukin(IL)-1β and IL-18 and induce a lytic type of cell death, termed pyroptosis that supports inflammation, immunity, and tissue repair. However, even at the cellular level, the consequences of gasdermin activation are diverse and range from induction of programmed cell death - pyroptosis or apoptosis - to poorly characterized protective mechanisms. The specific effects of gasdermin activation can vary between species, cell types, the membrane that is being permeabilized (plasma membrane, mitochondrial membrane, etc.), and the overall biological state of the local tissue/cells. In epithelia, gasdermins seem to play crucial roles. Keratinocytes represent the main cell type of the epidermis, which is the outermost skin layer with an essential barrier function. Compared to other tissues, keratinocytes express all members of the gasdermin family, in part in a differentiation-specific manner. That raises questions regarding the specific roles of individual GSDM family members in the skin, the mechanisms and consequences of their activation, and the potential crosstalk between them. In this review, we summarize the current knowledge about gasdermins with a focus on keratinocytes and the skin and discuss the possible roles of the different family members in immunity and disease.
    Keywords:  gasdermin (GSDM); inflammasome; interleukin - 1; pyroptosis; skin
    DOI:  https://doi.org/10.3389/fimmu.2023.1254150
  6. Immun Inflamm Dis. 2023 Sep;11(9): e997
    Interaction among inflammasome, PANoptosise, and innate immune cells in infection of influenza virus: Updated review.
    Li Wei, Xufang Wang, Huifei Zhou.
       BACKGROUND: Influenza virus (IV) is a leading cause of respiratory tract infections, eliciting responses from key innate immune cells such as Macrophages (MQs), Neutrophils, and Dendritic Cells (DCs). These cells employ diverse mechanisms to combat IV, with Inflammasomes playing a pivotal role in viral infection control. Cellular death mechanisms, including Pyroptosis, Apoptosis, and Necroptosis (collectively called PANoptosis), significantly contribute to the innate immune response.
    METHODS: In this updated review, we delve into the intricate relationship between PANoptosis and Inflammasomes within innate immune cells (MQs, Neutrophils, and DCs) during IV infections. We explore the strategies employed by IV to evade these immune defenses and the consequences of unchecked PANoptosis and inflammasome activation, including the potential development of severe complications such as cytokine storms and tissue damage.
    RESULTS: Our analysis underscores the interplay between PANoptosis and Inflammasomes as a critical aspect of the innate immune response against IV. We provide insights into IV's various mechanisms to subvert these immune pathways and highlight the importance of understanding these interactions to develop effective antiviral medications.
    CONCLUSION: A comprehensive understanding of the dynamic interactions between PANoptosis, Inflammasomes, and IV is essential for advancing our knowledge of innate immune responses to viral infections. This knowledge will be invaluable in developing targeted antiviral therapies to combat IV and mitigate potential complications, including cytokine storms and tissue damage.
    Keywords:  PANoptosis; inflammasome; influenza; innate immunity
    DOI:  https://doi.org/10.1002/iid3.997
  7. Microbiol Spectr. 2023 Sep 29. e0220123
    Transcriptional profiling and genetic analysis of a cystic fibrosis airway-relevant model shows asymmetric responses to growth in a polymicrobial community.
    Christopher A Kesthely, Rendi R Rogers, Bassam El Hafi, Fabrice Jean-Pierre, George A O'Toole.
      Bacterial infections in the lungs of persons with cystic fibrosis are typically composed of multispecies biofilm-like communities, which modulate clinically relevant phenotypes that cannot be explained in the context of a single species culture. Most analyses to date provide a picture of the transcriptional responses of individual pathogens; however, there is relatively little data describing the transcriptional landscape of clinically relevant multispecies communities. Harnessing a previously described cystic fibrosis-relevant, polymicrobial community model consisting of Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus sanguinis, and Prevotella melaninogenica, we performed an RNA-Seq analysis on the biofilm population to elucidate the transcriptional profiles of the community grown in artificial sputum medium (ASM) as compared to growth in monoculture, without mucin, and in fresh medium supplemented with tobramycin. We provide evidence that, although the transcriptional profile of P. aeruginosa is community agnostic, the transcriptomes of S. aureus and S. sanguinis are community aware. Furthermore, P. aeruginosa and P. melaninogenica are transcriptionally sensitive to the presence of mucin in ASM, whereas S. aureus and S. sanguinis largely do not alter their transcriptional profiles in the presence of mucin when grown in a community. Only P. aeruginosa shows a robust response to tobramycin. Genetic studies of mutants altered in community-specific growth provide complementary data regarding how these microbes adapt to a community context. IMPORTANCE Polymicrobial infections constitute the majority of infections in the cystic fibrosis (CF) airway, but their study has largely been neglected in a laboratory setting. Our lab previously reported a polymicrobial community that can help explain clinical outcomes in the lungs of persons with CF. Here, we obtained transcriptional profiles of the community versus monocultures to provide transcriptional information about how this model community responds to CF-related growth conditions and perturbations. Genetic studies provide complementary functional outputs to assess how the microbes adapt to life in a community.
    Keywords:  Prevotella; Pseudomonas; Staphylococcus; Streptococcus; community; cystic fibrosis; mutants; transcription
    DOI:  https://doi.org/10.1128/spectrum.02201-23
  8. Int J Mol Sci. 2023 Sep 20. pii: 14322. [Epub ahead of print]24(18):
    The Interaction between the Host Genome, Epigenome, and the Gut-Skin Axis Microbiome in Atopic Dermatitis.
    Rodrigo Pessôa, Patricia Bianca Clissa, Sabri Saeed Sanabani.
      Atopic dermatitis (AD) is a chronic inflammatory skin disease that occurs in genetically predisposed individuals. It involves complex interactions among the host immune system, environmental factors (such as skin barrier dysfunction), and microbial dysbiosis. Genome-wide association studies (GWAS) have identified AD risk alleles; however, the associated environmental factors remain largely unknown. Recent evidence suggests that altered microbiota composition (dysbiosis) in the skin and gut may contribute to the pathogenesis of AD. Examples of environmental factors that contribute to skin barrier dysfunction and microbial dysbiosis in AD include allergens, irritants, pollution, and microbial exposure. Studies have reported alterations in the gut microbiome structure in patients with AD compared to control subjects, characterized by increased abundance of Clostridium difficile and decreased abundance of short-chain fatty acid (SCFA)-producing bacteria such as Bifidobacterium. SCFAs play a critical role in maintaining host health, and reduced SCFA production may lead to intestinal inflammation in AD patients. The specific mechanisms through which dysbiotic bacteria and their metabolites interact with the host genome and epigenome to cause autoimmunity in AD are still unknown. By understanding the combination of environmental factors, such as gut microbiota, the genetic and epigenetic determinants that are associated with the development of autoantibodies may help unravel the pathophysiology of the disease. This review aims to elucidate the interactions between the immune system, susceptibility genes, epigenetic factors, and the gut microbiome in the development of AD.
    Keywords:  epigenetics; genetics; immuno-regulation; intestinal permeability; microbial dysbiosis; short-chain fatty acid; single nucleotide polymorphism; virome
    DOI:  https://doi.org/10.3390/ijms241814322
  9. Lung. 2023 Sep 26.
    Lung Microbiome as a Treatable Trait in Chronic Respiratory Disorders.
    Filippo Scialò, Maria Vitale, Vito D'Agnano, Domenica Francesca Mariniello, Fabio Perrotta, Alice Castaldo, Susan F M Campbell, Lucio Pastore, Mario Cazzola, Andrea Bianco.
      Once thought to be a sterile environment, it is now established that lungs are populated by various microorganisms that participate in maintaining lung function and play an important role in shaping lung immune surveillance. Although our comprehension of the molecular and metabolic interactions between microbes and lung cells is still in its infancy, any event causing a persistent qualitative or quantitative variation in the composition of lung microbiome, termed "dysbiosis", has been virtually associated with many respiratory diseases. A deep understanding of the composition and function of the "healthy" lung microbiota and how dysbiosis can cause or participate in disease progression will be pivotal in finding specific therapies aimed at preventing diseases and restoring lung function. Here, we review lung microbiome dysbiosis in different lung pathologies and the mechanisms by which these bacteria can cause or contribute to the severity of the disease. Furthermore, we describe how different respiratory disorders can be caused by the same pathogen, and that the real pathogenetic mechanism is not only dependent by the presence and amount of the main pathogen but can be shaped by the interaction it can build with other bacteria, fungi, and viruses present in the lung. Understanding the nature of this bacteria crosstalk could further our understanding of each respiratory disease leading to the development of new therapeutic strategies.
    Keywords:  Lung microbiome; Microbiome; Pathological mechanisms; Respiratory disorders
    DOI:  https://doi.org/10.1007/s00408-023-00645-3
  10. Front Immunol. 2023 ;14 1151422
    Cystic fibrosis autoantibody signatures associate with Staphylococcus aureus lung infection or cystic fibrosis-related diabetes.
    Ruchi Yadav, Quan-Zhen Li, Hanwen Huang, S Louis Bridges, J Michelle Kahlenberg, Arlene A Stecenko, Balázs Rada.
       Introduction: While cystic fibrosis (CF) lung disease is characterized by persistent inflammation and infections and chronic inflammatory diseases are often accompanied by autoimmunity, autoimmune reactivity in CF has not been studied in depth.
    Methods: In this work we undertook an unbiased approach to explore the systemic autoantibody repertoire in CF using autoantibody microarrays.
    Results and discussion: Our results show higher levels of several new autoantibodies in the blood of people with CF (PwCF) compared to control subjects. Some of these are IgA autoantibodies targeting neutrophil components or autoantigens linked to neutrophil-mediated tissue damage in CF. We also found that people with CF with higher systemic IgM autoantibody levels have lower prevalence of S. aureus infection. On the other hand, IgM autoantibody levels in S. aureus-infected PwCF correlate with lung disease severity. Diabetic PwCF have significantly higher levels of IgA autoantibodies in their circulation compared to nondiabetic PwCF and several of their IgM autoantibodies associate with worse lung disease. In contrast, in nondiabetic PwCF blood levels of IgA autoantibodies correlate with lung disease. We have also identified other autoantibodies in CF that associate with P. aeruginosa airway infection. In summary, we have identified several new autoantibodies and associations of autoantibody signatures with specific clinical features in CF.
    Keywords:  CF-related diabetes; CFRD; Staphylococcus aureus; autoantibody signature; autoimmunity; cystic fibrosis
    DOI:  https://doi.org/10.3389/fimmu.2023.1151422
  11. Cell Rep Methods. 2023 Sep 25. pii: S2667-2375(23)00220-5. [Epub ahead of print]3(9): 100576
    A computational method to dissect colonization resistance of the gut microbiota against pathogens.
    Shanlin Ke, Yandong Xiao, Scott T Weiss, Xinhua Chen, Ciarán P Kelly, Yang-Yu Liu.
      The mammalian gut microbiome protects the host through colonization resistance (CR) against the incursion of exogenous and often harmful microorganisms, but identifying the exact microbes responsible for the gut microbiota-mediated CR against a particular pathogen remains a challenge. To address this limitation, we developed a computational method: generalized microbe-phenotype triangulation (GMPT). We first systematically validated GMPT using a classical population dynamics model in community ecology and demonstrated its superiority over baseline methods. We then tested GMPT on simulated data generated from the ecological network inferred from a real community (GnotoComplex microflora) and real microbiome data on two mouse studies on Clostridioides difficile infection. We demonstrated GMPT's ability to streamline the discovery of microbes that are potentially responsible for microbiota-mediated CR against pathogens. GMPT holds promise to advance our understanding of CR mechanisms and facilitate the rational design of microbiome-based therapies for preventing and treating enteric infections.
    Keywords:  CP: Microbiology; CP: Systems biology; causal inference; colonization resistance; gut microbiota; infectious diseases
    DOI:  https://doi.org/10.1016/j.crmeth.2023.100576
  12. Int J Mol Sci. 2023 Sep 12. pii: 13990. [Epub ahead of print]24(18):
    Latest Review Papers in Molecular Microbiology.
    Andreas Burkovski.
      This Special Issue-dedicated to high-quality review papers in molecular microbiology-is highlighting two important developments in the field: (i) the analysis of microbiome data in health and disease and (ii) the search for strategies against bacteria showing antimicrobial resistance [...].
    DOI:  https://doi.org/10.3390/ijms241813990
  13. Inflammation. 2023 Sep 23.
    MDA5 Enhances Invasive Candida albicans Infection by Regulating Macrophage Apoptosis and Phagocytosis/Killing Functions.
    Yayun Chen, Qian Jiang, Furong Qing, Junxia Xue, Qiuxiang Xiao, Wenji He, Lina Sui, Zhiping Liu.
