bims-bac4me Biomed News
on Microbiome and trained immunity
Issue of 2023‒07‒23
seventeen papers selected by
Chun-Chi Chang
University Hospital Zurich

  1. Curr Opin Immunol. 2023 Jul 18. pii: S0952-7915(23)00088-2. [Epub ahead of print]84 102369
      Macrophages are phagocytic cells distributed across tissues that sustain homeostasis by constantly probing their local environment. Upon perturbations, macrophages rewire their energy metabolism to execute their immune programs. Intensive research in the field of immunometabolism highlights cell-intrinsic immunometabolites such as succinate and itaconate as immunomodulatory signals. A role for cell-extrinsic stimuli now emerges with evidence for signals that shape macrophages' metabolism in a tissue-specific manner. In this review, we will cover macrophage immunometabolism in the gut, a complex metabolic and immunologically active tissue. During homeostasis, gut macrophages are constantly exposed to pro-inflammatory ligands from the microbiota, and in contrast, are balanced by microbiota-derived anti-inflammatory metabolites. Given their extensive metabolic changes during activation, spatial analyses of the tissue will allow the characterization of metabolic niches of macrophage in the gut. Identifying metabolic perturbations of macrophage subsets during chronic inflammation and infection can direct future tissue-specific metabolotherapies.
  2. Front Immunol. 2023 ;14 1169560
      Most of the leading causes of death, such as cardiovascular diseases, cancer, dementia, neurodegenerative diseases, and many more, are associated with sterile inflammation, either as a cause or a consequence of these conditions. The ability to control the progression of inflammation toward tissue resolution before it becomes chronic holds significant clinical potential. During sterile inflammation, the initiation of inflammation occurs through damage-associated molecular patterns (DAMPs) in the absence of pathogen-associated molecules. Macrophages, which are primarily localized in the tissue, play a pivotal role in sensing DAMPs. Furthermore, macrophages can also detect and respond to resolution-associated molecular patterns (RAMPs) and specific pro-resolving mediators (SPMs) during sterile inflammation. Macrophages, being highly adaptable cells, are particularly influenced by changes in the microenvironment. In response to the tissue environment, monocytes, pro-inflammatory macrophages, and pro-resolution macrophages can modulate their differentiation state. Ultimately, DAMP and RAMP-primed macrophages, depending on the predominant subpopulation, regulate the balance between inflammatory and resolving processes. While sterile injury and pathogen-induced reactions may have distinct effects on macrophages, most studies have focused on macrophage responses induced by pathogens. In this review, which emphasizes available human data, we illustrate how macrophages sense these mediators by examining the expression of receptors for DAMPs, RAMPs, and SPMs. We also delve into the signaling pathways induced by DAMPs, RAMPs, and SPMs, which primarily contribute to the regulation of macrophage differentiation from a pro-inflammatory to a pro-resolution phenotype. Understanding the regulatory mechanisms behind the transition between macrophage subtypes can offer insights into manipulating the transition from inflammation to resolution in sterile inflammatory diseases.
    Keywords:  DAMP; RAMP; SPM; differentiation; macrophage; polarization; sterile inflammation
  3. Curr Res Immunol. 2023 ;4 100065
      The studies on the composition of the human microbiomes in healthy individuals, its variability in the course of inflammation, infection, antibiotic therapy, diets and different pathological conditions have revealed their intra and inter-kingdom relationships. The lung microbiome comprises of major species members of the phylum Bacteroidetes, Firmicutes, Actinobacteria, Fusobacteria and Proteobacteria, which are distributed in ecological niches along nasal cavity, nasopharynx, oropharynx, trachea and in the lungs. Commensal and pathogenic species are maintained in equilibrium as they have strong relationships. Bacterial overgrowth after dysbiosis and/or imbalanced of CD4+ helper T cells, CD8+ cytotoxic T cells and regulatory T cells (Treg) populations can promote lung inflammatory reactions and distress, and consequently acute and chronic respiratory diseases. This review is aimed to summarize the latest advances in resident lung microbiome and its participation in most common pulmonary infections and pneumonia, community-acquired pneumonia (CAP), ventilator-associated pneumonia (VAP), immunodeficiency associated pneumonia, SARS-CoV-2-associated pneumonia, acute respiratory distress syndrome (ARDS) and chronic obstructive pulmonary disease (COPD). We briefly describe physiological and immunological mechanisms that selectively create advantages or disadvantages for relative growth of pathogenic bacterial species in the respiratory tract. At the end, we propose some directions and analytical methods that may facilitate the identification of key genera and species of resident and transient microbes involved in the respiratory diseases' initiation and progression.
