bims-bac4me Biomed News
on Microbiome and trained immunity
Issue of 2023‒10‒08
forty-two papers selected by
Chun-Chi Chang, University Hospital Zurich
  1. Inflammasome-mediated glucose limitation induces antibiotic tolerance in Staphylococcus aureus.
  2. Trained immunity in diabetes and hyperlipidemia: Emerging opportunities to target cardiovascular complications and design new therapies.
  3. On the Path to Predicting Immune Responses in the Lung: Modeling the Pulmonary Innate Immune system at the Air-Liquid Interface (ALI).
  4. Different bacterial cargo in apoptotic cells drive distinct macrophage phenotypes.
  5. The Role of NLRP3 Inflammasomes in Trained Immunity.
  6. Epithelial-immune cell interactions in allergic diseases.
  7. An oral commensal attenuates Pseudomonas aeruginosa-induced airway inflammation and modulates nitrite flux in respiratory epithelium.
  8. RGS2 is an innate immune checkpoint for TLR4 and Gαq-mediated IFNγ generation and lung injury.
  9. Asthma-associated bacterial infections: Are they protective or deleterious?
  10. Comparative transcriptomic and proteomic signature of lung alveolar macrophages reveals the integrin CD11b as a regulatory hub during pneumococcal pneumonia infection.
  11. 3D in vitro hydrogel models to study the human lung extracellular matrix and fibroblast function.
  12. Lactate promotes Salmonella intracellular replication and systemic infection via driving macrophage M2 polarization.
  13. The great divide: rhamnolipids mediate separation between P. aeruginosa and S. aureus.
  14. Intestinal microbiota programming of alveolar macrophages influences severity of respiratory viral infection.
  15. Short-chain fatty acids ameliorate allergic airway inflammation via sequential induction of PMN-MDSCs and Treg cells.
  16. Peroxisomal ROS control cytosolic Mycobacterium tuberculosis replication in human macrophages.
  17. Bacteria- and Fungus-derived PAMPs Induce Innate Immune Memory via Similar Functional, Metabolic and Transcriptional Adaptations.
  18. Distinctive features of the oropharyngeal microbiome in Inuit of Nunavik and correlations of mild to moderate bronchial obstruction with dysbiosis.
  19. The effect of leptin on trained innate immunity and on systemic inflammation in subjects with obesity.
  20. Unlatching of the stem domains in the Staphylococcus aureus pore-forming leukocidin LukAB influences toxin oligomerization.
  21. Peptidylarginine deiminase 4 and ADAMTS13 activity in Staphylococcus aureus bacteraemia.
  22. Clinical Staphylococcus aureus inhibits human T-cell activity through interaction with the PD-1 receptor.
  23. Alveolar macrophages in tissue homeostasis, inflammation, and infection: evolving concepts of therapeutic targeting.
  24. NAD+ metabolism is a key modulator of bacterial respiratory epithelial infections.
  25. Mesenchymal Stromal Cells Facilitate Neutrophil Trained Immunity by Reprogramming Hematopoietic Stem Cells.
  26. The oxidative stress response of Streptococcus pneumoniae: its contribution to both extracellular and intracellular survival.
  27. Chronic rhinosinusitis with nasal polyps and allergic rhinitis as different multimorbid treatable traits in asthma.
  28. Preparation of human primary macrophages to study the polarization from monocyte-derived macrophages to pro- or anti-inflammatory macrophages at biomaterial interface in vitro.
  29. Ketogenesis promotes tolerance to Pseudomonas aeruginosa pulmonary infection.
  30. The role of lung microbiota in primary graft dysfunction in lung transplant recipients.
  31. Carbon metabolism in the regulation of macrophage functions.
  32. Characterization of 3D organotypic epithelial tissues reveals tonsil-specific differences in tonic interferon signaling.
  33. The multi-omics single-cell landscape of sinus mucosa in uncontrolled severe chronic rhinosinusitis with nasal polyps.
  34. Control of Cell Death in Health and Disease.
  35. Diverse roles of lung macrophages in the immune response to influenza A virus.
  36. Aberrant glucose metabolism underlies impaired macrophage differentiation in glycogen storage disease type Ib.
  37. Learning from the microbes: exploiting the microbiome to enforce T cell immunotherapy.
  38. α-ketoglutarate-dependent KDM6 histone demethylases regulate Interferon Stimulated Gene expression in Lupus.
