bims-bac4me Biomed News
on Microbiome and trained immunity
Issue of 2023‒09‒17
thirty-six papers selected by
Chun-Chi Chang, University Hospital Zurich

  1. Front Immunol. 2023 ;14 1209438
      Sepsis presents as a severe infectious disease frequently documented in clinical settings. Characterized by its systemic inflammatory response syndrome, sepsis has the potential to trigger multi-organ dysfunction and can escalate to becoming life-threatening. A common fallout from sepsis is acute lung injury (ALI), which often progresses to acute respiratory distress syndrome (ARDS). Macrophages, due to their significant role in the immune system, are receiving increased attention in clinical studies. Macrophage polarization is a process that hinges on an intricate regulatory network influenced by a myriad of signaling molecules, transcription factors, epigenetic modifications, and metabolic reprogramming. In this review, our primary focus is on the classically activated macrophages (M1-like) and alternatively activated macrophages (M2-like) as the two paramount phenotypes instrumental in sepsis' host immune response. An imbalance between M1-like and M2-like macrophages can precipitate the onset and exacerbate the progression of sepsis. This review provides a comprehensive understanding of the interplay between macrophage polarization and sepsis-induced acute lung injury (SALI) and elaborates on the intervention strategy that centers around the crucial process of macrophage polarization.
    Keywords:  ARDS (acute respiratory distress); SALI (sepsis-induced acute lung injury); inflammation; macrophages polarization; therapy
  2. Immunology. 2023 Sep 13.
      On the basis of the mechanisms of action and characteristics of immune effects, immunity is commonly categorized into innate and adaptive immunity. Adaptive immunity is associated with the response to non-self-entities and is characterized by high specificity and memory properties. In contrast, innate immunity has traditionally been considered devoid of memory characteristics. However, an increasing number of studies have sought to challenge this conventional immunological dogma and shown that innate immune cells exhibit a more robust and rapid response to secondary stimulation, thus providing evidence of the immunological memory in innate immunity. Macrophages, which are among the most important innate immune cells, can also acquire memory phenotype that facilitates the mediation of recall responses. Macrophage memory is a relatively new concept that is revolutionizing our understanding of macrophage biology and immunological memory and could lead to a new class of vaccines and immunotherapies. In this review, we describe the characteristics and mechanisms of macrophage memory, as well as its essential roles in various diseases.
    Keywords:  endowed immunity; epigenetic reprogramming; macrophage memory; trained immunity
  3. Annu Rev Microbiol. 2023 Sep 15. 77 451-477
      The immune system of multicellular organisms protects them from harmful microbes. To establish an infection in the face of host immune responses, pathogens must evolve specific strategies to target immune defense mechanisms. One such defense is the formation of intracellular protein complexes, termed inflammasomes, that are triggered by the detection of microbial components and the disruption of homeostatic processes that occur during bacterial infection. Formation of active inflammasomes initiates programmed cell death pathways via activation of inflammatory caspases and cleavage of target proteins. Inflammasome-activated cell death pathways such as pyroptosis lead to proinflammatory responses that protect the host. Bacterial infection has the capacity to influence inflammasomes in two distinct ways: activation and perturbation. In this review, we discuss how bacterial activities influence inflammasomes, and we discuss the consequences of inflammasome activation or evasion for both the host and pathogen.
    Keywords:  NLR; caspase-1; caspase-8; gasdermin; inflammasome; pyroptosis
  4. Exp Biol Med (Maywood). 2023 Sep 09. 15353702231187645
      The evolution of medical knowledge about oral microbiota has increased awareness of its important role for the entire human body health. A wide range of microbial species colonizing the oral cavity interact both with each other and with their host through complex pathways. Usually, these interactions lead to a harmonious coexistence (i.e. eubiosis). However, several factors - including diet, poor oral hygiene, tobacco smoking, and certain medications, among others - can disrupt this weak homeostatic balance (i.e. dysbiosis) with potential implications on both oral (i.e. development of caries and periodontal disease) and systemic health. This article is thus aimed at providing an overview on the importance of oral microbiota in mediating several physiological and pathological conditions affecting human health. In this context, strategies based on oral hygiene and diet as well as the role of probiotics supplementation are discussed.
    Keywords:  Human microbiota; dental caries; diet; microbiome; oral biofilm; oral dysbiosis; oral health; periodontitis; probiotics
  5. Front Pharmacol. 2023 ;14 1254317
      Nuclear receptors are ligand-regulated transcription factors that regulate vast cellular activities and serve as an important class of drug targets. Among them, peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor family and have been extensively studied for their roles in metabolism, differentiation, development, and cancer, among others. Recently, there has been considerable interest in understanding and defining the function of PPARs and their agonists in regulating innate and adaptive immune responses and their pharmacological potential in combating chronic inflammatory diseases. In this review, we focus on emerging evidence for the potential role of PPARγ in macrophage biology, which is the prior innate immune executive in metabolic and tissue homeostasis. We also discuss the role of PPARγ as a regulator of macrophage function in inflammatory diseases. Lastly, we discuss the possible application of PPARγ antagonists in metabolic pathologies.
