bims-bac4me Biomed News
on Microbiome and trained immunity
Issue of 2023‒01‒01
nine papers selected by
Chun-Chi Chang
University Hospital Zurich

  1. Clin Immunol. 2022 Dec 21. pii: S1521-6616(22)00289-3. [Epub ahead of print]246 109208
      The innate immune system can display heterologous memory-like responses termed trained immunity after stimulation by certain vaccinations or infections. In this randomized, placebo-controlled trial, we investigated the modulation of Bacille Calmette-Guérin (BCG)-induced trained immunity by BCG revaccination or high-dose BCG administration, in comparison to a standard dose. We show that monocytes from all groups of BCG-vaccinated individuals exerted increased TNFα production after ex-vivo stimulation with various unrelated pathogens. Similarly, we observed increased amounts of T-cell-derived IFNγ after M. tuberculosis exposure, regardless of the BCG intervention. NK cell cytokine production, especially after heterologous stimulation with the fungal pathogen Candida albicans, was predominantly boosted after high dose BCG administration. Cytokine production capacity before vaccination was inversely correlated with trained immunity. While the induction of a trained immunity profile is largely dose- or frequency independent, baseline cytokine production capacity is associated with the magnitude of the innate immune memory response after BCG vaccination.
    Keywords:  Bacille Calmette-Guérin; Booster; Innate immune memory; Mycobacterium tuberculosis; Non-specific beneficial effects; Revaccination
  2. Clin Immunol. 2022 Dec 23. pii: S1521-6616(22)00297-2. [Epub ahead of print] 109216
      Macrophages are a diverse population of phagocytic immune cells involved in the host defense mechanisms and regulation of homeostasis. Usually, macrophages maintain healthy functioning at the cellular level, but external perturbation in their balanced functions can lead to acute and chronic disease conditions. By sensing the cues from the tissue microenvironment, these phagocytes adopt a plethora of phenotypes, such as inflammatory or M1 to anti-inflammatory (immunosuppressive) or M2 subtypes, to fulfill their spectral range of functions. The existing evidence in the literature supports that in macrophages, regulation of metabolic switches and metabolic adaptations are associated with their functional behaviors under various physiological and pathological conditions. Since these macrophages play a crucial role in many disorders, therefore it is necessary to understand their heterogeneity and metabolic reprogramming. Consequently, these macrophages have also emerged as a promising target for diseases in which their role is crucial in driving the disease pathology and outcome (e.g., Cancers). In this review, we discuss the recent findings that link many metabolites with macrophage functions and highlight how this metabolic reprogramming can improve our understanding of cellular malfunction in the macrophages during inflammatory disorders. A systematic analysis of the interconnecting crosstalk between metabolic pathways with macrophages should inform the selection of immunomodulatory therapies for inflammatory diseases.
    Keywords:  Inflammatory diseases; Krebs cycle; Macrophages; Metabolic reprogramming; Therapeutics
  3. Cell Metab. 2022 Dec 21. pii: S1550-4131(22)00542-3. [Epub ahead of print]
      Apoptotic cell (AC) clearance (efferocytosis) is performed by phagocytes, such as macrophages, that inhabit harsh physiological environments. Here, we find that macrophages display enhanced efferocytosis under prolonged (chronic) physiological hypoxia, characterized by increased internalization and accelerated degradation of ACs. Transcriptional and translational analyses revealed that chronic physiological hypoxia induces two distinct but complimentary states. The first, "primed" state, consists of concomitant transcription and translation of metabolic programs in AC-naive macrophages that persist during efferocytosis. The second, "poised" state, consists of transcription, but not translation, of phagocyte function programs in AC-naive macrophages that are translated during efferocytosis. Mechanistically, macrophages efficiently flux glucose into a noncanonical pentose phosphate pathway (PPP) loop to enhance NADPH production. PPP-derived NADPH directly supports enhanced efferocytosis under physiological hypoxia by ensuring phagolysosomal maturation and redox homeostasis. Thus, macrophages residing under physiological hypoxia adopt states that support cell fitness and ensure performance of essential homeostatic functions rapidly and safely.