      Candida albicans is a common opportunistic pathogenic fungus. The innate immune system provides the first-line host defense against fungal infection. Innate immune receptors and downstream molecules have been shown to play various roles during fungal infection. The innate immune receptor MDA5, encoded by the gene Ifih1, enhances host resistance against viral and Aspergillus fumigatus infection by inducing the production of interferons (IFNs). However, the role of MDA5 in C. albicans infection is still unclear. Here, we found that the gene expression levels of IFIH1 were significantly increased in innate immune cells after C. albicans stimulation through human bioinformatics analysis or mouse experiments. Through in vivo study, MDA5 was shown to enhance host susceptibility to C. albicans infection independent of IFN production. Instead, MDA5 exerted its influence on macrophages and kidneys by modulating the expression of Noxa, Bcl2, and Bax, thereby promoting apoptosis. Additionally, MDA5 compromised killing capabilities of macrophage by inhibition iNOS expression. The introduction of the apoptosis inducer PAC1 further impaired macrophage functions, mimicking the enhancing effect of MDA5 on C. albicans infection. Furthermore, the administration of macrophage scavengers increased the susceptibility of Ifih1-/- mice to C. albicans. The founding suggests that MDA5 promote host susceptibility to invasive C. albicans by enhancing cell apoptosis and compromising macrophage functions, making MDA5 a target to treat candidiasis.
    Keywords:  Apoptosis; Candida albicans; MDA5; Macrophage
    DOI:  https://doi.org/10.1007/s10753-023-01903-5
  14. Exp Dermatol. 2023 Sep 28.
    Recent advances in understanding the role of the skin microbiome in the treatment of atopic dermatitis.
    Kyunghee Kim, Hyeji Jang, Eunyul Kim, Hyeju Kim, Gun Yong Sung.
      The skin is the largest organ in the human body, and histologically consists of the epidermis, dermis and subcutaneous tissue. Humans maintain a cooperative symbiotic relationship with their skin microbiota, a complex community of bacteria, fungi and viruses that live on the surface of the skin, and which act as a barrier to protect the body from the inside and outside. The skin is a 'habitat' and vast 'ecosystem' inhabited by countless microbes; as such, relationships have been forged through millions of years of coevolution. It is not surprising then that microbes are key participants in shaping and maintaining essential physiological processes. In addition to maintaining barrier function, the unique symbiotic microbiota that colonizes the skin increases the immune response and provides protection against pathogenic microbes. This review examines our current understanding of skin microbes in shaping and enhancing the skin barrier, as well as skin microbiome-host interactions and their roles in skin diseases, such as atopic dermatitis (AD). We also report on the current status of AD therapeutic drugs that target the skin microbiome, related research on current therapeutic strategies, and the limitations and future considerations of skin microbiome research. In particular, as a future strategy, we discuss the need for a skin-on-a-chip-based microphysiological system research model amenable to biomimetic in vitro studies and human skin equivalent models, including skin appendages.
    Keywords:  atopic dermatitis; hair follicle on-a-chip; microphysiological system; skin microbiome
    DOI:  https://doi.org/10.1111/exd.14940
  15. Enzymes. 2023 ;pii: S1874-6047(23)00006-9. [Epub ahead of print]53 33-68
    Coordination of cross-talk between metabolism and epigenetic regulation by the SIN3 complex.
    Imad Soukar, Anjalie Amarasinghe, Lori A Pile.
      Post-translational modifications of histone proteins control the expression of genes. Metabolites from central and one-carbon metabolism act as donor moieties to modify histones and regulate gene expression. Thus, histone modification and gene regulation are connected to the metabolite status of the cell. Histone modifiers, such as the SIN3 complex, regulate genes involved in proliferation and metabolism. The SIN3 complex contains a histone deacetylase and a histone demethylase, which regulate the chromatin landscape and gene expression. In this chapter, we review the cross-talk between metabolic pathways that produce donor moieties, and epigenetic complexes regulating proliferation and metabolic genes. This cross-talk between gene regulation and metabolism is tightly controlled, and disruption of this cross-talk leads to metabolic diseases. We discuss promising therapeutics that directly regulate histone modifiers, and can affect the metabolic status of the cell, alleviating some metabolic diseases.
    Keywords:  Diabetes; Epigenetics; Histone deacetylase; Histone demethylase; Metabolism; SIN3; Therapeutics; Transcription
    DOI:  https://doi.org/10.1016/bs.enz.2023.06.001
  16. Viruses. 2023 Sep 13. pii: 1916. [Epub ahead of print]15(9):
    Protective versus Pathogenic Type I Interferon Responses during Virus Infections.
    Kwang Il Jung, Savannah McKenna, Vijayamahantesh Vijayamahantesh, Ying He, Bumsuk Hahm.
      Following virus infections, type I interferons are synthesized to induce the expression of antiviral molecules and interfere with virus replication. The importance of early antiviral type I IFN response against virus invasion has been emphasized during COVID-19 as well as in studies on the microbiome. Further, type I IFNs can directly act on various immune cells to enhance protective host immune responses to viral infections. However, accumulating data indicate that IFN responses can be harmful to the host by instigating inflammatory responses or inducing T cell suppression during virus infections. Also, inhibition of lymphocyte and dendritic cell development can be caused by type I IFN, which is independent of the traditional signal transducer and activator of transcription 1 signaling. Additionally, IFNs were shown to impair airway epithelial cell proliferation, which may affect late-stage lung tissue recovery from the infection. As such, type I IFN-virus interaction research is diverse, including host antiviral innate immune mechanisms in cells, viral strategies of IFN evasion, protective immunity, excessive inflammation, immune suppression, and regulation of tissue repair. In this report, these IFN activities are summarized with an emphasis placed on the functions of type I IFNs recently observed during acute or chronic virus infections.
    Keywords:  host defense; immune stimulation; immune suppression; interferon
    DOI:  https://doi.org/10.3390/v15091916
  17. Clin Immunol. 2023 Sep 22. pii: S1521-6616(23)00539-9. [Epub ahead of print] 109776
    Potential impact of trained innate immunity on the pathophysiology of metabolic dysfunction-associated fatty liver disease.
    Jannis Kountouras, Evangelos Kazakos, Stergios A Polyzos, Apostolis Papaefthymiou, Christos Zavos, Maria Tzitiridou-Chatzopoulou, Dimitrios Chatzopoulos, Elisabeth Vardaka, Anthia Gatopoulou, Foteini Kyrailidi, Maria C Mouratidou, Michael Doulberis.
      Metabolic dysfunction-associated fatty liver disease (MAFLD) occurs in a low-grade inflammatory milieu dependent on highly complex networks that span well-beyond the hepatic tissue injury. Dysfunctional systemic metabolism that characterizes the disease, is further induced in response to environmental cues that modify energy and metabolic cellular demands, thereby altering the availability of specific substrates that profoundly regulate, through epigenetic mechanisms, the phenotypic heterogeneity of immune cells and influence hematopoietic stem cell differentiation fate. This immuno-metabolic signaling drives the initiation of downstream effector pathways and results in the decompensation of hepatic homeostasis that precedes pro-fibrotic events. Recent evidence suggests that innate immune cells reside in different tissues in a memory effector state, a phenomenon termed trained immunity, that may be activated by subsequent exogenous (e.g., microbial, dietary) or endogenous (e.g., metabolic, apoptotic) stimuli. This process leads to long-term modifications in the epigenetic landscape that ultimately precondition the cells towards enhanced transcription of inflammatory mediators that accelerates MAFLD development and/or progression. In this mini review we aimed to present current evidence on the potential impact of trained immunity on the pathophysiology of MAFLD, shedding light on the complex immunobiology of the disease and providing novel potential therapeutic strategies to restrain the burden of the disease.
    Keywords:  Autoimmune disorders; Epigenetic reprogramming; Metabolic dysfunction-associated fatty liver disease; Metabolic rewiring; Trained immunity
    DOI:  https://doi.org/10.1016/j.clim.2023.109776
  18. Biology (Basel). 2023 Aug 30. pii: 1187. [Epub ahead of print]12(9):
    Biodiversity of Skin Microbiota as an Important Biomarker for Wound Healing.
    Caglar Ersanli, Athina Tzora, Chrysoula Chrysa Voidarou, Stylianos Skoufos, Dimitrios I Zeugolis, Ioannis Skoufos.
      Cutaneous wound healing is a natural and complex repair process that is implicated within four stages. However, microorganisms (e.g., bacteria) can easily penetrate through the skin tissue from the wound bed, which may lead to disbalance in the skin microbiota. Although commensal and pathogenic bacteria are in equilibrium in normal skin, their imbalance in the wound area can cause the delay or impairment of cutaneous wounds. Moreover, skin microbiota is in constant crosstalk with the immune system and epithelial cells, which has significance for the healing of a wound. Therefore, understanding the major bacteria species in the cutaneous wound as well as their communication with the immune system has gained prominence in a way that allows for the emergence of a new perspective for wound healing. In this review, the major bacteria isolated from skin wounds, the role of the crosstalk between the cutaneous microbiome and immune system to heal wounds, the identification techniques of these bacteria populations, and the applied therapies to manipulate the skin microbiota are investigated.
    Keywords:  Lactobacilli; P. aeruginosa; S. aureus; coagulase-negative S. aureus; manipulation strategies; skin microbiota; wound healing
    DOI:  https://doi.org/10.3390/biology12091187
  19. Front Immunol. 2023 ;14 1241934
    The mechanisms and factors that induce trained immunity in arthropods and mollusks.
    Mingming Zhao, Zhongyang Lin, Zhihong Zheng, Defu Yao, Shen Yang, Yongzhen Zhao, Xiuli Chen, Jude Juventus Aweya, Yueling Zhang.
      Besides dividing the organism's immune system into adaptive and innate immunity, it has long been thought that only adaptive immunity can establish immune memory. However, many studies have shown that innate immunity can also build immunological memory through epigenetic reprogramming and modifications to resist pathogens' reinfection, known as trained immunity. This paper reviews the role of mitochondrial metabolism and epigenetic modifications and describes the molecular foundation in the trained immunity of arthropods and mollusks. Mitochondrial metabolism and epigenetic modifications complement each other and play a key role in trained immunity.
    Keywords:  arthropods; epigenetic modifications; metabolism; mollusks; trained immunity
    DOI:  https://doi.org/10.3389/fimmu.2023.1241934
  20. mBio. 2023 Sep 27. e0134223
    Molecular commensalism-how to investigate underappreciated health-associated polymicrobial communities.
    Alex Labossiere, Matthew Ramsey, Justin Merritt, Jens Kreth.
      The study of human commensal bacteria began with the first observation of prokaryotes >340 years ago. Since then, the study of human-associated microbes has been justifiably biased toward the study of infectious pathogens. However, the role of commensal microbes has in recent years begun to be understood with some appreciation of them as potential protectors of host health rather than bystanders. As our understanding of these valuable microbes grows, it highlights how much more remains to be learned about them and their roles in maintaining health. We note here that a thorough framework for the study of commensals, both in vivo and in vitro is overall lacking compared to well-developed methodologies for pathogens. The modification and application of methods for the study of pathogens can work well for the study of commensals but is not alone sufficient to properly characterize their relationships. This is because commensals live in homeostasis with the host and within complex communities. One difficulty is determining which commensals have a quantifiable impact on community structure and stability as well as host health, vs benign microbes that may indeed serve only as bystanders. Human microbiomes are composed of bacteria, archaea, fungi, and viruses. This review focuses particularly on oral bacteria, yet many of the principles of commensal impacts on host health observed in the mouth can translate well to other host sites. Here, we discuss the value of commensals, the shortcomings involved in model systems for their study, and some of the more notable impacts they have upon not only each other but host health.
    Keywords:  biofilm; commensals; health; microbiome; oral microbiology; polymicrobial
    DOI:  https://doi.org/10.1128/mbio.01342-23
  21. Front Microbiol. 2023 ;14 1236601
    Impact of breastfeeding and other early-life factors on the development of the oral microbiome.
    Roaa A Arishi, Ching T Lai, Donna T Geddes, Lisa F Stinson.
      The oral cavity is home to the second most diverse microbiome in the human body. This community contributes to both oral and systemic health. Acquisition and development of the oral microbiome is a dynamic process that occurs over early life; however, data regarding longitudinal assembly of the infant oral microbiome is scarce. While numerous factors have been associated with the composition of the infant oral microbiome, early feeding practices (breastfeeding and the introduction of solids) appear to be the strongest determinants of the infant oral microbiome. In the present review, we draw together data on the maternal, infant, and environmental factors linked to the composition of the infant oral microbiome, with a focus on early nutrition. Given evidence that breastfeeding powerfully shapes the infant oral microbiome, the review explores potential mechanisms through which human milk components, including microbes, metabolites, oligosaccharides, and antimicrobial proteins, may interact with and shape the infant oral microbiome. Infancy is a unique period for the oral microbiome. By enhancing our understanding of oral microbiome assembly in early life, we may better support both oral and systemic health throughout the lifespan.
