bims-bac4me Biomed News
on Microbiome and trained immunity
Issue of 2023–12–03
fifty-nine papers selected by
Chun-Chi Chang, University Hospital Zurich
  1. Metabolism shapes immune responses to Staphylococcus aureus.
  2. Metabolic immunity against microbes.
  3. The evolutionary tug-of-war of macrophage metabolism during bacterial infection.
  4. Microbiota configuration determines nutritional immune optimization.
  5. Mycobacterium tuberculosis Rv1987 protein attenuates inflammatory response and consequently alters microbiota in mouse lung.
  6. Editorial: Innate immune evasion strategies during microbial infection.
  7. Citrobacter koseri inhibits the growth of Staphylococcus epidermidis by suppressing iron utilization.
  8. Dysregulated monocyte-derived macrophage response to Group B Streptococcus in newborns.
  9. Editorial: Transcriptional regulation of macrophage function.
  10. Host-pathogen interactions from a metabolic perspective: methods of investigation.
  11. Caspase-8 activation by cigarette smoke induces pro-inflammatory cell death of human macrophages exposed to lipopolysaccharide.
  12. The potential roles and mechanisms of Chitinase-3-like-1 in the pathogenesis of type 2-biased airway diseases.
  13. The spatial dissimilarities and connections of the microbiota in the upper and lower respiratory tract of beef cattle.
  14. Validation of vaginal microbiome proxies for in vitro experiments that biomimic Lactobacillus-dominant vaginal cultures.
  15. Managing the Skin Microbiome as a New Bacteriotherapy for Inflammatory Atopic Dermatitis.
  16. A mechanistic insight into severe COPD: the nose as a surrogate for the airways.
  17. Mammary γδ T cells promote IL-17A-mediated immunity against Staphylococcus aureus-induced mastitis in a microbiota-dependent manner.
  18. Probiotic Bacillus spp. enhance TLR3-mediated TNF signalling in macrophages.
  19. Editorial: Plasticity of monocytes/macrophages: phenotypic changes during disease progression.
  20. Perspectives in Searching Antimicrobial Peptides (AMPs) Produced by the Microbiota.
  21. Integrating compositional and functional content to describe vaginal microbiomes in health and disease.
  22. Staphylococcus aureus epidemiology, pathophysiology, clinical manifestations and application of nano-therapeutics as a promising approach to combat methicillin resistant Staphylococcus aureus.
  23. Early cellular mechanisms of type I interferon-driven susceptibility to tuberculosis.
  24. The microbiome and the gut-lung axis in tuberculosis: interplay in the course of disease and treatment.
  25. Dupilumab Significantly Improves Skin Barrier Function in Patients With Moderate-to-Severe Atopic Dermatitis.
  26. In vitro co-culture studies and the crucial role of fibroblast-immune cell crosstalk in IPF pathogenesis.
  27. Advantages and disadvantages of treatment of experimental ARDS by M2-polarized RAW 264.7 macrophages.
  28. Unravelling host-pathogen interactions by biofilm infected human wound models.
  29. Itaconate as a key regulator of respiratory disease.
  30. Engineered Probiotic-Based Personalized Cancer Vaccine Potentiates Antitumor Immunity through Initiating Trained Immunity.
  31. Efferocytosis-induced lactate enables the proliferation of pro-resolving macrophages to mediate tissue repair.
  32. Resident microbes shape the vaginal epithelial glycan landscape.
  33. SNAREs: a double-edged sword for intravacuolar bacterial pathogens within host cells.
  34. Protective fibroblastic niches in secondary lymphoid organs.
  35. A human 3D immune competent full-thickness skin model mimicking dermal dendritic cell activation.
  36. Vaginal microbes alter epithelial transcriptomic and epigenomic modifications providing insight into the molecular mechanisms for susceptibility to adverse reproductive outcomes.
  37. Comprehensive probiogenomics analysis of the commensal Escherichia coli CEC15 as a potential probiotic strain.
  38. Staphylococcus aureus gets itchy.
  39. Community assembly of the human piercing microbiome.
  40. Microbial underdogs: exploring the significance of low-abundance commensals in host-microbe interactions.
  41. BCG vaccination stimulates integrated organ immunity by feedback of the adaptive immune response to imprint prolonged innate antiviral resistance.
  42. Regulation of pDC Fate Determination by Histone Deacetylase 3.
  43. Kicking sleepers out of bed: Macrophages promote reactivation of dormant Cryptococcus neoformans by extracellular vesicle release and non-lytic exocytosis.
  44. Targeted epigenetic silencing of UCHL1 expression suppresses collagen-1 production in human lung epithelial cells.
  45. Endopeptidase O promotes Streptococcus suis immune evasion by cleaving the host- defence peptide cathelicidins.
  46. Fibroblasts in immune-mediated inflammatory diseases: The soil of inflammation.
  47. Role of epithelial barrier function in inducing type 2 immunity following early-life viral infection.
  48. Mycobacterium tuberculosis Rv0928 protein facilitates macrophage control of mycobacterium infection by promoting mitochondrial intrinsic apoptosis and ROS-mediated inflammation.
  49. Crystalline silica-induced proinflammatory eicosanoid storm in novel alveolar macrophage model quelled by docosahexaenoic acid supplementation.
  50. Roles of S100A8, S100A9 and S100A12 in infection, inflammation and immunity.
  51. Uncoupling protein 2 modulates polarization and metabolism of human primary macrophages via glycolysis and the NF‑κB pathway.
  52. Immunomodulatory actions of myeloid-derived suppressor cells in the context of innate immunity.
  53. Lactate exacerbates lung damage induced by nanomicroplastic through the gut microbiota-HIF1a/PTBP1 pathway.
  54. Integrated NLRP3, AIM2, NLRC4, Pyrin inflammasome activation and assembly drive PANoptosis.
  55. Role of histamine-mediated macrophage differentiation in clearance of metastatic bacterial infection.
  56. Drugging the NLRP3 inflammasome: from signalling mechanisms to therapeutic targets.
  57. Horizontal transmission of gut microbiota attenuates mortality in lung fibrosis.
  58. LPS and type I&II interferons have opposing effects on epigenetic regulation of LAIR1 expression in mouse and human macrophages.
  59. Restoring the infected powerhouse: Mitochondrial quality control in sepsis.
  1. J Innate Immun. 2023 Nov 28.
    Metabolism shapes immune responses to Staphylococcus aureus.
    Prabhakar Arumugam, Tammy Kielian.
      Staphylococcus aureus (S. aureus) is a common cause of hospital- and community-acquired infections that can result in various clinical manifestations ranging from mild to severe disease. The bacterium utilizes different combinations of virulence factors and biofilm formation to establish a successful infection, and the emergence of methicillin- and vancomycin-resistant strains introduces additional challenges for infection management and treatment. Metabolic programming of immune cells regulates the balance of energy requirements for activation and dictates pro- vs. anti-inflammatory function. Recent investigations into metabolic adaptations of leukocytes and S. aureus during infection indicate that metabolic crosstalk plays a crucial role in pathogenesis. Furthermore, S. aureus can modify its metabolic profile to fit an array of niches for commensal or invasive growth. Here we focus on the current understanding of immunometabolism during S. aureus infection and explore how metabolic crosstalk between the host and S. aureus influences disease outcome. We also discuss how key metabolic pathways influence leukocyte responses to other bacterial pathogens when information for S. aureus is not available. A better understanding of how S. aureus and leukocytes adapt their metabolic profiles in distinct tissue niches may reveal novel therapeutic targets to prevent or control invasive infections.
    DOI:  https://doi.org/10.1159/000535482
  2. Trends Cell Biol. 2023 Nov 28. pii: S0962-8924(23)00231-3. [Epub ahead of print]
    Metabolic immunity against microbes.
    Sebastian Kreimendahl, Lena Pernas.
      Pathogens, including viruses, bacteria, fungi, and parasites, remodel the metabolism of their host to acquire the nutrients they need to proliferate. Thus, host cells are often perceived as mere exploitable nutrient pools during infection. Mounting reports challenge this perception and instead suggest that host cells can actively reprogram their metabolism to the detriment of the microbial invader. In this review, we present metabolic mechanisms that host cells use to defend against pathogens. We highlight the contribution of domesticated microbes to host defenses and discuss examples of host-pathogen arms races that are derived from metabolic conflict.
    Keywords:  infection; metabolic defenses; metabolic immunity; metabolism; microbiota; mitochondria; pathogens
    DOI:  https://doi.org/10.1016/j.tcb.2023.10.013
  3. Trends Endocrinol Metab. 2023 Nov 30. pii: S1043-2760(23)00241-2. [Epub ahead of print]
    The evolutionary tug-of-war of macrophage metabolism during bacterial infection.
    Luís Almeida, Ayesha Dhillon-LaBrooy, Tim Sparwasser.
      The function and phenotype of macrophages are intimately linked with pathogen detection. On sensing pathogen-derived signals and molecules, macrophages undergo a carefully orchestrated process of polarization to acquire pathogen-clearing properties. This phenotypic change must be adequately supported by metabolic reprogramming that is now known to support the acquisition of effector function, but also generates secondary metabolites with direct microbicidal activity. At the same time, bacteria themselves have adapted to both manipulate and take advantage of macrophage-specific metabolic adaptations. Here, we summarize the current knowledge on macrophage metabolism during infection, with a particular focus on understanding the 'arms race' between host immune cells and bacteria during immune responses.
    Keywords:  bacterial metabolism; host–pathogen interactions; immunometabolism; infection; macrophage metabolism
    DOI:  https://doi.org/10.1016/j.tem.2023.11.002
  4. Proc Natl Acad Sci U S A. 2023 Dec 05. 120(49): e2304905120
    Microbiota configuration determines nutritional immune optimization.
    Seong-Ji Han, Apollo Stacy, Dan Corral, Verena M Link, Mirian Krystel De Siqueira, Liang Chi, Ana Teijeiro, Daniel S Yong, P Juliana Perez-Chaparro, Nicolas Bouladoux, Ai Ing Lim, Michel Enamorado, Yasmine Belkaid, Nicholas Collins.
      Mild or transient dietary restriction (DR) improves many aspects of health and aging. Emerging evidence from us and others has demonstrated that DR also optimizes the development and quality of immune responses. However, the factors and mechanisms involved remain to be elucidated. Here, we propose that DR-induced optimization of immunological memory requires a complex cascade of events involving memory T cells, the intestinal microbiota, and myeloid cells. Our findings suggest that DR enhances the ability of memory T cells to recruit and activate myeloid cells in the context of a secondary infection. Concomitantly, DR promotes the expansion of commensal Bifidobacteria within the large intestine, which produce the short-chain fatty acid acetate. Acetate conditioning of the myeloid compartment during DR enhances the capacity of these cells to kill pathogens. Enhanced host protection during DR is compromised when Bifidobacteria expansion is prevented, indicating that microbiota configuration and function play an important role in determining immune responsiveness to this dietary intervention. Altogether, our study supports the idea that DR induces both memory T cells and the gut microbiota to produce distinct factors that converge on myeloid cells to promote optimal pathogen control. These findings suggest that nutritional cues can promote adaptation and co-operation between multiple immune cells and the gut microbiota, which synergize to optimize immunity and protect the collective metaorganism.
    Keywords:  dietary restriction; memory T cell; metabolites; microbiota; nutrition
    DOI:  https://doi.org/10.1073/pnas.2304905120
  5. Front Cell Infect Microbiol. 2023 ;13 1256866
    Mycobacterium tuberculosis Rv1987 protein attenuates inflammatory response and consequently alters microbiota in mouse lung.
    Yingying Liu, Jiaqi Zhang, Guangxian Leng, Junxing Hu, Wenzhen Wang, Guoying Deng, Yufang Ma, Shanshan Sha.
       Introduction: Healthy lung microbiota plays an important role in preventing Mycobacterium tuberculosis (Mtb) infections by activating immune cells and stimulating production of T-helper cell type 1 cytokines. The dynamic stability of lung microbiota relies mostly on lung homeostasis. In our previous studies, we found that Mtb virulence factor, Rv1987 protein, can mediate host immune response and enhance mycobacterial survival in host lung. However, the alteration of lung microbiota and the contribution of lung microbiota dysbiosis to mycobacterial evasion in this process are not clear so far.
    Methods: M. smegmatis which does not contain the ortholog of Rv1987 protein was selected as a model strain to study the effects of Rv1987 on host lung microbiota. The lung microbiota, immune state and metabolites of mice infected by M. smegmatis overexpressing Rv1987 protein (MS1987) were detected and analyzed.
    Results: The results showed that Rv1987 inhibited inflammatory response in mouse lung and anaerobic bacteria and Proteobacteria, Bacteroidota, Actinobacteriota and Acidobacteriota bacteria were enriched in the lung tissues correspondingly. The immune alterations and microbiota dysbiosis affected host metabolic profiles, and some of significantly altered bacteria in MS1987-infected mouse lung, such as Delftia acidovorans, Ralstonia pickettii and Escherichia coli, led to anti-inflammatory responses in mouse lung. The secretory metabolites of these altered bacteria also influenced mycobacterial growth and biofilm formation directly.
    Conclusion: All these results suggested that Rv1987 can attenuate inflammatory response and alter microbiota in the lung, which in turn facilitates mycobacterial survival in the host.