  39. Use of single-cell technology to improve our understanding of the role of TLR2 in macrophage-Mycobacterium tuberculosis interaction.
  40. HIF-1α activates NLRP3 inflammasome to regulate epithelial differentiation in chronic rhinosinusitis.
  41. Staphylococcus aureus adapts to the immunometabolite itaconic acid by inducing acid and oxidative stress responses including S-bacillithiolations and S-itaconations.
  42. The impact of helminth-induced immunity on infection with bacteria or viruses.
  1. iScience. 2023 Oct 20. 26(10): 107942
    Inflammasome-mediated glucose limitation induces antibiotic tolerance in Staphylococcus aureus.
    Jenna E Beam, Nikki J Wagner, Kuan-Yi Lu, Joshua B Parsons, Vance G Fowler, Sarah E Rowe, Brian P Conlon.
      Staphylococcus aureus is a leading human pathogen that frequently causes relapsing infections. The failure of antibiotics to eradicate infection contributes to infection relapse. Host-pathogen interactions have a substantial impact on antibiotic susceptibility and the formation of antibiotic tolerant cells. In this study, we interrogate how a major S. aureus virulence factor, α-toxin, interacts with macrophages to alter the microenvironment of the pathogen, thereby influencing its susceptibility to antibiotics. We find α-toxin-mediated activation of the NLRP3 inflammasome induces antibiotic tolerance. Induction of tolerance is driven by increased glycolysis in the host cells, resulting in glucose limitation and ATP depletion in S. aureus. Additionally, inhibition of NLRP3 activation improves antibiotic efficacy in vitro and in vivo, suggesting that this strategy has potential as a host-directed therapeutic to improve outcomes. Our findings identify interactions between S. aureus and the host that result in metabolic crosstalk that can determine the outcome of antimicrobial therapy.
    Keywords:  Cellular physiology; Immune response; Microbial physiology; Multi-drug resistant organisms
    DOI:  https://doi.org/10.1016/j.isci.2023.107942
  2. FASEB J. 2023 11;37(11): e23231
    Trained immunity in diabetes and hyperlipidemia: Emerging opportunities to target cardiovascular complications and design new therapies.
    Katherine A Robinson, Naveed Akbar, Kajus Baidžajevas, Robin P Choudhury.
      Some metabolic diseases, such as diabetes and hyperlipidemia, are associated with a state of inflammation, which adversely affects cardiovascular health. Emerging evidence suggests that long-term hyperactivation of innate immune cells and their bone marrow progenitors, termed trained immunity, functions to accelerate atherosclerosis and its complications in cardiometabolic diseases. This review will focus on how trained immunity is established, particularly through metabolic and epigenetic reprogramming, to cause persistent and deleterious changes in immune cell function, even after the original stimulus has been corrected or removed. Understanding the mechanisms driving maladaptive trained immunity and its fundamental contribution to cardiovascular disease might enable the development of novel disease-modifying therapeutics for the reduction in cardiovascular risk in diabetes, hyperlipidemia, and related cardiometabolic states.
    Keywords:  cardiovascular; diabetes; epigenetics; macrophages; metabolism; trained immunity
    DOI:  https://doi.org/10.1096/fj.202301078R
  3. Eur J Pharm Sci. 2023 Sep 26. pii: S0928-0987(23)00226-9. [Epub ahead of print] 106596
    On the Path to Predicting Immune Responses in the Lung: Modeling the Pulmonary Innate Immune system at the Air-Liquid Interface (ALI).
    Jodi Graf, Michael Trautmann-Rodriguez, Simone Sabnis, April M Kloxin, Catherine A Fromen.
      Chronic respiratory diseases and infections are among the largest contributors to death globally, many of which still have no cure, including chronic obstructive pulmonary disorder, idiopathic pulmonary fibrosis, and respiratory syncytial virus among others. Pulmonary therapeutics afford untapped potential for treating lung infection and disease through direct delivery to the site of action. However, the ability to innovate new therapeutic paradigms for respiratory diseases will rely on modeling the human lung microenvironment and including key cellular interactions that drive disease. One key feature of the lung microenvironment is the air-liquid interface (ALI). ALI interface modeling techniques, using cell-culture inserts, organoids, microfluidics, and precision lung slices (PCLS), are rapidly developing; however, one major component of these models is lacking-innate immune cell populations. Macrophages, neutrophils, and dendritic cells, among others, represent key lung cell populations, acting as the first responders during lung infection or injury. Innate immune cells respond to and modulate stromal cells and bridge the gap between the innate and adaptive immune system, controlling the bodies response to foreign pathogens and debris. In this article, we review the current state of ALI culture systems with a focus on innate immune cells and suggest ways to build on current models to add complexity and relevant immune cell populations.
