bims-bac4me Biomed News
on Microbiome and trained immunity
Issue of 2023‒06‒04
seventeen papers selected by
Chun-Chi Chang
University Hospital Zurich
  1. Commensal Staphylococcus epidermidis Defends against Staphylococcus aureus through SaeRS Two-Component System.
  2. Editorial: Host-pathogen interactions: the metabolic crossroads.
  3. Butyrate inhibits Staphylococcus aureus-aggravated dermal IL-33 expression and skin inflammation through histone deacetylase inhibition.
  4. Modulation of innate immunity in airway epithelium for host-directed therapy.
  5. Itaconate family-based host-directed therapeutics for infections.
  6. Gut microbiota derived bile acid metabolites maintain the homeostasis of gut and systemic immunity.
  7. Macrophage phagocytosis of SARS-CoV-2-infected cells mediates potent plasmacytoid dendritic cell activation.
  8. Uptake of tumor-derived microparticles induces metabolic reprogramming of macrophages in the early metastatic lung.
  9. Microbiota and Nod-like receptors balance inflammation and metabolism during obesity and diabetes.
  10. Norbergenin prevents LPS-induced inflammatory responses in macrophages through inhibiting NFκB, MAPK and STAT3 activation and blocking metabolic reprogramming.
  11. Peptidoglycan deacetylation controls type IV secretion and the intracellular survival of the bacterial pathogen Legionella pneumophila.
  12. Prolonged inflammatory resolution in allergic asthma relates to dysfunctional interactions between neutrophils and airway epithelium.
  13. Macrophage-endothelial cell crosstalk orchestrates neutrophil recruitment in inflamed mucosa.
  14. Cholesterol controls tolerogenic versus immunogenic DCs.
  15. Functional flexibility and plasticity in immune control of systemic Salmonella infection.
  16. BCG-induced trained immunity and emergency granulopoiesis in pathogen agnostic effects of the vaccine.
  17. Signaling is the pathway to macrophage function.
  1. ACS Omega. 2023 May 23. 8(20): 17712-17718
    Commensal Staphylococcus epidermidis Defends against Staphylococcus aureus through SaeRS Two-Component System.
    Nadira Nurxat, Lili Wang, Qichen Wang, Shujing Li, Chen Jin, Yaran Shi, Ayjiamali Wulamu, Na Zhao, Yanan Wang, Hua Wang, Min Li, Qian Liu.
      Staphylococcus aureus is a high-virulent Gram-positive pathogen that is responsible for a serious of diseases. The emergence of antibiotic-resistant S. aureus poses a significant challenge in terms of treatment. The recent research on the human microbiome suggested that the application of commensal bacteria is a new strategy for combating pathogenic infections. Staphylococcus epidermidis, one of the most abundant species in the nasal microbiome, is able to inhibit the colonization of S. aureus. However, during bacterial competition, S. aureus undergoes evolutionary changes to adapt to the diverse environment. Our study has demonstrated that the nasal colonized S. epidermidis possesses the ability to inhibit the hemolytic activity of S. aureus. Moreover, we deciphered another layer of mechanism to inhibit S. aureus colonization by S. epidermidis. The active component present in the cell-free culture of S. epidermidis was found to significantly reduce the hemolytic activity of S. aureus in SaeRS- and Agr-dependent manner. Specifically, the hemolytic inhibition on the S. aureus Agr-I type by S. epidermidis is primarily dependent on the SaeRS two-component system. The active component is characterized as a small molecule that is heat sensitive and protease resistant. Critically, S. epidermidis significantly inhibit the virulence of S. aureus in a mouse skin abscess model, suggesting that the active compound could potentially be used as a therapeutic agent for managing S. aureus infections.
    DOI:  https://doi.org/10.1021/acsomega.3c00263
  2. Front Cell Infect Microbiol. 2023 ;13 1212051
    Editorial: Host-pathogen interactions: the metabolic crossroads.