    Keywords:  Mycobacterium tuberculosis; Rv1987; immune response; lung microbiota; metabolites
    DOI:  https://doi.org/10.3389/fcimb.2023.1256866
  6. Front Cell Infect Microbiol. 2023 ;13 1332253
    Editorial: Innate immune evasion strategies during microbial infection.
    Selvakumar Subbian.
      
    Keywords:  host response; host-pathogen interactions; innate immunity; microbial infection; pathogens; vaccines
    DOI:  https://doi.org/10.3389/fcimb.2023.1332253
  7. Biochem Biophys Res Commun. 2023 Nov 19. pii: S0006-291X(23)01371-2. [Epub ahead of print]691 149277
    Citrobacter koseri inhibits the growth of Staphylococcus epidermidis by suppressing iron utilization.
    Tomotaka Ohkubo, Yasuhiko Matsumoto, Hiroaki Sasaki, Kaoru Kinoshita, Yuki Ogasawara, Takashi Sugita.
      The human skin microbiome consists of many species of bacteria, including Staphylococcus aureus and S. epidermidis. Individuals with atopic dermatitis (AD) have an increased relative abundance of S. aureus, which exacerbates the inflammation of AD. Although S. epidermidis, a main component of healthy skin microbiota, inhibits the growth of S. aureus, the balance between S. epidermidis and S. aureus is disrupted in the skin of individuals with AD. In this study, we found that Citrobacter koseri isolated from patients with AD produces substances that inhibit the growth of S. epidermidis. Heat-treated culture supernatant (CS) of C. koseri inhibited the growth of S. epidermidis but not S. aureus. The genome of C. koseri has gene clusters related to siderophores and the heat-treated CS of C. koseri contained a high concentration of siderophores compared with the control medium. The inhibitory activity of C. koseri CS against the growth of S. epidermidis was decreased by the addition of iron, but not copper or zinc. Deferoxamine, an iron-chelating agent, also inhibited the growth of S. epidermidis, but not that of S. aureus. These findings suggest that C. koseri inhibits the growth of S. epidermidis by interfering with its iron utilization.
    Keywords:  C. koseri, iron utilization; S. epidermidis; Siderophore; Skin microbiome
    DOI:  https://doi.org/10.1016/j.bbrc.2023.149277
  8. Front Immunol. 2023 ;14 1268804
    Dysregulated monocyte-derived macrophage response to Group B Streptococcus in newborns.
    Denho Ravi, Erato Ntinopoulou, Nessim Guetta, Manuela Weier, Verena Vogel, Barbara Spellerberg, Parham Sendi, Sandrine Gremlich, Thierry Roger, Eric Giannoni.
       Introduction: Streptococcus agalactiae (Group B Streptococcus, GBS) is a leading pathogen of neonatal sepsis. The host-pathogen interactions underlying the progression to life-threatening infection in newborns are incompletely understood. Macrophages are first line in host defenses against GBS, contributing to the initiation, amplification, and termination of immune responses. The goal of this study was to compare the response of newborn and adult monocyte-derived macrophages (MDMs) to GBS.
    Methods: Monocytes from umbilical cord blood of healthy term newborns and from peripheral blood of healthy adult subjects were cultured with M-CSF to induce MDMs. M-CSF-MDMs, GM-CSF- and IFNγ-activated MDMs were exposed to GBS COH1, a reference strain for neonatal sepsis.
    Results: GBS induced a greater release of IL-1β, IL-6, IL-10, IL-12p70 and IL-23 in newborn compared to adult MDMs, while IL-18, IL-21, IL-22, TNF, RANTES/CCL5, MCP-1/CCL2 and IL-8/CXCL8 were released at similar levels. MDM responses to GBS were strongly influenced by conditions of activation and were distinct from those to synthetic bacterial lipopeptides and lipopolysaccharides. Under similar conditions of opsonization, newborn MDMs phagocytosed and killed GBS as efficiently as adult MDMs.
    Discussion: Altogether, the production of excessive levels of Th1- (IL-12p70), Th17-related (IL-1β, IL-6, IL-23) and anti-inflammatory (IL-10) cytokines is consistent with a dysregulated response to GBS in newborns. The high responsiveness of newborn MDMs may play a role in the progression of GBS infection in newborns, possibly contributing to the development of life-threatening organ dysfunction.
    Keywords:  cytokine; group B streptococcus; innate immunity; macrophage; newborn; phagocytosis; streptococcus agalactiae
    DOI:  https://doi.org/10.3389/fimmu.2023.1268804
  9. Front Immunol. 2023 ;14 1321064
    Editorial: Transcriptional regulation of macrophage function.
    Zsolt Czimmerer, Andreas Patsalos, Marten A Hoeksema.
      
    Keywords:  macrophage ontogeny; macrophage responses; macrophages; transcription factors; transcriptional regulation
    DOI:  https://doi.org/10.3389/fimmu.2023.1321064
  10. Microbes Infect. 2023 Nov 23. pii: S1286-4579(23)00170-3. [Epub ahead of print] 105267
    Host-pathogen interactions from a metabolic perspective: methods of investigation.
    Caroline Demangel, Laura Surace.
      Metabolism shapes immune homeostasis in health and disease. This review presents the range of methods that are currently available to investigate the dialog between metabolism and immunity at the systemic, tissue and cellular levels, particularly during infection.
    DOI:  https://doi.org/10.1016/j.micinf.2023.105267
  11. Cell Death Dis. 2023 Nov 25. 14(11): 773
    Caspase-8 activation by cigarette smoke induces pro-inflammatory cell death of human macrophages exposed to lipopolysaccharide.
    Marta Cristaldi, Marco Buscetta, Maura Cimino, Agnese La Mensa, Maria Rita Giuffrè, Luigi Fiore, Claudia Carcione, Fabio Bucchieri, Francesca Rappa, Claudia Coronnello, Nicolina Sciaraffa, Santina Amato, Tommaso Silvano Aronica, Giovanna Lo Iacono, Alessandro Bertani, Elisabetta Pace, Chiara Cipollina.
      Cigarette smoking impairs the lung innate immune response making smokers more susceptible to infections and severe symptoms. Dysregulation of cell death is emerging as a key player in chronic inflammatory conditions. We have recently reported that short exposure of human monocyte-derived macrophages (hMDMs) to cigarette smoke extract (CSE) altered the TLR4-dependent response to lipopolysaccharide (LPS). CSE caused inhibition of the MyD88-dependent inflammatory response and activation of TRIF/caspase-8/caspase-1 pathway leading to Gasdermin D (GSDMD) cleavage and increased cell permeability. Herein, we tested the hypothesis that activation of caspase-8 by CSE increased pro-inflammatory cell death of LPS-stimulated macrophages. To this purpose, we measured apoptotic and pyroptotic markers as well as the expression/release of pro-inflammatory mediators in hMDMs exposed to LPS and CSE, alone or in combination, for 6 and 24 h. We show that LPS/CSE-treated hMDMs, but not cells treated with CSE or LPS alone, underwent lytic cell death (LDH release) and displayed apoptotic features (activation of caspase-8 and -3/7, nuclear condensation, and mitochondrial membrane depolarization). Moreover, the negative regulator of caspase-8, coded by CFLAR gene, was downregulated by CSE. Activation of caspase-3 led to Gasdermin E (GSDME) cleavage. Notably, lytic cell death caused the release of the damage-associated molecular patterns (DAMPs) heat shock protein-60 (HSP60) and S100A8/A9. This was accompanied by an impaired inflammatory response resulting in inhibited and delayed release of IL6 and TNF. Of note, increased cleaved caspase-3, higher levels of GSDME and altered expression of cell death-associated genes were found in alveolar macrophages of smoker subjects compared to non-smoking controls. Overall, our findings show that CSE sensitizes human macrophages to cell death by promoting pyroptotic and apoptotic pathways upon encountering LPS. We propose that while the delayed inflammatory response may result in ineffective defenses against infections, the observed cell death associated with DAMP release may contribute to establish chronic inflammation. CS exposure sensitizes human macrophages to pro-inflammatory cell death. Upon exposure to LPS, CS inhibits the TLR4/MyD88 inflammatory response, downregulating the pro-inflammatory genes TNF and IL6 and the anti-apoptotic gene CFLAR, known to counteract caspase-8 activity. CS enhances caspase-8 activation through TLR4/TRIF, with a partial involvement of RIPK1, resulting on the activation of caspase-1/GSDMD axis leading to increased cell permeability and DAMP release through gasdermin pores [19]. At later timepoints caspase-3 becomes strongly activated by caspase-8 triggering apoptotic events which are associated with mitochondrial membrane depolarization, gasdermin E cleavage and secondary necrosis with consequent massive DAMP release.
    DOI:  https://doi.org/10.1038/s41419-023-06318-6
  12. Clin Immunol. 2023 Nov 28. pii: S1521-6616(23)00620-4. [Epub ahead of print] 109856
    The potential roles and mechanisms of Chitinase-3-like-1 in the pathogenesis of type 2-biased airway diseases.
    Yian Zhou, Zheng Liu, Yang Liu.
      The immune modulation in the epithelium is a protective feature of the epithelial function in the mucosal airways. Dysfunction of the epithelium can lead to chronic allergic airway inflammatory diseases, such as chronic rhinosinusitis with nasal polyps (CRSwNP), allergic rhinitis (AR), and allergic asthma. Chitinase-3-like-1 (CHI3L1) is a key modulator in the epithelium against irritants, pathogens, and allergens and is involved in cancers, autoimmune diseases, neurological disorders, and other chronic diseases. Induction of epithelial cell-derived CHI3L1 is also confirmed to be implicated in the pathogenesis of Th2-related airway diseases like CRSwNP, AR, and allergic asthma, triggering a cascade of subsequent inflammatory reactions leading to the disease development. The techniques that block the biological function of CHI3L1 include small interfering RNA, neutralizing antibodies, and microRNAs and these methods proved to be successful in preclinical and clinical investigation in cancers, autoimmune diseases, asthma, and chronic obstructive pulmonary disease. Therefore, treatment with CHI3L1-blocking methods could open up therapeutic options for allergic airway diseases. This review article discusses the role of epithelial cell-derived CHI3L1 in the development of CRSwNP, AR, and allergic asthma and examines the use of CHI3L1 as a potential therapeutic agent for allergic airway diseases.
    Keywords:  Allergic rhinitis; Asthma; Biologic; Chitinase-3-like-1; Nasal polyps; Rhinosinusitis
    DOI:  https://doi.org/10.1016/j.clim.2023.109856
  13. Front Cell Infect Microbiol. 2023 ;13 1269726
    The spatial dissimilarities and connections of the microbiota in the upper and lower respiratory tract of beef cattle.
    Zhihao Zhang, Chengqian Zhang, Yikai Zhong, Shuli Yang, Feilong Deng, Ying Li, Jianmin Chai.
      Bovine respiratory disease (BRD) causes morbidity and mortality in cattle. The critical roles of the respiratory microbiota in BRD have been widely studied. The nasopharynx was the most popular sampling niche for BRD pathogen studies. The oral cavity and other niches within the respiratory tract, such as nostrils and lung, are less assessed. In this study, oropharyngeal swabs (OS), nasal swabs (NS), nasopharyngeal swabs (NP), and bronchoalveolar lavage (BAL) were collected from calves located in four countries and analyzed for investigation of the dissimilarities and connections of the respiratory microbiota. The results showed that the microbial diversity, structure, and composition in the upper and lower respiratory tract in beef cattle from China, the USA, Canada, and Italy were significantly different. The microbial taxa for each sampling niche were specific and associated with their local physiology and geography. The signature microbiota for OS, NS, NP, and BAL were identified using the LEfSe algorithm. Although the spatial dissimilarities among the respiratory niches existed, the microbial connections were observed in beef cattle regardless of geography. Notably, the nostril and nasopharynx had more similar microbiomes compared to lung communities. The major bacterial immigration patterns in the bovine respiratory tract were estimated and some of them were associated with geography. In addition, the contribution of oral microbiota to the nasal and lung ecosystems was confirmed. Lastly, microbial interactions were characterized to reveal the correlation between the commercial microbiota and BRD-associated pathogens. In conclusion, shared airway microbiota among niches and geography provides the possibility to investigate the common knowledge for bovine respiratory health and diseases. In spite of the dissimilarities of the respiratory microbiota in cattle, the spatial connections among these sampling niches not only allow us to deeply understand the airway ecosystem but also benefit the research and development of probiotics for BRD.
    Keywords:  bovine respiratory disease; geography; lung; nasopharynx; nostrils; oral cavity; respiratory microbiota
    DOI:  https://doi.org/10.3389/fcimb.2023.1269726
  14. Am J Reprod Immunol. 2023 Dec;90(6): e13797
    Validation of vaginal microbiome proxies for in vitro experiments that biomimic Lactobacillus-dominant vaginal cultures.
    Abir Zahra, Ramkumar Menon, Giovana Fernanda Cosi Bento, Jessica Selim, Brandie D Taylor, Kathleen L Vincent, Richard B Pyles, Lauren S Richardson.