    Keywords:  Air-liquid interface; Mucosal immunity; Pulmonary therapeutics; Respiratory Disease Modeling
    DOI:  https://doi.org/10.1016/j.ejps.2023.106596
  4. Apoptosis. 2023 Oct 05.
    Different bacterial cargo in apoptotic cells drive distinct macrophage phenotypes.
    Ana Carolina Guerta Salina, Letícia de Aquino Penteado, Naiara Naiana Dejani, Ludmilla Silva-Pereira, Breno Vilas Boas Raimundo, Gabriel Ferranti Corrêa, Karen Cristina Oliveira, Leandra Naira Zambelli Ramalho, Mèdéton Mahoussi Michaël Boko, Vânia L D Bonato, C Henrique Serezani, Alexandra Ivo Medeiros.
      The removal of dead cells (efferocytosis) contributes to the resolution of the infection and preservation of the tissue. Depending on the environment milieu, macrophages may show inflammatory (M1) or anti-inflammatory (M2) phenotypes. Inflammatory leukocytes are recruited during infection, followed by the accumulation of infected and non-infected apoptotic cells (AC). Efferocytosis of non-infected AC promotes TGF-β, IL-10, and PGE2 production and the polarization of anti-inflammatory macrophages. These M2 macrophages acquire an efficient ability to remove apoptotic cells that are involved in tissue repair and resolution of inflammation. On the other hand, the impact of efferocytosis of infected apoptotic cells on macrophage activation profile remains unknown. Here, we are showing that the efferocytosis of gram-positive Streptococcus pneumoniae-AC (Sp-AC) or gram-negative Klebsiella pneumoniae-AC (Kp-AC) promotes distinct gene expression and cytokine signature in macrophages. Whereas the efferocytosis of Kp-AC triggered a predominant M1 phenotype in vitro and in vivo, the efferocytosis of Sp-AC promoted a mixed M1/M2 activation in vitro and in vivo in a model of allergic asthma. Together, these findings suggest that the nature of the pathogen and antigen load into AC may have different impacts on inducing macrophage polarization.
    Keywords:  Efferocytosis; Infected apoptotic cells; Lung inflammation; Macrophages
    DOI:  https://doi.org/10.1007/s10495-023-01899-1
  5. Front Biosci (Landmark Ed). 2023 Sep 22. 28(9): 210
    The Role of NLRP3 Inflammasomes in Trained Immunity.
    Gilyoung Lee, Huijeong Ahn, Eunsong Lee, Geun-Shik Lee.
      Inflammasomes are cytosolic multi-protein complexes that play an important role in the innate immune system, inducing cytokine maturation and pyroptosis. Trained immunity is the induction of memory in innate immune cells by epigenetic reprogramming due to repeated inflammatory stimuli that alter the inflammatory response and increase resistance to infection or disease. Although it is speculated that nucleotide-binding oligomerization domain (NOD), leucine-rich repeat (LRR), and the NLR family pyrin domain containing 3 (NLRP3) inflammasomes respond to various inflammatory stimuli and are associated with trained immunity, the exact relationship is still unclear. This paper aims to introduce data from recent research on the role of inflammasomes in trained immunity through cellular immunometabolic and epigenetic reprogramming. It also suggests a new therapeutic strategy for inflammatory diseases through the complementary regulation of inflammasomes and trained immunity.
    Keywords:  NLRP3; inflammasome; inflammatory diseases; trained immunity
    DOI:  https://doi.org/10.31083/j.fbl2809210
  6. Eur J Immunol. 2023 Oct 07. e2249982
    Epithelial-immune cell interactions in allergic diseases.
    Melanie Albrecht, Holger Garn, Timo Buhl.
