bims-bac4me Biomed News
on Microbiome and trained immunity
Issue of 2023‒05‒14
eighteen papers selected by
Chun-Chi Chang
University Hospital Zurich

  1. EMBO Mol Med. 2023 May 09. e17084
      Bacillus Calmette-Guérin (BCG) still remains the only licensed vaccine for TB and has been shown to provide nonspecific protection against unrelated pathogens. This has been attributed to the ability of BCG to modulate the innate immune system, known as trained innate immunity (TII). Trained innate immunity is associated with innate immune cells being in a hyperresponsive state leading to enhanced host defense against heterologous infections. Both epidemiological evidence and prospective studies demonstrate cutaneous BCG vaccine-induced TII provides enhanced innate protection against heterologous pathogens. Regardless of the extensive progress made thus far, the effect of cutaneous BCG vaccination against heterologous respiratory bacterial infections and the underlying mechanisms still remain unknown. Here, we show that s.c. BCG vaccine-induced TII provides enhanced heterologous innate protection against pulmonary Streptococcus pneumoniae infection. We further demonstrate that this enhanced innate protection is mediated by enhanced neutrophilia in the lung and is independent of centrally trained circulating monocytes. New insight from this study will help design novel effective vaccination strategies against unrelated respiratory bacterial pathogens.
    Keywords:  Streptococcus pneumoniae infection; lung; subcutaneous BCG vaccine; tissue-resident macrophages; trained innate immunity
  2. Immunol Rev. 2023 May 09.
      The phagocytosis of dying cells by macrophages, termed efferocytosis, is a tightly regulated process that involves the sensing, binding, engulfment, and digestion of apoptotic cells. Efferocytosis not only prevents tissue necrosis and inflammation caused by secondary necrosis of dying cells, but it also promotes pro-resolving signaling in macrophages, which is essential for tissue resolution and repair following injury or inflammation. An important factor that contributes to this pro-resolving reprogramming is the cargo that is released from apoptotic cells after their engulfment and phagolysosomal digestion by macrophages. The apoptotic cell cargo contains amino acids, nucleotides, fatty acids, and cholesterol that function as metabolites and signaling molecules to bring about this re-programming. Here, we review efferocytosis-induced changes in macrophage metabolism that mediate the pro-resolving functions of macrophages. We also discuss various strategies, challenges, and future perspectives related to drugging efferocytosis-fueled macrophage metabolism as strategy to dampen inflammation and promote resolution in chronic inflammatory diseases.
    Keywords:  cell metabolism; efferocytosis; inflammation resolution; macrophages
  3. Front Immunol. 2023 ;14 1176044
      Patients with chronic lung disease suffer from persistent inflammation and are typically colonized by pro-inflammatory pathogenic bacteria. Besides these pathogens, a wide variety of commensal species is present in the lower airways but their role in inflammation is unclear. Here, we show that the lung microbiota contains several species able to inhibit activation of the pro-inflammatory NF-κB pathway and production of interleukin 8 (IL-8), triggered by lipopolysaccharide (LPS) or H2O2, in a physiologically relevant three-dimensional (3D) lung epithelial cell model. We demonstrate that the minimal dose needed for anti-inflammatory activity differs between species (with the lowest dose needed for Rothia mucilaginosa), and depends on the type of pro-inflammatory stimulus and read out. Furthermore, we evaluated synergistic activity between pairs of anti-inflammatory bacteria on the inhibition of the NF-κB pathway and IL-8 secretion. Synergistic anti-inflammatory activity was observed for 4/10 tested consortia. These findings indicate that various microbiota members can influence lung inflammation either alone or as a consortium. This information can contribute to a better understanding of the lung microbiota in chronic lung disease development and process, and could open up new avenues for treatment.
    Keywords:  beneficial commensal; chronic lung disease (CLD); host-microbe interaction; inflammation; lung microbiome
  4. Burns Trauma. 2023 ;11 tkad004
      Inflammatory bowel disease (IBD) is a chronic, non-specific, recurrent inflammatory disease, majorly affecting the gastrointestinal tract. Due to its unclear pathogenesis, the current therapeutic strategy for IBD is focused on symptoms alleviation. Autophagy is a lysosome-mediated catabolic process for maintaining cellular homeostasis. Genome-wide association studies and subsequent functional studies have highlighted the critical role of autophagy in IBD via a number of mechanisms, including modulating macrophage function. Macrophages are the gatekeepers of intestinal immune homeostasis, especially involved in regulating inflammation remission and tissue repair. Interestingly, many autophagic proteins and IBD-related genes have been revealed to regulate macrophage function, suggesting that macrophage autophagy is a potentially important process implicated in IBD regulation. Here, we have summarized current understanding of macrophage autophagy function in pathogen and apoptotic cell clearance, inflammation remission and tissue repair regulation in IBD, and discuss how this knowledge can be used as a strategy for IBD treatment.