      The vaginal microbiome includes diverse microbiota dominated by Lactobacillus [L.] spp. that protect against infections, modulate inflammation, and regulate vaginal homeostasis. Because it is challenging to incorporate vaginal microbiota into in vitro models, including organ-on-a-chip systems, we assessed microbial metabolites as reliable proxies in addition to traditional vaginal epithelial cultures (VECs). Human immortalized VECs cultured on transwells with an air-liquid interface generated stratified cell layers colonized by transplanted healthy microbiomes (L. jensenii- or L. crispatus-dominant) or a community representing bacterial vaginosis (BV). After 48-h, a qPCR array confirmed the expected donor community profiles. Pooled apical and basal supernatants were subjected to metabolomic analysis (untargeted mass spectrometry) followed by ingenuity pathways analysis (IPA). To determine the bacterial metabolites' ability to recreate the vaginal microenvironment in vitro, pooled bacteria-free metabolites were added to traditional VEC cultures. Cell morphology, viability, and cytokine production were assessed. IPA analysis of metabolites from colonized samples contained fatty acids, nucleic acids, and sugar acids that were associated with signaling networks that contribute to secondary metabolism, anti-fungal, and anti-inflammatory functions indicative of a healthy vaginal microbiome compared to sterile VEC transwell metabolites. Pooled metabolites did not affect cell morphology or induce cell death (∼5.5%) of VEC cultures (n = 3) after 72-h. However, metabolites created an anti-inflammatory milieu by increasing IL-10 production (p = .06, T-test) and significantly suppressing pro-inflammatory IL-6 (p = .0001), IL-8 (p = .009), and TNFα (p = .0007) compared to naïve VEC cultures. BV VEC conditioned-medium did not affect cell morphology nor viability; however, it induced a pro-inflammatory environment by elevating levels of IL-6 (p = .023), IL-8 (p = .031), and TNFα (p = .021) when compared to L.-dominate microbiome-conditioned medium. VEC transwells provide a suitable ex vivo system to support the production of bacterial metabolites consistent with the vaginal milieu allowing subsequent in vitro studies with enhanced accuracy and utility.
    Keywords:  anti-inflammatory; metabolites; vaginal epithelial cells
    DOI:  https://doi.org/10.1111/aji.13797
  15. Cureus. 2023 Nov;15(11): e48803
    Managing the Skin Microbiome as a New Bacteriotherapy for Inflammatory Atopic Dermatitis.
    Dian Andriani Ratna Dewi, Angki Perdiyana, Ni M Wiliantari, Farrasila Nadhira, Nabila Arkania, Cut A Salsabila, Clara V Allun, Arohid Allatib, Kelvin Dewantara.
      The microbiome, comprising various bacteria, assumes a significant role in the immune system's maturation and maintaining bodily homeostasis. Alterations in the microbial composition can contribute to the initiation and progression of inflammation. Recent studies reveal that changes in microbial composition and function, known as dysbiosis in the skin and gut, have been associated with altered immunological responses and skin barrier disruption. These changes are implicated in the development of several skin diseases, such as atopic dermatitis (AD). This review examines research demonstrating the potential of microbiome repair as a therapeutic approach to reduce the effect of inflammatory processes in the skin during atopic dermatitis. This way, corticosteroids in atopic dermatitis therapy can be reduced or even replaced with treatments focusing on controlling the skin microbiome. This study used scientific literature from recognized platforms, including PubMed, Scopus, Google Scholar, and ScienceDirect, covering publications from 2013 to 2023. The primary aim of this study was to assess the efficacy of skin microbiome management in treating atopic dermatitis. This study concludes that physicians must comprehensively understand the microbiome's involvement in atopic dermatitis, including its pathophysiological implications and its relevance to therapeutic interventions.
    Keywords:  atopic dermatitis; immune system and inflammation; microbial dysbiosis; skin and gut microbiome; skin barrier; therapeutic approve
    DOI:  https://doi.org/10.7759/cureus.48803
  16. ERJ Open Res. 2023 Nov;pii: 00647-2023. [Epub ahead of print]9(6):
    A mechanistic insight into severe COPD: the nose as a surrogate for the airways.
    Xin Yao, Ian M Adcock, Sharon Mumby.
      A severe COPD signature in bronchial and nasal epithelial cells reflects reduced tissue repair and ECM regulation https://bit.ly/476S3PJ.
    DOI:  https://doi.org/10.1183/23120541.00647-2023
  17. iScience. 2023 Dec 15. 26(12): 108453
    Mammary γδ T cells promote IL-17A-mediated immunity against Staphylococcus aureus-induced mastitis in a microbiota-dependent manner.
    Na Pan, Lei Xiu, Ying Xu, Xuemei Bao, Yanchen Liang, Haochi Zhang, Bohui Liu, Yuanyu Feng, Huibo Guo, Jing Wu, Haotian Li, Cheng Ma, Shouxin Sheng, Ting Wang, Xiao Wang.
      Mastitis, a common disease for female during lactation period that could cause a health risk for human or huge economic losses for animals, is mainly caused by S. aureus invasion. Here, we found that neutrophil recruitment via IL-17A-mediated signaling was required for host defense against S. aureus-induced mastitis in a mouse model. The rapid accumulation and activation of Vγ4+ γδ T cells in the early stage of infection triggered the IL-17A-mediated immune response. Interestingly, the accumulation and influence of γδT17 cells in host defense against S. aureus-induced mastitis in a commensal microbiota-dependent manner. Overall, this study, focusing on γδT17 cells, clarified innate immune response mechanisms against S. aureus-induced mastitis, and provided a specific response to target for future immunotherapies. Meanwhile, a link between commensal microbiota community and host defense to S. aureus mammary gland infection may unveil potential therapeutic strategies to combat these intractable infections.
    Keywords:  Bacteriology; Components of the immune system; Immunology; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2023.108453
  18. Immunology. 2023 Nov 29.
    Probiotic Bacillus spp. enhance TLR3-mediated TNF signalling in macrophages.
    Katrine Damgaard Winther, Erik Juncker Boll, Dorthe Sandvang, Andrew R Williams.
      Probiotics have been reported to have immunomodulatory properties in the context of infectious disease and inflammation, although the underlying mechanisms are not fully understood. Here, we aimed to determine how different probiotic bacterial strains modulated macrophage function during TLR3 stimulation mimicking viral infection. We screened 14 different strains for their ability to modulate TNF-α, IL-6 IL-10, IFN-α, IFN-β and IFN-γ secretion in RAW 264.7 macrophages with or without poly(I:C) stimulation. Seven strains were selected for further analysis using primary porcine alveolar macrophages. In-depth transcriptomic analysis on alveolar macrophages was conducted for two strains. Most strains induced a synergistic effect when co-incubated with poly(I:C) resulting in increased levels of IL-6 and TNF-α secretion from RAW 264.7 cells. This synergistic effect was found to be TLR2 independent. Only strains of Bacillus spp. could induce this effect in alveolar macrophages. Transcriptomic analysis indicated that the increased TNF-α secretion in alveolar macrophages after co-incubation with poly(I:C) correlated with significant upregulation of TNF and IL23A-related pathways. Collectively, our data show that probiotic bacteria possess strain-dependent immunomodulatory properties that may be harnessed to enhance innate immune responses to pathogens.
    Keywords:  TLRs; bacteria; cytokines; macrophage; probiotics
    DOI:  https://doi.org/10.1111/imm.13721
  19. Front Immunol. 2023 ;14 1328382
    Editorial: Plasticity of monocytes/macrophages: phenotypic changes during disease progression.
    Ruoxi Yuan, Yanan Ma, Chao Yang, Liwu Li.
      
    Keywords:  inflammation; innate immunity; macrophage heterogeneity; monocytes polarization; therapeutic targets
    DOI:  https://doi.org/10.3389/fimmu.2023.1328382
  20. Microb Ecol. 2023 Dec 01. 87(1): 8
    Perspectives in Searching Antimicrobial Peptides (AMPs) Produced by the Microbiota.
    Luigui Gallardo-Becerra, Melany Cervantes-Echeverría, Fernanda Cornejo-Granados, Luis E Vazquez-Morado, Adrian Ochoa-Leyva.
      Changes in the structure and function of the microbiota are associated with various human diseases. These microbial changes can be mediated by antimicrobial peptides (AMPs), small peptides produced by the host and their microbiota, which play a crucial role in host-bacteria co-evolution. Thus, by studying AMPs produced by the microbiota (microbial AMPs), we can better understand the interactions between host and bacteria in microbiome homeostasis. Additionally, microbial AMPs are a new source of compounds against pathogenic and multi-resistant bacteria. Further, the growing accessibility to metagenomic and metatranscriptomic datasets presents an opportunity to discover new microbial AMPs. This review examines the structural properties of microbiota-derived AMPs, their molecular action mechanisms, genomic organization, and strategies for their identification in any microbiome data as well as experimental testing. Overall, we provided a comprehensive overview of this important topic from the microbial perspective.
    Keywords:  Antimicrobial peptides (AMPs); Microbiome; Microbiota
    DOI:  https://doi.org/10.1007/s00248-023-02313-8
  21. Microbiome. 2023 Nov 30. 11(1): 259
    Integrating compositional and functional content to describe vaginal microbiomes in health and disease.
    Johanna B Holm, Michael T France, Pawel Gajer, Bing Ma, Rebecca M Brotman, Michelle Shardell, Larry Forney, Jacques Ravel.
       BACKGROUND: A Lactobacillus-dominated vaginal microbiome provides the first line of defense against adverse genital tract health outcomes. However, there is limited understanding of the mechanisms by which the vaginal microbiome modulates protection, as prior work mostly described its composition through morphologic assessment and marker gene sequencing methods that do not capture functional information. To address this gap, we developed metagenomic community state types (mgCSTs) which use metagenomic sequences to describe and define vaginal microbiomes based on both composition and functional potential.
    RESULTS: MgCSTs are categories of microbiomes classified using taxonomy and the functional potential encoded in their metagenomes. MgCSTs reflect unique combinations of metagenomic subspecies (mgSs), which are assemblages of bacterial strains of the same species, within a microbiome. We demonstrate that mgCSTs are associated with demographics such as age and race, as well as vaginal pH and Gram stain assessment of vaginal smears. Importantly, these associations varied between mgCSTs predominated by the same bacterial species. A subset of mgCSTs, including three of the six predominated by Gardnerella vaginalis mgSs, as well as mgSs of L. iners, were associated with a greater likelihood of bacterial vaginosis diagnosed by Amsel clinical criteria. This L. iners mgSs, among other functional features, encoded enhanced genetic capabilities for epithelial cell attachment that could facilitate cytotoxin-mediated cell lysis. Finally, we report a mgSs and mgCST classifier for which source code is provided and may be adapted for use by the microbiome research community.
    CONCLUSIONS: MgCSTs are a novel and easily implemented approach to reduce the dimension of complex metagenomic datasets while maintaining their functional uniqueness. MgCSTs enable the investigation of multiple strains of the same species and the functional diversity in that species. Future investigations of functional diversity may be key to unraveling the pathways by which the vaginal microbiome modulates the protection of the genital tract. Importantly, our findings support the hypothesis that functional differences between vaginal microbiomes, including those that may look compositionally similar, are critical considerations in vaginal health. Ultimately, mgCSTs may lead to novel hypotheses concerning the role of the vaginal microbiome in promoting health and disease, and identify targets for novel prognostic, diagnostic, and therapeutic strategies to improve women's genital health. Video Abstract.
    Keywords:  Bacterial vaginosis; Genital health; Metagenome; Sequencing; Vaginal microbiome
    DOI:  https://doi.org/10.1186/s40168-023-01692-x
  22. Pathog Glob Health. 2023 Nov 25. 1-23
    Staphylococcus aureus epidemiology, pathophysiology, clinical manifestations and application of nano-therapeutics as a promising approach to combat methicillin resistant Staphylococcus aureus.
    Raghad H F Bashabsheh, O'la Al-Fawares, Iyad Natsheh, Roba Bdeir, Rozan O Al-Khreshieh, Hasan H F Bashabsheh.
      Staphylococcus aureus is a Gram-positive bacterium and one of the most prevalent infectious disease-related causes of morbidity and mortality in adults. This pathogen can trigger a broad spectrum of diseases, from sepsis and pneumonia to severe skin infections that can be fatal. In this review, we will provide an overview of S. aureus and discuss the extensive literature on epidemiology, transmission, genetic diversity, evolution and antibiotic resistance strains, particularly methicillin resistant S. aureus (MRSA). While many different virulence factors that S. aureus produces have been investigated as therapeutic targets, this review examines recent nanotechnology approaches, which employ materials with atomic or molecular dimensions and are being used to diagnose, treat, or eliminate the activity of S. aureus. Finally, having a deeper understanding and clearer grasp of the roles and contributions of S. aureus determinants, antibiotic resistance, and nanotechnology will aid us in developing anti-virulence strategies to combat the growing scarcity of effective antibiotics against S. aureus.
    Keywords:  MDR; Staphylococcus aureus; antibiotic resistance; mesoporous silica nanoparticles; nanotechnology
    DOI:  https://doi.org/10.1080/20477724.2023.2285187
  23. Cell. 2023 Nov 18. pii: S0092-8674(23)01217-5. [Epub ahead of print]
    Early cellular mechanisms of type I interferon-driven susceptibility to tuberculosis.
    Dmitri I Kotov, Ophelia V Lee, Stefan A Fattinger, Charlotte A Langner, Jaresley V Guillen, Joshua M Peters, Andres Moon, Eileen M Burd, Kristen C Witt, Daniel B Stetson, David L Jaye, Bryan D Bryson, Russell E Vance.