    Crystal L Richards, Sébastien Bontemps-Gallo, Travis J Bourret.
      
    Keywords:  infection; metabolism; metabolites; microbiota; pathogens
    DOI:  https://doi.org/10.3389/fcimb.2023.1212051
  3. Front Immunol. 2023 ;14 1114699
    Butyrate inhibits Staphylococcus aureus-aggravated dermal IL-33 expression and skin inflammation through histone deacetylase inhibition.
    Chia-Hui Luo, Alan Chuan-Ying Lai, Ya-Jen Chang.
      Atopic dermatitis (AD) is an inflammatory skin disease caused by the disruption of skin barrier, and is dominated by the type 2 immune responses. Patients with AD have a high risk of developing Staphylococcus aureus infection. Interleukin-33 (IL-33), an alarmin, has been implicated in the pathophysiology of AD development. Butyrate, a short chain fatty acid known to be produced from the fermentation of glycerol by the commensal skin bacterium, Staphylococcus epidermidis, has been reported to possess antimicrobial and anti-inflammatory properties that suppress inflammatory dermatoses. However, little is known about the effects of butyrate on dermal IL-33 expression and associated immune response in S. aureus-aggravated skin inflammation in the context of AD. To decipher the underlying mechanism, we established an AD-like mouse model with epidermal barrier disruption by delipidizing the dorsal skin to induce AD-like pathophysiology, followed by the epicutaneous application of S. aureus and butyrate. We discovered that S. aureus infection exacerbated IL-33 release from keratinocytes and aggravated dermal leukocyte infiltration and IL-13 expression. Moreover, we showed that butyrate could attenuate S. aureus-aggravated skin inflammation with decreased IL-33, IL-13, and leukocyte infiltration in the skin. Mechanistically, we demonstrated that butyrate suppressed IL-33 expression and ameliorated skin inflammation through histone deacetylase 3 (HDAC3) inhibition. Overall, our findings revealed the potential positive effect of butyrate in controlling inflammatory skin conditions in AD aggravated by S. aureus infection.
    Keywords:  S. aureus; S. epidermidis; atopic dermatitis; butyrate; histone deacetylase; interleukin 33; keratinocytes
    DOI:  https://doi.org/10.3389/fimmu.2023.1114699
  4. Front Immunol. 2023 ;14 1197908
    Modulation of innate immunity in airway epithelium for host-directed therapy.
    Iwona T Myszor, Gudmundur Hrafn Gudmundsson.
      Innate immunity of the mucosal surfaces provides the first-line defense from invading pathogens and pollutants conferring protection from the external environment. Innate immune system of the airway epithelium consists of several components including the mucus layer, mucociliary clearance of beating cilia, production of host defense peptides, epithelial barrier integrity provided by tight and adherens junctions, pathogen recognition receptors, receptors for chemokines and cytokines, production of reactive oxygen species, and autophagy. Therefore, multiple components interplay with each other for efficient protection from pathogens that still can subvert host innate immune defenses. Hence, the modulation of innate immune responses with different inducers to boost host endogenous front-line defenses in the lung epithelium to fend off pathogens and to enhance epithelial innate immune responses in the immunocompromised individuals is of interest for host-directed therapy. Herein, we reviewed possibilities of modulation innate immune responses in the airway epithelium for host-directed therapy presenting an alternative approach to standard antibiotics.
    Keywords:  airway epithelium; epigenetics; innate immune memory; innate immunity; microbiota metabolites
    DOI:  https://doi.org/10.3389/fimmu.2023.1197908
  5. Front Immunol. 2023 ;14 1203756
    Itaconate family-based host-directed therapeutics for infections.
    Jae-Min Yuk, Eun-Jin Park, In Soo Kim, Eun-Kyeong Jo.