    Keywords:  HMOs; breastfeeding; infant diet; lactoferrin; lysozyme; oral microbiome; sIgA
    DOI:  https://doi.org/10.3389/fmicb.2023.1236601
  22. Bio Protoc. 2023 Sep 20. 13(18): e4818
    Differentiation of Bone Marrow Monocytes into Alveolar Macrophages-like Cells through Co-culture with Lung Epithelial Cells and Group 2 Innate Lymphoid Cells.
    Pauline Loos, Thomas Marichal, Bénédicte Machiels, Laurent Gillet.
      During life, the embryonic alveolar macrophage (AM) population undergoes successive waves of depletion and replenishment in response to infectious and inflammatory episodes. While resident AMs are traditionally described as from embryonic origin, their ontogeny following inflammation or infection is much more complex. Indeed, it appears that the contribution of monocytes (MOs) to the AM pool is variable and depends on the type of inflammation, its severity, and the signals released in the microenvironment of the pulmonary niche (peripheral imprinting) and/or in the bone marrow (central imprinting). Deciphering the cellular and molecular mechanisms regulating the differentiation of MOs into AMs remains an area of intense investigation, as this could potentially explain part of the inter-individual susceptibility to respiratory immunopathologies. Here, we detail a relevant ex vivo co-culture model to investigate how lung epithelial cells (ECs) and group 2 lung innate lymphoid cells (ILC2s) contribute to the differentiation of recruited MOs into AMs. Interestingly, the presence of lung ILC2s and ECs provides the necessary niche signals to ensure the differentiation of bone marrow MOs into AMs, thus establishing an accessible model to study the underlying mechanisms following different infection or inflammation processes. Key features • Ex vivo co-culture model of the alveolar niche. • Deciphering the particular niche signals underlying the differentiation of MO into AMs and their functional polarization.
    Keywords:  Alveolar Niche; Alveolar macrophages; Co-culture; Group 2 innate lymphoid cells; Monocytes; Monocytes differentiation and polarization
    DOI:  https://doi.org/10.21769/BioProtoc.4818
  23. Sci Rep. 2023 Sep 29. 13(1): 16393
    Skin microbiota secretomes modulate cutaneous innate immunity against Borrelia burgdorferi s.s.
    F Baquer, B Jaulhac, C Barthel, M Paz, J Wolfgramm, A Müller, N Boulanger, A Grillon.
      In Lyme borreliosis, the skin constitutes a major interface for the host, the bacteria and the tick. Skin immunity is provided by specialized immune cells but also by the resident cells: the keratinocytes and the fibroblasts. Discoveries on the role of the microbiome in the modulation of skin inflammation and immunity have reinforced the potential importance of the skin in vector-borne diseases. In this study, we analyzed in vitro the interaction of human primary keratinocytes and fibroblasts with Borrelia burgdorferi sensu stricto N40 in presence or absence of bacterial commensal supernatants. We aimed to highlight the role of resident skin cells and skin microbiome on the inflammation induced by B. burgdorferi s.s.. The secretomes of Staphylococcus epidermidis, Corynebacterium striatum and Cutibacterium acnes showed an overall increase in the expression of IL-8, CXCL1, MCP-1 and SOD-2 by fibroblasts, and of IL-8, CXCL1, MCP-1 and hBD-2 in the undifferentiated keratinocytes. Commensal bacteria showed a repressive effect on the expression of IL-8, CXCL1 and MCP-1 by differentiated keratinocytes. Besides the inflammatory effect observed in the presence of Borrelia on all cell types, the cutaneous microbiome appears to promote a rapid innate response of resident skin cells during the onset of Borrelia infection.
    DOI:  https://doi.org/10.1038/s41598-023-43566-0
  24. Infect Immun. 2023 Sep 27. e0020123
    Mycobacterium tuberculosis infection drives differential responses in the bone marrow hematopoietic stem and progenitor cells.
    Suhas Bobba, Nicole C Howard, Shibali Das, Mushtaq Ahmed, Nargis Khan, Ignacio Marchante, Luis B Barreiro, Joaquin Sanz, Maziar Divangahi, Shabaana A Khader.
      Hematopoietic stem and progenitor cells (HSPCs) play a vital role in the host response to infection through the rapid and robust production of mature immune cells. These HSPC responses can be influenced, directly and indirectly, by pathogens as well. Infection with Mycobacterium tuberculosis (Mtb) can drive lymphopoiesis through modulation of type I interferon (IFN) signaling. We have previously found that the presence of a drug resistance (DR)-conferring mutation in Mtb drives altered host-pathogen interactions and heightened type I IFN production in vitro. But the impacts of this DR mutation on in vivo host responses to Mtb infection, particularly the hematopoietic compartment, remain unexplored. Using a mouse model, we show that, while drug-sensitive Mtb infection induces expansion of HSPC subsets and a skew toward lymphopoiesis, DR Mtb infection fails to induce an expansion of these subsets and an accumulation of mature granulocytes in the bone marrow. Using single-cell RNA sequencing, we show that the HSCs from DR Mtb-infected mice fail to upregulate pathways related to cytokine signaling across all profiled HSC subsets. Collectively, our studies report a novel finding of a chronic infection that fails to induce a potent hematopoietic response that can be further investigated to understand pathogen-host interaction at the level of hematopoiesis.
    Keywords:  Mycobacterium tuberculosis; hematopoiesis; infectious disease; stem cells
    DOI:  https://doi.org/10.1128/iai.00201-23
  25. Elife. 2023 Sep 29. pii: e87392. [Epub ahead of print]12
    The chemorepellent, SLIT2, bolsters innate immunity against Staphylococcus aureus.
    Vikrant K Bhosle, Chunxiang Sun, Sajedabanu Patel, Tse Wing Winnie Ho, Johannes Westman, Dustin A Ammendolia, Fatemeh Mirshafiei Langari, Noah Fine, Nicole Toepfner, Zhubing Li, Manraj Sharma, Judah Glogauer, Mariana I Capurro, Nicola L Jones, Jason T Maynes, Warren L Lee, Michael Glogauer, Sergio Grinstein, Lisa A Robinson.
      Neutrophils are essential for host defense against Staphylococcus aureus (S. aureus). The neuro-repellent, SLIT2, potently inhibits neutrophil chemotaxis, and might, therefore, be expected to impair antibacterial responses. We report here that, unexpectedly, neutrophils exposed to the N-terminal SLIT2 (N-SLIT2) fragment kill extracellular S. aureus more efficiently. N-SLIT2 amplifies reactive oxygen species production in response to the bacteria by activating p38 mitogen-activated protein kinase that in turn phosphorylates NCF1, an essential subunit of the NADPH oxidase complex. N-SLIT2 also enhances the exocytosis of neutrophil secondary granules. In a murine model of S. aureus skin and soft tissue infection (SSTI), local SLIT2 levels fall initially but increase subsequently, peaking at 3 days after infection. Of note, the neutralization of endogenous SLIT2 worsens SSTI. Temporal fluctuations in local SLIT2 levels may promote neutrophil recruitment and retention at the infection site and hasten bacterial clearance by augmenting neutrophil oxidative burst and degranulation. Collectively, these actions of SLIT2 coordinate innate immune responses to limit susceptibility to S. aureus.
    Keywords:  LL-37; ROBO1; SLIT2; cell biology; human; infectious disease; microbiology; mouse; neutrophils; p38 MAPK; staphylococcus
    DOI:  https://doi.org/10.7554/eLife.87392
  26. Int J Mol Sci. 2023 Sep 18. pii: 14229. [Epub ahead of print]24(18):
    Unraveling the Role of Epithelial Cells in the Development of Chronic Rhinosinusitis.
    Jong-Gyun Ha, Hyung-Ju Cho.
      The pathophysiology of CRS is multifactorial and complex yet needs to be completed. Recent evidence emphasizes the crucial part played by epithelial cells in the development of CRS. The epithelial cells act as physical barriers and play crucial roles in host defense, including initiating and shaping innate and adaptive immune responses. This review aims to present a comprehensive understanding of the significance of nasal epithelial cells in CRS. New research suggests that epithelial dysfunction plays a role in developing CRS through multiple mechanisms. This refers to issues with a weakened barrier function, disrupted mucociliary clearance, and irregular immune responses. When the epithelial barrier is compromised, it can lead to the passage of pathogens and allergens, triggering inflammation in the body. Furthermore, impaired mucociliary clearance can accumulate pathogens and secretions of inflammatory mediators, promoting chronic inflammation. Epithelial cells can release cytokines and chemokines, which attract and activate immune cells. This can result in an imbalanced immune response that continues to cause inflammation. The interaction between nasal epithelial cells and various immune cells leads to the production of cytokines and chemokines, which can either increase or decrease inflammation. By comprehending the role of epithelial cells in CRS, we can enhance our understanding of the disease's pathogenesis and explore new therapeutics.
    Keywords:  epithelial cell; immune; interaction; nasal; nasal polyp; rhinosinusitis
    DOI:  https://doi.org/10.3390/ijms241814229
  27. bioRxiv. 2023 Sep 13. pii: 2023.09.12.556572. [Epub ahead of print]
    Plasma membrane abundance dictates phagocytic capacity and functional crosstalk in myeloid cells.
    Benjamin Y Winer, Alexander H Settle, Alexandrina M Yakimov, Carlos Jeronimo, Tomi Lazarov, Murray Tipping, Michelle Saoi, Anjelique Sawh, Anna-Liisa L Sepp, Michael Galiano, Yung Yu Wong, Justin S A Perry, Frederic Geissmann, Justin Cross, Ting Zhou, Lance C Kam, Hilda Amalia Pasoli, Tobias Hohl, Jason G Cyster, Orion D Weiner, Morgan Huse.
      Professional phagocytes like neutrophils and macrophages tightly control what they eat, how much they eat, and when they move after eating. We show that plasma membrane abundance is a key arbiter of these cellular behaviors. Neutrophils and macrophages lacking the G-protein subunit Gβ4 exhibit profound plasma membrane expansion due to enhanced production of sphingolipids. This increased membrane allocation dramatically enhances phagocytosis of bacteria, fungus, apoptotic corpses, and cancer cells. Gβ4 deficient neutrophils are also defective in the normal inhibition of migration following cargo uptake. In Gβ4 knockout mice, myeloid cells exhibit enhanced phagocytosis of inhaled fungal conidia in the lung but also increased trafficking of engulfed pathogens to other organs. These results reveal an unexpected, biophysical control mechanism lying at the heart of myeloid functional decision-making.
    DOI:  https://doi.org/10.1101/2023.09.12.556572
  28. PLoS Pathog. 2023 Sep 29. 19(9): e1011686
    SifA SUMOylation governs Salmonella Typhimurium intracellular survival via modulation of lysosomal function.
    Hridya Chandrasekhar, Gayatree Mohapatra, Kirti Kajal, Mukesh Singh, Kshitiz Walia, Sarika Rana, Navneet Kaur, Sheetal Sharma, Amit Tuli, Prasenjit Das, Chittur V Srikanth.
      One of the mechanisms shaping the pathophysiology during the infection of enteric pathogen Salmonella Typhimurium is host PTM machinery utilization by the pathogen encoded effectors. Salmonella Typhimurium (S. Tm) during infection in host cells thrives in a vacuolated compartment, Salmonella containing vacuole (SCV), which sequentially acquires host endosomal and lysosomal markers. Long tubular structures, called as Salmonella induced filaments (SIFs), are further generated by S. Tm, which are known to be required for SCV's nutrient acquisition, membran maintenance and stability. A tightly coordinated interaction involving prominent effector SifA and various host adapters PLEKHM1, PLEKHM2 and Rab GTPases govern SCV integrity and SIF formation. Here, we report for the first time that the functional regulation of SifA is modulated by PTM SUMOylation at its 11th lysine. S. Tm expressing SUMOylation deficient lysine 11 mutants of SifA (SifAK11R) is defective in intracellular proliferation due to compromised SIF formation and enhanced lysosomal acidification. Furthermore, murine competitive index experiments reveal defective in vivo proliferation and weakened virulence of SifAK11R mutant. Concisely, our data reveal that SifAK11R mutant nearly behaves like a SifA knockout strain which impacts Rab9-MPR mediated lysosomal acidification pathway, the outcome of which culminates in reduced bacterial load in in vitro and in vivo infection model systems. Our results bring forth a novel pathogen-host crosstalk mechanism where the SUMOylation of effector SifA regulated S. Tm intracellular survival.
    DOI:  https://doi.org/10.1371/journal.ppat.1011686
  29. mBio. 2023 Sep 27. e0198723
    Butyrate protects against MRSA pneumonia via regulating gut-lung microbiota and alveolar macrophage M2 polarization.
    Yan Zhao, Haoming Sun, Yiwei Chen, Qiang Niu, Yiting Dong, Mei Li, Ye Yuan, Xiaojun Yang, Qingzhu Sun.