      Mycobacterium tuberculosis (Mtb) causes 1.6 million deaths annually. Active tuberculosis correlates with a neutrophil-driven type I interferon (IFN) signature, but the cellular mechanisms underlying tuberculosis pathogenesis remain poorly understood. We found that interstitial macrophages (IMs) and plasmacytoid dendritic cells (pDCs) are dominant producers of type I IFN during Mtb infection in mice and non-human primates, and pDCs localize near human Mtb granulomas. Depletion of pDCs reduces Mtb burdens, implicating pDCs in tuberculosis pathogenesis. During IFN-driven disease, we observe abundant DNA-containing neutrophil extracellular traps (NETs) described to activate pDCs. Cell-type-specific disruption of the type I IFN receptor suggests that IFNs act on IMs to inhibit Mtb control. Single-cell RNA sequencing (scRNA-seq) indicates that type I IFN-responsive cells are defective in their response to IFNγ, a cytokine critical for Mtb control. We propose that pDC-derived type I IFNs act on IMs to permit bacterial replication, driving further neutrophil recruitment and active tuberculosis disease.
    Keywords:  Mycobacterium tuberculosis; innate immunology; interstitial macrophages; lung; mice; neutrophil extracellular traps; neutrophils; plasmacytoid dendritic cells; type I interferons
    DOI:  https://doi.org/10.1016/j.cell.2023.11.002
  24. Front Microbiol. 2023 ;14 1237998
    The microbiome and the gut-lung axis in tuberculosis: interplay in the course of disease and treatment.
    Néstor Alvarado-Peña, David Galeana-Cadena, Itzel Alejandra Gómez-García, Xavier Soberón Mainero, Eugenia Silva-Herzog.
      Tuberculosis is a chronic infectious disease caused by Mycobacterium tuberculosis (MTB) that remains a significant global health challenge. The extensive use of antibiotics in tuberculosis treatment, disrupts the delicate balance of the microbiota in various organs, including the gastrointestinal and respiratory systems. This gut-lung axis involves dynamic interactions among immune cells, microbiota, and signaling molecules from both organs. The alterations of the microbiome resulting from anti-TB treatment can significantly influence the course of tuberculosis, impacting aspects such as complete healing, reinfection, and relapse. This review aims to provide a comprehensive understanding of the gut-lung axis in the context of tuberculosis, with a specific focus on the impact of anti-TB treatment on the microbiome.
    Keywords:  Mycobacterium tuberculosis (MTB); anti-tuberculosis treatment; gut-lung axis; microbiome; microbiota; tuberculosis
    DOI:  https://doi.org/10.3389/fmicb.2023.1237998
  25. Pediatrics. 2023 Dec 01. 152(Suppl 3): S27-S28
    Dupilumab Significantly Improves Skin Barrier Function in Patients With Moderate-to-Severe Atopic Dermatitis.
    Alennie C Lopez, Elinor Simons.
      
    DOI:  https://doi.org/10.1542/peds.2023-064344HI
  26. Respir Res. 2023 Nov 27. 24(1): 298
    In vitro co-culture studies and the crucial role of fibroblast-immune cell crosstalk in IPF pathogenesis.
    Fama Thiam, Sakshi Phogat, Filsan Ahmed Abokor, Emmanuel Twumasi Osei.
      IPF is a fatal lung disease characterized by intensive remodeling of lung tissue leading to respiratory failure. The remodeling in IPF lungs is largely characterized by uncontrolled fibrosis. Fibroblasts and their contractile phenotype the myofibroblast are the main cell types responsible for typical wound healing responses, however in IPF, these responses are aberrant and result in the overactivation of fibroblasts which contributes to the inelasticity of the lung leading to a decrease in lung function. The specific mechanisms behind IPF pathogenesis have been elusive, but recently the innate and adaptive immunity have been implicated in the fibrotic processes of the disease. In connection with this, several in vitro co-culture models have been used to investigate the specific interactions occurring between fibroblasts and immune cells and how this contributes to the pathobiology of IPF. In this review, we discuss the in vitro models that have been used to examine the abnormal interactions between fibroblasts and cells of the innate and adaptive immune system, and how these contribute to the fibrotic processes in the lungs of IPF patients.
    Keywords:  Co-culture models; Extracellular matrix; Fibrosis; Idiopathic pulmonary fibrosis; Multicellular crosstalk; Pulmonary fibroblasts; Pulmonary immune cells
    DOI:  https://doi.org/10.1186/s12931-023-02608-x
  27. Heliyon. 2023 Nov;9(11): e21880
    Advantages and disadvantages of treatment of experimental ARDS by M2-polarized RAW 264.7 macrophages.
    A M Kosyreva, P A Vishnyakova, I S Tsvetkov, V V Kiseleva, D Sh Dzhalilova, E A Miroshnichenko, A V Lokhonina, O V Makarova, T H Fatkhudinov.
      Innate immunity reactions are core to any immunological process, including systemic inflammation and such extremes as acute respiratory distress syndrome (ARDS) and cytokine storm. Macrophages, the key cells of innate immunity, show high phenotypic plasticity: depending on microenvironmental cues, they can polarize into M1 (classically activated, pro-inflammatory) or M2 (alternatively activated, anti-inflammatory). The anti-inflammatory M2 macrophage polarization-based cell therapies constitute a novel prospective modality. Systemic administration of 'educated' macrophages is intended at their homing in lungs in order to mitigate the pro-inflammatory cytokine production and reduce the risks of 'cytokine storm' and related severe complications. Acute respiratory distress syndrome (ARDS) is the main mortality factor in pneumonia including SARS-CoV-associated cases. This study aimed to evaluate the influence of infusions of RAW 264.7 murine macrophage cell line polarized towards M2 phenotype on the development of LPS-induced ARDS in mouse model. The results indicate that the M2-polarized RAW 264.7 macrophage infusions in the studied model of ARDS promote relocation of lymphocytes from their depots in immune organs to the lungs. In addition, the treatment facilitates expression of M2-polarization markers Arg1, Vegfa and Tgfb and decreases of M1-polarization marker Cd38 in lung tissues, which can indicate the anti-inflammatory response activation. However, treatment of ARDS with M2-polarized macrophages didn't change the neutrophil numbers in the lungs. Moreover, the level of the Arg1 protein in lungs decreased throughtout the treatment with M2 macrophages, which is probably because of the pro-inflammatory microenvironment influence on the polarization of macrophages towards M1. Thus, the chemical polarization of macrophages is unstable and depends on the microenvironment. This adverse effect can be reduced through the use of primary autologous macrophages or some alternative methods of M2 polarization, notably siRNA-mediated.
    Keywords:  ARDS; Immune system; Inflammation; LPS; Lung; Macrophage; Polarization; Therapy
    DOI:  https://doi.org/10.1016/j.heliyon.2023.e21880
  28. Biofilm. 2023 Dec 15. 6 100164
    Unravelling host-pathogen interactions by biofilm infected human wound models.
    Jana Wächter, Pia K Vestweber, Viktoria Planz, Maike Windbergs.
      Approximately 80 % of persistent wound infections are affected by the presence of bacterial biofilms, resulting in a severe clinical challenge associated with prolonged healing periods, increased morbidity, and high healthcare costs. Unfortunately, in vitro models for wound infection research almost exclusively focus on early infection stages with planktonic bacteria. In this study, we present a new approach to emulate biofilm-infected human wounds by three-dimensional human in vitro systems. For this purpose, a matured biofilm consisting of the clinical key wound pathogen Pseudomonas aeruginosa was pre-cultivated on electrospun scaffolds allowing for non-destructive transfer of the matured biofilm to human in vitro wound models. We infected tissue-engineered human in vitro skin models as well as ex vivo human skin explants with the biofilm and analyzed structural tissue characteristics, biofilm growth behavior, and biofilm-tissue interactions. The structural development of biofilms in close proximity to the tissue, resulting in high bacterial burden and in vivo-like morphology, confirmed a manifest wound infection on all tested wound models, validating their applicability for general investigations of biofilm growth and structure. The extent of bacterial colonization of the wound bed, as well as the subsequent changes in molecular composition of skin tissue, were inherently linked to the characteristics of the underlying wound models including their viability and origin. Notably, the immune response observed in viable ex vivo and in vitro models was consistent with previous in vivo reports. While ex vivo models offered greater complexity and closer similarity to the in vivo conditions, in vitro models consistently demonstrated higher reproducibility. As a consequence, when focusing on direct biofilm-skin interactions, the viability of the wound models as well as their advantages and limitations should be aligned to the particular research question of future studies. Altogether, the novel model allows for a systematic investigation of host-pathogen interactions of bacterial biofilms and human wound tissue, also paving the way for development and predictive testing of novel therapeutics to combat biofilm-infected wounds.
    Keywords:  Bacterial biofilms; Host-biofilm interactions; In vitro skin infection model; Innate immune response; Persistent wound infections
    DOI:  https://doi.org/10.1016/j.bioflm.2023.100164
  29. Clin Exp Immunol. 2023 Nov 29. pii: uxad127. [Epub ahead of print]
    Itaconate as a key regulator of respiratory disease.
    Christina Michalaki, Gesa J Albers, Adam J Byrne.
      Macrophage activation results in the accumulation of endogenous metabolites capable of adopting immunomodulatory roles; one such bioactive metabolite is itaconate. After macrophage stimulation, the TCA-cycle intermediate cis-aconitate is converted to itaconate (by aconitate decarboxylase-1, ACOD1) in the mitochondrial matrix. Recent studies have highlighted the potential of targeting itaconate as a therapeutic strategy for lung diseases such as asthma, idiopathic pulmonary fibrosis (IPF), and respiratory infections. This review aims to bring together evidence which highlights a role for itaconate in chronic lung diseases (such as asthma and pulmonary fibrosis) and respiratory infections (such as SARS-CoV-2, influenza and Mycobacterium tuberculosis infection). A better understanding of the role of itaconate in lung disease could pave the way for novel therapeutic interventions and improve patient outcomes in respiratory disorders.
    Keywords:  Respiratory disease; itaconate; macrophages
    DOI:  https://doi.org/10.1093/cei/uxad127
  30. Adv Sci (Weinh). 2023 Nov 27. e2305081
    Engineered Probiotic-Based Personalized Cancer Vaccine Potentiates Antitumor Immunity through Initiating Trained Immunity.
    Zhaoxia Chen, Tuying Yong, Zhaohan Wei, Xiaoqiong Zhang, Xin Li, Jiaqi Qin, Jianye Li, Jun Hu, Xiangliang Yang, Lu Gan.
      Cancer vaccines hold great potential for clinical cancer treatment by eliciting T cell-mediated immunity. However, the limited numbers of antigen-presenting cells (APCs) at the injection sites, the insufficient tumor antigen phagocytosis by APCs, and the presence of a strong tumor immunosuppressive microenvironment severely compromise the efficacy of cancer vaccines. Trained innate immunity may promote tumor antigen-specific adaptive immunity. Here, a personalized cancer vaccine is developed by engineering the inactivated probiotic Escherichia coli Nissle 1917 to load tumor antigens and β-glucan, a trained immunity inducer. After subcutaneous injection, the cancer vaccine delivering model antigen OVA (BG/OVA@EcN) is highly accumulated and phagocytosed by macrophages at the injection sites to induce trained immunity. The trained macrophages may recruit dendritic cells (DCs) to facilitate BG/OVA@EcN phagocytosis and the subsequent DC maturation and T cell activation. In addition, BG/OVA@EcN remarkably enhances the circulating trained monocytes/macrophages, promoting differentiation into M1-like macrophages in tumor tissues. BG/OVA@EcN generates strong prophylactic and therapeutic efficacy to inhibit tumor growth by inducing potent adaptive antitumor immunity and long-term immune memory. Importantly, the cancer vaccine delivering autologous tumor antigens efficiently prevents postoperative tumor recurrence. This platform offers a facile translatable strategy to efficiently integrate trained immunity and adaptive immunity for personalized cancer immunotherapy.
    Keywords:  antitumor immunity; cancer vaccines; probiotics; trained immunity; β-glucan
    DOI:  https://doi.org/10.1002/advs.202305081
  31. Nat Metab. 2023 Nov 27.
    Efferocytosis-induced lactate enables the proliferation of pro-resolving macrophages to mediate tissue repair.
    David Ngai, Maaike Schilperoort, Ira Tabas.
      The clearance of apoptotic cells by macrophages (efferocytosis) prevents necrosis and inflammation and activates pro-resolving pathways, including continual efferocytosis. A key resolution process in vivo is efferocytosis-induced macrophage proliferation (EIMP), in which apoptotic cell-derived nucleotides trigger Myc-mediated proliferation of pro-resolving macrophages. Here we show that EIMP requires a second input that is integrated with cellular metabolism, notably efferocytosis-induced lactate production. Lactate signalling via GPR132 promotes Myc protein stabilization and subsequent macrophage proliferation. This mechanism is validated in vivo using a mouse model of dexamethasone-induced thymocyte apoptosis, which elevates apoptotic cell burden and requires efferocytosis to prevent inflammation and necrosis. Thus, EIMP, a key process in tissue resolution, requires inputs from two independent processes: a signalling pathway induced by apoptotic cell-derived nucleotides and a cellular metabolism pathway involving lactate production. These findings illustrate how seemingly distinct pathways in efferocytosing macrophages are integrated to carry out a key process in tissue resolution.