      Itaconate is a crucial anti-infective and anti-inflammatory immunometabolite that accumulates upon disruption of the Krebs cycle in effector macrophages undergoing inflammatory stress. Esterified derivatives of itaconate (4-octyl itaconate and dimethyl itaconate) and its isomers (mesaconate and citraconate) are promising candidate drugs for inflammation and infection. Several itaconate family members participate in host defense, immune and metabolic modulation, and amelioration of infection, although opposite effects have also been reported. However, the precise mechanisms by which itaconate and its family members exert its effects are not fully understood. In addition, contradictory results in different experimental settings and a lack of clinical data make it difficult to draw definitive conclusions about the therapeutic potential of itaconate. Here we review how the immune response gene 1-itaconate pathway is activated during infection and its role in host defense and pathogenesis in a context-dependent manner. Certain pathogens can use itaconate to establish infections. Finally, we briefly discuss the major mechanisms by which itaconate family members exert antimicrobial effects. To thoroughly comprehend how itaconate exerts its anti-inflammatory and antimicrobial effects, additional research on the actual mechanism of action is necessary. This review examines the current state of itaconate research in infection and identifies the key challenges and opportunities for future research in this field.
    Keywords:  host defense; inflammation; innate immunity; itaconate; toll-like receptor
    DOI:  https://doi.org/10.3389/fimmu.2023.1203756
  6. Front Immunol. 2023 ;14 1127743
    Gut microbiota derived bile acid metabolites maintain the homeostasis of gut and systemic immunity.
    Xiaomin Su, Yunhuan Gao, Rongcun Yang.
      Bile acids (BAs) as cholesterol-derived molecules play an essential role in some physiological processes such as nutrient absorption, glucose homeostasis and regulation of energy expenditure. They are synthesized in the liver as primary BAs such as cholic acid (CA), chenodeoxycholic acid (CDCA) and conjugated forms. A variety of secondary BAs such as deoxycholic acid (DCA) and lithocholic acid (LCA) and their derivatives is synthesized in the intestine through the involvement of various microorganisms. In addition to essential physiological functions, BAs and their metabolites are also involved in the differentiation and functions of innate and adaptive immune cells such as macrophages (Macs), dendritic cells (DCs), myeloid derived suppressive cells (MDSCs), regulatory T cells (Treg), Breg cells, T helper (Th)17 cells, CD4 Th1 and Th2 cells, CD8 cells, B cells and NKT cells. Dysregulation of the BAs and their metabolites also affects development of some diseases such as inflammatory bowel diseases. We here summarize recent advances in how BAs and their metabolites maintain gut and systemic homeostasis, including the metabolism of the BAs and their derivatives, the role of BAs and their metabolites in the differentiation and function of immune cells, and the effects of BAs and their metabolites on immune-associated disorders.
    Keywords:  bile acids; deoxycholic acid; gut microbiota; lithocholic acid; regulatory B cells; regulatory T cells; tolerogenic macrophages
    DOI:  https://doi.org/10.3389/fimmu.2023.1127743
  7. Cell Mol Immunol. 2023 May 30.
    Macrophage phagocytosis of SARS-CoV-2-infected cells mediates potent plasmacytoid dendritic cell activation.
    O García-Nicolás, A Godel, G Zimmer, A Summerfield.
      Early and strong interferon type I (IFN-I) responses are usually associated with mild COVID-19 disease, whereas persistent or unregulated proinflammatory cytokine responses are associated with severe disease outcomes. Previous work suggested that monocyte-derived macrophages (MDMs) are resistant and unresponsive to SARS-CoV-2 infection. Here, we demonstrate that upon phagocytosis of SARS-CoV-2-infected cells, MDMs are activated and secrete IL-6 and TNF. Importantly, activated MDMs in turn mediate strong activation of plasmacytoid dendritic cells (pDCs), leading to the secretion of high levels of IFN-α and TNF. Furthermore, pDC activation promoted IL-6 production by MDMs. This kind of pDC activation was dependent on direct integrin-mediated cell‒cell contacts and involved stimulation of the TLR7 and STING signaling pathways. Overall, the present study describes a novel and potent pathway of pDC activation that is linked to the macrophage-mediated clearance of infected cells. These findings suggest that a high infection rate by SARS-CoV-2 may lead to exaggerated cytokine responses, which may contribute to tissue damage and severe disease.