    Keywords:  PPARγ; antagonists; anti-inflammatory; inflammatory diseases; macrophage
  6. Exp Mol Med. 2023 Sep 11.
      Our bodies are inhabited by trillions of microorganisms. The host immune system constantly interacts with the microbiota in barrier organs, including the intestines. Over decades, numerous studies have shown that our mucosal immune system is dynamically shaped by a variety of microbiota-derived signals. Elucidating the mediators of these interactions is an important step for understanding how the microbiota is linked to mucosal immune homeostasis and gut-associated diseases. Interestingly, the efficacy of cancer immunotherapies that manipulate costimulatory and coinhibitory pathways has been correlated with the gut microbiota. Moreover, adverse effects of these therapies in the gut are linked to dysregulation of the intestinal immune system. These findings suggest that costimulatory pathways in the immune system might serve as a bridge between the host immune system and the gut microbiota. Here, we review mechanisms by which commensal microorganisms signal immune cells and their potential impact on costimulation. We highlight how costimulatory pathways modulate the mucosal immune system through not only classical antigen-presenting cells but also innate lymphocytes, which are highly enriched in barrier organs. Finally, we discuss the adverse effects of immune checkpoint inhibitors in the gut and the possible relationship with the gut microbiota.
  7. bioRxiv. 2023 Aug 31. pii: 2023.08.30.555580. [Epub ahead of print]
      Innate immune memory is the process by which pathogen exposure elicits cell-intrinsic states to alter the strength of future immune challenges. Such altered memory states drive monocyte dysregulation during sepsis, promoting pathogenic behavior characterized by pro-inflammatory, immunosuppressive gene expression in concert with emergency hematopoiesis. Epigenetic changes, notably in the form of histone modifications, have been shown to underlie innate immune memory, but the contribution of DNA methylation to this process remains poorly understood. Using an ex vivo sepsis model, we discovered broad changes in DNA methylation throughout the genome of exhausted monocytes, including at several genes previously implicated as major drivers of immune dysregulation during sepsis and Covid-19 infection (e.g. Plac8 ). Methylome alterations are driven in part by Wnt signaling inhibition in exhausted monocytes, and can be reversed through treatment with DNA methyltransferase inhibitors, Wnt agonists, or immune training molecules. Importantly, these changes are recapitulated in septic mice following cecal slurry injection, resulting in stable changes at critical immune genes that support the involvement of DNA methylation in acute and long-term monocyte dysregulation during sepsis.
  8. Nat Commun. 2023 Sep 12. 14(1): 5627
      Tissue-resident macrophage populations constitute a mosaic of phenotypes, yet how their metabolic states link to the range of phenotypes and functions in vivo is still poorly defined. Here, using high-dimensional spectral flow cytometry, we observe distinct metabolic profiles between different organs and functionally link acetyl CoA carboxylase activity to efferocytotic capacity. Additionally, differences in metabolism are evident within populations from a specific site, corresponding to relative stages of macrophage maturity. Immune perturbation with intestinal helminth infection increases alternative activation and metabolic rewiring of monocyte-derived macrophage populations, while resident TIM4+ intestinal macrophages remain immunologically and metabolically hyporesponsive. Similar metabolic signatures in alternatively-activated macrophages are seen from different tissues using additional helminth models, but to different magnitudes, indicating further tissue-specific contributions to metabolic states. Thus, our high-dimensional, flow-based metabolic analyses indicates complex metabolic heterogeneity and dynamics of tissue-resident macrophage populations at homeostasis and during helminth infection.
  9. Trends Immunol. 2023 Sep 14. pii: S1471-4906(23)00162-X. [Epub ahead of print]
      pH is tightly maintained at cellular, tissue, and systemic levels, and altered pH - particularly in the acidic range - is associated with infection, injury, solid tumors, and physiological and pathological inflammation. However, how pH is sensed and regulated and how it influences immune responses remain poorly understood at the tissue level. Applying conceptual frameworks of homeostatic and inflammatory circuitries, we categorize cellular and tissue components engaged in pH regulation, drawing parallels from established cases in physiology. By expressing various intracellular (pHi) and extracellular pH (pHe)-sensing receptors, the immune system may integrate information on tissue and cellular states into the regulation of homeostatic and inflammatory programs. We introduce the novel concept of resistance and adaptation responses to rationalize pH-dependent immunomodulation intertwined with homeostatic equilibrium and inflammatory control. We discuss emerging challenges and opportunities in understanding the immunological roles of pH sensing, which might reveal new strategies to combat inflammation and restore tissue homeostasis.
