bims-bac4me Biomed News
on Microbiome and trained immunity
Issue of 2023‒07‒09
nineteen papers selected by
Chun-Chi Chang
University Hospital Zurich

  1. Elife. 2023 07 04. pii: RP87026. [Epub ahead of print]12
      The bloodstream represents a hostile environment that bacteria must overcome to cause bacteraemia. To understand how the major human pathogen Staphylococcus aureus manages this we have utilised a functional genomics approach to identify a number of new loci that affect the ability of the bacteria to survive exposure to serum, the critical first step in the development of bacteraemia. The expression of one of these genes, tcaA, was found to be induced upon exposure to serum, and we show that it is involved in the elaboration of a critical virulence factor, the wall teichoic acids (WTA), within the cell envelope. The activity of the TcaA protein alters the sensitivity of the bacteria to cell wall attacking agents, including antimicrobial peptides, human defence fatty acids, and several antibiotics. This protein also affects the autolytic activity and lysostaphin sensitivity of the bacteria, suggesting that in addition to changing WTA abundance in the cell envelope, it also plays a role in peptidoglycan crosslinking. With TcaA rendering the bacteria more susceptible to serum killing, while simultaneously increasing the abundance of WTA in the cell envelope, it was unclear what effect this protein may have during infection. To explore this, we examined human data and performed murine experimental infections. Collectively, our data suggests that whilst mutations in tcaA are selected for during bacteraemia, this protein positively contributes to the virulence of S. aureus through its involvement in altering the cell wall architecture of the bacteria, a process that appears to play a key role in the development of bacteraemia.
    Keywords:  Staphylococcus aureus; TcaA; bacteraemia; infectious disease; microbiology; staphylococcus aureus
  2. Front Immunol. 2023 ;14 1183066
      Dysregulated inflammation involving innate immune cells, particularly of the monocyte/macrophage lineage, is a key contributor to the pathogenesis of Duchenne muscular dystrophy (DMD). Trained immunity is an evolutionarily ancient protective mechanism against infection, in which epigenetic and metabolic alterations confer non-specific hyperresponsiveness of innate immune cells to various stimuli. Recent work in an animal model of DMD (mdx mice) has shown that macrophages exhibit cardinal features of trained immunity, including the presence of innate immune system "memory". The latter is reflected by epigenetic changes and durable transmissibility of the trained phenotype to healthy non-dystrophic mice by bone marrow transplantation. Mechanistically, it is suggested that a Toll-like receptor (TLR) 4-regulated, memory-like capacity of innate immunity is induced at the level of the bone marrow by factors released from the damaged muscles, leading to exaggerated upregulation of both pro- and anti-inflammatory genes. Here we propose a conceptual framework for the involvement of trained immunity in DMD pathogenesis and its potential to serve as a new therapeutic target.
    Keywords:  chronic inflammatory diseases; immune memory; innate immunity; macrophages; mdx mouse; muscular dystrophies; sterile inflammation
  3. Respir Res. 2023 Jul 05. 24(1): 175
      BACKGROUND: Early studies indicated that vitamin D (VD) exerted pleiotropic extra-skeletal effects in the airway, but the definite linkage between VD deficiency and airway host responses remains unclear.METHODS: 142 cases of clinical data from Department of Otolaryngology, the Seventh Affiliated Hospital of Sun Yat-sen University, were collected to characterize the relationship between VD deficiency and chronic rhinosinusitis (CRS). Based on the clinical observations, 2.5-D airway epithelial organoids cultured at the air-liquid interface (ALI) were used to simulate the effects of VD treatment in the development of airway epithelium and the modulation of the host responses against influenza H1N1 virus (representing viral infections) and Staphylococcus aureus (representing bacterial infections) infections in the airway. The intrinsic mechanisms of VD deficiency underlying epithelial remodeling were mapped by transcriptomic as well as proteomic analyses.