    Keywords:  ARDS; COPD; Community-acquired pneumonia; Inflammation; Microbiomes; Respiratory diseases
  4. Front Immunol. 2023 ;14 1202009
      Background: Cystic fibrosis (CF) airway disease is characterized by chronic inflammation, featuring neutrophil influx to the lumen. Airway macrophages (AMs) can promote both inflammation and resolution, and are thus critical to maintaining and restoring homeostasis. CF AM functions, specifically scavenging activity and resolution of inflammation, have been shown to be impaired, yet underlying processes remain unknown. We hypothesized that impaired CF AM function results from an altered expression of receptors that mediate or regulate scavenging, and set out to investigate changes in expression of these markers during the early stages of CF lung disease.Methods: Bronchoalveolar lavage fluid (BALF) was collected from 50 children with CF aged 1, 3 or 5 years. BALF cells were analyzed using flow cytometry. Expression levels of surface markers on AMs were expressed as median fluorescence intensities (MFI) or percentage of AMs positive for these markers. The effect of age and neutrophilic inflammation, among other variables, on marker expression was assessed with a multivariate linear regression model.
    Results: AM expression of scavenger receptor CD163 decreased with age (p = 0.016) and was negatively correlated with BALF %neutrophils (r = -0.34, p = 0.016). AM expression of immune checkpoint molecule SIRPα also decreased with age (p = 0.0006), but did not correlate with BALF %neutrophils. Percentage of AMs expressing lipid scavenger CD36 was low overall (mean 20.1% ± 16.5) and did not correlate with other factors. Conversely, expression of immune checkpoint PD-1 was observed on the majority of AMs (mean PD-1pos 72.9% ± 11.8), but it, too, was not affected by age or BALF %neutrophils. Compared to matched blood monocytes, AMs had a higher expression of CD16, CD91, and PD-1, and a lower expression of CD163, SIRPα and CD36.
    Conclusion: In BALF of preschool children with CF, higher age and/or increased neutrophilic inflammation coincided with decreased expression of scavenger receptors on AMs. Expression of scavenging receptors and regulators showed a distinctly different pattern in AMs compared to blood monocytes. These findings suggest AM capacity to counter inflammation and promote homeostasis reduces during initiation of CF airway disease and highlight new avenues of investigation into impaired CF AM function.
    Keywords:  airway macrophages; children; cystic fibrosis; inflammation; lung disease; neutrophils; resolution; scavenger receptor
  5. Curr Opin Immunol. 2023 Jul 12. pii: S0952-7915(23)00085-7. [Epub ahead of print]84 102366
      In addition to housing the major energy-producing pathways in cells, mitochondria are active players in innate immune responses. One critical way mitochondria fulfill this role is by releasing damage-associated molecular patterns (mtDAMPs) that are recognized by innate sensors to activate pathways including, but not limited to, cytokine expression, selective autophagy, and cell death. Mitochondrial reactive oxygen species (mtROS) is a multifunctional mtDAMP linked to pro- and antimicrobial immune outcomes. Formed as a by-product of energy generation, mtROS links mitochondrial metabolism with downstream innate immune responses. As a result, altered cellular metabolism can change mtROS levels and impact downstream antimicrobial responses in a variety of ways. MtROS has emerged as a particularly important mediator of pathogenesis during infection with Mycobacterium tuberculosis (Mtb), an intracellular bacterial pathogen that continues to pose a significant threat to global public health. Here, we will summarize how Mtb modulates mtROS levels in infected macrophages and how mtROS dictates Mtb infection outcomes by controlling inflammation, lipid peroxidation, and cell death. We propose that mtROS may serve as a biomarker to predict tuberculosis patient outcomes and/or a target for host-directed therapeutics.
  6. Front Immunol. 2023 ;14 1211221
      Cellular metabolism plays a critical role in determining the fate and function of cells. Metabolic reprogramming and its byproducts have a complex impact on cellular activities. In quiescent T cells, oxidative phosphorylation (OXPHOS) is the primary pathway for survival. However, upon antigen activation, T cells undergo rapid metabolic reprogramming, characterized by an elevation in both glycolysis and OXPHOS. While both pathways are induced, the balance predominantly shifts towards glycolysis, enabling T cells to rapidly proliferate and enhance their functionality, representing the most distinctive signature during activation. Metabolic processes generate various small molecules resulting from enzyme-catalyzed reactions, which also modulate protein function and exert regulatory control. Notably, recent studies have revealed the direct modification of histones, known as lactylation, by lactate derived from glycolysis. This lactylation process influences gene transcription and adds a novel variable to the regulation of gene expression. Protein lactylation has been identified as an essential mechanism by which lactate exerts its diverse functions, contributing to crucial biological processes such as uterine remodeling, tumor proliferation, neural system regulation, and metabolic regulation. This review focuses on the metabolic reprogramming of T cells, explores the interplay between lactate and the immune system, highlights the impact of lactylation on cellular function, and elucidates the intersection of metabolic reprogramming and epigenetics.