      Methicillin-resistant Staphylococcus aureus (MRSA) is a well-recognized cause of bacterial pneumonia in general. The gut microbiota and their metabolic byproducts act as important modulators of the gut-lung axis. Our investigation indicates a significant reduction in the abundance of butyrate producer unclassified_f__Lachnospiraceae within the lung and gut microbiota of MRSA-infected mice, as well as a significant decrease in the levels of butyrate in gut and serum. Additionally, supplementary sodium butyrate (NaB) significantly reduces bacteria colonization in the lung, suppresses pro-inflammatory cytokines expression, and enhances lung tissue morphology in MRSA-treated mice. The results of high-throughput 16S rDNA sequencing demonstrate that NaB reshapes the gut and lung microbiota by drastically reducing the abundance of potential pathogenic bacteria in the gut and cell motility-related bacteria in the lung, which are induced by MRSA. Moreover, NaB treatment augments the gut and circulating butyrate levels. Mechanistically, NaB promotes signal transducer and activator of transcription 1 (STAT1) acetylation and inhibits dimer STAT1 phosphorylation by reducing the binding of histone deacetylase 3 to STAT1, thereby altering alveolar macrophage polarization toward the M2 phenotype. Collectively, our findings suggest that NaB exerts a preventative effect against MRSA-induced pneumonia by enhancing the gut-lung microbiota and promoting macrophage polarization toward an anti-inflammatory M2 phenotype. The prophylactic administration of NaB emerges as a promising strategy for combating MRSA pneumonia. IMPORTANCE Pneumonia caused by methicillin-resistant Staphylococcus aureus (MRSA) continues to carry a high burden in terms of mortality. With the roles of gut microbiota in mediating lung diseases being gradually uncovered, the details of the molecular mechanism of the "gut-lung axis" mediated by beneficial microorganisms and small-molecule metabolites have gradually attracted the attention of researchers. However, further studies are still necessary to determine the efficacy of microbial-based interventions. Our findings indicate that sodium butyrate (NaB) alleviates MRSA-induced pulmonary inflammation by improving gut-lung microbiota and promoting M2 polarization of alveolar macrophages. Therefore, the preventive administration of NaB might be explored as an effective strategy to control MRSA pneumonia.
    Keywords:  M2 polarization; MRSA pneumonia; alveolar macrophage; gut microbiota; lung microbiota; sodium butyrate
    DOI:  https://doi.org/10.1128/mbio.01987-23
  30. mBio. 2023 Sep 28. e0120823
    M2a macrophages facilitate resolution of chemically-induced colitis in TLR4-SNP mice.
    Alexandra M Vlk, Daniel Prantner, Kari Ann Shirey, Darren J Perkins, Marguerite S Buzza, Vivek Thumbigere-Math, Achsah D Keegan, Stefanie N Vogel.
      Toll-like receptor 4 (TLR4) is an innate immune receptor responsive to lipopolysaccharide (LPS). Single nucleotide polymorphisms (SNPs) in human TLR4 that encode an A896G transition at SNP rs4986790 (D299G) and a C1196T transition at SNP rs4986791 (T399I) render individuals hyporesponsive to LPS. In humans, these SNPs are also associated with increased susceptibility to inflammatory bowel diseases (IBDs). Using knock-in mice engineered to express the murine homologs of these human TLR4 mutations ("TLR4-SNP" mice), we have shown that TLR4-SNP mice develop significantly more severe colitis induced by dextran sodium sulfate (DSS) than wild-type (WT) mice, similar to IBD in humans expressing these SNPs. Previous studies have provided indirect evidence for "tissue repair" M2 macrophages (Mφ) in the resolution of colitis. Signaling through the IL-4/IL-13 receptor, IL-4Rα, and the transcription factor, peroxisome proliferator-activated receptor (PPARγ), have been shown to be required for induction of M2a Mφ, and our data provide direct evidence for the involvement of both in the repair of DSS-induced colonic damage. In response to DSS, colons of TLR4-SNP mice produced reduced levels of M2a Mφ marker mRNA and protein, including PPARγ, and therapeutic administration of the PPARγ agonist ligand, rosiglitazone, resolved colitis in TLR4-SNP mice, and increased expression of the M2a protein, Ym1. Together, these data indicate that the failure of TLR4-SNP mice to resolve DSS-induced colitis may be secondary to their failure to induce "tissue repair" M2a Mφ. IMPORTANCE Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, impacts millions of individuals worldwide and severely impairs the quality of life for patients. Dysregulation of innate immune signaling pathways reduces barrier function and exacerbates disease progression. Macrophage (Mφ) signaling pathways are potential targets for IBD therapies. While multiple treatments are available for IBD, (i) not all patients respond, (ii) responses may diminish over time, and (iii) treatments often have undesirable side effects. Genetic studies have shown that the inheritance of two co-segregating SNPs expressed in the innate immune receptor, TLR4, is associated with human IBD. Mice expressing homologous SNPs ("TLR4-SNP" mice) exhibited more severe colitis than WT mice in a DSS-induced colonic inflammation/repair model. We identified a critical role for M2a "tissue repair" Mφ in the resolution of colitis. Our findings provide insight into potential development of novel therapies targeting Mφ signaling pathways that aim to alleviate the debilitating symptoms experienced by individuals with IBD.
    Keywords:  DSS-induced colitis; IL-4Rα; M2a macrophages; PPARγ; TLR4 SNPs; rosiglitazone
    DOI:  https://doi.org/10.1128/mbio.01208-23
  31. Neurochem Int. 2023 Sep 23. pii: S0197-0186(23)00142-0. [Epub ahead of print] 105614
    The immunometabolic reprogramming of microglia in Alzheimer's disease.
    Hongli Chen, Zichen Guo, Yaxuan Sun, Xueling Dai.
      Alzheimer's disease (AD) is an age-related neurodegenerative disorder (NDD). In the central nervous system (CNS), immune cells like microglia could reprogram intracellular metabolism to alter or exert cellular immune functions in response to environmental stimuli. In AD, microglia could be activated and differentiated into pro-inflammatory or anti-inflammatory phenotypes, and these differences in cellular phenotypes resulted in variance in cellular energy metabolism. Considering the enormous energy requirement of microglia for immune functions, the changes in mitochondria-centered energy metabolism and substrates of microglia are crucial for the cellular regulation of immune responses. Here we reviewed the mechanisms of microglial metabolic reprogramming by analyzing their flexible metabolic patterns and changes that occurred in their metabolism during the development of AD. Further, we summarized the role of drugs in modulating immunometabolic reprogramming to prevent neuroinflammation, which may shed light on a new research direction for AD treatment.
    Keywords:  Alzheimer's disease; Immunometabolism; Microglia; Neuroinflammation; Reprogramming
    DOI:  https://doi.org/10.1016/j.neuint.2023.105614
  32. Biology (Basel). 2023 Sep 20. pii: 1262. [Epub ahead of print]12(9):
    Exploring Longitudinal Gut Microbiome towards Metabolic Functional Changes Associated in Atopic Dermatitis in Early Childhood.
    Preecha Patumcharoenpol, Amornthep Kingkaw, Massalin Nakphaichit, Pantipa Chatchatee, Narissara Suratannon, Gianni Panagiotou, Wanwipa Vongsangnak.
      Atopic dermatitis (AD) is a prevalent inflammatory skin disease that has been associated with changes in gut microbial composition in early life. However, there are limited longitudinal studies examining the gut microbiome in AD. This study aimed to explore taxonomy and metabolic functions across longitudinal gut microbiomes associated with AD in early childhood from 9 to 30 months of age using integrative data analysis within the Thai population. Our analysis revealed that gut microbiome diversity was not different between healthy and AD groups; however, significant taxonomic differences were observed. Key gut bacteria with short-chain fatty acids (SCFAs) production potentials, such as Anaerostipes, Butyricicoccus, Ruminococcus, and Lactobacillus species, showed a higher abundance in the AD group. In addition, metabolic alterations between the healthy and AD groups associated with vitamin production and host immune response, such as biosynthesis of menaquinol, succinate, and (Kdo)2-lipid A, were observed. This study serves as the first framework for monitoring longitudinal microbial imbalances and metabolic functions associated with allergic diseases in Thai children during early childhood.
    Keywords:  atopic dermatitis; early childhood; longitudinal gut microbiome; metabolic functions
    DOI:  https://doi.org/10.3390/biology12091262
  33. Nature. 2023 Aug 16.
    A way to wipe a cell's memory.
      
    Keywords:  Epigenetics; Stem cells
    DOI:  https://doi.org/10.1038/d41586-023-02381-3
  34. Biomolecules. 2023 09 18. pii: 1404. [Epub ahead of print]13(9):
    Tea Tree Essential Oil Kills Escherichia coli and Staphylococcus epidermidis Persisters.
    LeeAnn Nguyen, Brianna DeVico, Maliha Mannan, Matthew Chang, Cristina Rada Santacruz, Christopher Siragusa, Sydney Everhart, Christopher H Fazen.
      Persister cells are a small subpopulation of non-growing bacteria within a population that can survive long exposures to antibiotic treatment. Following antibiotic removal, persister cells can regrow and populate, playing a key role in the chronic reoccurrence of bacterial infections. The development of new molecules and methods to kill bacterial persisters is critical. Essential oils and other natural products have long been studied for their antimicrobial effects. Here, we studied the effectiveness of tea tree essential oil (TTO), a common component in many commercial care products, against Escherichia coli and Staphylococcus epidermidis persister cells. Using biphasic kill curve assays, we found that concentrations of 0.5% and 1.0% TTO for E. coli and S. epidermidis, respectively, completely eradicated persister cells over a period of 24 h, with the component terpinen-4-ol responsible for most of the killing. Using a colorimetric assay, it was determined that the TTO exhibited its anti-persister effects through a membrane disruption mechanism.
    Keywords:  bacterial persisters; essential oils; tea tree essential oil
    DOI:  https://doi.org/10.3390/biom13091404
  35. Front Immunol. 2023 ;14 1243548
    Mitochondrial PGAM5-Drp1 signaling regulates the metabolic reprogramming of macrophages and regulates the induction of inflammatory responses.
    Bo-Ram Bang, Haruka Miki, Young Jun Kang.
      Macrophages play a critical role in the regulation of inflammation and tissue homeostasis. In addition to their vital functions for cell survival and physiology, mitochondria play a crucial role in innate immunity as a platform for the induction of inflammatory responses by regulating cell signaling and dynamics. Dynamin-related protein 1 (Drp1) plays a role in the induction of inflammatory responses and the subsequent development of various diseases. PGAM5 (phosphoglycerate mutase member 5) is a mitochondrial outer membrane phosphatase that dephosphorylates its substrate, Drp1. Previous studies showed that PGAM5 regulates the phosphorylation of Drp1 for the activation of NKT cells and T cells. However, it is not clear how PGAM5 regulates Drp1 activity for the induction of inflammation in macrophages. Here, we demonstrate that PGAM5 activity regulates the dephosphorylation of Drp1 in macrophages, leading to the induction of proinflammatory responses in macrophages. In TLR signaling, PGAM5 regulates the expression and production of inflammatory cytokines by regulating the activation of downstream signaling pathways, including the NF-κB and MAPK pathways. Upon LPS stimulation, PGAM5 interacts with Drp1 to form a complex, leading to the production of mtROS. Furthermore, PGAM5-Drp1 signaling promotes the polarization of macrophages toward a proinflammatory phenotype. Our study further demonstrates that PGAM5-Drp1 signaling promotes metabolic reprogramming by upregulating glycolysis and mitochondrial metabolism in macrophages. Altogether, PGAM5 signaling is a linker between alterations in Drp1-mediated mitochondrial dynamics and inflammatory responses in macrophages and may be a target for the treatment of inflammatory diseases.
    Keywords:  inflammatory response; innate immunity; macrophages; metabolism; mitochondria; signaling/signaling pathways
    DOI:  https://doi.org/10.3389/fimmu.2023.1243548
  36. Front Immunol. 2023 ;14 1219895
    The effect of Staphylococcus aureus on innate and adaptive immunity and potential immunotherapy for S. aureus-induced osteomyelitis.
    Yingqi Chen, Zixian Liu, Zexin Lin, Mincheng Lu, Yong Fu, Guanqiao Liu, Bin Yu.
      Osteomyelitis is a chronic inflammatory bone disease caused by infection of open fractures or post-operative implants. Particularly in patients with open fractures, the risk of osteomyelitis is greatly increased as the soft tissue damage and bacterial infection are often more severe. Staphylococcus aureus, one of the most common pathogens of osteomyelitis, disrupts the immune response through multiple mechanisms, such as biofilm formation, virulence factor secretion, and metabolic pattern alteration, which attenuates the effectiveness of antibiotics and surgical debridement toward osteomyelitis. In osteomyelitis, immune cells such as neutrophils, macrophages and T cells are activated in response to pathogenic bacteria invasion with excessive inflammatory factor secretion, immune checkpoint overexpression, and downregulation of immune pathway transcription factors, which enhances osteoclastogenesis and results in bone destruction. Therefore, the study of the mechanisms of abnormal immunity will be a new breakthrough in the treatment of osteomyelitis.