    DOI:  https://doi.org/10.1038/s42255-023-00921-9
  32. Sci Transl Med. 2023 Nov 29. 15(724): eabp9599
    Resident microbes shape the vaginal epithelial glycan landscape.
    Kavita Agarwal, Biswa Choudhury, Lloyd S Robinson, Sydney R Morrill, Yasmine Bouchibiti, Daisy Chilin-Fuentes, Sara B Rosenthal, Kathleen M Fisch, Jeffrey F Peipert, Carlito B Lebrilla, Jenifer E Allsworth, Amanda L Lewis, Warren G Lewis.
      Epithelial cells are covered in carbohydrates (glycans). This glycan coat or "glycocalyx" interfaces directly with microbes, providing a protective barrier against potential pathogens. Bacterial vaginosis (BV) is a condition associated with adverse health outcomes in which bacteria reside in direct proximity to the vaginal epithelium. Some of these bacteria, including Gardnerella, produce glycosyl hydrolase enzymes. However, glycans of the human vaginal epithelial surface have not been studied in detail. Here, we elucidate key characteristics of the "normal" vaginal epithelial glycan landscape and analyze the impact of resident microbes on the surface glycocalyx. In human BV, glycocalyx staining was visibly diminished in electron micrographs compared to controls. Biochemical and mass spectrometric analysis showed that, compared to normal vaginal epithelial cells, BV cells were depleted of sialylated N- and O-glycans, with underlying galactose residues exposed on the surface. Treatment of primary epithelial cells from BV-negative women with recombinant Gardnerella sialidases generated BV-like glycan phenotypes. Exposure of cultured VK2 vaginal epithelial cells to recombinant Gardnerella sialidase led to desialylation of glycans and induction of pathways regulating cell death, differentiation, and inflammatory responses. These data provide evidence that vaginal epithelial cells exhibit an altered glycan landscape in BV and suggest that BV-associated glycosidic enzymes may lead to changes in epithelial gene transcription that promote cell turnover and regulate responses toward the resident microbiome.
    DOI:  https://doi.org/10.1126/scitranslmed.abp9599
  33. Trends Microbiol. 2023 Nov 30. pii: S0966-842X(23)00320-7. [Epub ahead of print]
    SNAREs: a double-edged sword for intravacuolar bacterial pathogens within host cells.
    Ritika Chatterjee, Subba Rao Gangi Setty, Dipshikha Chakravortty.
      In the tug-of-war between host and pathogen, both evolve to combat each other's defence arsenals. Intracellular phagosomal bacteria have developed strategies to modify the vacuolar niche to suit their requirements best. Conversely, the host tries to target the pathogen-containing vacuoles towards the degradative pathways. The host cells use a robust system through intracellular trafficking to maintain homeostasis inside the cellular milieu. In parallel, intracellular bacterial pathogens have coevolved with the host to harbour strategies to manipulate cellular pathways, organelles, and cargoes, facilitating the conversion of the phagosome into a modified pathogen-containing vacuole (PCV). Key molecular regulators of intracellular traffic, such as changes in the organelle (phospholipid) composition, recruitment of small GTPases and associated effectors, soluble N-ethylmaleimide-sensitive factor-activating protein receptors (SNAREs), etc., are hijacked to evade lysosomal degradation. Legionella, Salmonella, Coxiella, Chlamydia, Mycobacterium, and Brucella are examples of pathogens which diverge from the endocytic pathway by using effector-mediated mechanisms to overcome the challenges and establish their intracellular niches. These pathogens extensively utilise and modulate the end processes of secretory pathways, particularly SNAREs, in repurposing the PCV into specialised compartments resembling the host organelles within the secretory network; at the same time, they avoid being degraded by the host's cellular mechanisms. Here, we discuss the recent research advances on the host-pathogen interaction/crosstalk that involves host SNAREs, conserved cellular processes, and the ongoing host-pathogen defence mechanisms in the molecular arms race against each other. The current knowledge of SNAREs, and intravacuolar bacterial pathogen interactions, enables us to understand host cellular innate immune pathways, maintenance of homeostasis, and potential therapeutic strategies to combat ever-growing antimicrobial resistance.
    Keywords:  SNARE proteins and pathogen-containing vacuole; host–pathogen interaction; intravacuolar bacterial pathogens; phagosome modification
    DOI:  https://doi.org/10.1016/j.tim.2023.11.002
  34. J Exp Med. 2024 Jan 01. pii: e20221220. [Epub ahead of print]221(1):
    Protective fibroblastic niches in secondary lymphoid organs.
    Angelina De Martin, Yves Stanossek, Natalia Barbara Pikor, Burkhard Ludewig.
      Fibroblastic reticular cells (FRCs) are specialized fibroblasts of secondary lymphoid organs that provide the structural foundation of the tissue. Moreover, FRCs guide immune cells to dedicated microenvironmental niches where they provide lymphocytes and myeloid cells with homeostatic growth and differentiation factors. Inflammatory processes, including infection with pathogens, induce rapid morphological and functional adaptations that are critical for the priming and regulation of protective immune responses. However, adverse FRC reprogramming can promote immunopathological tissue damage during infection and autoimmune conditions and subvert antitumor immune responses. Here, we review recent findings on molecular pathways that regulate FRC-immune cell crosstalk in specialized niches during the generation of protective immune responses in the course of pathogen encounters. In addition, we discuss how FRCs integrate immune cell-derived signals to ensure protective immunity during infection and how therapies for inflammatory diseases and cancer can be developed through improved understanding of FRC-immune cell interactions.
    DOI:  https://doi.org/10.1084/jem.20221220
  35. Front Immunol. 2023 ;14 1276151
    A human 3D immune competent full-thickness skin model mimicking dermal dendritic cell activation.
    Johanna Maria Hölken, Katja Friedrich, Marion Merkel, Nelli Blasius, Ursula Engels, Timo Buhl, Karsten Rüdiger Mewes, Lars Vierkotten, Nicole Elisabeth Teusch.
      We have integrated dermal dendritic cell surrogates originally generated from the cell line THP-1 as central mediators of the immune reaction in a human full-thickness skin model. Accordingly, sensitizer treatment of THP-1-derived CD14-, CD11c+ immature dendritic cells (iDCs) resulted in the phosphorylation of p38 MAPK in the presence of 1-chloro-2,4-dinitrobenzene (DNCB) (2.6-fold) as well as in degradation of the inhibitor protein kappa B alpha (IκBα) upon incubation with NiSO4 (1.6-fold). Furthermore, NiSO4 led to an increase in mRNA levels of IL-6 (2.4-fold), TNF-α (2-fold) and of IL-8 (15-fold). These results were confirmed on the protein level, with even stronger effects on cytokine release in the presence of NiSO4: Cytokine secretion was significantly increased for IL-8 (147-fold), IL-6 (11.8-fold) and IL-1β (28.8-fold). Notably, DNCB treatment revealed an increase for IL-8 (28.6-fold) and IL-1β (5.6-fold). Importantly, NiSO4 treatment of isolated iDCs as well as of iDCs integrated as dermal dendritic cell surrogates into our full-thickness skin model (SM) induced the upregulation of the adhesion molecule clusters of differentiation (CD)54 (iDCs: 1.2-fold; SM: 1.3-fold) and the co-stimulatory molecule and DC maturation marker CD86 (iDCs ~1.4-fold; SM:~1.5-fold) surface marker expression. Noteworthy, the expression of CD54 and CD86 could be suppressed by dexamethasone treatment on isolated iDCs (CD54: 1.3-fold; CD86: 2.1-fold) as well as on the tissue-integrated iDCs (CD54: 1.4-fold; CD86: 1.6-fold). In conclusion, we were able to integrate THP-1-derived iDCs as functional dermal dendritic cell surrogates allowing the qualitative identification of potential sensitizers on the one hand, and drug candidates that potentially suppress sensitization on the other hand in a 3D human skin model corresponding to the 3R principles ("replace", "reduce" and "refine").
    Keywords:  CD86; DNCB; NF-κB; dermal dendritic cell; full-thickness skin model; nickel; p38 MAPK
    DOI:  https://doi.org/10.3389/fimmu.2023.1276151
  36. Res Sq. 2023 Nov 16. pii: rs.3.rs-3580132. [Epub ahead of print]
    Vaginal microbes alter epithelial transcriptomic and epigenomic modifications providing insight into the molecular mechanisms for susceptibility to adverse reproductive outcomes.
    Michal Elovitz, Lauren Anton, Ana Cristancho, Briana Ferguson, Andrea Joseph, Jacques Ravel.
      The cervicovaginal microbiome is highly associated with women's health with microbial communities dominated by Lactobacillus spp. being considered optimal. Conversely, a lack of lactobacilli and a high abundance of strict and facultative anaerobes including Gardnerella vaginalis , have been associated with adverse reproductive outcomes. However, the molecular pathways modulated by microbe interactions with the cervicovaginal epithelia remain unclear. Using RNA-sequencing, we characterize the in vitro cervicovaginal epithelial transcriptional response to different vaginal bacteria and their culture supernatants. We showed that G. vaginalis upregulated genes were associated with an activated innate immune response including anti-microbial peptides and inflammasome pathways, represented by NLRP3-mediated increases in caspase-1, IL-1β and cell death. Cervicovaginal epithelial cells exposed to L. crispatus showed limited transcriptomic changes, while exposure to L. crispatus culture supernatants resulted in a shift in the epigenomic landscape of cervical epithelial cells. ATAC-sequencing confirmed epigenetic changes with reduced chromatin accessibility. This study reveals new insight into host-microbe interactions in the lower reproductive tract and suggest potential therapeutic strategies leveraging the vaginal microbiome to improve reproductive health.
    DOI:  https://doi.org/10.21203/rs.3.rs-3580132/v1
  37. BMC Microbiol. 2023 Nov 27. 23(1): 364
    Comprehensive probiogenomics analysis of the commensal Escherichia coli CEC15 as a potential probiotic strain.
    Tales Fernando da Silva, Rafael de Assis Glória, Thiago Jesus de Sousa, Monique Ferrary Americo, Andria Dos Santos Freitas, Marcus Vinicius Canário Viana, Luís Cláudio Lima de Jesus, Ligia Carolina da Silva Prado, Nathalie Daniel, Olivia Ménard, Marie-Françoise Cochet, Didier Dupont, Julien Jardin, Amanda Dias Borges, Simone Odília Antunes Fernandes, Valbert Nascimento Cardoso, Bertram Brenig, Enio Ferreira, Rodrigo Profeta, Flavia Figueira Aburjaile, Rodrigo Dias Oliveira de Carvalho, Philippe Langella, Yves Le Loir, Claire Cherbuy, Gwénaël Jan, Vasco Azevedo, Éric Guédon.
       BACKGROUND: Probiotics have gained attention for their potential maintaining gut and immune homeostasis. They have been found to confer protection against pathogen colonization, possess immunomodulatory effects, enhance gut barrier functionality, and mitigate inflammation. However, a thorough understanding of the unique mechanisms of effects triggered by individual strains is necessary to optimize their therapeutic efficacy. Probiogenomics, involving high-throughput techniques, can help identify uncharacterized strains and aid in the rational selection of new probiotics. This study evaluates the potential of the Escherichia coli CEC15 strain as a probiotic through in silico, in vitro, and in vivo analyses, comparing it to the well-known probiotic reference E. coli Nissle 1917. Genomic analysis was conducted to identify traits with potential beneficial activity and to assess the safety of each strain (genomic islands, bacteriocin production, antibiotic resistance, production of proteins involved in host homeostasis, and proteins with adhesive properties). In vitro studies assessed survival in gastrointestinal simulated conditions and adhesion to cultured human intestinal cells. Safety was evaluated in BALB/c mice, monitoring the impact of E. coli consumption on clinical signs, intestinal architecture, intestinal permeability, and fecal microbiota. Additionally, the protective effects of both strains were assessed in a murine model of 5-FU-induced mucositis.
    RESULTS: CEC15 mitigates inflammation, reinforces intestinal barrier, and modulates intestinal microbiota. In silico analysis revealed fewer pathogenicity-related traits in CEC15, when compared to Nissle 1917, with fewer toxin-associated genes and no gene suggesting the production of colibactin (a genotoxic agent). Most predicted antibiotic-resistance genes were neither associated with actual resistance, nor with transposable elements. The genome of CEC15 strain encodes proteins related to stress tolerance and to adhesion, in line with its better survival during digestion and higher adhesion to intestinal cells, when compared to Nissle 1917. Moreover, CEC15 exhibited beneficial effects on mice and their intestinal microbiota, both in healthy animals and against 5FU-induced intestinal mucositis.
    CONCLUSIONS: These findings suggest that the CEC15 strain holds promise as a probiotic, as it could modulate the intestinal microbiota, providing immunomodulatory and anti-inflammatory effects, and reinforcing the intestinal barrier. These findings may have implications for the treatment of gastrointestinal disorders, particularly some forms of diarrhea.
    Keywords:  Escherichia coli CEC15; Escherichia coli Nissle 1917; Gastrointestinal tract; Genomics; Immunomodulation; Mucositis; Probiogenomics; Probiotics
    DOI:  https://doi.org/10.1186/s12866-023-03112-4
  38. Nat Rev Microbiol. 2023 Nov 30.
    Staphylococcus aureus gets itchy.