    Keywords:  acidic environment; adaptation; inflammatory response; pH homeostasis; pH sensing; resistance
  10. Cell. 2023 Sep 14. pii: S0092-8674(23)00851-6. [Epub ahead of print]186(19): 4007-4037
      The TGF-β regulatory system plays crucial roles in the preservation of organismal integrity. TGF-β signaling controls metazoan embryo development, tissue homeostasis, and injury repair through coordinated effects on cell proliferation, phenotypic plasticity, migration, metabolic adaptation, and immune surveillance of multiple cell types in shared ecosystems. Defects of TGF-β signaling, particularly in epithelial cells, tissue fibroblasts, and immune cells, disrupt immune tolerance, promote inflammation, underlie the pathogenesis of fibrosis and cancer, and contribute to the resistance of these diseases to treatment. Here, we review how TGF-β coordinates multicellular response programs in health and disease and how this knowledge can be leveraged to develop treatments for diseases of the TGF-β system.
  11. Apoptosis. 2023 Sep 14.
      Pulmonary fibrosis (PF) is a disease in which excessive extracellular matrix (ECM) accumulation occurs in pulmonary mesenchyme, which induces the destruction of alveolar structures and poor prognosis. Macrophage death is responsible for ECM accumulation after alveolar epithelial injury in PF. Depending on the local micro-environments, macrophages can be polarized to either classically activated (M1) or alternatively activated (M2) macrophage phenotypes. In general, M1 macrophages can promote inflammation and sterilization, stop the continuous damage process and prevent excessive repair, while M2 macrophages are anti-inflammatory and promote tissue repair, and excessive M2 macrophage activity may inhibit the absorption and degradation of ECM. Emerging evidence has revealed that death forms such as pyroptosis mediated by inflammasome affect polarization direction and ultimately lead to the development of PF. Pharmacological manipulation of macrophages death signals may serve as a logical therapeutic strategy for PF. This review will focus on the current state of knowledge regarding the regulation and underlying mechanisms of macrophages and their mediators in the influence of macrophage death on the development of PF. We expect to provide help in developing effective therapeutic strategies in clinical settings.
    Keywords:  Alternatively activated (M2) macrophages phenotypes; Classically activated (M1) macrophages phenotypes; Macrophage polarization; Pulmonary fibrosis; Pyroptosis
  12. J Thorac Dis. 2023 Aug 31. 15(8): 4396-4412
      Background: As the first line of defense, epithelial cells play a vital role in the initiation and control of both innate and adaptive immunity, which participate in the development of disease. Despite its therapeutic significance, little is understood about the specific interaction between pathogenic microorganisms and lung epithelial cells.Methods: In this study, we performed a head-to-head comparison of the virulence and infection mechanisms of Klebsiella pneumoniae (K. pneumoniae) and Mycobacterium smegmatis (M. smegmatis), which represent Gram-negative/positive respiratory pathogens, respectively, in lung epithelial cell models for the first time.
    Results: Through scanning electron microscopy combined with bacterial infection experiments, we confirmed the ability of K. pneumoniae and M. smegmatis strains to form biofilm and cord factor out of the cell wall. M. smegmatis has stronger adhesion and intracellular retention ability, while K. pneumoniae is more likely to induce acute infection. These pathogens could stay and proliferate in lung epithelial cells and stimulate the secretion of specific cytokines and chemokines through a gene transcription regulator. M. smegmatis infection can promote crosstalk among epithelial cells and other immune cells in the lung from a very early stage by prompting the secretion of pro-inflammatory cytokines. Meanwhile, there were significant correlations between K. pneumonia infection and higher levels of interleukin-15 (IL-15), interleukin-1Rα (IL-1Rα), fibroblast growth factor (FGF) basic, and granulocyte colony-stimulating factor (G-CSF). At the same time, K. pneumonia infection also led to changes in the expression of cytoskeletal proteins in epithelial cells.
    Conclusions: Our results emphasized the immunoprotection and immunomodulation of lung epithelial cells against exogenous pathogenic microorganisms, indicating that different pathogens damaged the host through different strategies and induced varying innate immune responses. At the same time, they provided important clues and key immune factors for dealing with complicated pulmonary infections.