    RESULTS: In this study we observed prevailing VD deficiency among inpatients suffering from CRS, a common disease predominantly characterized by epithelial impairment and remodeling. Relative to control organoids cultured without VD, long-term incubation with VD accelerated basal cell proliferation during nasal epithelial development. Under infectious conditions, VD treatment protected the organoids against influenza H1N1 virus and Staphylococcus aureus invasions by reinforcing the respiratory host defenses, including upregulation of LL37, suppression (or inhibition) of proinflammatory cytokines, strengthening of epithelial integrity, and mucociliary clearance. In silico analysis of transcriptomics and proteomics suggested that VD modulated the epithelial development and remodeling, involving epithelial cell proliferation/differentiation, epithelial-mesenchymal transition (EMT), and cytokine signaling in the immune system, as well as responses to microbe, cell junction organization, and extracellular matrix organization via PTEN signaling, independent of TGF-β signaling.
    CONCLUSIONS: Our findings emphasize the importance of managing VD deficiency in clinical settings for the sake of alleviating pathological epithelial remodeling. Vitamin D promotes epithelial tissue repair and host defense responses against influenza H1N1 and Staphylococcus aureus infections.
    Keywords:  Airway epithelial remodeling; Airway epithelium; Airway organoids; Host responses; Vitamin D
  4. Expert Rev Clin Immunol. 2023 Jul 06.
      INTRODUCTION: Staphylococcus aureus (S. aureus) is a common pathogen that frequently colonizes the sinonasal cavity. Recent studies demonstrated the essential role of Staphylococcus aureus in the pathophysiology of uncontrolled severe chronic rhinosinusitis with nasal polyps (NP) by initiating an immune response to the germ and its products, resulting in type 2 inflammation.AREAS COVERED: This review aims to summarize the evidence for the role of S. aureus in the development of NP disease including S. aureus-related virulence factors, the pathophysiologic mechanisms used by S. aureus, and the synergistic effects of S. aureus and other pathogens. It also describes the current management of S. aureus associated with NPs as well as potential therapeutic strategies that are used in clinical practice.
    EXPERT OPINION: S. aureus is able to damage the nasal mucosal epithelial barrier, impair the clearance of the host immune system, and trigger adaptive and innate immune reactions which lead to the formation of inflammation and nasal polyp growth. Further studies should focus on the development of novel therapeutic strategies, such as biologics, bacteriophages, probiotics, and nanomedicine, which could be used to treat S. aureus and its immunological consequences in the future.
    Keywords:  Biologics; Chronic rhinosinusitis; Nasal polyps; Staphylococcus aureus
  5. Nat Immunol. 2023 Jul 06.
      Respiratory infections are common in infants and young children. However, the immune system develops and matures as the child grows, thus the effects of infection during this time of dynamic change may have long-term consequences. The infant immune system develops in conjunction with the seeding of the microbiome at the respiratory mucosal surface, at a time that the lungs themselves are maturing. We are now recognizing that any disturbance of this developmental trajectory can have implications for lifelong lung health. Here, we outline our current understanding of the molecular mechanisms underlying relationships between immune and structural cells in the lung with the local microorganisms. We highlight the importance of gaining greater clarity as to what constitutes a healthy respiratory ecosystem and how environmental exposures influencing this network will aid efforts to mitigate harmful effects and restore lung immune health.
  6. Cell Rep. 2023 Jun 30. pii: S2211-1247(23)00719-2. [Epub ahead of print]42(7): 112708
      Autophagy is an essential cellular process that is deeply integrated with innate immune signaling; however, studies that examine the impact of autophagic modulation in the context of inflammatory conditions are lacking. Here, using mice with a constitutively active variant of the autophagy gene Beclin1, we show that increased autophagy dampens cytokine production during a model of macrophage activation syndrome and in adherent-invasive Escherichia coli (AIEC) infection. Moreover, loss of functional autophagy through conditional deletion of Beclin1 in myeloid cells significantly enhances innate immunity in these contexts. We further analyzed primary macrophages from these animals with a combination of transcriptomics and proteomics to identify mechanistic targets downstream of autophagy. Our study reveals glutamine/glutathione metabolism and the RNF128/TBK1 axis as independent regulators of inflammation. Altogether, our work highlights increased autophagic flux as a potential approach to reduce inflammation and defines independent mechanistic cascades involved in this control.