      Epithelial/immune-interactions are characterized by the different properties of the various epithelial tissues, the mediators involved, and the varying immune cells that initiate, sustain, or abrogate allergic diseases on the surface. The intestinal mucosa, respiratory mucosa, and regular skin feature structural differences according to their primary function and surroundings. In the context of these specialized functions, the active role of the epithelium in shaping immune responses is increasingly recognizable. Crosstalk between epithelial cells and immune cells plays an important role in maintaining homeostatic conditions. While cells of the myeloid cell lineage, mainly macrophages, are the dominating immune cell population in the skin and the respiratory tract, lymphocytes comprise most intraepithelial immune cells in the intestine under healthy conditions. Common to all surface epithelia is the fact that innate immune cells represent the first line of immunosurveillance that either directly defeats invading pathogens or initiates and coordinates more effective successive immune responses involving adaptive immune cells and effector cells. Pharmacological approaches for the treatment of allergic and chronic inflammatory diseases involving epithelial barriers target immunological mediators downstream of the epithelium (such as IL-4, IL-5, IL-13, and IgE). The next generation of therapeutics is involving upstream events of the inflammatory cascade, such as epithelial-derived alarmins and related mediators. This article is protected by copyright. All rights reserved.
    Keywords:  allergic diseases; asthma; atopic dermatitis; epithelium; immune system
    DOI:  https://doi.org/10.1002/eji.202249982
  7. Microbiol Spectr. 2023 Oct 06. e0219823
    An oral commensal attenuates Pseudomonas aeruginosa-induced airway inflammation and modulates nitrite flux in respiratory epithelium.
    Joshua J Baty, Sara N Stoner, Melissa S McDaniel, Joshua T Huffines, Sara E Edmonds, Nicholas J Evans, Lea Novak, Jessica A Scoffield.
      Polymicrobial airway infections in persons with cystic fibrosis (pwCF) can positively or negatively impact the course of disease. A major CF pathogen, Pseudomonas aeruginosa, often establishes a chronic infection leading to lung deterioration. Interestingly, the presence of certain oral commensal streptococci is correlated with improved outcomes for pwCF. We previously reported that hydrogen peroxide production by these commensals combined with nitrite generates reactive nitrogen intermediates (RNI), which inhibit P. aeruginosa in vitro. In this study, we utilized a rat co-infection lung model to assess whether oral commensal-generated RNI can restrict the pathogenesis of a CF isolate of P. aeruginosa. We report that the oral commensal Streptococcus parasanguinis and nitrite reduce P. aeruginosa-induced host inflammation in wild-type rats. To better recapitulate CF-specific airway conditions, we used a bronchial epithelial cell culture model to gain a better understanding of how S. parasanguinis and nitrite may influence P. aeruginosa burden during a CF infection. Hence, we co-infected wild-type and cystic fibrosis transconductance regulator (CFTR) channel-deficient bronchial epithelial cells with P. aeruginosa and S. parasanguinis with or without nitrite. Strikingly, S. parasanguinis reduced the bacterial burden of P. aeruginosa without nitrite, promoted epithelial cell viability, and stimulated nitrite production in the wild-type and CFTR-deficient epithelial cells, where nitrite induction was more apparent in the CFTR mutant cells. Taken together, our study demonstrates that the commensal S. parasanguinis may provide protection against P. aeruginosa-induced inflammation and cell death, as well as modulate nitrite flux in airway epithelial cells. IMPORTANCE Respiratory infections are a leading cause of morbidity and mortality in people with cystic fibrosis (CF). These infections are polymicrobial in nature with overt pathogens and other colonizing microbes present. Microbiome data have indicated that the presence of oral commensal bacteria in the lungs is correlated with improved outcomes. We hypothesize that one oral commensal, Streptococcus parasanguinis, inhibits CF pathogens and modulates the host immune response. One major CF pathogen is Pseudomonas aeruginosa, a Gram-negative, opportunistic bacterium with intrinsic drug resistance and an arsenal of virulence factors. We have previously shown that S. parasanguinis inhibits P. aeruginosa in vitro in a nitrite-dependent manner through the production of reactive nitrogen intermediates. In this study, we demonstrate that while this mechanism is evident in a cell culture model of the CF airway, an alternative mechanism by which S. parasanguinis may improve outcomes for people with CF is through immunomodulation.
    Keywords:  Pseudomonas aeruginosa; Streptococcus parasanguinis; airway inflammation; commensal; nitrosative stress
    DOI:  https://doi.org/10.1128/spectrum.02198-23
  8. bioRxiv. 2023 Sep 23. pii: 2023.09.22.559016. [Epub ahead of print]
    RGS2 is an innate immune checkpoint for TLR4 and Gαq-mediated IFNγ generation and lung injury.