    Keywords:   A549; Klebsiella pneumoniae (K. pneumoniae); Mycobacterium smegmatis (M. smegmatis); RNA-seq; cytokines
  13. Int Arch Allergy Immunol. 2023 Sep 08. 1-10
      INTRODUCTION: The composition and co-occurrence network of the airway microbiome might influence the asthma inflammatory phenotype. Airway microbiota change with asthma phenotypes, and the structure of the bacterial community in the airway might differ between different asthma inflammatory phenotypes and may also influence therapy results. Identifying airway microbiota can help to investigate the role that microbiota play in the asthma inflammatory process.METHODS: Induced sputum from 55 subjects and 12 healthy subjects from Beijing, China, was collected and analyzed for bacterial microbiota. Microbiome diversity, composition, co-occurrence networks, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were predicted and compared between the study groups.
    RESULTS: Significant differences in the sputum microbiome composition, co-occurrence network, and predicted functional pathways were observed between the two inflammatory phenotypes. Asthmatics in the low FeNO group exhibited lower α-diversity in the sputum microbiota and had higher abundance of the phylum Proteobacteria compared with that of the high FeNO group. The network in the high FeNO group was more "closed" and "connected" compared with that of the low FeNO group, and an alteration in the abundance of keystone species T. socranskii was found. Significantly different predicted metabolic subfunctions including nucleotide metabolism, lipid metabolism, energy metabolism, replication and repair, and drug resistance antimicrobial and carbohydrate metabolism between the two studied phenotypes were also observed.
    CONCLUSION: Our findings confirm that the airway microbiota is associated with the asthma inflammation process. The differences in the airway microbiome composition and co-occurrence network may affect distinct asthma inflammatory phenotypes, suggesting the possibility that more targeted therapies could be applied based on the airway bacterial genera.
    Keywords:  Asthma; Co-occurrence network; FeNO; Inflammatory phenotype; Microbiome
  14. BMC Infect Dis. 2023 Sep 13. 23(1): 596
      Acute otitis media (AOM) is the most common childhood bacterial infectious disease requiring antimicrobial therapy. Most cases of AOM are caused by translocation of Streptococcus pneumoniae or Haemophilus influenzae from the nasopharynx to the middle ear during an upper respiratory tract infection (URI). Ongoing genomic surveillance of these pathogens is important for vaccine design and tracking of emerging variants, as well as for monitoring patterns of antibiotic resistance to inform treatment strategies and stewardship.In this work, we examined the ability of a genomics-based workflow to determine microbiological and clinically relevant information from cultured bacterial isolates obtained from patients with AOM or an URI. We performed whole genome sequencing (WGS) and analysis of 148 bacterial isolates cultured from the nasopharynx (N = 124, 94 AOM and 30 URI) and ear (N = 24, all AOM) of 101 children aged 6-35 months presenting with AOM or an URI. We then performed WGS-based sequence typing and antimicrobial resistance profiling of each strain and compared results to those obtained from traditional microbiological phenotyping.WGS of clinical isolates resulted in 71 S. pneumoniae genomes and 76 H. influenzae genomes. Multilocus sequencing typing (MSLT) identified 33 sequence types for S. pneumoniae and 19 predicted serotypes including the most frequent serotypes 35B and 3. Genome analysis predicted 30% of S. pneumoniae isolates to have complete or intermediate penicillin resistance. AMR predictions for S. pneumoniae isolates had strong agreement with clinical susceptibility testing results for beta-lactam and non beta-lactam antibiotics, with a mean sensitivity of 93% (86-100%) and a mean specificity of 98% (94-100%). MLST identified 29 H. influenzae sequence types. Genome analysis identified beta-lactamase genes in 30% of H. influenzae strains, which was 100% in agreement with clinical beta-lactamase testing. We also identified a divergent highly antibiotic-resistant strain of S. pneumoniae, and found its closest sequenced strains, also isolated from nasopharyngeal samples from over 15 years ago.Ultimately, our work provides the groundwork for clinical WGS-based workflows to aid in detection and analysis of H. influenzae and S. pneumoniae isolates.
    Keywords:  Acute otitis media; Antibiotics; Antimicrobial resistance; Genomic surveillance; Haemophilus influenzae; Pathogens; Streptococcus pneumoniae; Upper respiratory infection
  15. Trends Mol Med. 2023 Sep 08. pii: S1471-4914(23)00196-X. [Epub ahead of print]
      Toxicants such as smoke, biofuel, and pollutants constantly challenge our respiratory health, but little is known about the pathophysiological processes involved. In a new report, Lin et al. provide evidence that our bacterial and fungal lung populations orchestrate the interplay between environmental exposure and lung functions, thereby conditioning health outcomes.