    Keywords:  epigenetics; glycolysis; lactate; lactylation; metabolic reprogramming
  7. Immunity. 2023 Jul 12. pii: S1074-7613(23)00280-7. [Epub ahead of print]
      Invasive fungal infections are associated with high mortality rates, and the lack of efficient treatment options emphasizes an urgency to identify underlying disease mechanisms. We report that disseminated Candida albicans infection is facilitated by interleukin-1 receptor antagonist (IL-1Ra) secreted from macrophages in two temporally and spatially distinct waves. Splenic CD169+ macrophages release IL-1Ra into the bloodstream, impeding early neutrophil recruitment. IL-1Ra secreted by monocyte-derived tissue macrophages further impairs pathogen containment. Therapeutic IL-1Ra neutralization restored the functional competence of neutrophils, corrected maladapted hyper-inflammation, and eradicated the otherwise lethal infection. Conversely, augmentation of macrophage-secreted IL-1Ra by type I interferon severely aggravated disease mortality. Our study uncovers how a fundamental immunoregulatory mechanism mediates the high disease susceptibility to invasive candidiasis. Furthermore, interferon-stimulated IL-1Ra secretion may exacerbate fungal dissemination in human patients with secondary candidemia. Macrophage-secreted IL-1Ra should be considered as an additional biomarker and potential therapeutic target in severe systemic candidiasis.
    Keywords:  disseminated candidiasis; inflammation; interferon; interleukin 1 receptor antagonist; interleukin-1; invasive fungal infection; macrophage; marginal zone; neutrophil; sepsis
  8. Adv Exp Med Biol. 2023 ;1426 265-285
      Innate immune responses (IIR) of the epithelium play a critical role in the initiation and progression of asthma. The core of the IIR is an intracellular signaling pathway activated by pattern recognition receptors (PRRs) to limit the spread of infectious organisms. This chapter will focus on the epithelium as the major innate sentinel cell and its role in acute exacerbations (AEs). Although the pathways of how the IIR activates the NFκB transcription factor, triggering cytokine secretion, dendritic cell activation, and Th2 polarization are well-described, recent exciting work has developed mechanistic insights into how chronic activation of the IIR is linked to mucosal adaptive responses. These adaptations include changes in cell state, now called epithelial-mesenchymal plasticity (EMP). EMP is a coordinated, genomic response to airway injury disrupting epithelial barrier function, expanding the basal lamina, and producing airway remodeling. EMP is driven by activation of the unfolded protein response (UPR), a transcriptional response producing metabolic shunting of glucose through the hexosamine biosynthetic pathway (HBP) to protein N-glycosylation. NFκB signaling and UPR activation pathways potentiate each other in remodeling the basement membrane. Understanding of injury-repair process of epithelium provides new therapeutic targets for precision approaches to the treatment of asthma exacerbations and their sequelae.
    Keywords:  Acute exacerbations; Bromodomain containing protein 4 (BRD4); Chromatin remodeling; Club cells; Endoplasmic reticulum stress; Epithelial mesenchymal transition; Epithelial mesenchymal trophic unit (EMTU); Extracellular matrix (ECM); Inositol-requiring enzyme 1 (IRE1); Interferon; Mucosa; Plasticity; Secretoglobin; Sentinel cells; Unfolded protein response (UPR); X-box binding protein
  9. Contact Dermatitis. 2023 Jul 18.
      BACKGROUND: The role and causality of the microbial ecosystem on the skin in relation to the development of hand eczema (HE) is still unknown.OBJECTIVES: To investigate the prevalence of different bacterial colonisations in HE patients and their association with the severity, symptoms and aetiology of the disease.
    METHODS: In a retrospective cohort study of 167 HE patients, bacterial swabs from lesional skin were collected for culturing. Patients were categorised according to bacterial colonisation, HE severity, HE symptoms and HE aetiology.