    Keywords:  Autophagy; Efferocytosis; Inflammation; Inflammatory bowel diseases; Macrophage; Tissue repair
  5. Front Immunol. 2023 ;14 1180488
      Innate immune responses to pathogens, mediated by activation of pattern recognition receptors and downstream signal transduction cascades, trigger rapid transcriptional and epigenetic changes to support increased expression of pro-inflammatory cytokines and other effector molecules. Innate immune cells also rapidly rewire their metabolism. The most prominent metabolic alteration following innate immune activation is rapid up-regulation of glycolysis. In this mini-review, we summarize recent advances regarding the mechanisms of rapid glycolytic activation in innate immune cells, highlighting the relevant signaling components. We also discuss the impact of glycolytic activation on inflammatory responses, including the recently elucidated links of metabolism and epigenetics. Finally, we highlight unresolved mechanistic details of glycolytic activation and possible avenues of future research in this area.
    Keywords:  dendritic cell; glycolysis; inflammation; macrophage; metabolism; pattern recognition receptors
  6. Cell Rep. 2023 May 10. pii: S2211-1247(23)00505-3. [Epub ahead of print]42(5): 112494
      During inflammation, the skin deploys antimicrobial peptides (AMPs) yet during allergic inflammation it becomes more susceptible to Staphylococcus aureus. To understand this contradiction, single-cell sequencing of Il4ra-/- mice combined with skin microbiome analysis reveals that lower production of AMPs from interleukin-4 receptor α (IL-4Rα) activation selectively inhibits survival of antibiotic-producing strains of coagulase-negative Staphylococcus (CoNS). Diminished AMPs under conditions of T helper type 2 (Th2) inflammation enable expansion of CoNS strains without antibiotic activity and increase Staphylococcus aureus (S. aureus), recapitulating the microbiome on humans with atopic dermatitis. This response is rescued in Camp-/- mice or after topical steroids, since further inhibition of AMPs enables survival of antibiotic-producing CoNS strains. In conditions of Th17 inflammation, a higher expression of host AMPs is sufficient to directly inhibit S. aureus survival. These results show that antimicrobials produced by the host and commensal bacteria each act to control S. aureus on the skin.
    Keywords:  CP: Immunology; CP: Microbiology; Cramp; Interleukin-4 receptor alpha; Staphylococcus hominis; atopic dermatitis; bacteriocin; cathelicidin; coagulase negative Staphylococcus; infection; lantibiotic
  7. Int Immunopharmacol. 2023 May 05. pii: S1567-5769(23)00390-9. [Epub ahead of print]119 110069
      The redox state is essential to the process of cell life, which determines cell fate. As an important signaling molecule of the redox state, reactive oxygen species (ROS) are crucial for the homeostasis of immune cells and participate in the pathological processes of different diseases. We discuss the underlying mechanisms and possible signaling pathways of ROS to fine-tune the proliferation, differentiation, polarization and function of immune cells, including T cells, B cells, neutrophils, macrophages, myeloid-derived inhibitory cells (MDSCs) and dendritic cells (DCs). We further emphasize how excessive ROS lead to programmed immune cell death such as apoptosis, ferroptosis, pyroptosis, NETosis and necroptosis, providing valuable insights for future therapeutic strategies in human diseases.
    Keywords:  Antioxidant; Immune cells; Reactive oxygen species; Redox signaling
  8. Curr Med Chem. 2023 May 09.
      Identifying metabolic signatures induced by the immune response to vaccines allows to discriminate vaccinated from non-vaccinated subjects and decipher the molecular mechanisms associated with the host immune response. This review illustrates and discusses the results of metabolomics-based studies on the innate and adaptive immune response to vaccines, long-term functional reprogramming (immune memory), and adverse reactions. Glycolysis is not overexpressed by vaccines, suggesting that the immune cell response to vaccinations does not require rapid energy availability as that is necessary during an infection. Vaccines strongly impact lipids metabolism, including saturated or unsaturated fatty acids, inositol phosphate, and cholesterol. Cholesterol is strategic for synthesizing 25-hydroxycholesterol in activated macrophages and dendritic cells and stimulates the conversion of macrophages and T cells in M2 macrophage and Treg, respectively. In conclusion, the large-scale application of metabolomics enables the identification of candidate predictive biomarkers of vaccine efficacy/tolerability.