    Jagdish Chandra Joshi, Bhagwati Joshi, Cuiping Zhang, Somenath Banerjee, Vigneshwaran Vellingiri, Vijay Avin Balaji Raghunathrao, Lianghui Zhang, Ruhul Amin, Yuanlin Song, Dolly Mehta.
      IFNγ, a type II interferon secreted by immune cells, augments tissue responses to injury following pathogenic infections leading to lethal acute lung injury (ALI). Alveolar macrophages (AM) abundantly express Toll-like receptor-4 and represent the primary cell type of the innate immune system in the lungs. A fundamental question remains whether AM generation of IFNg leads to uncontrolled innate response and perpetuated lung injury. LPS induced a sustained increase in IFNg levels and unresolvable inflammatory lung injury in the mice lacking RGS2 but not in RGS2 null chimeric mice receiving WT bone marrow or receiving the RGS2 gene in AM. Thus, indicating RGS2 serves as a gatekeeper of IFNg levels in AM and thereby lung's innate immune response. RGS2 functioned by forming a complex with TLR4 shielding Gaq from inducing IFNg generation and AM inflammatory signaling. Thus, inhibition of Gaq blocked IFNg generation and subverted AM transcriptome from being inflammatory to reparative type in RGS2 null mice, resolving lung injury.Highlights: RGS2 levels are inversely correlated with IFNγ in ARDS patient's AM.RGS2 in alveolar macrophages regulate the inflammatory lung injury.During pathogenic insult RGS2 functioned by forming a complex with TLR4 shielding Gαq from inducing IFNγ generation and AM inflammatory signaling.
    eToc Blurb: Authors demonstrate an essential role of RGS2 in macrophages in airspace to promoting anti-inflammatory function of alveolar macrophages in lung injury. The authors provided new insight into the dynamic control of innate immune response by Gαq and RGS2 axis to prevent ALI.
    DOI:  https://doi.org/10.1101/2023.09.22.559016
  9. J Allergy Clin Immunol Glob. 2023 Feb;2(1): 14-22
    Asthma-associated bacterial infections: Are they protective or deleterious?
    Thais Fernanda de Campos Fraga-Silva, Mèdéton Mahoussi Michaël Boko, Núbia Sabrina Martins, Andrea Antunes Cetlin, Momtchilo Russo, Elcio Oliveira Vianna, Vania Luiza Deperon Bonato.
      Eosinophilic, noneosinophilic, or mixed granulocytic inflammations are the hallmarks of asthma heterogeneity. Depending on the priming of lung immune and structural cells, subjects with asthma might generate immune responses that are TH2-prone or TH17-prone immune response. Bacterial infections caused by Haemophilus, Moraxella, or Streptococcus spp. induce the secretion of IL-17, which in turn recruit neutrophils into the airways. Clinical studies and experimental models of asthma indicated that neutrophil infiltration induces a specific phenotype of asthma, characterized by an impaired response to corticosteroid treatment. The understanding of pathways that regulate the TH17-neutrophils axis is critical to delineate and develop host-directed therapies that might control asthma and its exacerbation episodes that course with infectious comorbidities. In this review, we outline clinical and experimental studies on the role of airway epithelial cells, S100A9, and high mobility group box 1, which act in concert with the IL-17-neutrophil axis activated by bacterial infections, and are related with asthma that is difficult to treat. Furthermore, we report critically our view in the light of these findings in an attempt to stimulate further investigations and development of immunotherapies for the control of severe asthma.
    Keywords:  IL-17; Severe asthma; bacterial infections; lung inflammation; neutrophil
    DOI:  https://doi.org/10.1016/j.jacig.2022.08.003
  10. Front Immunol. 2023 ;14 1227191
    Comparative transcriptomic and proteomic signature of lung alveolar macrophages reveals the integrin CD11b as a regulatory hub during pneumococcal pneumonia infection.
    Kristina Zec, Stephanie Thiebes, Jenny Bottek, Devon Siemes, Philippa Spangenberg, Duc Viet Trieu, Nils Kirstein, Nirojah Subramaniam, Robin Christ, Diana Klein, Verena Jendrossek, Maria Loose, Florian Wagenlehner, Jadwiga Jablonska, Thilo Bracht, Barbara Sitek, Bettina Budeus, Ludger Klein-Hitpass, Dirk Theegarten, Olga Shevchuk, Daniel R Engel.