    Keywords:  Staphylococcus aureus; adaptive immunity; immune response; innate immunity; osteomyelitis
    DOI:  https://doi.org/10.3389/fimmu.2023.1219895
  37. Front Immunol. 2023 ;14 1230266
    Dynamic atlas of immune cells reveals multiple functional features of macrophages associated with progression of pulmonary fibrosis.
    Jiaoyan Lv, Haoxiang Gao, Jie Ma, Jiachen Liu, Yujie Tian, Chunyuan Yang, Mansheng Li, Yue Zhao, Zhimin Li, Xuegong Zhang, Yunping Zhu, Jianhong Zhang, Li Wu.
      Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease with a high mortality rate and unclarified aetiology. Immune response is elaborately regulated during the progression of IPF, but immune cells subsets are complicated which has not been detailed described during IPF progression. Therefore, in the current study, we sought to investigate the role of immune regulation by elaborately characterize the heterogeneous of immune cells during the progression of IPF. To this end, we performed single-cell profiling of lung immune cells isolated from four stages of bleomycin-induced pulmonary fibrosis-a classical mouse model that mimics human IPF. The results revealed distinct components of immune cells in different phases of pulmonary fibrosis and close communication between macrophages and other immune cells along with pulmonary fibrosis progression. Enriched signals of SPP1, CCL5 and CXCL2 were found between macrophages and other immune cells. The more detailed definition of the subpopulations of macrophages defined alveolar macrophages (AMs) and monocyte-derived macrophages (mo-Macs)-the two major types of primary lung macrophages-exhibited the highest heterogeneity and dynamic changes in expression of profibrotic genes during disease progression. Our analysis suggested that Gpnmb and Trem2 were both upregulated in macrophages and may play important roles in pulmonary fibrosis progression. Additionally, the metabolic status of AMs and mo-Macs varied with disease progression. In line with the published data on human IPF, macrophages in the mouse model shared some features regarding gene expression and metabolic status with that of macrophages in IPF patients. Our study provides new insights into the pathological features of profibrotic macrophages in the lung that will facilitate the identification of new targets for disease intervention and treatment of IPF.
    Keywords:  dynamic atlas; macrophages; pathogenesis; pulmonary fibrosis; single-cell RNA sequencing
    DOI:  https://doi.org/10.3389/fimmu.2023.1230266
  38. Arch Dermatol Res. 2023 Sep 27.
    Bleach baths enhance skin barrier, reduce itch but do not normalize skin dysbiosis in atopic dermatitis.
    Ania Stolarczyk, Nelissa Perez-Nazario, Sara A Knowlden, Ellen Chinchilli, Alex Grier, Amy Paller, Steven R Gill, Anna De Benedetto, Takeshi Yoshida, Lisa A Beck.
      Studies have demonstrated that bleach baths improve atopic dermatitis (AD) severity; however, the effects on itch, skin barrier, and cutaneous microbial composition are less clear. We examined whether bleach baths reduce itch, normalize skin barrier function, reduce S. aureus absolute abundance, and increase microbial diversity in adults with AD who were colonized with S. aureus on their non-lesional skin. This was an open label, non-randomized, controlled trial performed at a single academic center. Fifteen AD and five non-atopic healthy controls (NA) were instructed to take two bleach baths (0.005% NaClO; 5-10 min duration) per week for a total of 12 weeks as add-on therapy. Adults 18 to 65 years (inclusive) with mild to severe AD were recruited with EASI score > 6.0, S. aureus culture positivity, access to a bathtub, and ability and willingness to maintain current topical or systemic treatments. They were evaluated at baseline (before bleach baths), 6 weeks, and 12 weeks after the intervention of twice-weekly bleach baths. Efficacy measurements included EASI as well as 5-D Pruritus and ItchyQoL™. Transepidermal water loss (TEWL) and stratum corneum (SC) integrity assay were performed to assess the skin barrier. Skin dysbiosis was measured by S. aureus cultivation, S. aureus abundance (qPCR of thermonuclease gene), and V1-V3 16S rRNA gene sequencing on non-lesional and lesional AD skin. After 12 weeks of bleach baths, 8/15 (53.3%) AD subjects achieved an EASI50 and a significant reduction in itch as measured by 5-D pruritus and Itchy QoL. Eighty-seven percent reported improvements in sleep quality. At study entry, AD subjects had higher non-lesional TEWL values than NA subjects, and only AD subjects experienced a reduction with bleach baths (p = 0.006). Similarly, SC integrity improved as early as 6 weeks after bleach baths in AD subjects. Notably, bleach baths had no significant effect on S. aureus culture-positivity, qPCR absolute abundance, or microbial diversity. The addition of twice-weekly bleach baths improves investigator-assessed AD severity, patient-reported pruritus and sleep as well as physiological measures of skin barrier function in adult AD subjects while having no effect on qualitative and quantitative measures of cutaneous S. aureus. Trial Registration: ClinicalTrials.gov Identifier: NCT01996150, Date of registration: November 27th, 2013.
    Keywords:  Atopic dermatitis; Bleach baths; Itch; Skin barrier; Skin microbiome; Staphylococcus aureus
    DOI:  https://doi.org/10.1007/s00403-023-02723-1
  39. J Leukoc Biol. 2023 Sep 29. pii: qiad117. [Epub ahead of print]
    Lysosomal control of dendritic cell function.
    Jia Yang, Shan-Jie Rong, Hai-Feng Zhou, Chao Yang, Fei Sun, Jun-Yi Li.
      Lysosomal compartments undergo extensive remodeling during dendritic cell (DC) activation to meet the dynamic functional requirements of DCs. Instead of being regarded as stationary and digestive organelles, recent studies have increasingly appreciated the versatile roles of lysosomes in regulating key aspects of DC biology. Lysosomes actively control DC motility by linking calcium efflux to the actomyosin contraction, while enhanced DC lysosomal membrane permeability (LMP) contributes to the inflammasome activation. Besides, lysosomes provide a platform for the transduction of innate immune signaling and the intricate host-pathogen interplay. Lysosomes and lysosome-associated structures are also critically engaged in antigen presentation and cross-presentation processes, which are pivotal for the induction of antigen specific adaptive immune response. Through the current review, we emphasize that lysosome targeting strategies serve as vital DC based immunotherapies in fighting against tumor, infectious diseases and autoinflammatory disorders.
    Keywords:  DC based immunotherapy; Dendritic cell (DC); Immune response; Lysosome
    DOI:  https://doi.org/10.1093/jleuko/qiad117
  40. BMC Microbiol. 2023 Sep 29. 23(1): 273
    A simplified bacterial community found within the epidermis than at the epidermal surface of atopic dermatitis patients and healthy controls.
    Christopher J Barnes, Maria Asplund, Maja-Lisa Clausen, Linett Rasmussen, Caroline Meyer Olesen, Yasemin Topal Yüksel, Paal Skytt Andersen, Thomas Litman, Kim Holmstrøm, Lene Bay, Blaine Gabriel Fritz, Thomas Bjarnsholt, Tove Agner, Anders Johannes Hansen.
      There has been considerable research into the understanding of the healthy skin microbiome. Similarly, there is also a considerable body of research into whether specific microbes contribute to skin disorders, with atopic dermatitis (AD) routinely linked to increased Staphylococcus aureus (S. aureus) colonisation. In this study, the epidermal surface of participants was sampled using swabs, while serial tape-stripping (35 tapes) was performed to sample through the stratum corneum. Samples were taken from AD patients and healthy controls, and the bacterial communities were profiled by metabarcoding the universal V3-V4 16S rRNA region. Results show that the majority of bacterial richness is located within the outermost layers of the stratum corneum, however there were many taxa that were found almost exclusively at the very outermost layer of the epidermis. We therefore hypothesise that tape-stripping can be performed to investigate the 'core microbiome' of participants by removing environmental contaminants. Interestingly, significant community variation between AD patients and healthy controls was only observable at the epidermal surface, yet a number of individual taxa were found to consistently differ with AD status across the entire epidermis (i.e. both the epidermal surface and within the epidermis). Sampling strategy could therefore be tailored dependent on the hypothesis, with sampling for forensic applications best performed using surface swabs and outer tapes, while profiling sub-surface communities may better reflect host genome and immunological status.
    Keywords:  Atopic dermatitis; Bacteria; Epidermis; Fluorescent in situ hybridisation; Skin microbiome; Staphylococcus aureus
    DOI:  https://doi.org/10.1186/s12866-023-03012-7
  41. Eur J Immunol. 2023 Sep 24. e2350446
    SHIP1 and its role for innate immune regulation - novel targets for immunotherapy.
    Wen Jie Yeoh, Philippe Krebs.
      Phosphoinositide-3-kinase/AKT (PI3K/AKT) signaling plays key roles for the regulation of cellular activity in both health and disease. In immune cells, this PI3K/AKT pathway is critically regulated by the phosphoinositide phosphatase SHIP1, which has been reported to modulate the function of most immune subsets. In this review, we summarize our current knowledge of SHIP1 with a focus on innate immune cells, where we reflect on the most pertinent aspects described in the current literature. We also present the several small molecule agonists and antagonists of SHIP1 developed the last two decades, which have led to improved outcomes in several pre-clinical models of disease. We outline these promising findings and put them in relation with human diseases with unmet medical needs, where we discuss the most attractive targets for immune therapies based on SHIP1 modulation. This article is protected by copyright. All rights reserved.
    Keywords:  SHIP1; immunoregulation; immunotherapy; innate immunity; therapeutics
    DOI:  https://doi.org/10.1002/eji.202350446
  42. Microorganisms. 2023 Sep 13. pii: 2307. [Epub ahead of print]11(9):
    Oral Microbiota: The Influences and Interactions of Saliva, IgA, and Dietary Factors in Health and Disease.
    Daisuke Nagakubo, Yuichiro Kaibori.
      Recent advances in metagenomic analyses have made it easier to analyze microbiota. The microbiota, a symbiotic community of microorganisms including bacteria, archaea, fungi, and viruses within a specific environment in tissues such as the digestive tract and skin, has a complex relationship with the host. Recent studies have revealed that microbiota composition and balance particularly affect the health of the host and the onset of disease. Influences such as diet, food preferences, and sanitation play crucial roles in microbiota composition. The oral cavity is where the digestive tract directly communicates with the outside. Stable temperature and humidity provide optimal growth environments for many bacteria. However, the oral cavity is a unique environment that is susceptible to pH changes, salinity, food nutrients, and external pathogens. Recent studies have emphasized the importance of the oral microbiota, as changes in bacterial composition and balance could contribute to the development of systemic diseases. This review focuses on saliva, IgA, and fermented foods because they play critical roles in maintaining the oral bacterial environment by regulating its composition and balance. More attention should be paid to the oral microbiota and its regulatory factors in oral and systemic health.
    Keywords:  IgA; fermented food; oral microbiota; saliva
    DOI:  https://doi.org/10.3390/microorganisms11092307
  43. Cell Mol Life Sci. 2023 Sep 28. 80(10): 308
    Omentin-1 induces mechanically activated fibroblasts lipogenic differentiation through pkm2/yap/pparγ pathway to promote lung fibrosis resolution.
    Yunna Zhang, Jiafeng Fu, Chen Li, Yanfen Chang, Xiaohong Li, Haipeng Cheng, Yujia Qiu, Min Shao, Yang Han, Dandan Feng, Shaojie Yue, Zhengwang Sun, Ziqiang Luo, Yan Zhou.
      Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease characterized by extensive extracellular matrix (ECM) deposition by activated myofibroblasts, which are specialized hyper-contractile cells that promote ECM remodeling and matrix stiffening. New insights on therapeutic strategies aimed at reversing fibrosis by targeting myofibroblast fate are showing promise in promoting fibrosis resolution. Previously, we showed that a novel adipocytokine, omentin-1, attenuated bleomycin (BLM)-induced lung fibrosis by reducing the number of myofibroblasts. Apoptosis, deactivation, and reprogramming of myofibroblasts are important processes in the resolution of fibrosis. Here we report that omentin-1 reverses established lung fibrosis by promoting mechanically activated myofibroblasts dedifferentiation into lipofibroblasts. Omentin-1 promotes myofibroblasts lipogenic differentiation by inhibiting dimerization and nuclear translocation of glycolytic enzymes pyruvate kinase isoform M2 (PKM2) and activation of the downstream Yes-associated protein (YAP) by increasing the cofactor fructose-1,6-bisphosphate (F1, 6BP, FBP). Moreover, omentin-1 activates proliferator-activated receptor gamma (PPARγ) signaling, the master regulator of lipogenesis, and promotes the upregulation of the lipogenic differentiation-related protein perilipin 2 (PLIN2) by suppressing the PKM2-YAP pathway. Ultimately, omentin-1 facilitates myofibroblasts transformation into the lipofibroblast phenotype, with reduced collagen synthesis and enhanced degradation properties, which are crucial mechanisms to clear the ECM deposition in fibrotic tissue, leading to fibrosis resolution. Our results indicate that omentin-1 targets mechanical signal accelerates fibrosis resolution and reverses established lung fibrosis by promoting myofibroblasts lipogenic differentiation, which is closely associated with ECM clearance in fibrotic tissue. These findings suggest that targeting mechanical force to promote myofibroblast lipogenic differentiation is a promising therapeutic strategy against persistent lung fibrosis.