    Keywords:  immune cells; metabolic reprogramming; metabolomics; system vaccinology; trained immunity; vaccines
  9. Microbiol Spectr. 2023 May 08. e0525522
      Staphylococcus aureus is a Gram-positive commensal and opportunistic pathogen able to cause diseases ranging from mild skin infections to life-threatening endocarditis and toxic shock syndrome. The ability to cause such an array of diseases is due to the complex S. aureus regulatory network controlling an assortment of virulence factors, including adhesins, hemolysins, proteases, and lipases. This regulatory network is controlled by both protein and RNA elements. We previously identified a novel regulatory protein called ScrA, which, when overexpressed, leads to the increased activity and expression of the SaeRS regulon. In this study, we further explore the role of ScrA and examine the consequences to the bacterial cell of scrA gene disruption. These results demonstrate that scrA is required for several virulence-related processes, and in many cases, the phenotypes of the scrA mutant are inverse to those observed in cells overexpressing ScrA. Interestingly, while the majority of ScrA-mediated phenotypes appear to rely on the SaeRS system, our results also indicate that ScrA may also act independently of SaeRS when regulating hemolytic activity. Finally, using a murine model of infection, we demonstrate that scrA is required for virulence, potentially in an organ-specific manner. IMPORTANCE Staphylococcus aureus is the cause of several potentially life-threatening infections. An assortment of toxins and virulence factors allows such a wide range of infections. However, an assortment of toxins or virulence factors requires complex regulation to control expression under all of the different conditions encountered by the bacterium. Understanding the intricate web of regulatory systems allows the development of novel approaches to combat S. aureus infections. Here, we have shown that the small protein ScrA, which was previously identified by our laboratory, influences several virulence-related functions through the SaeRS global regulatory system. These findings add ScrA to the growing list of virulence regulators in S. aureus.
    Keywords:  SaeRS; ScrA; Staphylococcus aureus; clumping; gene regulation; hemolysis; two-component system; virulence
  10. Crit Rev Microbiol. 2023 May 11. 1-20
      The oral cavity is inhabited by abundant microbes which continuously interact with the host and influence the host's health. Such host-microbe interactions (HMI) are dynamic and complex processes involving e.g. oral tissues, microbial communities and saliva. Due to difficulties in mimicking the in vivo complexity, it is still unclear how exactly HMI influence the transition between healthy status and disease conditions in the oral cavity. As an advanced approach, three-dimensional (3D) organotypic oral tissues (epithelium and mucosa/gingiva) are being increasingly used to study underlying mechanisms. These in vitro models were designed with different complexity depending on the research questions to be answered. In this review, we summarised the existing 3D oral HMI models, comparing designs and readouts, discussing applications as well as future perspectives.
    Keywords:  Organotypic model; biofilm; host-microbe interaction; oral microbiota; oral mucosa
  11. Front Cell Infect Microbiol. 2023 ;13 1196905
    Keywords:  bacteria-host interaction; cellular microbiology; flow cytometry; microbiota; microscopy; pathogens; single cell analysis
  12. J Exp Med. 2023 Aug 07. pii: e20220727. [Epub ahead of print]220(8):
      Type I interferons are important antiviral cytokines, but prolonged interferon production is detrimental to the host. The TLR3-driven immune response is crucial for mammalian antiviral immunity, and its intracellular localization determines induction of type I interferons; however, the mechanism terminating TLR3 signaling remains obscure. Here, we show that the E3 ubiquitin ligase ZNRF1 controls TLR3 sorting into multivesicular bodies/lysosomes to terminate signaling and type I interferon production. Mechanistically, c-Src kinase activated by TLR3 engagement phosphorylates ZNRF1 at tyrosine 103, which mediates K63-linked ubiquitination of TLR3 at lysine 813 and promotes TLR3 lysosomal trafficking and degradation. ZNRF1-deficient mice and cells are resistant to infection by encephalomyocarditis virus and SARS-CoV-2 because of enhanced type I interferon production. However, Znrf1-/- mice have exacerbated lung barrier damage triggered by antiviral immunity, leading to enhanced susceptibility to respiratory bacterial superinfections. Our study highlights the c-Src-ZNRF1 axis as a negative feedback mechanism controlling TLR3 trafficking and the termination of TLR3 signaling.