    Keywords:  CP: Immunology; RNF128; TBK1 signaling; autophagy; glutamine metabolism; glutathione metabolism; infection; inflammation; macrophages; proteogenomics
  7. mSphere. 2023 Jul 05. e0004623
      Cystic fibrosis (CF) is a heritable disease that causes altered physiology at mucosal sites; these changes result in chronic infections in the lung, significant gastrointestinal complications as well as dysbiosis of the gut microbiome, although the latter has been less well explored. Here, we describe the longitudinal development of the gut microbiome in a cohort of children with CF (cwCF) from birth through early childhood (0-4 years of age) using 16S rRNA gene amplicon sequencing of stool samples as a surrogate for the gut microbiota. Similar to healthy populations, alpha diversity of the gut microbiome increases significantly with age, but diversity plateaus at ~2 years of age for this CF cohort. Several taxa that have been associated with dysbiosis in CF change with age toward a more healthy-like composition; notable exceptions include Akkermansia, which decreases with age, and Blautia, which increases with age. We also examined the relative abundance and prevalence of nine taxa associated with CF lung disease, several of which persist across early life, highlighting the possibility of the lung being seeded directly from the gut early in life. Finally, we applied the Crohn's Dysbiosis Index to each sample, and found that high Crohn's-associated dysbiosis early in life (<2 years) was associated with significantly lower Bacteroides in samples collected from 2 to 4 years of age. Together, these data comprise an observational study that describes the longitudinal development of the CF-associated gut microbiota and suggest that early markers associated with inflammatory bowel disease may shape the later gut microbiota of cwCF. IMPORTANCE Cystic fibrosis is a heritable disease that disrupts ion transport at mucosal surfaces, causing a buildup of mucus and dysregulation of microbial communities in both the lungs and the intestines. Persons with CF are known to have dysbiotic gut microbial communities, but the development of these communities over time beginning at birth has not been thoroughly studied. Here, we describe an observation study following the development of the gut microbiome of cwCF throughout the first 4 years of life, during the critical window of both gut microbiome and immune development. Our findings indicate the possibility of the gut microbiota as a reservoir of airway pathogens and a surprisingly early indication of a microbiota associated with inflammatory bowel disease.
    Keywords:  Crohn’s disease; cystic fibrosis; gut; microbiome
  8. Arch Microbiol. 2023 Jul 04. 205(8): 273
      Respiratory tract is a complex system comprising of unique microbiota inhabitants. Neisseria meningitidis, Staphylococcus aureus, Streptococcus pyogenes, Pseudomonas aeruginosa and Klebsiella pneumoniae are few prevalent bacteria in the community composition during lung infections. Although, N. meningitidis resides asymptomatically in nasopharynx of the human host, it can cause fatal infections like meningitis. However, factors affecting transit from carriage to symptomatic infection are not well understood. Various host metabolites and environmental conditions affect the virulence of bacteria. Here, we report that presence of co-colonizers significantly reduces the initial attachment of N. meningitidis to A549 nasopharyngeal epithelial cells. Further, significant decrease in invasion to A549 nasopharyngeal epithelial cells was observed. Moreover, survival in J774A.1 murine macrophage also increases significantly when conditioned media (CM) from S. pyogenes and L. rhamnosus is used for culturing N. meningitidis. The increase in survival could be attributed to increased capsule synthesis. The gene expression studies revealed increased expression of siaC and ctrB in CM prepared from the growth S. pyogenes and L. rhamnosus. Overall, the results suggest change in the virulence of N. meningitidis is assisted by lung microbiota.