    Keywords:  Aspergillus; airway microbiome; environment; exposome; mycobiome; particulate matter; smoking
  16. Semin Immunol. 2023 Sep 11. pii: S1044-5323(23)00132-X. [Epub ahead of print]70 101841
      Cells undergo an inflammatory programmed lytic cell death called 'pyroptosis' (with the Greek roots 'fiery'), often featuring morphological hallmarks such as large ballooning protrusions and subsequent bursting. Originally described as a caspase-1-dependent cell death in response to bacterial infection, pyroptosis has since been re-defined in 2018 as a cell death dependent on plasma membrane pores by a gasdermin (GSDM) family member [1,2]. GSDMs form pores in the plasma membrane as well as organelle membranes, thereby initiating membrane destruction and the rapid and lytic demise of a cell. The gasdermin family plays a profound role in the execution of pyroptosis in the context of infection, inflammation, tumor pathogenesis, and anti-tumor therapy. More recently, cell-death-independent functions for some of the GSDMs have been proposed. Therefore, a comprehensive understanding of gasdermin gene regulation, including mechanisms in both homeostatic conditions and during inflammation, is essential. In this review, we will summarize the role of gasdermins in pyroptosis and focus our discussion on the transcriptional and epigenetic mechanisms controlling the expression of GSDMs.
    Keywords:  Epigenetic regulation; Gasdermins; Isoforms; Pyroptosis; Transcriptional regulation
  17. J Allergy Clin Immunol. 2023 Sep 07. pii: S0091-6749(23)01115-6. [Epub ahead of print]
      Global warming has direct and indirect effects, as well as short- and long-term impacts on the respiratory and skin barriers. Extreme temperature directly affects the airway epithelial barrier by disrupting the structural proteins and by triggering airway inflammation and hyperreactivity. It enhances tidal volume and respiratory rate by affecting the thermoregulatory system, causing specific airway resistance and reflex bronchoconstriction via activation of bronchopulmonary vagal C-fibers and upregulation of transient receptor potential vanilloid (TRPV) 1 and TRPV4. Heat shock proteins are activated under heat stress and contribute to both epithelial barrier dysfunction and airway inflammation. Accordingly, the frequency and severity of allergic rhinitis and asthma have been increasing. Heat activates TRPV3 in keratinocytes causing the secretion of inflammatory mediators and eventually pruritus. Exposure to air pollutants alters the expression of genes that control skin barrier integrity and triggers an immune response, increasing the incidence and prevalence of atopic dermatitis (AD). There is evidence that extreme temperature, heavy rains and floods, air pollution and wildfires increase AD flares. In this narrative review, focused on the last 3 years of literature, we explore the effects of global warming on respiratory and skin barrier and their clinical consequences.
    Keywords:  allergic diseases; allergic rhinitis; asthma; atopic dermatitis; climate change; epithelial barrier; extreme temperature; global warming; pollution
  18. Crit Rev Microbiol. 2023 Sep 11. 1-22
      The oral cavity contains a site-specific microbiota that interacts with host cells to regulate many physiological processes in the human body. Emerging evidence has suggested that changes in the oral microbiota can increase the risk of lung cancer (LC), and the oral microbiota is also altered in patients with LC. Human and animal studies have shown that oral microecological disorders and/or specific oral bacteria may play an active role in the occurrence and development of LC through direct and/or indirect mechanisms. These studies support the potential of oral microbiota in the clinical treatment of LC. Oral microbiota may therefore be used in the prevention and treatment of LC and to improve the side effects of anticancer therapy by regulating the balance of the oral microbiome. Specific oral microbiota in LC may also be used as screening or predictive biomarkers. This review summarizes the main findings in research on oral microbiome-related LC and discusses current challenges and future research directions.
    Keywords:  Oral microbiota; diagnosis; lung cancer; mechanism; prevention
  19. Nat Rev Microbiol. 2023 Sep 12.
      The human oral microbiota is highly diverse and has a complex ecology, comprising bacteria, microeukaryotes, archaea and viruses. These communities have elaborate and highly structured biogeography that shapes metabolic exchange on a local scale and results from the diverse microenvironments present in the oral cavity. The oral microbiota also interfaces with the immune system of the human host and has an important role in not only the health of the oral cavity but also systemic health. In this Review, we highlight recent advances including novel insights into the biogeography of several oral niches at the species level, as well as the ecological role of candidate phyla radiation bacteria and non-bacterial members of the oral microbiome. In addition, we summarize the relationship between the oral microbiota and the pathology of oral diseases and systemic diseases. Together, these advances move the field towards a more holistic understanding of the oral microbiota and its role in health, which in turn opens the door to the study of novel preventive and therapeutic strategies.