    Keywords:  Extracellular matrix stiffness; Lipofibroblast; Myofibroblast; Omentin-1; Pulmonary fibrosis
    DOI:  https://doi.org/10.1007/s00018-023-04961-y
  44. Biomedicines. 2023 Aug 25. pii: 2384. [Epub ahead of print]11(9):
    Interplay of Chemokines Receptors, Toll-like Receptors, and Host Immunological Pathways.
    Yuan-Tung Chu, Min-Tser Liao, Kuo-Wang Tsai, Kuo-Cheng Lu, Wan-Chung Hu.
      A comprehensive framework has been established for understanding immunological pathways, which can be categorized into eradicated and tolerable immune responses. Toll-like receptors (TLRs) are associated with specific immune responses. TH1 immunity is related to TLR7, TLR8, and TLR9, while TH2 immunity is associated with TLR1, TLR2, and TLR6. TH22 immunity is linked to TLR2, TLR4, and TLR5, and THαβ (Tr1) immunity is related to TLR3, TLR7, and TLR9. The chemokine receptor CXCR5 is a marker of follicular helper T cells, and other chemokine receptors can also be classified within a framework based on host immunological pathways. On the basis of a literature review on chemokines and immunological pathways, the following associations were identified: CCR5 with TH1 responses, CCR1 with TH1-like responses, CCR4 (basophils) and CCR3 (eosinophils) with TH2 and TH9 responses, CCR10 with TH22 responses, CCR6 with TH17 responses, CXCR3 with THαβ responses, CCR8 with regulatory T cells (Treg), and CCR2 with TH3 responses. These findings contribute to the identification of biomarkers for immune cells and provide insights into host immunological pathways. Understanding the chemokine and Toll-like receptor system is crucial for comprehending the function of the innate immune system, as well as adaptive immune responses.
    Keywords:  T helper cells; Toll-like receptors; chemokine receptors
    DOI:  https://doi.org/10.3390/biomedicines11092384
  45. Nat Commun. 2023 Sep 23. 14(1): 5943
    Bifidobacteria shape antimicrobial T-helper cell responses during infancy and adulthood.
    Katrin Vogel, Aditya Arra, Holger Lingel, Dirk Bretschneider, Florian Prätsch, Denny Schanze, Martin Zenker, Silke Balk, Dunja Bruder, Robert Geffers, Thomas Hachenberg, Christoph Arens, Monika C Brunner-Weinzierl.
      Microbial infections early in life are challenging for the unexperienced immune system. The SARS-CoV-2 pandemic again has highlighted that neonatal, infant, child, and adult T-helper(Th)-cells respond differently to infections, and requires further understanding. This study investigates anti-bacterial T-cell responses against Staphylococcus aureus aureus, Staphylococcus epidermidis and Bifidobacterium longum infantis in early stages of life and adults and shows age and pathogen-dependent mechanisms. Beside activation-induced clustering, T-cells stimulated with Staphylococci become Th1-type cells; however, this differentiation is mitigated in Bifidobacterium-stimulated T-cells. Strikingly, prestimulation of T-cells with Bifidobacterium suppresses the activation of Staphylococcus-specific T-helper cells in a cell-cell dependent manner by inducing FoxP3+CD4+ T-cells, increasing IL-10 and galectin-1 secretion and showing a CTLA-4-dependent inhibitory capacity. Furthermore Bifidobacterium dampens Th responses of severely ill COVID-19 patients likely contributing to resolution of harmful overreactions of the immune system. Targeted, age-specific interventions may enhance infection defence, and specific immune features may have potential cross-age utilization.
    DOI:  https://doi.org/10.1038/s41467-023-41630-x
  46. Biomedicines. 2023 Aug 28. pii: 2403. [Epub ahead of print]11(9):
    Small Heterodimer Partner Modulates Macrophage Differentiation during Innate Immune Response through the Regulation of Peroxisome Proliferator Activated Receptor Gamma, Mitogen-Activated Protein Kinase, and Nuclear Factor Kappa B Pathways.
    Forkan Ahamed, Natalie Eppler, Elizabeth Jones, Lily He, Yuxia Zhang.
      Hepatic macrophages act as the liver's first line of defense against injury. Their differentiation into proinflammatory or anti-inflammatory subpopulations is a critical event that maintains a delicate balance between liver injury and repair. In our investigation, we explored the influence of the small heterodimer partner (SHP), a nuclear receptor primarily associated with metabolism, on macrophage differentiation during the innate immune response. During macrophage differentiation, we observed significant alterations in Shp mRNA expression. Deletion of Shp promoted M1 differentiation while interfering with M2 polarization. Conversely, overexpression of SHP resulted in increased expression of peroxisome proliferator activated receptor gamma (Pparg), a master regulator of anti-inflammatory macrophage differentiation, thereby inhibiting M1 differentiation. Upon lipopolysaccharide (LPS) injection, there was a notable increase in the proinflammatory M1-like macrophages, accompanied by exacerbated infiltration of monocyte-derived macrophages (MDMs) into the livers of Shp myeloid cell specific knockout (Shp-MKO). Concurrently, we observed significant induction of tumor necrosis factor alpha (Tnfa) and chemokine (C-C motif) ligand 2 (Ccl2) expression in LPS-treated Shp-MKO livers. Additionally, the mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) pathways were activated in LPS-treated Shp-MKO livers. Consistently, both pathways were hindered in SHP overexpression macrophages. Finally, we demonstrated that SHP interacts with p65, thereby influencing macrophage immune repones. In summary, our study uncovered a previously unrecognized role of SHP in promoting anti-inflammatory macrophage differentiation during the innate immune response. This was achieved by SHP acting as a regulator for the Pparg, MAPK, and NF-κB pathways.
    Keywords:  differentiation; knockout; macrophage; nuclear receptor; small heterodimer partner (SHP)
    DOI:  https://doi.org/10.3390/biomedicines11092403
  47. Glycobiology. 2023 Sep 23. pii: cwad073. [Epub ahead of print]
    The role of the glycome in symbiotic host-microbe interactions.
    Rustam Aminov, Leila Aminova.
      Glycosylation plays a crucial role in many aspects of cell biology, including cellular and organismal integrity, structure-and-function of many glycosylated molecules in the cell, signal transduction, development, cancer, and in a number of diseases. Besides, at the inter-organismal level of interaction, a variety of glycosylated molecules are involved in the host-microbiota recognition and initiation of downstream signalling cascades depending on the outcomes of the glycome-mediated ascertainment. The role of glycosylation in host-microbe interactions is better elaborated within the context of virulence and pathogenicity in bacterial infection processes but the symbiotic host-microbe relationships also involve substantive glycome-mediated interactions. The works in the latter field have been reviewed to a much lesser extent, and the main aim of this mini-review is to compensate for this deficiency and summarise the role of glycomics in host-microbe symbiotic interactions.
    Keywords:  glycome; glycosylation; host-microbe interaction; mucosal surfaces; symbiosis
    DOI:  https://doi.org/10.1093/glycob/cwad073
  48. Front Immunol. 2023 ;14 1216402
    Pivotal role of tissue-resident memory lymphocytes in the control of mucosal infections: can mucosal vaccination induce protective tissue-resident memory T and B cells?
    Stephanie Longet, Stephane Paul.
      
    Keywords:  infectious diseases; mucosal immunity; protection; tissue-resident memory immune responses; vaccination
    DOI:  https://doi.org/10.3389/fimmu.2023.1216402
  49. Expert Rev Respir Med. 2023 Sep 25.
    Epithelial alarmins: a new target to treat chronic respiratory diseases.
    Denislava Nedeva, Krzysztof Kowal, Stefan Mihaicuta, Guillermo Guidos Fogelbach, Paschalis Steiropoulos, Herberto Jose Chong-Neto, Angelica Tiotiu.
       INTRODUCTION: In response to injury, epithelial cells release alarmins including thymic stromal lymphopoietin (TSLP), high mobility group-box-1 (HMGB1), interleukin (IL)-33 and -25 that can initiate innate immune responses. These alarmins are recognized as activators of T2-immune responses characteristic for asthma, but recent evidence highlighted their role in non-T2 inflammation, airway remodeling and pulmonary fibrosis making them an attractive therapeutic target for chronic respiratory diseases (CRD).
    AREAS COVERED: In this review, firstly we discuss the role of TSLP, IL-33, IL-25 and HMGB1 in the pathogenesis of asthma, COPD, idiopathic pulmonary fibrosis and cystic fibrosis according to the published data. In the second part, we summarize the current evidence concerning the efficacy of the antialarmin therapies in CRD. Recent clinical trials showed that anti-TSLP and IL-33/R antibodies can improve severe asthma outcomes. Blocking the IL-33-mediated pathway decreased the exacerbation rates in COPD patients with more important benefit for former-smokers.
    EXPERT OPINION: Despite progress in the understanding of the alarmins' role in the pathogenesis of CRD, all their mechanisms of action are not yet identified. Blocking IL-33 and TSLP pathways offer an interesting option to treat severe asthma and COPD but future investigations are needed to established their place in the treatment strategies.
    Keywords:  Alarmins; biologics; chronic respiratory diseases; exacerbations; lung function
    DOI:  https://doi.org/10.1080/17476348.2023.2262920
  50. Nat Microbiol. 2023 Sep 28.
    Systematic analysis of drug combinations against Gram-positive bacteria.
    Elisabetta Cacace, Vladislav Kim, Vallo Varik, Michael Knopp, Manuela Tietgen, Amber Brauer-Nikonow, Kemal Inecik, André Mateus, Alessio Milanese, Marita Torrissen Mårli, Karin Mitosch, Joel Selkrig, Ana Rita Brochado, Oscar P Kuipers, Morten Kjos, Georg Zeller, Mikhail M Savitski, Stephan Göttig, Wolfgang Huber, Athanasios Typas.
      Drug combinations can expand options for antibacterial therapies but have not been systematically tested in Gram-positive species. We profiled ~8,000 combinations of 65 antibacterial drugs against the model species Bacillus subtilis and two prominent pathogens, Staphylococcus aureus and Streptococcus pneumoniae. Thereby, we recapitulated previously known drug interactions, but also identified ten times more novel interactions in the pathogen S. aureus, including 150 synergies. We showed that two synergies were equally effective against multidrug-resistant S. aureus clinical isolates in vitro and in vivo. Interactions were largely species-specific and synergies were distinct from those of Gram-negative species, owing to cell surface and drug uptake differences. We also tested 2,728 combinations of 44 commonly prescribed non-antibiotic drugs with 62 drugs with antibacterial activity against S. aureus and identified numerous antagonisms that might compromise the efficacy of antimicrobial therapies. We identified even more synergies and showed that the anti-aggregant ticagrelor synergized with cationic antibiotics by modifying the surface charge of S. aureus. All data can be browsed in an interactive interface ( https://apps.embl.de/combact/ ).
    DOI:  https://doi.org/10.1038/s41564-023-01486-9
  51. mSphere. 2023 Sep 26. e0024923
    Clinical rel mutations in Staphylococcus aureus prime pathogen expansion under nutrient stress.
    Edwin Chen, Marla G Shaffer, Robert E Bilodeau, Raymond E West, Patrick J Oberly, Thomas D Nolin, Matthew J Culyba.