    Keywords:  Inflammatory cytokines; Interferon-α; Monocyte-derived macrophages; Plasmacytoid dendritic cell; SARS-CoV-2; COVID-19
    DOI:  https://doi.org/10.1038/s41423-023-01039-4
  8. Cell Rep. 2023 May 30. pii: S2211-1247(23)00593-4. [Epub ahead of print]42(6): 112582
    Uptake of tumor-derived microparticles induces metabolic reprogramming of macrophages in the early metastatic lung.
    Kelly Kersten, Ran You, Sophia Liang, Kevin M Tharp, Joshua Pollack, Valerie M Weaver, Matthew F Krummel, Mark B Headley.
      Pre-metastatic niche formation is a critical step during the metastatic spread of cancer. One way by which primary tumors prime host cells at future metastatic sites is through the shedding of tumor-derived microparticles as a consequence of vascular sheer flow. However, it remains unclear how the uptake of such particles by resident immune cells affects their phenotype and function. Here, we show that ingestion of tumor-derived microparticles by macrophages induces a rapid metabolic and phenotypic switch that is characterized by enhanced mitochondrial mass and function, increased oxidative phosphorylation, and upregulation of adhesion molecules, resulting in reduced motility in the early metastatic lung. This reprogramming event is dependent on signaling through the mTORC1, but not the mTORC2, pathway and is induced by uptake of tumor-derived microparticles. Together, these data support a mechanism by which uptake of tumor-derived microparticles induces reprogramming of macrophages to shape their fate and function in the early metastatic lung.
    Keywords:  CP: Cancer; CP: Metabolism; infinity flow; lung; macrophages; metastasis
    DOI:  https://doi.org/10.1016/j.celrep.2023.112582
  9. Biomed J. 2023 May 30. pii: S2319-4170(23)00047-1. [Epub ahead of print] 100610
    Microbiota and Nod-like receptors balance inflammation and metabolism during obesity and diabetes.
    Rodrigo Rodrigues E-Lacerda, Han Fang, Nazli Robin, Arshpreet Bhatwa, Daniel M Marko, Jonathan D Schertzer.
      Gut microbiota influence host immunity and metabolism during obesity. Bacterial sensors of the innate immune system relay signals from specific bacterial components (i.e., postbiotics) that can have opposing outcomes on host metabolic inflammation. NOD-like receptors (NLRs) such as Nod1 and Nod2 both recruit receptor-interacting protein kinase 2 (RIPK2) but have opposite effects on blood glucose control. Nod1 connects bacterial cell wall-derived signals to metabolic inflammation and insulin resistance, whereas Nod2 can promote immune tolerance, insulin sensitivity, and better blood glucose control during obesity. NLR family pyrin domain containing (NLRP) inflammasomes can also generate divergent metabolic outcomes. NLRP1 protects against obesity and metabolic inflammation potentially because of a bias toward IL-18 regulation, whereas NLRP3 appears to have a bias toward IL-1β-mediated metabolic inflammation and insulin resistance. Targeting specific postbiotics that improve immunometabolism is a key goal. The Nod2 ligand, muramyl dipeptide (MDP) is a short-acting insulin sensitizer during obesity or during inflammatory lipopolysaccharide (LPS) stress. LPS with underacylated lipid-A antagonizes TLR4 and counteracts the metabolic effects of inflammatory LPS. Providing underacylated LPS derived from Rhodobacter sphaeroides improved insulin sensitivity in obese mice. Therefore, certain types of LPS can generate metabolically beneficial metabolic endotoxemia. Engaging protective adaptive immunoglobulin immune responses can also improve blood glucose during obesity. A bacterial vaccine approach using an extract of the entire bacterial community in the upper gut promotes protective adaptive immune response and long-lasting improvements in blood glucose control. A key future goal is to identify and combine postbiotics that cooperate to improve blood glucose control.