    Keywords:  Carriage; Conditioned media; Microbiota; Pathogenesis; Virulence
  9. mSphere. 2023 Jul 05. e0017723
      The microbiota mediate multiple aspects of skin barrier function, including colonization resistance to pathogens such as Staphylococcus aureus. The endogenous skin microbiota limits S. aureus colonization via competition and direct inhibition. Novel mechanisms of colonization resistance are promising therapeutic targets for drug-resistant infections, such as those caused by methicillin-resistant S. aureus (MRSA). Here, we developed and characterized a swine model of topical microbiome perturbation and MRSA colonization. As in other model systems, topical antimicrobial treatment had a little discernable effect on community diversity though the overall microbial load was sensitive to multiple types of intervention, including swabbing. In parallel, we established a porcine skin culture collection and screened 7,700 isolates for MRSA inhibition. Using genomic and phenotypic criteria, we curated three isolates to investigate whether prophylactic colonization would inhibit MRSA colonization in vivo. The three-member consortium together, but not individually, provided protection against MRSA colonization, suggesting cooperation and/or synergy among the strains. Inhibitory isolates were represented across all major phyla of the pig skin microbiota and did not have a strong preference for inhibiting closely related species, suggesting that relatedness is not a condition of antagonism. These findings reveal the porcine skin as an underexplored reservoir of skin commensal species with the potential to prevent MRSA colonization and infection. IMPORTANCE The skin microbiota is protective against pathogens or opportunists such as S. aureus, the most common cause of skin and soft tissue infections. S. aureus can colonize normal skin and nasal passages, and colonization is a risk factor for infection, especially on breach of the skin barrier. Here, we established a pig model to study the competitive mechanisms of the skin microbiota and their role in preventing colonization by MRSA. This drug-resistant strain is also a livestock pathogen, and swine herds can be reservoirs of MRSA carriage. From 7,700 cultured skin isolates, we identified 37 unique species across three phyla that inhibited MRSA. A synthetic community of three inhibitory isolates provided protection together, but not individually, in vivo in a murine model of MRSA colonization. These findings suggest that antagonism is widespread in the pig skin microbiota, and these competitive interactions may be exploited to prevent MRSA colonization.
    Keywords:  Staphylococcus aureus; antagonism; colonization resistance; microbe–microbe interactions; porcine skin; skin; skin microbiome
  10. Immune Netw. 2023 Jun;23(3): e24
      In acute lung injury, two subsets of lung macrophages exist in the alveoli: tissue-resident alveolar macrophages (AMs) and monocyte-derived alveolar macrophages (MDMs). However, it is unclear whether these 2 subsets of macrophages have different functions and characteristics during the recovery phase. RNA-sequencing of AMs and MDMs from the recovery period of LPS-induced lung injury mice revealed their differences in proliferation, cell death, phagocytosis, inflammation and tissue repair. Using flow cytometry, we found that AMs showed a higher ability to proliferate, whereas MDMs expressed a larger amount of cell death. We also compared the ability of phagocytosing apoptotic cells and activating adaptive immunity and found that AMs have a stronger ability to phagocytose, while MDMs are the cells that activate lymphocytes during the resolving phase. By testing surface markers, we found that MDMs were more prone to the M1 phenotype, but expressed a higher level of pro-repairing genes. Finally, analysis of a publicly available set of single-cell RNA-sequencing data on bronchoalveolar lavage cells from patients with SARS-CoV-2 infection validated the double-sided role of MDMs. Blockade of inflammatory MDM recruitment using CCR2-/- mice effectively attenuates lung injury. Therefore, AMs and MDMs exhibited large differences during recovery. AMs are long-lived M2-like tissue-resident macrophages that have a strong ability to proliferate and phagocytose. MDMs are a paradoxical group of macrophages that promote the repair of tissue damage despite being strongly pro-inflammatory early in infection, and they may undergo cell death as inflammation fades. Preventing the massive recruitment of inflammatory MDMs or promoting their transition to pro-repairing phenotype may be a new direction for the treatment of acute lung injury.