  20. Am J Physiol Cell Physiol. 2023 Sep 11.
      Pulmonary fibrosis (PF) results from a plethora of abnormal pathogenetic events. In Idiopathic Pulmonary Fibrosis (IPF), inhalational, environmental, or occupational exposures in genetically and epigenetically predisposed individuals, triggers recurrent cycles of alveolar epithelial cell injury, activation of coagulation pathways, chemoattraction, and differentiation of monocytes into monocyte-derived alveolar macrophages (Mo-AMs). When these events happen intermittently and repeatedly throughout the individual's life cycle, the wound repair process becomes aberrant leading to bronchiolization of distal airspaces, fibroblast accumulation, extracellular matrix deposition and loss of the alveolar-capillary architecture. The role of immune dysregulation in IPF pathogenesis and progression has been underscored in the past mainly after the disappointing results of immunosuppressant use in IPF patients, however, recent reports highlighting the prognostic and mechanistic roles of monocytes and Mo-AMs revived the interest of immune dysregulation in IPF. In this review, we will discuss the role of these cells in the onset and progression of IPF, as well as potential targeted therapies.
    Keywords:  biomarkers; immune dysregulation; macrophages; monocytes; pulmonary fibrosis
  21. Therap Adv Gastroenterol. 2023 ;16 17562848231176889
      Inflammatory bowel disease (IBD) is a chronic gastrointestinal inflammatory disease that involves host genetics, the microbiome, and inflammatory responses. The current consensus is that the disruption of the intestinal mucosal barrier is the core pathogenesis of IBD, including intestinal microbial factors, abnormal immune responses, and impaired intestinal mucosal barrier. Cumulative data show that nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs) are dominant mediators in maintaining the homeostasis of the intestinal mucosal barrier, which play critical roles in sensing the commensal microbiota, maintaining homeostasis, and regulating intestinal inflammation. Blocking NLRs inflammasome activation by botanicals may be a promising way to prevent IBD progression. In this review, we systematically introduce the multiple roles of NLRs in regulating intestinal mucosal barrier homeostasis and focus on summarizing the activities and potential mechanisms of natural products against IBD. Aiming to propose new directions on the pathogenesis and precise treatment of IBD.
    Keywords:  IBD; NLRs; intestinal mucosal barrier; natural products; pathogenesis
  22. J Clin Invest. 2023 Sep 12. pii: e171982. [Epub ahead of print]
    Keywords:  Bacterial infections; Immunology; Infectious disease; Innate immunity; Macrophages
  23. Front Immunol. 2023 ;14 1240327
      Ischemia causes an inflammatory response featuring monocyte-derived macrophages (MF) involved in angiogenesis and tissue repair. Angiogenesis and ischemic macrophage differentiation are regulated by Notch signaling via Notch ligand Delta-like 1 (Dll1). Colony stimulating factor 1 (CSF-1) is an essential MF lineage factor, but its role in ischemic macrophage development and the interaction with Notch signaling is so far unclear. Using a mouse model of hind limb ischemia with CSF-1 inhibitor studies and Dll1 heterozygous mice we show that CSF-1 is induced in the ischemic niche by a subpopulation of stromal cells expressing podoplanin, which was paralleled by the development of ischemic macrophages. Inhibition of CSF-1 signaling with small molecules or blocking antibodies impaired macrophage differentiation but prolonged the inflammatory response, resulting in impaired perfusion recovery and tissue regeneration. Yet, despite high levels of CSF-1, macrophage maturation and perfusion recovery were impaired in mice with Dll1 haploinsufficiency, while inflammation was exaggerated. In vitro, CSF-1 was not sufficient to induce full MF differentiation from donor monocytes in the absence of recombinant DLL1, while the presence of DLL1 in a dose-dependent manner stimulated MF differentiation in combination with CSF-1. Thus, CSF-1 is an ischemic niche factor that cooperates with Notch signaling in a non-redundant fashion to instruct macrophage cell fate and maturation, which is required for ischemic perfusion recovery and tissue repair.
    Keywords:  CSF-1; CSF-1 inhibition; inflammation; ischemia; macrophages; notch signaling
  24. Cell Rep. 2023 Sep 08. pii: S2211-1247(23)01080-X. [Epub ahead of print] 113069
      Outcomes of severe bacterial infections are determined by the interplay between host, pathogen, and treatments. While human genomics has provided insights into host factors impacting Staphylococcus aureus infections, comparatively little is known about S. aureus genotypes and disease severity. Building on the hypothesis that bacterial pathoadaptation is a key outcome driver, we developed a genome-wide association study (GWAS) framework to identify adaptive mutations associated with treatment failure and mortality in S. aureus bacteremia (1,358 episodes). Our research highlights the potential of vancomycin-selected mutations and vancomycin minimum inhibitory concentration (MIC) as key explanatory variables to predict infection severity. The contribution of bacterial variation was much lower for clinical outcomes (heritability <5%); however, GWASs allowed us to identify additional, MIC-independent candidate pathogenesis loci. Using supervised machine learning, we were able to quantify the predictive potential of these adaptive signatures. Our statistical genomics framework provides a powerful means to capture adaptive mutations impacting severe bacterial infections.