    RESULTS: The majority of the patients were tested positive for Staphylococcus aureus (S. aureus) (n = 131, 78.4%) and/or commensal skin flora (CSF; n = 130, 77.8%), while other bacteria species were found only sporadically. Severe HE was significantly more prevalent in skin with S. aureus (odds ratio [OR]: 5.13, 95% confidence interval [CI]: 2.21-11.94) and less common in skin with CSF (OR: 0.20, 95% CI: 0.05-0.88). S. aureus colonisation was also associated with atopic HE aetiology (p < 0.001) and acute HE symptoms such as blisters, erosions and crusts (p = 0.003).
    CONCLUSIONS: The main colonisation of HE patients is with S. aureus and is associated with disease severity, acute HE symptoms and atopic HE aetiology. CSF is associated with mild HE, which could result in new therapeutic approaches.
    Keywords:  Staphylococcus aureus; atopic hand eczema; colonisation; commensal skin flora; hand eczema
  10. J Clin Invest. 2023 07 17. pii: e170498. [Epub ahead of print]133(14):
      Mesenchymal cells are uniquely located at the interface between the epithelial lining and the stroma, allowing them to act as a signaling hub among diverse cellular compartments of the lung. During embryonic and postnatal lung development, mesenchyme-derived signals instruct epithelial budding, branching morphogenesis, and subsequent structural and functional maturation. Later during adult life, the mesenchyme plays divergent roles wherein its balanced activation promotes epithelial repair after injury while its aberrant activation can lead to pathological remodeling and fibrosis that are associated with multiple chronic pulmonary diseases, including bronchopulmonary dysplasia, idiopathic pulmonary fibrosis, and chronic obstructive pulmonary disease. In this Review, we discuss the involvement of the lung mesenchyme in various morphogenic, neomorphogenic, and dysmorphogenic aspects of lung biology and health, with special emphasis on lung fibroblast subsets and smooth muscle cells, intercellular communication, and intrinsic mesenchymal mechanisms that drive such physiological and pathophysiological events throughout development, homeostasis, injury repair, regeneration, and aging.
  11. Bull Exp Biol Med. 2023 Jul 19.
      The aim of this study was the development of a methodology for the integral study of the antagonistic activity of normal human microbiota against Staphylococcus aureus to enable direct selection (without prior isolation of pure cultures) of potentially highly efficient probiotic preparations. The selection of bacterial representatives of normal human nasal microbiota capable of antagonizing S. aureus was carried out using two complimentary methods: replica-plating and deferred antagonism procedures. The material of the anterior nares from healthy human subjects was plated onto the surface of different nutrient media agar plates followed by incubation under appropriate conditions. The grown bacterial colonies were replica-plated to Petri dishes with nutrient agar overlayed with a thin layer of a soft agar which contained the culture of an indicator S. aureus strain. This agar also supported the growth of potential probiotic strains. The potential probiotic strains were selected by their ability to suppress the growth of S. aureus around their colonies. Most active strains-inhibitors may be used to develop probiotic preparations with targeted activity against S. aureus.
    Keywords:  Staphylococcus aureus; otolaryngology; probiotics
  12. Sci Immunol. 2023 Jul 21. 8(85): eabo4767
      Endotoxin-bacterial lipopolysaccharide (LPS)-is a driver of lethal infection sepsis through excessive activation of innate immune responses. When delivered to the cytosol of macrophages, cytosolic LPS (cLPS) induces the assembly of an inflammasome that contains caspases-4/5 in humans or caspase-11 in mice. Whereas activation of all other inflammasomes is triggered by sensing of pathogen products by a specific host cytosolic pattern recognition receptor protein, whether pattern recognition receptors for cLPS exist has remained unclear, because caspase-4, caspase-5, and caspase-11 bind and activate LPS directly in vitro. Here, we show that the primate-specific protein NLRP11 is a pattern recognition receptor for cLPS that is required for efficient activation of the caspase-4 inflammasome in human macrophages. In human macrophages, NLRP11 is required for efficient activation of caspase-4 during infection with intracellular Gram-negative bacteria or upon electroporation of LPS. NLRP11 could bind LPS and separately caspase-4, forming a high-molecular weight complex with caspase-4 in HEK293T cells. NLRP11 is present in humans and other primates but absent in mice, likely explaining why it has been overlooked in screens looking for innate immune signaling molecules, most of which have been carried out in mice. Our results demonstrate that NLRP11 is a component of the caspase-4 inflammasome activation pathway in human macrophages.