      Persistent infection by Staphylococcus aureus has been linked to the bacterial stringent response (SR), a conserved stress response pathway regulated by the Rel protein. Rel synthesizes (p)ppGpp "alarmones" in response to amino acid starvation, which enables adaptation to stress by modulating bacterial growth and virulence. We previously identified five novel protein-altering mutations in rel that arose in patients with persistent methicillin-resistant S. aureus bacteremia. The mutations mapped to both the enzymatic and regulatory protein domains of Rel. Here, we set out to characterize the phenotype of these mutations to understand how they may have been selected in vivo. After introducing each mutation into S. aureus strain JE2, we analyzed growth, fitness, and antibiotic profiles. Despite being located in different protein domains, we found that all of the mutations converged on the same phenotype. Each shortened the time of lag phase growth and imparted a fitness advantage in nutritionally depleted conditions. Through quantification of intracellular (p)ppGpp, we link this phenotype to increased SR activation, specifically during the stationary phase of growth. In contrast to two previously identified clinical rel mutations, we find that our rel mutations do not cause antibiotic tolerance. Instead, our findings suggest that in vivo selection was due to an augmented SR that primes cells for growth in nutrient-poor conditions, which may be a strategy for evading host-imposed nutritional immunity. IMPORTANCE Host and pathogen compete for available nutrition during infection. For bacteria, the stringent response (SR) regulator Rel responds to amino acid deprivation by signaling the cell to modulate its growth rate, metabolism, and virulence. In this report, we characterize five rel mutations that arose during cases of persistent methicillin-resistant Staphylococcus aureus bacteremia. We find that all of the mutations augmented SR signaling specifically under nutrient-poor conditions, enabling the cell to more readily grow and survive. Our findings reveal a strategy used by bacterial pathogens to evade the nutritional immunity imposed by host tissues during infection.
    Keywords:  Staphylococcus aureus; bacteremia; mrsa; persistence; stringent response
    DOI:  https://doi.org/10.1128/msphere.00249-23
  52. Am J Reprod Immunol. 2023 Oct;90(4): e13781
    Metabolic signature for a dysbiotic microbiome in the female genital tract: A systematic review and meta-analysis.
    Biban Gill, Ingrid Schwecht, Nuzhat Rahman, Tushar Dhawan, Chris Verschoor, Aisha Nazli, Charu Kaushic.
       BACKGROUND: The vaginal microbiome (VMB) is a critical determinant of reproductive health, where a microbial shift towards a dysbiotic environment has implications for susceptibility to, and clinical presentation of sexually transmitted infections (STIs). Metabolomic profiling of the vaginal microenvironment has led to the identification of metabolic responses to clinical conditions of dysbiosis. However, no studies have examined metabolic markers that are common across conditions and can serve as a signature for vaginal dysbiosis.
    METHOD OF STUDY: We have conducted a comprehensive systematic review and meta-analysis to identify consistently deregulated metabolites along with their impact on host and microbial metabolism during dysbiosis. We employed two complementary approaches including a vote counting analysis for all eligible studies identified in the systematic review, in addition to a meta-analysis for a subset of studies with sufficient available data. Significantly deregulated metabolites were then selected for pathway enrichment analysis.
    RESULTS: Our results revealed a total of 502 altered metabolites reported across 10 dysbiotic conditions from 16 studies. Following a rigorous, collective analysis, six metabolites which were consistently downregulated and could be generalized to all dysbiotic conditions were identified. In addition, five downregulated and one upregulated metabolite was identified from a bacterial vaginosis (BV) focused sub-analysis. These metabolites have the potential to serve as a metabolic signature for vaginal dysbiosis. Their role in eight altered metabolic pathways indicates a disruption of amino acid, carbohydrate, and energy metabolism during dysbiosis.
    CONCLUSION: Based on this analysis, we propose a schematic model outlining the common metabolic perturbations associated with vaginal dysbiosis, which can be potential targets for therapeutics and prophylaxis.
    Keywords:  dysbiosis4; female genital tract1; meta-analysis5; systematic review5; vaginal metabolome3; vaginal microbiome2
    DOI:  https://doi.org/10.1111/aji.13781
  53. Pharmaceutics. 2023 Sep 04. pii: 2278. [Epub ahead of print]15(9):
    The Contribution of Antimicrobial Peptides to Immune Cell Function: A Review of Recent Advances.
    Hanxiao Li, Junhui Niu, Xiaoli Wang, Mingfu Niu, Chengshui Liao.
      The development of novel antimicrobial agents to replace antibiotics has become urgent due to the emergence of multidrug-resistant microorganisms. Antimicrobial peptides (AMPs), widely distributed in all kingdoms of life, present strong antimicrobial activity against a variety of bacteria, fungi, parasites, and viruses. The potential of AMPs as new alternatives to antibiotics has gradually attracted considerable interest. In addition, AMPs exhibit strong anticancer potential as well as anti-inflammatory and immunomodulatory activity. Many studies have provided evidence that AMPs can recruit and activate immune cells, controlling inflammation. This review highlights the scientific literature focusing on evidence for the anti-inflammatory mechanisms of different AMPs in immune cells, including macrophages, monocytes, lymphocytes, mast cells, dendritic cells, neutrophils, and eosinophils. A variety of immunomodulatory characteristics, including the abilities to activate and differentiate immune cells, change the content and expression of inflammatory mediators, and regulate specific cellular functions and inflammation-related signaling pathways, are summarized and discussed in detail. This comprehensive review contributes to a better understanding of the role of AMPs in the regulation of the immune system and provides a reference for the use of AMPs as novel anti-inflammatory drugs for the treatment of various inflammatory diseases.
    Keywords:  anti-inflammatory; antimicrobial peptides; immune cell; immunomodulatory; inflammatory mediators; signaling pathways
    DOI:  https://doi.org/10.3390/pharmaceutics15092278
  54. Int Immunopharmacol. 2023 Sep 23. pii: S1567-5769(23)01296-1. [Epub ahead of print]124(Pt B): 110971
    Gut microbiota-derived autoinducer-2 regulates lung inflammation through the gut-lung axis.
    Xianghao Zeng, Huawen Yue, Ling Zhang, Guimei Chen, Qiao Zheng, Qing Hu, Xinhao Du, Qian Tian, Xinyu Zhao, Lanfan Liang, Ziyi Yang, Hang Bai, Yanqin Liu, Ming Zhao, Xiangsheng Fu.
       OBJECTIVE: This study aimed to determine whether autoinducer-2 (AI-2), a crucial bacterial metabolite and quorum sensing molecule, is involved in lung immunity through the gut-lung axis.
    METHODS: The level of AI-2 and the gut microbiome composition were analysed in the stools from pneumonic patients and the mouse model of acute lung injury. The effect of AI-2 on lung inflammation was further investigated in the mouse model.
    RESULTS: The diversity of the faecal microbiota was reduced in pneumonic patients treated with antibiotics compared with healthy volunteers. The AI-2 level in the stool was positively correlated with inflammatory molecules in the serum of pneumonic patients. Intraperitoneal injection of AI-2 reinforced lung inflammation in the acute lung injury mouse model, characterized by increased secretion of inflammatory molecules, including IL-6, IL-1β, C-C chemokines, and CXCL chemokines, which were alleviated by the AI-2 inhibitor D-ribose.
    CONCLUSIONS: Our results suggested that gut microbiota-derived AI-2 could modulate lung inflammation through the gut-lung axis.
    Keywords:  Autoinducer-2; Gut microbiota; Gut-lung axis; Lung immunity; Quorum sensing
    DOI:  https://doi.org/10.1016/j.intimp.2023.110971
  55. Cytometry A. 2023 Sep 29.
    OMIP-096: A 24-color flow cytometry panel to identify and characterize CD4+ and CD8+ tissue-resident T cells in human skin, intestinal, and type II mucosal tissue.
    Thomas R O'Neil, Andrew N Harman, Anthony L Cunningham, Najla Nasr, Kirstie M Bertram.
      There is a great need to understand human immune cells within tissue, where disease manifests and infection occurs. Tissue-resident memory T cells (TRMs) were discovered over a decade ago, there is a great need to understand their role in human disease. We developed a 24-color flow cytometry panel to comprehensively interrogate CD4+ and CD8+ TRMs isolated from human tissues. When interrogating cells within human tissue, enzymatic methods used to liberate cells from within the tissue can cause cleavage of cell surface markers needed to phenotype these cells. Here we carefully select antibody clones and evaluate the effect of enzymatic digestion on the expression of markers relevant to the identification of T cell residency, as well as markers relevant to the activation and immunoregulation status of these cells. We have designed this panel to be applicable across a range of human tissues including skin, intestine, and type II mucosae such as the vagina.
    Keywords:  CD4+ T cells; CD8+ T cells; enzymatic digestion; flow cytometry; human tissue; tissue-resident memory T cells
    DOI:  https://doi.org/10.1002/cyto.a.24782
  56. Front Immunol. 2023 ;14 1232764
    BCG mediated protection of the lung against experimental SARS-CoV-2 infection.
    Kerry L Hilligan, Sivaranjani Namasivayam, Alan Sher.
      The observation of reduced COVID-19 incidence and severity in populations receiving neonatal intradermal BCG vaccination vaccine raised the question of whether BCG can induce non-specific protection against the SARS-CoV-2 (SCV2) virus. Subsequent epidemiologic studies and clinical trials have largely failed to support this hypothesis. Furthermore, in small animal model studies all investigators have failed to observe resistance to viral challenge in response to BCG immunization by the conventional and clinically acceptable intradermal or subcutaneous routes. Nevertheless, BCG administered by the intravenous (IV) route has been shown to strongly protect both hamsters and mice against SCV2 infection and disease. In this Perspective, we review the current data on the effects of BCG vaccination on resistance to COVID-19 as well as summarize recent work in rodent models on the mechanisms by which IV administered BCG promotes resistance to the virus and discuss the translational implications of these findings.
    Keywords:  Bacille Calmette-Guérin (BCG); COVID-19; interferon gamma (IFNγ); lung; trained immunity
    DOI:  https://doi.org/10.3389/fimmu.2023.1232764
  57. NPJ Biofilms Microbiomes. 2023 Sep 26. 9(1): 71
    Metabolic inputs in the probiotic bacterium Lacticaseibacillus rhamnosus contribute to cell-wall remodeling and increased fitness.
    Ronit Suissa, Tsviya Olender, Sergey Malitsky, Ofra Golani, Sondra Turjeman, Omry Koren, Michael M Meijler, Ilana Kolodkin-Gal.
      Lacticaseibacillus rhamnosus GG (LGG) is a Gram-positive beneficial bacterium that resides in the human intestinal tract and belongs to the family of lactic acid bacteria (LAB). This bacterium is a widely used probiotic and was suggested to provide numerous benefits for human health. However, as in most LAB strains, the molecular mechanisms that mediate the competitiveness of probiotics under different diets remain unknown. Fermentation is a fundamental process in LAB, allowing the oxidation of simple carbohydrates (e.g., glucose, mannose) for energy production under oxygen limitation, as in the human gut. Our results indicate that fermentation reshapes the metabolome, volatilome, and proteome architecture of LGG. Furthermore, fermentation alters cell envelope remodeling and peptidoglycan biosynthesis, which leads to altered cell wall thickness, aggregation properties, and cell wall composition. In addition, fermentable sugars induced the secretion of known and novel metabolites and proteins targeting the enteric pathogens Enterococcus faecalis and Salmonella enterica Serovar Typhimurium. Overall, our results link simple carbohydrates with cell wall remodeling, aggregation to host tissues, and biofilm formation in probiotic strains and connect them with the production of broad-spectrum antimicrobial effectors.
    DOI:  https://doi.org/10.1038/s41522-023-00431-2
  58. Bull Exp Biol Med. 2023 Sep 28.
    The Formation of Non-Specific Immunological Memory Phenotype in Human Monocyte-Like THP-1 and U-937 Cell Lines.
    A P Lykov, S N Belogorodtsev, E K Nemkova, A Vetlugina, T M Terekhova, Y Sh Schwartz.
      We studied the formation of the phenotype of non-specific immunological memory (trained immunity) in human monocyte-like THP-1 and U-937 cell lines. The absence of the lag phase after primary contact with the pathogen (Mycobacterium bovis, BCG vaccine) does not contribute to the formation of the trained immunity phenotype in the cells. The presence of the lag phase promotes the development of the trained immunity phenotype, especially in THP-1 cells. The second stimulation (bacterial LPS) did not increase the production of lactate, nitric oxide, and glucose consumption by cells, which can be a consequence of the Warburg phenomenon in these monocyte-like human cell lines.
    Keywords:  cytokines; glucose; lactate; monocyte-like lines; trained immunity
    DOI:  https://doi.org/10.1007/s10517-023-05890-3
  59. Int J Mol Sci. 2023 Sep 07. pii: 13783. [Epub ahead of print]24(18):
    Probiotics Modulate Host Immune Response and Interact with the Gut Microbiota: Shaping Their Composition and Mediating Antibiotic Resistance.
    Walaa K Mousa, Sara Mousa, Rose Ghemrawi, Dana Obaid, Muhammad Sarfraz, Fadia Chehadeh, Shannon Husband.