    Keywords:  NLRs; T2D; glucose; insulin; insulin resistance; microbiome; microbiota; obesity
    DOI:  https://doi.org/10.1016/j.bj.2023.100610
  10. Front Immunol. 2023 ;14 1117638
    Norbergenin prevents LPS-induced inflammatory responses in macrophages through inhibiting NFκB, MAPK and STAT3 activation and blocking metabolic reprogramming.
    Wan Li, Zhengnan Cai, Florian Schindler, Sheyda Bahiraii, Martin Brenner, Elke H Heiss, Wolfram Weckwerth.
      Inflammation is thought to be a key cause of many chronic diseases and cancer. However, current therapeutic agents to control inflammation have limited long-term use potential due to various side-effects. This study aimed to examine the preventive effects of norbergenin, a constituent of traditional anti-inflammatory recipes, on LPS-induced proinflammatory signaling in macrophages and elucidate the underlying mechanisms by integrative metabolomics and shotgun label-free quantitative proteomics platforms. Using high-resolution mass spectrometry, we identified and quantified nearly 3000 proteins across all samples in each dataset. To interpret these datasets, we exploited the differentially expressed proteins and conducted statistical analyses. Accordingly, we found that LPS-induced production of NO, IL1β, TNFα, IL6 and iNOS in macrophages was alleviated by norbergenin via suppressed activation of TLR2 mediated NFκB, MAPKs and STAT3 signaling pathways. In addition, norbergenin was capable of overcoming LPS-triggered metabolic reprogramming in macrophages and restrained the facilitated glycolysis, promoted OXPHOS, and restored the aberrant metabolites within the TCA cycle. This is linked to its modulation of metabolic enzymes to support its anti-inflammatory activity. Thus, our results uncover that norbergenin regulates inflammatory signaling cascades and metabolic reprogramming in LPS stimulated macrophages to exert its anti-inflammatory potential.
    Keywords:  MAPK pathways; NFκB signaling pathway; TLR - toll-like receptor; anti-inflammation; macrophages; metabolomics; norbergenin; proteomics
    DOI:  https://doi.org/10.3389/fimmu.2023.1117638
  11. Proc Natl Acad Sci U S A. 2023 Jun 06. 120(23): e2119658120
    Peptidoglycan deacetylation controls type IV secretion and the intracellular survival of the bacterial pathogen Legionella pneumophila.
    David Boamah, Michael C Gilmore, Sarah Bourget, Anushka Ghosh, Mohammad J Hossain, Joseph P Vogel, Felipe Cava, Tamara J O'Connor.
      Peptidoglycan is a critical component of the bacteria cell envelope. Remodeling of the peptidoglycan is required for numerous essential cellular processes and has been linked to bacterial pathogenesis. Peptidoglycan deacetylases that remove the acetyl group of the N-acetylglucosamine (NAG) subunit protect bacterial pathogens from immune recognition and digestive enzymes secreted at the site of infection. However, the full extent of this modification on bacterial physiology and pathogenesis is not known. Here, we identify a polysaccharide deacetylase of the intracellular bacterial pathogen Legionella pneumophila and define a two-tiered role for this enzyme in Legionella pathogenesis. First, NAG deacetylation is important for the proper localization and function of the Type IVb secretion system, linking peptidoglycan editing to the modulation of host cellular processes through the action of secreted virulence factors. As a consequence, the Legionella vacuole mis-traffics along the endocytic pathway to the lysosome, preventing the formation of a replication permissive compartment. Second, within the lysosome, the inability to deacetylate the peptidoglycan renders the bacteria more sensitive to lysozyme-mediated degradation, resulting in increased bacterial death. Thus, the ability to deacetylate NAG is important for bacteria to persist within host cells and in turn, Legionella virulence. Collectively, these results expand the function of peptidoglycan deacetylases in bacteria, linking peptidoglycan editing, Type IV secretion, and the intracellular fate of a bacterial pathogen.