    Keywords:  apoptotic cell clearance; cellular adaptation; efferocytosis; homeostasis; metabolism; oxygen; pentose phosphate pathway; physiological hypoxia
  4. Evol Lett. 2022 Dec;6(6): 412-425
      The absence of microbial exposure early in life leaves individuals vulnerable to immune overreaction later in life, manifesting as immunopathology, autoimmunity, or allergies. A key factor is thought to be a "critical window" during which the host's immune system can "learn" tolerance, and beyond which learning is no longer possible. Animal models indicate that many mechanisms have evolved to enable critical windows, and that their time limits are distinct and consistent. Such a variety of mechanisms, and precision in their manifestation suggest the outcome of strong evolutionary selection. To strengthen our understanding of critical windows, we explore their underlying evolutionary ecology using models encompassing demographic and epidemiological transitions, identifying the length of the critical window that would maximize fitness in different environments. We characterize how direct effects of microbes on host mortality, but also indirect effects via microbial ecology, will drive the optimal length of the critical window. We find that indirect effects such as magnitude of transmission, duration of infection, rates of reinfection, vertical transmission, host demography, and seasonality in transmission all have the effect of redistributing the timing and/or likelihood of encounters with microbial taxa across age, and thus increasing or decreasing the optimal length of the critical window. Declining microbial population abundance and diversity are predicted to result in increases in immune dysfunction later in life. We also make predictions for the length of the critical window across different taxa and environments. Overall, our modeling efforts demonstrate how critical windows will be impacted over evolution as a function of both host-microbiome/pathogen interactions and dispersal, raising central questions about potential mismatches between these evolved systems and the current loss of microbial diversity and/or increases in infectious disease.
    Keywords:  Critical window; host evolution; microbiome
  5. Microbiome. 2022 Dec 26. 10(1): 239
      BACKGROUND: The opportunistic pathogen Staphylococcus aureus is an asymptomatically carried member of the microbiome of about one third of the human population at any given point in time. Body sites known to harbor S. aureus are the skin, nasopharynx, and gut. In particular, the mechanisms allowing S. aureus to pass the gut epithelial barrier and to invade the bloodstream were so far poorly understood. Therefore, the objective of our present study was to investigate the extent to which genetic differences between enteric S. aureus isolates and isolates that caused serious bloodstream infections contribute to the likelihood of invasive disease.RESULTS: Here, we present genome-wide association studies (GWAS) that compare the genome sequences of 69 S. aureus isolates from enteric carriage by healthy volunteers and 95 isolates from bloodstream infections. We complement our GWAS results with a detailed characterization of the cellular and extracellular proteomes of the representative gut and bloodstream isolates, and by assaying the virulence of these isolates with infection models based on human gut epithelial cells, human blood cells, and a small animal infection model. Intriguingly, our results show that enteric and bloodstream isolates with the same sequence type (ST1 or ST5) are very similar to each other at the genomic and proteomic levels. Nonetheless, bloodstream isolates are not necessarily associated with an invasive profile. Furthermore, we show that the main decisive factor preventing infection of gut epithelial cells in vitro is the presence of a tight barrier.
    CONCLUSIONS: Our data show that virulence is a highly variable trait, even within a single clone. Importantly, however, there is no evidence that blood stream isolates possess a higher virulence potential than those from the enteric carriage. In fact, some gut isolates from healthy carriers were more virulent than bloodstream isolates. Based on our present observations, we propose that the integrity of the gut epithelial layer, rather than the pathogenic potential of the investigated enteric S. aureus isolates, determines whether staphylococci from the gut microbiome will become invasive pathogens. Video Abstract.