    Andrea Du Toit.
      
    DOI:  https://doi.org/10.1038/s41579-023-01000-2
  39. Proc Biol Sci. 2023 Nov 29. 290(2011): 20231174
    Community assembly of the human piercing microbiome.
    Charles C Y Xu, Juliette Lemoine, Avery Albert, Élise Mac Whirter, Rowan D H Barrett.
      Predicting how biological communities respond to disturbance requires understanding the forces that govern their assembly. We propose using human skin piercings as a model system for studying community assembly after rapid environmental change. Local skin sterilization provides a 'clean slate' within the novel ecological niche created by the piercing. Stochastic assembly processes can dominate skin microbiomes due to the influence of environmental exposure on local dispersal, but deterministic processes might play a greater role within occluded skin piercings if piercing habitats impose strong selection pressures on colonizing species. Here we explore the human ear-piercing microbiome and demonstrate that community assembly is predominantly stochastic but becomes significantly more deterministic with time, producing increasingly diverse and ecologically complex communities. We also observed changes in two dominant and medically relevant antagonists (Cutibacterium acnes and Staphylococcus epidermidis), consistent with competitive exclusion induced by a transition from sebaceous to moist environments. By exploiting this common yet uniquely human practice, we show that skin piercings are not just culturally significant but also represent ecosystem engineering on the human body. The novel habitats and communities that skin piercings produce may provide general insights into biological responses to environmental disturbances with implications for both ecosystem and human health.
    Keywords:  16S; bacteria; biodiversity; ecological niche; environmental change; skin microbiome
    DOI:  https://doi.org/10.1098/rspb.2023.1174
  40. Exp Mol Med. 2023 Dec 01.
    Microbial underdogs: exploring the significance of low-abundance commensals in host-microbe interactions.
    Geongoo Han, Shipra Vaishnava.
      Our understanding of host-microbe interactions has broadened through numerous studies over the past decades. However, most investigations primarily focus on the dominant members within ecosystems while neglecting low-abundance microorganisms. Moreover, laboratory animals usually do not have microorganisms beyond bacteria. The phenotypes observed in laboratory animals, including the immune system, have displayed notable discrepancies when compared to real-world observations due to the diverse microbial community in natural environments. Interestingly, recent studies have unveiled the beneficial roles played by low-abundance microorganisms. Despite their rarity, these keystone taxa play a pivotal role in shaping the microbial composition and fulfilling specific functions in the host. Consequently, understanding low-abundance microorganisms has become imperative to unravel true commensalism. In this review, we provide a comprehensive overview of important findings on how low-abundance commensal microorganisms, including low-abundance bacteria, fungi, archaea, and protozoa, interact with the host and contribute to host phenotypes, with emphasis on the immune system. Indeed, low-abundance microorganisms play vital roles in the development of the host's immune system, influence disease status, and play a key role in shaping microbial communities in specific niches. Understanding the roles of low-abundance microbes is important and will lead to a better understanding of the true host-microbe relationships.
    DOI:  https://doi.org/10.1038/s12276-023-01120-y
  41. Nat Immunol. 2023 Nov 30.
    BCG vaccination stimulates integrated organ immunity by feedback of the adaptive immune response to imprint prolonged innate antiviral resistance.
    Audrey Lee, Katharine Floyd, Shengyang Wu, Zhuoqing Fang, Tze Kai Tan, Heather M Froggatt, John M Powers, Sarah R Leist, Kendra L Gully, Miranda L Hubbard, Chunfeng Li, Harold Hui, David Scoville, Alistaire D Ruggiero, Yan Liang, Anna Pavenko, Victor Lujan, Ralph S Baric, Garry P Nolan, Prabhu S Arunachalam, Mehul S Suthar, Bali Pulendran.
      Bacille Calmette-Guérin (BCG) vaccination can confer nonspecific protection against heterologous pathogens. However, the underlying mechanisms remain mysterious. We show that mice vaccinated intravenously with BCG exhibited reduced weight loss and/or improved viral clearance when challenged with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 B.1.351) or PR8 influenza. Protection was first evident between 14 and 21 d post-vaccination and lasted ∼3 months. Notably, BCG induced a biphasic innate response and robust antigen-specific type 1 helper T cell (TH1 cell) responses in the lungs. MyD88 signaling was essential for innate and TH1 cell responses, and protection against SARS-CoV-2. Depletion of CD4+ T cells or interferon (IFN)-γ activity before infection obliterated innate activation and protection. Single-cell and spatial transcriptomics revealed CD4-dependent expression of IFN-stimulated genes in lung myeloid and epithelial cells. Notably, BCG also induced protection against weight loss after mouse-adapted SARS-CoV-2 BA.5, SARS-CoV and SHC014 coronavirus infections. Thus, BCG elicits integrated organ immunity, where CD4+ T cells feed back on tissue myeloid and epithelial cells to imprint prolonged and broad innate antiviral resistance.
    DOI:  https://doi.org/10.1038/s41590-023-01700-0
  42. Elife. 2023 Nov 27. pii: e80477. [Epub ahead of print]12
    Regulation of pDC Fate Determination by Histone Deacetylase 3.
    Yijun Zhang, Tao Wu, Zhimin He, Wenlong Lai, Xiangyi Shen, Jiaoyan Lv, Yuanhao Wang, Li Wu.
      Dendritic cells (DCs), the key antigen-presenting cells, are primary regulators of immune responses. Transcriptional regulation of DC development had been one of the major research interests in DC biology, however, the epigenetic regulatory mechanisms during DC development remains unclear. Here, we report that Histone deacetylase 3 (Hdac3), an important epigenetic regulator, is highly expressed in pDCs, and its deficiency profoundly impaired the development of pDCs. Significant disturbance of homeostasis of hematopoietic progenitors was also observed in HDAC3-deficient mice, manifested by altered cell numbers of these progenitors and defective differentiation potentials for pDCs. Using the in vitro Flt3L supplemented DC culture system, we further demonstrated that HDAC3 was required for the differentiation of pDCs from progenitors at all developmental stages. Mechanistically, HDAC3 deficiency resulted in enhanced expression of cDC1-associated genes, owing to markedly elevated H3K27 acetylation (H3K27ac) at these gene sites in BM pDCs. In contrast, the expression of pDC-associated genes was significantly downregulated, leading to defective pDC differentiation.
    Keywords:  cell biology; immunology; inflammation; mouse
    DOI:  https://doi.org/10.7554/eLife.80477
  43. PLoS Pathog. 2023 Nov 30. 19(11): e1011841
    Kicking sleepers out of bed: Macrophages promote reactivation of dormant Cryptococcus neoformans by extracellular vesicle release and non-lytic exocytosis.
    Raffael Júnio Araújo de Castro, Clara Luna Marina, Aude Sturny-Leclère, Christian Hoffmann, Pedro Henrique Bürgel, Sarah Sze Wah Wong, Vishukumar Aimanianda, Hugo Varet, Ruchi Agrawal, Anamélia Lorenzetti Bocca, Alexandre Alanio.
      Macrophages play a key role in disseminated cryptococcosis, a deadly fungal disease caused by Cryptococcus neoformans. This opportunistic infection can arise following the reactivation of a poorly characterized latent infection attributed to dormant C. neoformans. Here, we investigated the mechanisms underlying reactivation of dormant C. neoformans using an in vitro co-culture model of viable but non-culturable (VBNC; equivalent of dormant) yeast cells with bone marrow-derived murine macrophages (BMDMs). Comparative transcriptome analysis of BMDMs incubated with log, stationary phase or VBNC cells of C. neoformans showed that VBNC cells elicited a reduced transcriptional modification of the macrophage but retaining the ability to regulate genes important for immune response, such as NLRP3 inflammasome-related genes. We further confirmed the maintenance of the low immunostimulatory capacity of VBNC cells using multiplex cytokine profiling, and analysis of cell wall composition and dectin-1 ligands exposure. In addition, we evaluated the effects of classic (M1) or alternative (M2) macrophage polarization on VBNC cells. We observed that intracellular residence sustained dormancy, regardless of the polarization state of macrophages and despite indirect detection of pantothenic acid (or its derivatives), a known reactivator for VBNC cells, in the C. neoformans-containing phagolysosome. Notably, M0 and M2, but not M1 macrophages, induced extracellular reactivation of VBNC cells by the secretion of extracellular vesicles and non-lytic exocytosis. Our results indicate that VBNC cells retain the low immunostimulatory profile required for persistence of C. neoformans in the host. We also describe a pro-pathogen role of macrophage-derived extracellular vesicles in C. neoformans infection and reinforce the impact of non-lytic exocytosis and the macrophage profile on the pathophysiology of cryptococcosis.
    DOI:  https://doi.org/10.1371/journal.ppat.1011841
  44. Epigenetics. 2023 Dec;18(1): 2175522
    Targeted epigenetic silencing of UCHL1 expression suppresses collagen-1 production in human lung epithelial cells.
    Dan-Dan Wu, Andy T Y Lau, Yan-Ming Xu, Marjan Reinders-Luinge, Mihaly Koncz, Antal Kiss, Wim Timens, Marianne G Rots, Machteld N Hylkema.
      Ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) is highly expressed in smokers, but little is known about the molecular mechanism of UCHL1 in airway epithelium and its possible role in affecting extracellular matrix (ECM) remodelling in the underlying submucosa. Since cigarette smoking is a major cause of lung diseases, we studied its effect on UCHL1 expression and DNA methylation patterns in human bronchial epithelial cells, obtained after laser capture micro-dissection (LCM) or isolated from residual tracheal/main stem bronchial tissue. Targeted regulation of UCHL1 expression via CRISPR/dCas9 based-epigenetic editing was used to explore the function of UCHL1 in lung epithelium. Our results show that cigarette smoke extract (CSE) stimulated the expression of UCHL1 in vitro. The methylation status of the UCHL1 gene was negatively associated with UCHL1 transcription in LCM-obtained airway epithelium at specific sites. Treatment with a UCHL1 inhibitor showed that the TGF-β1-induced upregulation of the ECM gene COL1A1 can be prevented by the inhibition of UCHL1 activity in cell lines. Furthermore, upon downregulation of UCHL1 by epigenetic editing using CRISPR/dCas-EZH2, mRNA expression of COL1A1 and fibronectin was reduced. In conclusion, we confirmed higher UCHL1 expression in current smokers compared to non- and ex-smokers, and induced downregulation of UCHL1 by epigenetic editing. The subsequent repression of genes encoding ECM proteins suggest a role for UCHL1 as a therapeutic target in fibrosis-related disease.
    Keywords:  DNA methylation; UCHL1; epigenetic editing; extracellular matrix; smoking
    DOI:  https://doi.org/10.1080/15592294.2023.2175522
  45. Virulence. 2023 Dec;14(1): 2283896
    Endopeptidase O promotes Streptococcus suis immune evasion by cleaving the host- defence peptide cathelicidins.
    Mingjie Jin, Siyu Liang, Jing Wang, Huihui Zhang, Yueling Zhang, Wanjiang Zhang, Siguo Liu, Fang Xie.
      Streptococcus suis is a zoonotic Gram-positive bacterium that causes invasive infections such as sepsis and meningitis, threatening public health worldwide. For successful establishment of infection, the bacterium should subvert the innate effectors of immune defence, including the cathelicidin family of host-defence peptides that combat pathogenic bacteria by directly disrupting cell membranes and coordinating immune responses. Here, our study shows that an extracellular endopeptidase O (PepO) of S. suis contributes to assisting the bacterium to resist cathelicidin-mediated killing, as the deletion of the pepO gene makes S. suis more sensitive to the human cathelicidin LL-37, as well as its mouse equivalent, mCRAMP. This protease targets and cleaves both LL-37 and mCRAMP, degrading them into shorter peptides with only a few amino acids, thereby abrogating their ability to kill S. suis. By cleaving LL-37 and mCRAMP, PepO impairs their chemotactic properties for neutrophil migration and undermines their anti-apoptosis activity, which is required for prolonging neutrophil lifespan. Also, PepO inhibits the ability of LL-37 and mCRAMP to promote lysosome development in macrophages. Moreover, the loss of PepO attenuates organ injury and decreases bacterial burdens in a murine model of S. suis bacteraemia. Taken together, these data provide novel insights into the role of the intrinsic proteolytic characteristics of PepO in S. suis-host interaction. Our findings demonstrate that S. suis utilizes the PepO protease to cleave cathelicidins, which is an immunosuppressive strategy adopted by this bacterium to facilitate pathogenesis.
    Keywords:  LL-37; Streptococcus suis; cathelicidin; host-defence peptide; mCRAMP; protease
    DOI:  https://doi.org/10.1080/21505594.2023.2283896
  46. Clin Immunol. 2023 Nov 24. pii: S1521-6616(23)00613-7. [Epub ahead of print] 109849
    Fibroblasts in immune-mediated inflammatory diseases: The soil of inflammation.
    Yifan Zhou, Tianyu Cao, Zhiguo Li, Hongjiang Qiao, Erle Dang, Shuai Shao, Gang Wang.