    Keywords:  DotK; Legionella; peptidoglycan; polysaccharide deacetylase; type IV secretion system
    DOI:  https://doi.org/10.1073/pnas.2119658120
  12. Ann Allergy Asthma Immunol. 2023 May 31. pii: S1081-1206(23)00400-3. [Epub ahead of print]
    Prolonged inflammatory resolution in allergic asthma relates to dysfunctional interactions between neutrophils and airway epithelium.
    Sandra Ekstedt, Vilma Lagebro, Susanna Kumlien Georén, Lars Olaf Cardell.
      BACKGROUND: Allergic asthma is a heterogeneous disorder involving chronic airway inflammation, reversible airflow limitation and tissue remodeling, causing chronic airflow limitation. Most of the asthma research has been focused on elucidating the pro-inflammatory pathways underlying disease pathogenesis. Paradoxically, the necessity of appropriate termination and resolution of inflammation has not been recognized until recently. The latter has led to the concept of chronic inflammation developing as a result of lack of specific 'stop' signals for the inflammatory process.OBJECTIVE: This study is designed to investigate the interaction between neutrophils and airway epithelium during inflammatory resolution in patients with allergic asthma.
    METHODS: An in vitro scratch assay with cultured epithelial cells, based on live imaging microscopy, was used to evaluate regeneration and the influence of neutrophils on resolution. Epithelial cells and autologous neutrophils were derived from healthy donors and patients with allergic asthma. Supernatants and cells were collected for ELISA and transcriptional analyses at the end of the experiment.
    RESULTS: Healthy epithelial cells regenerated faster than epithelial cells from patients with allergic asthma. Autologous neutrophils improved the regeneration of healthy epithelial cells but not asthmatic epithelial cells. IL-8 and β-catenin were downregulated in healthy epithelial cells after resolution, but not in allergic asthmatic epithelial cells.
    CONCLUSION: The prolonged duration of inflammation in the respiratory tract in patients with allergic asthma could be due to the impaired healing pattern of epithelial cells and their compromised interactions with the neutrophils.
    Keywords:  Allergic asthma; Epithelial cells; Inflammation; Neutrophil; Resolution
    DOI:  https://doi.org/10.1016/j.anai.2023.05.030
  13. J Clin Invest. 2023 Jun 01. pii: e170733. [Epub ahead of print]
    Macrophage-endothelial cell crosstalk orchestrates neutrophil recruitment in inflamed mucosa.
    Xingsheng Ren, Laura D Manzanares, Enzo B Piccolo, Jessica M Urbanczyk, David P Sullivan, Lenore K Yalom, Triet M Bui, Connor Lantz, Hinda Najem, Parambir S Dulai, Amy B Heimberger, Edward B Thorp, Ronen Sumagin.
      Neutrophil (PMN) mobilization to sites of insult is critical for host defense and requires transendothelial migration (TEM). TEM involves several well-studied sequential adhesive interactions with vascular endothelial cells (ECs); however, what initiates or terminates this process is not well-understood. Here we describe what we believe to be a new mechanism where vessel associated macrophages (VAMs) through localized interactions primed EC responses to form ICAM-1 "hot spots", to support PMN TEM. Using real-time intravital microscopy (IVM) on lipopolysaccharide (LPS)-inflamed intestines in CX3CR1-EGFP macrophage-reporter mice, complemented by whole-mount tissue imaging and flow cytometry, we found that macrophage vessel association is critical for the initiation of PMN-EC adhesive interactions, PMN TEM and subsequent accumulation in the intestinal mucosa. Anti-colony stimulating factor 1 receptor (CSF1R) antibody-mediated macrophage depletion in the lamina propria and at the vessel wall resulted in elimination of ICAM-1 hot spots impeding PMN-EC interactions and TEM. Mechanistically, the use of human clinical specimens, TNFα knockout macrophage chimeras, TNFα/TNF receptor (TNFR) neutralization and multi-cellular macrophage-EC-PMN cocultures revealed that macrophage-derived TNFα and EC TNFR2 axis mediated this regulatory mechanism and was required for PMN TEM. As such, our findings identified clinically relevant mechanism by which macrophages regulate PMN trafficking in inflamed mucosa.