    Keywords:  Bacteremia; Barrier; Enteric carriage; S. aureus, Gut; Virulence
  6. ACS Bio Med Chem Au. 2022 Dec 21. 2(6): 586-599
      Staphylococcus aureus (S. aureus) is an invasive and life-threatening pathogen that has undergone extensive coevolution with its mammalian hosts. Its molecular adaptations include elaborate mechanisms for immune escape and hijacking of the coagulation and fibrinolytic pathways. These capabilities are enacted by virulence factors including microbial surface components recognizing adhesive matrix molecules (MSCRAMMs) and the plasminogen-activating enzyme staphylokinase (SAK). Despite the ability of S. aureus to modulate coagulation, until now the sensitivity of S. aureus virulence factors to digestion by proteases of the coagulation system was unknown. Here, we used protein engineering, biophysical assays, and mass spectrometry to study the susceptibility of S. aureus MSCRAMMs to proteolytic digestion by human thrombin, plasmin, and plasmin/SAK complexes. We found that MSCRAMMs were highly resistant to proteolysis, and that SAK binding to plasmin enhanced this resistance. We mapped thrombin, plasmin, and plasmin/SAK cleavage sites of nine MSCRAMMs and performed biophysical, bioinformatic, and stability analysis to understand structural and sequence features common to protease-susceptible sites. Overall, our study offers comprehensive digestion patterns of S. aureus MSCRAMMs by thrombin, plasmin, and plasmin/SAK complexes and paves the way for new studies into this resistance and virulence mechanism.
  7. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2022 Nov;34(11): 1209-1212
      Sepsis is a clinical syndrome of life-threatening organ dysfunction caused by infection. When an infection occurs, as the first line of defense of the body's immune system, neutrophils are first recruited to the site of infection to capture and kill pathogens by releasing neutrophil elastase (NE). However, a large amount of NE release will injury the surrounding normal tissues and induce organ dysfunction or failure. NE inhibitors can inhibit NE activity and reduce inflammatory response, which may be a promising drug for the treatment of sepsis. Currently, a variety of NE inhibitors have been developed and reported, but there is no systematic overview of their characteristics, and the role and underlying mechanisms of NE and related inhibitors in sepsis have not been thoroughly discussed. This article will make a review in this regard, in order to elucidate the effect of NE and its inhibitors in sepsis.
  8. Curr Opin Clin Nutr Metab Care. 2022 Dec 26.
      PURPOSE OF REVIEW: The unique and complex array of cutaneous lipids include essential components of the skin structure and signalling molecules mediating homeostasis and inflammation. Understanding skin lipid biology and metabolism can support our comprehension of health and disease, including systemic conditions with cutaneous involvement.RECENT FINDINGS: Lipids found on the skin surface, produced by both the host and resident microbes, maintain and regulate the skin microbiome and the epidermal barrier, whilst altered contributions from either source can be detrimental to skin health. The unique lipid composition of the epidermal barrier is essential for its function, and recent studies have expanded our understanding of epidermal ceramide production. This has been supported by improved models available for skin research, including organotypic skin models enabling in-vitro production of complex acylceramides for the first time, and model systems facilitating in-silico exploration of the lipid profile changes observed in clinical samples. Studies have revealed further involvement of lipid mediators such as eicosanoids in cutaneous inflammation, as well as immune regulation in both healthy and diseased skin.
    SUMMARY: Skin lipids offer exciting opportunities as therapeutic targets for many conditions, whether through topical interventions or nutritional supplementation.
  9. Chin Med J (Engl). 2022 Oct 20. 135(20): 2417-2426
      ABSTRACT: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), which are characterized by excessive inflammation and accompanied by diffuse injury of alveoli, can result in severe respiratory failures. The morbidity and mortality of patients remain high because the major treatments for ALI/ARDS are mainly supportive due to the lack of effective therapies. Numerous studies have demonstrated that the aggravation of coronavirus disease 2019 (COVID-19) leads to severe pneumonia and even ARDS. Pyroptosis, a biological process identified as a type of programed cell death, is mainly triggered by inflammatory caspase activation and is directly meditated by the gasdermin protein family, as well as being associated with the secretion and release of pro-inflammatory cytokines. Clinical and experimental evidence corroborates that pyroptosis of various cells in the lung, such as immune cells and structural cells, may play an important role in the pathogenesis of "cytokine storms" in ALI/ARDS, including those induced by COVID-19. Here, with a focus on ALI/ARDS and COVID-19, we summarized the recent advances in this field and proposed the theory of an inflammatory cascade in pyroptosis to identify new targets and pave the way for new approaches to treat these diseases.