      As one of the most abundant stromal cells, fibroblasts are primarily responsible for the production and remodeling of the extracellular matrix. Traditionally, fibroblasts have been viewed as quiescent cells. However, recent advances in multi-omics technologies have demonstrated that fibroblasts exhibit remarkable functional diversity at the single-cell level. Additionally, fibroblasts are heterogeneous in their origins, tissue locations, and transitions with stromal cells. The dynamic nature of fibroblasts is further underscored by the fact that disease stages can impact their heterogeneity and behavior, particularly in immune-mediated inflammatory diseases such as psoriasis, inflammatory bowel diseases, and rheumatoid arthritis, etc. Fibroblasts can actively contribute to the disease initiation, progression, and relapse by responding to local microenvironmental signals, secreting downstream inflammatory factors, and interacting with immune cells during the pathological process. Here we focus on the development, plasticity, and heterogeneity of fibroblasts in inflammation, emphasizing the need for a developmental and dynamic perspective on fibroblasts.
    Keywords:  Fibroblast; Heterogeneity; Immune-mediated inflammatory diseases; Single-cell RNA sequencing
    DOI:  https://doi.org/10.1016/j.clim.2023.109849
  47. Clin Exp Allergy. 2023 Nov 27.
    Role of epithelial barrier function in inducing type 2 immunity following early-life viral infection.
    Kunyuan Tian, Prakrati Dangarh, Haina Zhang, Christian L Hines, Andrew Bush, Hannah J Pybus, James A Harker, Clare M Lloyd, Reiko J Tanaka, Sejal Saglani.
       BACKGROUND: Preschool wheeze attacks triggered by recurrent viral infections, including respiratory syncytial virus (RSV), are associated with an increased risk of childhood asthma. However, mechanisms that lead to asthma following early-life viral wheezing remain uncertain.
    METHODS: To investigate a causal relationship between early-life RSV infections and onset of type 2 immunity, we developed a neonatal murine model of recurrent RSV infection, in vivo and in silico, and evaluated the dynamical changes of altered airway barrier function and downstream immune responses, including eosinophilia, mucus secretion and type 2 immunity.
    RESULTS: RSV infection of neonatal BALB/c mice at 5 and 15 days of age induced robust airway eosinophilia, increased pulmonary CD4+ IL-13+ and CD4+ IL-5+ cells, elevated levels of IL-13 and IL-5 and increased airway mucus at 20 days of age. Increased bronchoalveolar lavage albumin levels, suggesting epithelial barrier damage, were present and persisted following the second RSV infection. Computational in silico simulations demonstrated that recurrent RSV infection resulted in severe damage of the airway barrier (epithelium), triggering the onset of type 2 immunity. The in silico results also demonstrated that recurrent infection is not always necessary for the development of type 2 immunity, which could also be triggered with single infection of high viral load or when the epithelial barrier repair is compromised.
    CONCLUSIONS: The neonatal murine model demonstrated that recurrent RSV infection in early life alters airway barrier function and promotes type 2 immunity. A causal relationship between airway barrier function and type 2 immunity was suggested using in silico model simulations.
    Keywords:  in silico modelling; neonatal murine model; pre-school wheeze; recurrent viral infections; respiratory syncytial virus
    DOI:  https://doi.org/10.1111/cea.14425
  48. Front Microbiol. 2023 ;14 1291358
    Mycobacterium tuberculosis Rv0928 protein facilitates macrophage control of mycobacterium infection by promoting mitochondrial intrinsic apoptosis and ROS-mediated inflammation.
    Chenling Xu, Yan Yue, Sidong Xiong.
      Macrophages are the main target cells for Mycobacterium tuberculosis (Mtb) infection. Previous studies have shown that Mtb actively upregulates phosphorus transport proteins, such as Rv0928 protein (also known as PstS3), to increase inorganic phosphate uptake and promote their survival under low phosphorus culture conditions in vitro. However, it is unclear whether this upregulation of PstS3 affects the intracellular survival of Mtb, as the latter is also largely dependent on the immune response of infected macrophages. By using Rv0928-overexpressing Mycobacterium smegmatis (Ms::Rv0928), we unexpectedly found that Rv0928 not only increased apoptosis, but also augmented the inflammatory response of infected macrophages. These enhanced cellular defense mechanisms ultimately led to a dramatic reduction in intracellular bacterial load. By investigating the underlying mechanisms, we found that Rv0928 interacted with the macrophage mitochondrial phosphate carrier protein SLC25A3, reduced mitochondrial membrane potential and caused mitochondrial cytochrome c release, which ultimately activated caspase-9-mediated intrinsic apoptosis. In addition, Rv0928 amplified macrophage mitochondrial ROS production, further enhancing pro-inflammatory cytokine production by promoting activation of NF-κB and MAPK pathways. Our study suggested that Mtb Rv0928 up-regulation enhanced the immune defense response of macrophages. These findings may help us to better understand the complex process of mutual adaptation and mutual regulation between Mtb and macrophages during infection.
    Keywords:  Mycobacterium tuberculosis; Rv0928; SLC25A3; apoptosis; inflammation; mitochondrion
    DOI:  https://doi.org/10.3389/fmicb.2023.1291358
  49. Front Immunol. 2023 ;14 1274147
    Crystalline silica-induced proinflammatory eicosanoid storm in novel alveolar macrophage model quelled by docosahexaenoic acid supplementation.
    Olivia K Favor, Lichchavi D Rajasinghe, Kathryn A Wierenga, Krishna R Maddipati, Kin Sing Stephen Lee, Andrew J Olive, James J Pestka.
       Introduction: Phagocytosis of inhaled crystalline silica (cSiO2) particles by tissue-resident alveolar macrophages (AMs) initiates generation of proinflammatory eicosanoids derived from the ω-6 polyunsaturated fatty acid (PUFA) arachidonic acid (ARA) that contribute to chronic inflammatory disease in the lung. While supplementation with the ω-3 PUFA docosahexaenoic acid (DHA) may influence injurious cSiO2-triggered oxylipin responses, in vitro investigation of this hypothesis in physiologically relevant AMs is challenging due to their short-lived nature and low recovery numbers from mouse lungs. To overcome these challenges, we employed fetal liver-derived alveolar-like macrophages (FLAMs), a self-renewing surrogate that is phenotypically representative of primary lung AMs, to discern how DHA influences cSiO2-induced eicosanoids.
    Methods: We first compared how delivery of 25 µM DHA as ethanolic suspensions or as bovine serum albumin (BSA) complexes to C57BL/6 FLAMs impacts phospholipid fatty acid content. We subsequently treated FLAMs with 25 µM ethanolic DHA or ethanol vehicle (VEH) for 24 h, with or without LPS priming for 2 h, and with or without cSiO2 for 1.5 or 4 h and then measured oxylipin production by LC-MS lipidomics targeting for 156 oxylipins. Results were further related to concurrent proinflammatory cytokine production and cell death induction.
    Results: DHA delivery as ethanolic suspensions or BSA complexes were similarly effective at increasing ω-3 PUFA content of phospholipids while decreasing the ω-6 PUFA arachidonic acid (ARA) and the ω-9 monounsaturated fatty acid oleic acid. cSiO2 time-dependently elicited myriad ARA-derived eicosanoids consisting of prostaglandins, leukotrienes, thromboxanes, and hydroxyeicosatetraenoic acids in unprimed and LPS-primed FLAMs. This cSiO2-induced eicosanoid storm was dramatically suppressed in DHA-supplemented FLAMs which instead produced potentially pro-resolving DHA-derived docosanoids. cSiO2 elicited marked IL-1α, IL-1β, and TNF-α release after 1.5 and 4 h of cSiO2 exposure in LPS-primed FLAMs which was significantly inhibited by DHA. DHA did not affect cSiO2-triggered death induction in unprimed FLAMs but modestly enhanced it in LPS-primed FLAMs.
    Discussion: FLAMs are amenable to lipidome modulation by DHA which suppresses cSiO2-triggered production of ARA-derived eicosanoids and proinflammatory cytokines. FLAMs are a potential in vitro alternative to primary AMs for investigating interventions against early toxicant-triggered inflammation in the lung.
    Keywords:  alveolar macrophage; crystalline silica; docosahexaenoic acid; lipidome; oxylipin
    DOI:  https://doi.org/10.3389/fimmu.2023.1274147
  50. Immunology. 2023 Nov 27.
    Roles of S100A8, S100A9 and S100A12 in infection, inflammation and immunity.
    Pengpeng Xia, Xingduo Ji, Li Yan, Siqi Lian, Ziyue Chen, Yi Luo.
      S100 proteins are small proteins that are only expressed in vertebrates. They are widely expressed in many different cell types and are involved in the regulation of calcium homeostasis, glucose metabolism, cell proliferation, apoptosis, inflammation and tumorigenesis. As members of the S100 protein subfamily of myeloid-related proteins, S100A8, S100A9 and S100A12 play a crucial role in resisting microbial infection and maintaining immune homeostasis. These proteins chelate the necessary metal nutrients of pathogens invading the host by means of 'nutritional immunity' and directly inhibit the growth of pathogens in the host. They interact with receptors on the cell surface to initiate inflammatory signal transduction, induce cytokine expression and participate in the inflammatory response and immune regulation. Furthermore, the increased content of these proteins during the pathological process makes them useful as disease markers for screening and detecting related diseases. This article summarizes the structure and function of the proteins S100A8, S100A9 and S100A12 and lays the foundation for further understanding their roles in infection, immunity and inflammation, as well as their potential applications in the prevention and treatment of infectious diseases.
    Keywords:  S100 proteins; anti-infective immunity; inflammation; signal transduction
    DOI:  https://doi.org/10.1111/imm.13722
  51. Exp Ther Med. 2023 Dec;26(6): 583
    Uncoupling protein 2 modulates polarization and metabolism of human primary macrophages via glycolysis and the NF‑κB pathway.
    Liguo Lang, Dongju Zheng, Qingjun Jiang, Ting Meng, Xiaohu Ma, Yang Yang.
      Metabolic abnormalities, particularly the M1/M2 macrophage imbalance, play a critical role in the development of various diseases, leading to severe inflammatory responses. The present study aimed to investigate the role of uncoupling protein 2 (UCP2) in regulating macrophage polarization, glycolysis, metabolic reprogramming, reactive oxygen species (ROS) and inflammation. Primary human macrophages were first polarized into M1 and M2 subtypes, and these two subtypes were infected by lentivirus-mediated UCP2 overexpression or knockdown, followed by enzyme-linked immunosorbent assay, reverse transcription-quantitative PCR, western blotting and flow cytometry to analyze the effects of UCP2 on glycolysis, oxidative phosphorylation (OXPHOS), ROS production and cytokine secretion, respectively. The results demonstrated that UCP2 expression was suppressed in M1 macrophages and increased in M2 macrophages, suggesting its regulatory role in macrophage polarization. UCP2 overexpression decreased macrophage glycolysis, increased OXPHOS, decreased ROS production, and led to the conversion of M1 polarization to M2 polarization. This process involved NF-κB signaling to regulate the secretion profile of cytokines and chemokines and affected the expression of key enzymes of glycolysis and a key factor for maintaining mitochondrial homeostasis (nuclear respiratory factor 1). UCP2 knockdown in M2 macrophages exacerbated inflammation and oxidative stress by promoting glycolysis, which was attenuated by the glycolysis inhibitor 2-deoxyglucose. These findings highlight the critical role of UCP2 in regulating macrophage polarization, metabolism, inflammation and oxidative stress through its effects on glycolysis, providing valuable insights into potential therapeutic strategies for macrophage-driven inflammatory and metabolic diseases.
    Keywords:  NF-κB; OXPHOS; UCP2; glycolysis; macrophage polarization
    DOI:  https://doi.org/10.3892/etm.2023.12282
  52. Innate Immun. 2023 Nov 28. 17534259231215581
    Immunomodulatory actions of myeloid-derived suppressor cells in the context of innate immunity.
    Nikoleta Bizymi, Andreas M Matthaiou, Irene Mavroudi, Aristea Batsali, Helen A Papadaki.
      Myeloid-derived suppressor cells (MDSCs) are notable innate immune cells, which are further divided into two subpopulations, i.e., monocytic and granulocytic. These cells are traditionally considered to mainly suppress the T-cell responses. However, more updated data indicate that their properties are rather immunomodulatory than solely immunosuppressive. Indeed, MDSCs display extensive crosstalk with other either innate or adaptive immune cells, and, according to the situation under which they are triggered, they may enhance or attenuate the immune response. However, their positive role in host's defense mechanisms under specific conditions is rarely discussed in the literature. In this mini-review, the authors briefly summarise the mechanisms of action of MDSCs under distinct conditions, such as infections and malignancies, with a particular emphasis on their role as components of the innate immunity system.
    Keywords:  infection; innate immune cells; innate immune response; innate immunity; myeloid-derived suppressor cells
    DOI:  https://doi.org/10.1177/17534259231215581
  53. Exp Mol Med. 2023 Dec 01.
    Lactate exacerbates lung damage induced by nanomicroplastic through the gut microbiota-HIF1a/PTBP1 pathway.
    Lihui Xuan, Zheng Xu, Jinhua Luo, Yin Wang, Yuhui Yan, Can Qu, Zuozhong Xie, Magdalena Skonieczna, Ping-Kun Zhou, Ruixue Huang.