    Keywords:  CP: Genomics; CP: Microbiology; Staphylococcus aureus; bacteraemia; bacterial GWAS; machine learning; vancomycin resistance
  25. bioRxiv. 2023 Sep 02. pii: 2023.07.21.549941. [Epub ahead of print]
      The role of the intestinal microbiota in host health is increasingly revealed in its contributions to disease states. The host-microbiome interaction is multifactorial and dynamic. One of the factors that has recently been strongly associated with host physiological responses is peptidoglycan from bacterial cell walls. Peptidoglycan from gut commensal bacteria activate peptidoglycan sensors in human cells, including the Nucleotide-binding oligomerization domain containing protein 2 (NOD2). When present in the gastrointestinal tract, both the polymeric form (sacculi) and de-polymerized fragments can modulate host physiology, including checkpoint anticancer therapy efficacy, body temperature and appetite, and postnatal growth. To leverage this growing area of biology towards therapeutic prescriptions, it will be critical to directly analyze a key feature of the host-microbiome interaction from living hosts in a reproducible and non-invasive way. Here we show that metabolically labeled peptidoglycan/sacculi can be readily isolated from fecal samples collected from both mice and humans. Analysis of fecal samples provided a non-invasive route to probe the gut commensal community including the metabolic synchronicity with the host circadian clock. Together, these results pave the way for non-invasive diagnostic tools to interrogate the causal nature of peptidoglycan in host health and disease.
  26. Front Immunol. 2023 ;14 1227024
      Background: The mechanisms of hypertrophic scar formation and its tissue inflammation remain unknown.Methods: We collected 33 hypertrophic scar (HS) and 36 normal skin (NS) tissues, and detected the tissue inflammation and bacteria using HE staining, Gram staining, and transmission electronic microscopy (TEM), in situ hybridization and immunohistochemistry for MCP-1, TNF-α, IL-6 and IL-8. In addition, the samples were assayed by 16S rRNA sequencing to investigate the microbiota diversity in HS, and the correlation between the microbiota and the indices of Vancouver Scar Scale(VSS)score.
    Results: HE staining showed that a dramatically increased number of inflammatory cells accumulated in HS compared with NS, and an enhanced number of bacteria colonies was found in HS by Gram staining, even individual bacteria could be clearly observed by TEM. In situ hybridization demonstrated that the bacteria and inflammation cells co-localized in the HS tissues, and immunohistochemistry indicated the expression of MCP-1, TNF-α, IL-6, and IL-8 were significantly upregulated in HS than that in NS. In addition, there was a significantly different microbiota composition between HS and NS. At the phylum level, Firmicutes was significantly higher in HS than NS. At the genus level, S. aureus was the dominant species, which was significantly higher in HS than NS, and was strongly correlated with VSS indices.
    Conclusion: Microbiome dysbiosis, dominated by S. aureus, occurred in HS formation, which is correlated with chronic inflammation and scar formation, targeting the microbiome dysbiosis is perhaps a supplementary way for future scar management.
    Keywords:  S. aureus; Vancouver Scar Score; hypertrophic scar; inflammation; microbiome dysbiosis
  27. Helicobacter. 2023 Sep 10. e13020
      Helicobacter pylori (H. pylori) is a gram-negative, microaerobic bacterium that colonizes the gastric mucosa in about half of the world's population. H. pylori infection can lead to various diseases. Chronic infection by H. pylori exposes the gastric mucosa to bacterial components such as lipopolysaccharide (LPS), outer membrane vesicles (OMVs), and several toxic proteins. Infected with H. pylori activates the release of pro-inflammatory factors and triggers inflammatory responses that damage the gastric mucosa. As the only microorganism that permanently colonizes the human stomach, H. pylori can suppress host immunity to achieve long-term colonization. Toll-like receptors (TLRs) play a crucial role in T-cell activation, promoting innate immune responses and immune tolerance during H. pylori infection. Among the 10 TLRs found in humans, TLR2, TLR4, TLR5, and TLR9 have been thoroughly investigated in relation to H. pylori-linked immune regulation. In the present review, we provide a comprehensive analysis of the various mechanisms employed by different TLRs in the induction of immune tolerance upon H. pylori infection, which will contribute to the research of pathogenic mechanism of H. pylori.