    Keywords:  Acute Lung Injury; Alveolar Macrophage; Inflammation; Monocyte-Derived Macrophage
  11. bioRxiv. 2023 Jun 13. pii: 2023.06.13.544785. [Epub ahead of print]
      Myeloid phagocytes of the respiratory immune system, such as neutrophils, monocytes, and alveolar macrophages, are essential for immunity to Aspergillus fumigatus , the most common etiologic agent of mold pneumonia worldwide. Following engulfment of A. fumigatus conidia, fusion of the phagosome with the lysosome, is a critical process for killing conidia. TFEB and TFE3 are transcription factors that regulate lysosomal biogenesis under stress and are activated by inflammatory stimuli in macrophages, but it is unknown whether TFEB and TFE3 contribute to anti- Aspergillus immunity during infection. We found that lung neutrophils express TFEB and TFE3, and their target genes were upregulated during A. fumigatus lung infection. Additionally, A. fumigatus infection induced nuclear accumulation of TFEB and TFE3 in macrophages in a process regulated by Dectin-1 and CARD9 signaling. Genetic deletion of Tfeb and Tfe3 impaired macrophage killing of A. fumigatus conidia. However, in a murine immune competent Aspergillus infection model with genetic deficiency of Tfeb and Tfe3 in hematopoietic cells, we surprisingly found that lung myeloid phagocytes had no defects in conidial phagocytosis or killing. Loss of TFEB and TFE3 did not impact murine survival or clearance of A. fumigatus from the lungs. Our findings indicate that myeloid phagocytes activate TFEB and TFE3 in response to A. fumigatus , and while this pathway promotes macrophage fungicidal activity in vitro , genetic loss can be functionally compensated at the portal of infection in the lung, resulting in no measurable defect in fungal control and host survival.
  12. Front Immunol. 2023 ;14 1060258
      The skin is the body's largest organ. It serves as a barrier to pathogen entry and the first site of immune defense. In the event of a skin injury, a cascade of events including inflammation, new tissue formation and tissue remodeling contributes to wound repair. Skin-resident and recruited immune cells work together with non-immune cells to clear invading pathogens and debris, and guide the regeneration of damaged host tissues. Disruption to the wound repair process can lead to chronic inflammation and non-healing wounds. This, in turn, can promote skin tumorigenesis. Tumors appropriate the wound healing response as a way of enhancing their survival and growth. Here we review the role of resident and skin-infiltrating immune cells in wound repair and discuss their functions in regulating both inflammation and development of skin cancers.
    Keywords:  innate response; skin adaptive immunity; skin cancer immunity; skin immunity; skin wound healing
  13. Front Cell Infect Microbiol. 2023 ;13 1231253
    Keywords:  complement; glycosidases; host-pathogen interaction; immune evasion; pneumococcal vaccine; pneumococcus (Streptococcus pneumoniae)
  14. Ann Gastroenterol. 2023 Jul-Aug;36(4):36(4): 360-368
      One of the primary methods by which the gut microbiome interacts with its host is through the interactions that occur through the production of the metabolites produced, either directly, or indirectly, through microbial metabolism. Decades of research has demonstrated that these metabolic products play a vital role in human health, either for its benefit or detriment. This review article highlights the main metabolites produced by the interactions between diet and the gut microbiome, bile acids and the gut microbiome, and products produced by the gut microbiome alone. Additionally, this article reviews the literature on the effects that these metabolites play on human health.
    Keywords:  Gut metabolites; bile acids; microbiome; short chain fatty acids; trimethylamine-N-oxide
  15. Mol Med. 2023 Jul 05. 29(1): 90
      Abnormal microbial colonization in the gut at an early stage of life affects growth, development, and health, resulting in short- and long-term adverse effects. Microbial colonization patterns of preterm infants differ from those of full-term infants in that preterm babies and their mothers have more complicated prenatal and postnatal medical conditions. Maternal complications, antibiotic exposure, delivery mode, feeding type, and the use of probiotics may significantly shape the gut microbiota of preterm infants at an early stage of life; however, these influences subside with age. Although some factors and processes are difficult to intervene in or avoid, understanding the potential factors and determinants will help in developing timely strategies for a healthy gut microbiota in preterm infants. This review discusses potential determinants of gut microbial colonization in preterm infants and their underlying mechanisms.