  13. Front Cell Infect Microbiol. 2023 ;13 1113744
      Introduction: Tuberculosis (TB) still kills over 1 million people annually. The only approved vaccine, BCG, prevents disseminated disease in children but shows low efficacy at preventing pulmonary TB. Myeloid dendritic cells (mDCs) are promising targets for vaccines and immunotherapies to combat infectious diseases due to their essential role in linking innate and adaptive immune responses. DCs undergo metabolic reprogramming following exposure to TLR agonists, which is thought to be a prerequisite for a successful host response to infection. We hypothesized that metabolic rewiring also plays a vital role in the maturation and migration of DCs stimulated with BCG. Consequently, we investigated the role of glycolysis in the activation of primary human myeloid CD1c+ DCs in response to BCG.Methods/results: We show that CD1c+ mDC mature and acquire a more energetic phenotype upon challenge with BCG. Pharmacological inhibition of glycolysis with 2-deoxy-D-glucose (2-DG) decreased cytokine secretion and altered cell surface expression of both CD40 and CCR7 on BCG-challenged, compared to untreated, mDCs. Furthermore, inhibition of glycolysis had differential effects on infected and uninfected bystander mDCs in BCG-challenged cultures. For example, CCR7 expression was increased by 2-DG treatment following challenge with BCG and this increase in expression was seen only in BCG-infected mDCs. Moreover, although 2-DG treatment inhibited CCR7-mediated migration of bystander CD1C+ DCs in a transwell assay, migration of BCG-infected cells proceeded independently of glycolysis.
    Discussion: Our results provide the first evidence that glycolysis plays divergent roles in the maturation and migration of human CD1c+ mDC exposed to BCG, segregating with infection status. Further investigation of cellular metabolism in DC subsets will be required to determine whether glycolysis can be targeted to elicit better protective immunity against Mtb.
    Keywords:  Bacille Calmette-Guérin vaccine (BCG); Mycobacterium bovis; Mycobacterium tuberculosis; dendritic cell; glycolysis; immunometabolism; tuberculosis; vaccines
  14. PLoS Pathog. 2023 07;19(7): e1011493
      S100A8/A9 has important immunomodulatory roles in antibacterial defense, but its relevance in focal pneumonia caused by Streptococcus pneumoniae (S. pneumoniae) is understudied. We show that S100A9 was significantly increased in BAL fluids of patients with bacterial but not viral pneumonia and correlated with procalcitonin and sequential organ failure assessment scores. Mice deficient in S100A9 exhibited drastically elevated Zn2+ levels in lungs, which led to bacterial outgrowth and significantly reduced survival. In addition, reduced survival of S100A9 KO mice was characterized by excessive release of neutrophil elastase, which resulted in degradation of opsonophagocytically important collectins surfactant proteins A and D. All of these features were attenuated in S. pneumoniae-challenged chimeric WT→S100A9 KO mice. Similarly, therapy of S. pneumoniae-infected S100A9 KO mice with a mutant S100A8/A9 protein showing increased half-life significantly decreased lung bacterial loads and lung injury. Collectively, S100A9 controls central antibacterial immune mechanisms of the lung with essential relevance to survival of pneumococcal pneumonia. Moreover, S100A9 appears to be a promising biomarker to distinguish patients with bacterial from those with viral pneumonia. Trial registration: Clinical Trials register (DRKS00000620).
  15. Cell Rep Med. 2023 Jul 18. pii: S2666-3791(23)00252-5. [Epub ahead of print]4(7): 101124
      Abnormal immune responses to the resident gut microbiome can drive inflammatory bowel disease (IBD). Here, we combine high-resolution, culture-based shotgun metagenomic sequencing and analysis with matched host transcriptomics across three intestinal sites (terminal ileum, cecum, rectum) from pediatric IBD (PIBD) patients (n = 58) and matched controls (n = 42) to investigate this relationship. Combining our site-specific approach with bacterial culturing, we establish a cohort-specific bacterial culture collection, comprising 6,620 isolates (170 distinct species, 32 putative novel), cultured from 286 mucosal biopsies. Phylogeny-based, clade-specific metagenomic analysis identifies key, functionally distinct Enterococcus clades associated with either IBD or health. Strain-specific in vitro validation demonstrates differences in cell cytotoxicity and inflammatory signaling in intestinal epithelial cells, consistent with the colonic mucosa-specific response measured in patients with IBD. This demonstrates the importance of strain-specific phenotypes and consideration of anatomical sites in exploring the dysregulated host-bacterial interactions in IBD.
    Keywords:  Enterococcus; cell death; epithelial cells; gastrointestinal tract; host-microbe interactions; inflammatory bowel disease; metagenomic; microbiome; pediatric IBD; ulcerative colitis