    Keywords:  Cell Biology; Cell migration/adhesion; Inflammation; Macrophages; Neutrophils
    DOI:  https://doi.org/10.1172/JCI170733
  14. Nat Rev Immunol. 2023 Jun 02.
    Cholesterol controls tolerogenic versus immunogenic DCs.
    Lucy Bird.
      
    DOI:  https://doi.org/10.1038/s41577-023-00900-x
  15. Curr Opin Immunol. 2023 May 26. pii: S0952-7915(23)00062-6. [Epub ahead of print]83 102343
    Functional flexibility and plasticity in immune control of systemic Salmonella infection.
    Sven Engel, Annabell Bachem, Richard A Strugnell, Andreas Strasser, Marco J Herold, Sammy Bedoui.
      Immunity to systemic Salmonella infection depends on multiple effector mechanisms. Lymphocyte-derived interferon gamma (IFN-γ) enhances cell-intrinsic bactericidal capabilities to antagonize the hijacking of phagocytes as replicative niches for Salmonella. Programmed cell death (PCD) provides another means through which phagocytes fight against intracellular Salmonella. We describe remarkable levels of flexibility with which the host coordinates and adapts these responses. This involves interchangeable cellular sources of IFN-γ regulated by innate and adaptive cues, and the rewiring of PCD pathways in previously unknown ways. We discuss that such plasticity is likely the consequence of host-pathogen coevolution and raise the possibility of further functional overlap between these seemingly distinct processes.
    DOI:  https://doi.org/10.1016/j.coi.2023.102343
  16. J Mol Biol. 2023 May 30. pii: S0022-2836(23)00256-5. [Epub ahead of print] 168169
    BCG-induced trained immunity and emergency granulopoiesis in pathogen agnostic effects of the vaccine.
    Henok Andualem, Elysia Hollams, Tobias R Kollmann, Nelly Amenyogbe.
      Bacille Calmette-Guérin (BCG) is the most commonly administered vaccine in human history. The medical application of BCG extends far beyond the fight against tuberculosis. Despite its stellar medical record over 100 years, insight into how BCG provides this vast range of benefits is surprisingly limited, both for its pathogen-specific (tuberculosis) as well as pathogen-agnostic (other infections, autoimmunity, allergies, and cancer) effects. Trained immunity and emergency granulopoiesis have been identified as mediating BCG's pathogen-agnostic effects, for which some of the molecular mechanisms have been delineated. Upon review of the existing evidence, we postulate that emergency granulopoiesis and trained immunity are a continuum of the same effect cascade. In this context, we highlight that BCG's pathogen-agnostic benefits could be optimized by taking advantage of the age of the recipient and route of BCG administration.
    Keywords:  BCG; Emergency granulopoiesis; Mechanism; Modulators; Trained Immunity
    DOI:  https://doi.org/10.1016/j.jmb.2023.168169
  17. Trends Immunol. 2023 May 29. pii: S1471-4906(23)00080-7. [Epub ahead of print]
    Signaling is the pathway to macrophage function.
    Rachel A Gottschalk.
      Tissue and inflammatory contexts are well appreciated to shape macrophage function to promote health or disease. However, there has been minimal progress towards understanding how these contexts modify signaling-to-transcription networks. Integration of mechanistic modeling and data-driven approaches will be crucial for investigating how cell state impacts macrophage decision-making.
    Keywords:  computational modeling; signal integration; signaling-to-transciption; systems immunology; tissue macrophage
    DOI:  https://doi.org/10.1016/j.it.2023.04.007
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