    Keywords:  Antibiotics; Delivery mode; Dysbiosis; Gut microbiota; Human breast milk; Microbial colonization; Preterm infant; Probiotics
  16. Immunity. 2023 Jun 27. pii: S1074-7613(23)00263-7. [Epub ahead of print]
      Hypodermis is the predominant site of Staphylococcus aureus infections that cause cellulitis. Given the importance of macrophages in tissue remodeling, we examined the hypodermal macrophages (HDMs) and their impact on host susceptibility to infection. Bulk and single-cell transcriptomics uncovered HDM subsets with CCR2-dichotomy. HDM homeostasis required the fibroblast-derived growth factor CSF1, ablation of which abrogated HDMs from the hypodermal adventitia. Loss of CCR2- HDMs resulted in accumulation of the extracellular matrix component, hyaluronic acid (HA). HDM-mediated HA clearance required sensing by the HA receptor, LYVE-1. Cell-autonomous IGF1 was required for accessibility of AP-1 transcription factor motifs that controlled LYVE-1 expression. Remarkably, loss of HDMs or IGF1 limited Staphylococcus aureus expansion via HA and conferred protection against cellulitis. Our findings reveal a function for macrophages in the regulation of HA with an impact on infection outcomes, which may be harnessed to limit the establishment of infection in the hypodermal niche.
    Keywords:  Staphylococcus aureus; extracellular matrix; hyaluronic acid; hypodermis; insulin-like growth factor 1; macrophages; skin
  17. Proc Natl Acad Sci U S A. 2023 07 11. 120(28): e2301115120
      Enteric bacterial pathogens pose significant threats to human health; however, the mechanisms by which they infect the mammalian gut in the face of daunting host defenses and an established microbiota remain poorly defined. For the attaching and effacing (A/E) bacterial family member and murine pathogen Citrobacter rodentium, its virulence strategy likely involves metabolic adaptation to the host's intestinal luminal environment, as a necessary precursor to reach and infect the mucosal surface. Suspecting this adaptation involved the intestinal mucus layer, we found that C. rodentium was able to catabolize sialic acid, a monosaccharide derived from mucins, and utilize it as its sole carbon source for growth. Moreover, C. rodentium also sensed and displayed chemotactic activity toward sialic acid. These activities were abolished when the nanT gene, encoding a sialic acid transporter, was deleted (ΔnanT). Correspondingly, the ΔnanT C. rodentium strain was significantly impaired in its ability to colonize the murine intestine. Intriguingly, sialic acid was also found to induce the secretion of two autotransporter proteins, Pic and EspC, which possess mucinolytic and host-adherent properties. As a result, sialic acid enhanced the ability of C. rodentium to degrade intestinal mucus (through Pic), as well as to adhere to intestinal epithelial cells (through EspC). We thus demonstrate that sialic acid, a monosaccharide constituent of the intestinal mucus layer, functions as an important nutrient and a key signal for an A/E bacterial pathogen to escape the colonic lumen and directly infect its host's intestinal mucosa.
    Keywords:  bacterial pathogens; intestinal mucus; sialic acid
  18. Annu Rev Microbiol. 2023 Jul 05.
      Bacteria are single-celled organisms that carry a comparatively small set of genetic information, typically consisting of a few thousand genes that can be selectively activated or repressed in an energy-efficient manner and transcribed to encode various biological functions in accordance with environmental changes. Research over the last few decades has uncovered various ingenious molecular mechanisms that allow bacterial pathogens to sense and response to different environmental cues or signals to activate or suppress the expression of specific genes in order to suppress host defenses and establish infections. In the setting of infection, pathogenic bacteria have evolved various intelligent mechanisms to reprogram their virulence to adapt to environmental changes and maintain a dominant advantage over host and microbial competitors in new niches. This review summarizes the bacterial virulence programming mechanisms that enable pathogens to switch from acute to chronic infection, from local to systemic infection, and from infection to colonization. It also discusses the implications of these findings for the development of new strategies to combat bacterial infections. Expected final online publication date for the Annual Review of Microbiology, Volume 77 is September 2023. Please see for revised estimates.