  13. BMC Microbiol. 2023 05 09. 23(1): 124
      BACKGROUND: Circadian rhythms, observed across all domains of life, enable organisms to anticipate and prepare for diel changes in environmental conditions. In bacteria, a circadian clock mechanism has only been characterized in cyanobacteria to date. These clocks regulate cyclical patterns of gene expression and metabolism which contribute to the success of cyanobacteria in their natural environments. The potential impact of self-generated circadian rhythms in other bacterial and microbial populations has motivated extensive research to identify novel circadian clocks.MAIN TEXT: Daily oscillations in microbial community composition and function have been observed in ocean ecosystems and in symbioses. These oscillations are influenced by abiotic factors such as light and the availability of nutrients. In the ocean ecosystems and in some marine symbioses, oscillations are largely controlled by light-dark cycles. In gut systems, the influx of nutrients after host feeding drastically alters the composition and function of the gut microbiota. Conversely, the gut microbiota can influence the host circadian rhythm by a variety of mechanisms including through interacting with the host immune system. The intricate and complex relationship between the microbiota and their host makes it challenging to disentangle host behaviors from bacterial circadian rhythms and clock mechanisms that might govern the daily oscillations observed in these microbial populations.
    CONCLUSIONS: While the ability to anticipate the cyclical behaviors of their host would likely be enhanced by a self-sustained circadian rhythm, more evidence and further studies are needed to confirm whether host-associated heterotrophic bacteria possess such systems. In addition, the mechanisms by which heterotrophic bacteria might respond to diel cycles in environmental conditions has yet to be uncovered.
    Keywords:  Circadian clock; Circadian rhythm; Diel cycle; Diurnal cycle; Gut microbiota; Oscillations; Symbiosis
  14. Commun Biol. 2023 May 09. 6(1): 501
      Nitric oxide (NO) is produced as an innate immune response against microbial infections. Salmonella Typhimurium (S. Typhimurium), the major causative pathogen of human gastroenteritis, induces more severe systemic disease in mice. However, host factors contributing to the difference in species-related virulence are unknown. Here, we report that host NO production promotes S. Typhimurium replication in mouse macrophages at the early infection stage by activating Salmonella pathogenicity island-2 (SPI-2). The NO signaling-induced SPI-2 activation is mediated by Fnr and PhoP/Q two-component system. NO significantly induced fnr transcription, while Fnr directly activated phoP/Q transcription. Mouse infection assays revealed a NO-dependent increase in bacterial burden in systemic organs during the initial days of infection, indicating an early contribution of host NO to virulence. This study reveals a host signaling-mediated virulence activation pathway in S. Typhimurium that contributes significantly to its systemic infection in mice, providing further insights into Salmonella pathogenesis and host-pathogen interaction.
  15. Clin Microbiol Rev. 2023 May 10. e0015722
      Clostridioides difficile infection (CDI) represents a significant challenge to public health. C. difficile-associated mortality and morbidity have led the U.S. CDC to designate it as an urgent threat. Moreover, recurrence or relapses can occur in up to a third of CDI patients, due in part to antibiotics being the primary treatment for CDI and the major cause of the disease. In this review, we summarize the current knowledge of innate immune responses, adaptive immune responses, and the link between innate and adaptive immune responses of the host against CDI. The other major determinants of CDI, such as C. difficile toxins, the host microbiota, and related treatments, are also described. Finally, we discuss the known therapeutic approaches and the current status of immunization strategies for CDI, which might help to bridge the knowledge gap in the generation of therapy against CDI.
    Keywords:  Clostridium difficile; fecal microbiota transplant; host immune response; innate lymphoid cells; microbiome; vaccine
  16. Curr Clin Microbiol Rep. 2023 ;10(2): 55-65
      Abstract: Purpose of Review: The fungus Candida albicans has evolved to live in close association with warm-blooded hosts and is found frequently on mucosal surfaces of healthy humans. As an opportunistic pathogen, C. albicans can also cause mucosal and disseminated infections (candidiasis). This review describes the features that differentiate the fungus in the commensal versus pathogenic state and the main factors underlying C. albicans commensal-to-pathogen transition.
    Recent Findings: Adhesion, invasion, and tissue damage are critical steps in the infection process. Especially invasion and damage require transcriptional and morphological changes that differentiate C. albicans in the pathogenic from the commensal state. While the commensal-to-pathogen transition has some conserved causes and features in the oral cavity, the female urogenital tract, and the gut, site-specific differences have been identified in recent years.
    Summary: This review highlights how specific factors in the different mucosal niches affect development of candidiasis. Recent evidence suggests that colonization of the gut is not only a risk factor for systemic candidiasis but might also provide beneficial effects to the host.
    Keywords:  Candidiasis; Mucosa; Oral cavity; Pathogenesis; Vulvovaginal; gut