      The consortium of microbes inhabiting the human body, together with their encoded genes and secreted metabolites, is referred to as the "human microbiome." Several studies have established a link between the composition of the microbiome and its impact on human health. This impact spans local gastrointestinal inflammation to systemic autoimmune disorders and neurodegenerative diseases such as Alzheimer's and Autism. Some of these links have been validated by rigorous experiments that identify specific strains as mediators or drivers of a particular condition. Consequently, the development of probiotics to compensate for a missing beneficial microbe(s) has advanced and become popular, especially in the treatment of irritable bowel diseases and to restore disrupted gut flora after antibiotic administration. The widespread use of probiotics is often advocated as a natural ecological therapy. However, this perception is not always accurate, as there is a potential for unexpected interactions when administering live microbial cultures. Here, we designed this research to explore the intricate interactions among probiotics, the host, and microbes through a series of experiments. Our objectives included assessing their immunomodulatory effects, response to oral medications, impact on microbial population dynamics, and mediation of antibiotic resistance. To achieve these goals, we employed diverse experimental protocols, including cell-based enzyme -linked immunosorbent assay (ELISA), antibiotic susceptibility testing, antimicrobial activity assays, computational prediction of probiotic genes responsible for antibiotic resistance, polymerase chain reaction (PCR)-based validation of predicted genes, and survival assays of probiotics in the presence of selected oral medications. Our findings highlight that more than half of the tested probiotics trigger an inflammatory response in the Caco-2 cell line, are influenced by oral medications, exhibit antibacterial activity, and possess genes encoding antimicrobial resistance. These results underscore the necessity for a reevaluation of probiotic usage and emphasize the importance of establishing regulations to govern probiotic testing, approval, and administration.
    Keywords:  antibiotics; immune reactions; inflammation; microbiome; probiotics; resistance
    DOI:  https://doi.org/10.3390/ijms241813783
  60. PLoS Pathog. 2023 Sep 25. 19(9): e1011674
    Functional and structural analyses reveal that a dual domain sialidase protects bacteria from complement killing through desialylation of complement factors.
    Nicholas D Clark, Christopher Pham, Kurni Kurniyati, Ching Wooen Sze, Laurynn Coleman, Qin Fu, Sheng Zhang, Michael G Malkowski, Chunhao Li.
      The complement system is the first line of innate immune defense against microbial infections. To survive in humans and cause infections, bacterial pathogens have developed sophisticated mechanisms to subvert the complement-mediated bactericidal activity. There are reports that sialidases, also known as neuraminidases, are implicated in bacterial complement resistance; however, its underlying molecular mechanism remains elusive. Several complement proteins (e.g., C1q, C4, and C5) and regulators (e.g., factor H and C4bp) are modified by various sialoglycans (glycans with terminal sialic acids), which are essential for their functions. This report provides both functional and structural evidence that bacterial sialidases can disarm the complement system via desialylating key complement proteins and regulators. The oral bacterium Porphyromonas gingivalis, a "keystone" pathogen of periodontitis, produces a dual domain sialidase (PG0352). Biochemical analyses reveal that PG0352 can desialylate human serum and complement factors and thus protect bacteria from serum killing. Structural analyses show that PG0352 contains a N-terminal carbohydrate-binding module (CBM) and a C-terminal sialidase domain that exhibits a canonical six-bladed β-propeller sialidase fold with each blade composed of 3-4 antiparallel β-strands. Follow-up functional studies show that PG0352 forms monomers and is active in a broad range of pH. While PG0352 can remove both N-acetylneuraminic acid (Neu5Ac) and N-glycolyl-neuraminic acid (Neu5Gc), it has a higher affinity to Neu5Ac, the most abundant sialic acid in humans. Structural and functional analyses further demonstrate that the CBM binds to carbohydrates and serum glycoproteins. The results shown in this report provide new insights into understanding the role of sialidases in bacterial virulence and open a new avenue to investigate the molecular mechanisms of bacterial complement resistance.
    DOI:  https://doi.org/10.1371/journal.ppat.1011674
  61. Genes (Basel). 2023 Aug 29. pii: 1724. [Epub ahead of print]14(9):
    A Review of the Epigenetic Clock: Emerging Biomarkers for Asthma and Allergic Disease.
    Denitsa Vasileva, Celia M T Greenwood, Denise Daley.
      DNA methylation (DNAm) is a dynamic, age-dependent epigenetic modification that can be used to study interactions between genetic and environmental factors. Environmental exposures during critical periods of growth and development may alter DNAm patterns, leading to increased susceptibility to diseases such as asthma and allergies. One method to study the role of DNAm is the epigenetic clock-an algorithm that uses DNAm levels at select age-informative Cytosine-phosphate-Guanine (CpG) dinucleotides to predict epigenetic age (EA). The difference between EA and calendar age (CA) is termed epigenetic age acceleration (EAA) and reveals information about the biological capacity of an individual. Associations between EAA and disease susceptibility have been demonstrated for a variety of age-related conditions and, more recently, phenotypes such as asthma and allergic diseases, which often begin in childhood and progress throughout the lifespan. In this review, we explore different epigenetic clocks and how they have been applied, particularly as related to childhood asthma. We delve into how in utero and early life exposures (e.g., smoking, air pollution, maternal BMI) result in methylation changes. Furthermore, we explore the potential for EAA to be used as a biomarker for asthma and allergic diseases and identify areas for further study.
    Keywords:  allergy; asthma; biomarker; epigenetic clock
    DOI:  https://doi.org/10.3390/genes14091724
  62. Biomolecules. 2023 08 24. pii: 1295. [Epub ahead of print]13(9):
    Beneficial Effects of Lactobacilli Species on Intestinal Homeostasis in Low-Grade Inflammation and Stress Rodent Models and Their Implication in the Modulation of the Adhesive Junctional Complex.
    Célia Chamignon, Geoffroy Mallaret, Julie Rivière, Marthe Vilotte, Sead Chadi, Alejandra de Moreno de LeBlanc, Jean Guy LeBlanc, Frédéric Antonio Carvalho, Marco Pane, Pierre-Yves Mousset, Philippe Langella, Sophie Lafay, Luis G Bermúdez-Humarán.
      Intestinal barrier integrity is essential in order to maintain the homeostasis of mucosal functions and efficient defensive reactions against chemical and microbial challenges. An impairment of the intestinal barrier has been observed in several chronic diseases. The gut microbiota and its impact on intestinal homeostasis is well described and numerous studies suggest the ability of some probiotic strains to protect the intestinal epithelial integrity and host homeostasis. In this work, we aimed to assess the beneficial effects of three Lactobacillus strains (Lacticaseibacillus rhamnosus LR04, Lacticaseibacillus casei LC03, and Lactiplantibacillus plantarum CNCM I-4459) and their mechanism of action in low-grade inflammation or neonatal maternal separation models in mice. We compared the impact of these strains to that of the well-known probiotic Lacticaseibacillus rhamnosus GG. Our results demonstrated that the three strains have the potential to restore the barrier functions by (i) increasing mucus production, (ii) restoring normal permeability, and (iii) modulating colonic hypersensitivity. Moreover, gene expression analysis of junctional proteins revealed the implication of Claudin 2 and Cingulin in the mechanisms that underlie the interactions between the strains and the host. Taken together, our data suggest that LR04, CNCM I-4459, and LC03 restore the functions of an impaired intestinal barrier.
    Keywords:  Lactobacillus; barrier functions; chronic diseases; leaky gut; probiotics
    DOI:  https://doi.org/10.3390/biom13091295
  63. Front Immunol. 2023 ;14 1272920
    Immune predisposition drives susceptibility to pneumococcal pneumonia after mild influenza A virus infection in mice.
    Sunil Palani, Md Bashir Uddin, Michael McKelvey, Shengjun Shao, Keer Sun.
       Introduction: A frequent sequela of influenza A virus (IAV) infection is secondary bacterial pneumonia. Therefore, it is clinically important to understand the genetic predisposition to IAV and bacterial coinfection.
    Methods: BALB/c and C57BL/6 (B6) mice were infected with high or low-pathogenic IAV and Streptococcus pneumoniae (SPn). The contribution of cellular and molecular immune factors to the resistance/susceptibility of BALB/c and B6 mice were dissected in nonlethal and lethal IAV/SPn coinfection models.
    Results: Low-virulent IAV X31 (H3N2) rendered B6 mice extremely susceptible to SPn superinfection, while BALB/c mice remained unaffected. X31 infection alone barely induces IFN-γresponse in two strains of mice; however, SPn superinfection significantly enhances IFN-γ production in the susceptible B6 mice. As a result, IFN-γ signaling inhibits neutrophil recruitment and bacterial clearance, leading to lethal X31/SPn coinfection in B6 mice. Conversely, the diminished IFN-γ and competent neutrophil responses enable BALB/c mice highly resistant to X31/SPn coinfection.
    Discussion: The results establish that type 1 immune predisposition plays a key role in lethal susceptibility of B6 mice to pneumococcal pneumonia after mild IAV infection.
    Keywords:  Streptococcus pneumoniae; coinfection; genetic predisposition; influenza; pneumonia
    DOI:  https://doi.org/10.3389/fimmu.2023.1272920
  64. Microorganisms. 2023 Aug 29. pii: 2183. [Epub ahead of print]11(9):
    The World's First Acne Dysbiosis-like Model of Human 3D Ex Vivo Sebaceous Gland Colonized with Cutibacterium acnes and Staphylococcus epidermidis.
    Nico Forraz, Cécile Bize, Anne-Laure Desroches, Clément Milet, Pauline Payen, Pauline Chanut, Catherine Kern, Christine Garcia, Colin McGuckin.
      Acne-prone skin is associated with dysbiosis involving Cutibacterium acnes (C. acnes) and Staphylococcus epidermidis (S. epidermidis) causing increased seborrhea in sebaceous glands (SG) and inflammation. Human primary sebocytes were cultivated using 1.106 UFC/mL C. acnes Type IA (facial acne, ATCC6919) and/or 1.105 UFC/mL S. epidermidis (unknown origin, ATCC12228) for 48 h in our SEB4GLN-optimized media without antibiotics. Bacteria and sebocytes were enumerated and assessed to determine their viability. Lipid production was imaged and quantified via Nile Red staining. SG with hair follicles were microdissected from healthy skin and cultured using 1.105 UFC/mL C. acnes Type 1A and/or 1.104 UFC/mL S. epidermidis (wild-type facial skin strain) through prior fixation and immunostaining for MC5R, C. acnes and nuclei (DAPI) via Z-stack confocal microscopy bioimaging (Leica SP5X & FIJI software, Version 2.9.0). C. acnes growth was not impacted when co-cultivated with sebocytes (2D) or SG (3D) models. Phylotype IA stimulated sebocyte lipid production, which had no impact on viability. The S. epidermidis reference strain overproliferated, inducing sebocyte mortality. For 3D SG model, culture conditions were optimized using a wild-type facial skin strain at a lower concentration, 1:10 ratio to C. acnes, reduced contact time, sequential inoculation and rinsing step. Bioimaging revealed strong C. acnes labeling in the active areas of the pilosebaceous unit. S. epidermidis formed biofilm, which was distributed across the SG via non-specific fluorescence imaging. We developed an innovative model of a sebaceous gland that mimics acne-prone skin with lipid overproduction and virulent phylotype IA C. acnes inoculation.
    Keywords:  acne; bacteria; microbiota; sebaceous glands; sebocytes; sebum; skin; tissue engineering
    DOI:  https://doi.org/10.3390/microorganisms11092183
  65. Int J Mol Sci. 2023 Sep 07. pii: 13803. [Epub ahead of print]24(18):
    Fucoxanthin Ameliorates Sepsis via Modulating Microbiota by Targeting IRF3 Activation.
    Jingqian Su, Biyun Guan, Qiaofen Su, Shan Hu, Shun Wu, Zhiyong Tong, Fen Zhou.
      To improve patient survival in sepsis, it is necessary to curtail exaggerated inflammatory responses. Fucoxanthin (FX), a carotenoid derived from brown algae, efficiently suppresses pro-inflammatory cytokine expression via IRF3 activation, thereby reducing mortality in a mouse model of sepsis. However, the effects of FX-targeted IRF3 on the bacterial flora (which is disrupted in sepsis) and the mechanisms by which it impacts sepsis development remain unclear. This study aims to elucidate how FX-targeted IRF3 modulates intestinal microbiota compositions, influencing sepsis development. FX significantly reduced the bacterial load in the abdominal cavity of mice with cecal ligation and puncture (CLP)-induced sepsis via IRF3 activation and increased short-chain fatty acids, like acetic and propionic acids, with respect to their intestines. FX also altered the structure of the intestinal flora, notably elevating beneficial Verrucomicrobiota and Akkermansia spp. while reducing harmful Morganella spp. Investigating the inflammation-flora link, we found positive correlations between the abundances of Morganella spp., Proteus spp., Escherichia spp., and Klebsiella spp. and pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α) induced by CLP. These bacteria were negatively correlated with acetic and propionic acid production. FX alters microbial diversity and promotes short-chain fatty acid production in mice with CLP-induced sepsis, reshaping gut homeostasis. These findings support the value of FX for the treatment of sepsis.
    Keywords:  aloe emodin; cecal ligation puncture; gut microbiota; inflammation; sepsis
    DOI:  https://doi.org/10.3390/ijms241813803
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