      Exposure to nanomicroplastics (nano-MPs) can induce lung damage. The gut microbiota is a critical modulator of the gut-lung axis. However, the mechanisms underlying these interactions have not been elucidated. This study explored the role of lactate, a key metabolite of the microbiota, in the development of lung damage induced by nano-MPs (LDMP). After 28 days of exposure to nano-MPs (50-100 nm), mice mainly exhibited damage to the lungs and intestinal mucosa and dysbiosis of the gut microbiota. Lactate accumulation was observed in the lungs, intestines and serum and was strongly associated with the imbalance in lactic acid bacteria in the gut. Furthermore, no lactate accumulation was observed in germ-free mice, while the depletion of the gut microbiota using a cocktail of antibiotics produced similar results, suggesting that lactate accumulation in the lungs may have been due to changes in the gut microbiota components. Mechanistically, elevated lactate triggers activation of the HIF1a/PTBP1 pathway, exacerbating nano-MP-induced lung damage through modulation of the epithelial-mesenchymal transition (EMT). Conversely, mice with conditional knockout of Ptbp1 in the lungs (Ptbp1flfl) and PTBP1-knockout (PTBP1-KO) human bronchial epithelial (HBE) cells showed reversal of the effects of lactate through modulation of the HIF1a/PTBP1 signaling pathway. These findings indicate that lactate is a potential target for preventing and treating LDMP.
    DOI:  https://doi.org/10.1038/s12276-023-01129-3
  54. Cell Mol Immunol. 2023 Dec;20(12): 1513-1526
    Integrated NLRP3, AIM2, NLRC4, Pyrin inflammasome activation and assembly drive PANoptosis.
    SuHyeon Oh, Jihye Lee, Jueun Oh, Gyoengju Yu, Haesun Ryu, Daesik Kim, SangJoon Lee.
      Inflammasomes are important sentinels of innate immune defense; they sense pathogens and induce the cell death of infected cells, playing key roles in inflammation, development, and cancer. Several inflammasome sensors detect and respond to specific pathogen- and damage-associated molecular patterns (PAMPs and DAMPs, respectively) by forming a multiprotein complex with the adapters ASC and caspase-1. During disease, cells are exposed to several PAMPs and DAMPs, leading to the concerted activation of multiple inflammasomes. However, the molecular mechanisms that integrate multiple inflammasome sensors to facilitate optimal host defense remain unknown. Here, we discovered that simultaneous inflammasome activation by multiple ligands triggered multiple types of programmed inflammatory cell death, and these effects could not be mimicked by treatment with a pure ligand of any single inflammasome. Furthermore, NLRP3, AIM2, NLRC4, and Pyrin were determined to be members of a large multiprotein complex, along with ASC, caspase-1, caspase-8, and RIPK3, and this complex drove PANoptosis. Furthermore, this multiprotein complex was released into the extracellular space and retained as multiple inflammasomes. Multiple extracellular inflammasome particles could induce inflammation after their engulfment by neighboring macrophages. Collectively, our findings define a previously unknown regulatory connection and molecular interaction between inflammasome sensors, which drives the assembly of a multiprotein complex that includes multiple inflammasome sensors and cell death regulators. The discovery of critical interactions among NLRP3, AIM2, NLRC4, and Pyrin represents a new paradigm in understanding the functions of these molecules in innate immunity and inflammasome biology as well as identifying new therapeutic targets for NLRP3-, AIM2-, NLRC4- and Pyrin-mediated diseases.
    Keywords:  Excellular ASC; Inflammatory Cell Death; Multiple Inflammasome; PANoptosis; PANoptosome
    DOI:  https://doi.org/10.1038/s41423-023-01107-9
  55. Front Immunol. 2023 ;14 1290191
    Role of histamine-mediated macrophage differentiation in clearance of metastatic bacterial infection.
    Kwang H Kim, Donghwan Park, Soo Young Cho, Yejin Cho, Buhyun Lee, Haengdueng Jeong, Yura Lee, Yourim Lee, Ki Taek Nam.
      Macrophages are highly heterogeneous immune cells with a role in maintaining tissue homeostasis, especially in activating the defense response to bacterial infection. Using flow cytometric and single-cell RNA-sequencing analyses of peritoneal cells, we here show that small peritoneal macrophage and immature macrophage populations are enriched in histamine-deficient (Hdc -/-) mice, characterized by a CD11bmiF4/80loCCR2+MHCIIhi and CD11bloF4/80miTHBS1+IL-1α+ phenotype, respectively. Molecular characterization revealed that immature macrophages represent an abnormally differentiated form of large peritoneal macrophages with strong inflammatory properties. Furthermore, deficiency in histamine signaling resulted in significant impairment of the phagocytic activity of peritoneal macrophage populations, conferring high susceptibility to bacterial infection. Collectively, this study reveals the importance of histamine signaling in macrophage differentiation at the molecular level to maintain tissue homeostasis, offering a potential therapeutic target for bacterial infection-mediated diseases.
    Keywords:  bacterial infection; histamine; macrophage differentiation; peritoneal cells; single-cell RNA sequencing
    DOI:  https://doi.org/10.3389/fimmu.2023.1290191
  56. Nat Rev Drug Discov. 2023 Nov 29.
    Drugging the NLRP3 inflammasome: from signalling mechanisms to therapeutic targets.
    Lieselotte Vande Walle, Mohamed Lamkanfi.
      Diseases associated with chronic inflammation constitute a major health burden across the world. As central instigators of the inflammatory response to infection and tissue damage, inflammasomes - and the NACHT, LRR and PYD domain-containing protein 3 (NLRP3) inflammasome in particular - have emerged as key regulators in diverse rheumatic, metabolic and neurodegenerative diseases. Similarly to other inflammasome sensors, NLRP3 assembles a cytosolic innate immune complex that activates the cysteine protease caspase-1, which in turn cleaves gasdermin D (GSDMD) to induce pyroptosis, a regulated mode of lytic cell death. Pyroptosis is highly inflammatory, partly because of the concomitant extracellular release of the inflammasome-dependent cytokines IL-1β and IL-18 along with a myriad of additional danger signals and intracellular antigens. Here, we discuss how NLRP3 and downstream inflammasome effectors such as GSDMD, apoptosis-associated speck-like protein containing a CARD (ASC) and nerve injury-induced protein 1 (NINJ1) have gained significant traction as therapeutic targets. We highlight the recent progress in developing small-molecule and biologic inhibitors that are advancing into the clinic and serving to harness the broad therapeutic potential of modulating the NLRP3 inflammasome.
    DOI:  https://doi.org/10.1038/s41573-023-00822-2
  57. JCI Insight. 2023 Nov 28. pii: e164572. [Epub ahead of print]
    Horizontal transmission of gut microbiota attenuates mortality in lung fibrosis.
    Stephen J Gurczynski, Jay H Lipinski, Joshua Y Strauss, Shafiul Alam, Gary B Huffnagle, Piyush Ranjan, Lucy H Kennedy, Bethany B Moore, David N O'Dwyer.
      Pulmonary fibrosis is a chronic and often fatal disease. The pathogenesis is characterized by aberrant repair of lung parenchyma resulting in loss of physiological homeostasis, respiratory failure and death. The immune response in pulmonary fibrosis is dysregulated. The gut microbiome is a key regulator of immunity. The role of the gut microbiome in regulating the pulmonary immunity in lung fibrosis is poorly understood. Here, we determine the impact of gut microbiota on pulmonary fibrosis in C57BL/6 mice derived from different vendors (C57BL/6J and C57BL/6NCrl). We use germ free models, fecal microbiota transplantation and cohousing to transmit gut microbiota. Metagenomic studies of feces establish keystone species between sub-strains. Pulmonary fibrosis is microbiota dependent in C57BL/6 mice. Gut microbiota are distinct by β diversity (PERMANOVA P<0.001) and α diversity (P<0.0001). Mortality and lung fibrosis are attenuated in C57BL/6NCrl mice. Elevated CD4+ IL-10+ T cells and lower IL-6 occur in C57BL/6NCrl mice. Horizontal transmission of microbiota by cohousing attenuates mortality in C57BL/6J mice and promotes a transcriptionally altered pulmonary immunity. Temporal changes in lung and gut microbiota demonstrates that gut microbiota contribute largely to immunological phenotype. Key regulatory gut microbiota contribute to lung fibrosis generating rationale for human studies.
    Keywords:  Adaptive immunity; Fibrosis; Microbiology; Pulmonology
    DOI:  https://doi.org/10.1172/jci.insight.164572
  58. J Leukoc Biol. 2023 Nov 27. pii: qiad148. [Epub ahead of print]
    LPS and type I&II interferons have opposing effects on epigenetic regulation of LAIR1 expression in mouse and human macrophages.
    Hannah K Dorando, Evan C Mutic, Joanna Y Li, Ezri P Perrin, Mellisa K Wurtz, Chaz C Quinn, Jacqueline E Payton.
      Inhibitory immune receptors are important for maintaining immune homeostasis. We identified epigenetic alterations in two members of this group, LAIR1 and LAIR2, in lymphoma patients with inflammatory tissue damage and susceptibility to infection. We predicted that the expression of LAIR genes is controlled by immune mediators acting on transcriptional regulatory elements. Using flow cytometry, qRT-PCR, and RNAseq, we measured LAIR1 and LAIR2 in human and murine immune cell subsets at baseline and post-treatment with immune mediators, including type I and II interferons, tumor necrosis factor-alpha, and lipopolysaccharide (LPS). We identified candidate regulatory elements using epigenome profiling and measured their regulatory activity using luciferase reporters. LAIR1 expression substantially increases during monocyte differentiation to macrophages in both species. In contrast, murine and human macrophages exhibited opposite changes in LAIR1 in response to immune stimuli: human LAIR1 increased with LPS while mouse LAIR1 increased with IFNγ. LAIR genes had distinct patterns of enhancer activity with variable responses to immune stimuli. To identify relevant transcription factors (TF), we developed integrative bioinformatic techniques applied to TF-ChIPseq, RNAseq, and luciferase activity, revealing distinct sets of TFs for each LAIR gene. Most strikingly, LAIR1 TFs include NFKB factors RELA and RELB, while Lair1 and LAIR2 instead include STAT3 and/or STAT5. Regulation by NFKB factors may therefore explain the LPS-induced increase in LAIR1 expression, in contrast to Lair1 decrease. Our findings reveal new insights into transcriptional mechanisms that control distinct expression patterns of LAIR genes in response to inflammatory stimuli in human and murine myeloid and lymphoid cells.
    Keywords:  epigenetics; gene regulation; inflammatory stimuli; inhibitory immune receptor; macrophage
    DOI:  https://doi.org/10.1093/jleuko/qiad148
  59. Redox Biol. 2023 Nov 23. pii: S2213-2317(23)00369-5. [Epub ahead of print]68 102968
    Restoring the infected powerhouse: Mitochondrial quality control in sepsis.
    F M Lira Chavez, L P Gartzke, F E van Beuningen, S E Wink, R H Henning, G Krenning, H R Bouma.
      Sepsis is a dysregulated host response to an infection, characterized by organ failure. The pathophysiology is complex and incompletely understood, but mitochondria appear to play a key role in the cascade of events that culminate in multiple organ failure and potentially death. In shaping immune responses, mitochondria fulfil dual roles: they not only supply energy and metabolic intermediates crucial for immune cell activation and function but also influence inflammatory and cell death pathways. Importantly, mitochondrial dysfunction has a dual impact, compromising both immune system efficiency and the metabolic stability of end organs. Dysfunctional mitochondria contribute to the development of a hyperinflammatory state and loss of cellular homeostasis, resulting in poor clinical outcomes. Already in early sepsis, signs of mitochondrial dysfunction are apparent and consequently, strategies to optimize mitochondrial function in sepsis should not only prevent the occurrence of mitochondrial dysfunction, but also cover the repair of the sustained mitochondrial damage. Here, we discuss mitochondrial quality control (mtQC) in the pathogenesis of sepsis and exemplify how mtQC could serve as therapeutic target to overcome mitochondrial dysfunction. Hence, replacing or repairing dysfunctional mitochondria may contribute to the recovery of organ function in sepsis. Mitochondrial biogenesis is a process that results in the formation of new mitochondria and is critical for maintaining a pool of healthy mitochondria. However, exacerbated biogenesis during early sepsis can result in accumulation of structurally aberrant mitochondria that fail to restore bioenergetics, produce excess reactive oxygen species (ROS) and exacerbate the disease course. Conversely, enhancing mitophagy can protect against organ damage by limiting the release of mitochondrial-derived damage-associated molecules (DAMPs). Furthermore, promoting mitophagy may facilitate the growth of healthy mitochondria by blocking the replication of damaged mitochondria and allow for post sepsis organ recovery through enabling mitophagy-coupled biogenesis. The remaining healthy mitochondria may provide an undamaged scaffold to reproduce functional mitochondria. However, the kinetics of mtQC in sepsis, specifically mitophagy, and the optimal timing for intervention remain poorly understood. This review emphasizes the importance of integrating mitophagy induction with mtQC mechanisms to prevent undesired effects associated with solely the induction of mitochondrial biogenesis.
    Keywords:  Mitochondrial biogenesis; Mitochondrial dynamics; Mitochondrial quality control; Mitophagy; Sepsis
    DOI:  https://doi.org/10.1016/j.redox.2023.102968
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