    Keywords:   H. pylori ; immune tolerance; toll-like receptor
  28. Nat Commun. 2023 Sep 12. 14(1): 5628
      The postnatal interaction between microbiota and the immune system establishes lifelong homeostasis at mucosal epithelial barriers, however, the barrier-specific physiological activities that drive the equilibrium are hardly known. During weaning, the oral epithelium, which is monitored by Langerhans cells (LC), is challenged by the development of a microbial plaque and the initiation of masticatory forces capable of damaging the epithelium. Here we show that microbial colonization following birth facilitates the differentiation of oral LCs, setting the stage for the weaning period, in which adaptive immunity develops. Despite the presence of the challenging microbial plaque, LCs mainly respond to masticatory mechanical forces, inducing adaptive immunity, to maintain epithelial integrity that is also associated with naturally occurring alveolar bone loss. Mechanistically, masticatory forces induce the migration of LCs to the lymph nodes, and in return, LCs support the development of immunity to maintain epithelial integrity in a microbiota-independent manner. Unlike in adult life, this bone loss is IL-17-independent, suggesting that the establishment of oral mucosal homeostasis after birth and its maintenance in adult life involve distinct mechanisms.
  29. PLoS Pathog. 2023 Sep 11. 19(9): e1011138
      Pneumonia is a worldwide threat, making discovery of novel means to combat lower respiratory tract infection an urgent need. Manipulating the lungs' intrinsic host defenses by therapeutic delivery of certain pathogen-associated molecular patterns protects mice against pneumonia in a reactive oxygen species (ROS)-dependent manner. Here we show that antimicrobial ROS are induced from lung epithelial cells by interactions of CpG oligodeoxynucleotides (ODN) with mitochondrial voltage-dependent anion channel 1 (VDAC1). The ODN-VDAC1 interaction alters cellular ATP/ADP/AMP localization, increases delivery of electrons to the electron transport chain (ETC), increases mitochondrial membrane potential (ΔΨm), differentially modulates ETC complex activities and consequently results in leak of electrons from ETC complex III and superoxide formation. The ODN-induced mitochondrial ROS yield protective antibacterial effects. Together, these studies identify a therapeutic metabolic manipulation strategy to broadly protect against pneumonia without reliance on antibiotics.
  30. Nat Metab. 2023 Sep 11.
      Lipids can be of endogenous or exogenous origin and affect diverse biological functions, including cell membrane maintenance, energy management and cellular signalling. Here, we report >800 lipid species, many of which are associated with health-to-disease transitions in diabetes, ageing and inflammation, as well as cytokine-lipidome networks. We performed comprehensive longitudinal lipidomic profiling and analysed >1,500 plasma samples from 112 participants followed for up to 9 years (average 3.2 years) to define the distinct physiological roles of complex lipid subclasses, including large and small triacylglycerols, ester- and ether-linked phosphatidylethanolamines, lysophosphatidylcholines, lysophosphatidylethanolamines, cholesterol esters and ceramides. Our findings reveal dynamic changes in the plasma lipidome during respiratory viral infection, insulin resistance and ageing, suggesting that lipids may have roles in immune homoeostasis and inflammation regulation. Individuals with insulin resistance exhibit disturbed immune homoeostasis, altered associations between lipids and clinical markers, and accelerated changes in specific lipid subclasses during ageing. Our dataset based on longitudinal deep lipidome profiling offers insights into personalized ageing, metabolic health and inflammation, potentially guiding future monitoring and intervention strategies.
  31. J Exp Med. 2023 Nov 06. pii: e20230106. [Epub ahead of print]220(11):
      Major histocompatibility complex (MHC) II is dynamically expressed on mucosal epithelial cells and is induced in response to inflammation and parasitic infections, upon exposure to microbiota, and is increased in chronic inflammatory diseases. However, the regulation of epithelial cell-specific MHC II during homeostasis is yet to be explored. We discovered a novel role for IL-22 in suppressing epithelial cell MHC II partially via the regulation of endoplasmic reticulum (ER) stress, using animals lacking the interleukin-22-receptor (IL-22RA1), primary human and murine intestinal and respiratory organoids, and murine models of respiratory virus infection or with intestinal epithelial cell defects. IL-22 directly downregulated interferon-γ-induced MHC II on primary epithelial cells by modulating the expression of MHC II antigen A α (H2-Aα) and Class II transactivator (Ciita), a master regulator of MHC II gene expression. IL-22RA1-knockouts have significantly higher MHC II expression on mucosal epithelial cells. Thus, while IL-22-based therapeutics improve pathology in chronic disease, their use may increase susceptibility to viral infections.