      Introduction: Streptococcus pneumoniae is one of the main causes of community-acquired infections in the lung alveoli in children and the elderly. Alveolar macrophages (AM) patrol alveoli in homeostasis and under infectious conditions. However, the molecular adaptations of AM upon infections with Streptococcus pneumoniae are incompletely resolved.Methods: We used a comparative transcriptomic and proteomic approach to provide novel insights into the cellular mechanism that changes the molecular signature of AM during lung infections. Using a tandem mass spectrometry approach to murine cell-sorted AM, we revealed significant proteomic changes upon lung infection with Streptococcus pneumoniae.
    Results: AM showed a strong neutrophil-associated proteomic signature, such as expression of CD11b, MPO, neutrophil gelatinases, and elastases, which was associated with phagocytosis of recruited neutrophils. Transcriptomic analysis indicated intrinsic expression of CD11b by AM. Moreover, comparative transcriptomic and proteomic profiling identified CD11b as the central molecular hub in AM, which influenced neutrophil recruitment, activation, and migration.
    Discussion: In conclusion, our study provides novel insights into the intrinsic molecular adaptations of AM upon lung infection with Streptococcus pneumoniae and reveals profound alterations critical for effective antimicrobial immunity.
    Keywords:  alveolar macrophage; bioinformatics; infection; proteomics; transcriptomics
    DOI:  https://doi.org/10.3389/fimmu.2023.1227191
  11. Respir Res. 2023 Oct 05. 24(1): 242
    3D in vitro hydrogel models to study the human lung extracellular matrix and fibroblast function.
    Sakshi Phogat, Fama Thiam, Safiya Al Yazeedi, Filsan Ahmed Abokor, Emmanuel Twumasi Osei.
      The pulmonary extracellular matrix (ECM) is a macromolecular structure that provides mechanical support, stability and elastic recoil for different pulmonary cells including the lung fibroblasts. The ECM plays an important role in lung development, remodeling, repair, and the maintenance of tissue homeostasis. Biomechanical and biochemical signals produced by the ECM regulate the phenotype and function of various cells including fibroblasts in the lungs. Fibroblasts are important lung structural cells responsible for the production and repair of different ECM proteins (e.g., collagen and fibronectin). During lung injury and in chronic lung diseases such as asthma, idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD), an abnormal feedback between fibroblasts and the altered ECM disrupts tissue homeostasis and leads to a vicious cycle of fibrotic changes resulting in tissue remodeling. In line with this, using 3D hydrogel culture models with embedded lung fibroblasts have enabled the assessment of the various mechanisms involved in driving defective (fibrotic) fibroblast function in the lung's 3D ECM environment. In this review, we provide a summary of various studies that used these 3D hydrogel models to assess the regulation of the ECM on lung fibroblast phenotype and function in altered lung ECM homeostasis in health and in chronic respiratory disease.
    Keywords:  3D hydrogels; ECM stiffness; Extracellular matrix (ECM); Fibrosis; Lung fibroblasts
    DOI:  https://doi.org/10.1186/s12931-023-02548-6
  12. Microbiol Spectr. 2023 Oct 05. e0225323
    Lactate promotes Salmonella intracellular replication and systemic infection via driving macrophage M2 polarization.
    Xinyue Wang, Bin Yang, Shuangshuang Ma, Xiaolin Yan, Shuai Ma, Hongmin Sun, Yuyang Sun, Lingyan Jiang.
      Salmonella is one of the most important enteric pathogens worldwide, which is able to cause lethal systemic infection via survival and replication in host macrophages. Lactate, a byproduct of anaerobic or aerobic glycolysis, can induce macrophage M2 polarization, but the relationship between lactate-mediated macrophage M2 polarization and bacterial infection is poorly understood. Here, we evaluated the role of lactate and lactate-mediated macrophage M2 polarization in the pathogenicity of Salmonella. We found that lactate levels were significantly increased in Salmonella-infected macrophages, and the increased lactate was derived from the host. Macrophage and mouse infection assays showed that the addition of lactate enhanced Salmonella replication within macrophages and the colonization of mouse systemic loci, while pharmacological or genetic inhibition of host lactate production impaired Salmonella intracellular replication and its virulence in mice. Further analysis revealed that lactate promotes M2 polarization of Salmonella-infected macrophages, and the induction of macrophage M2 polarization by lactate is responsible for lactate-mediated Salmonella growth promotion. Moreover, we showed that macrophage-derived lactate induces the Salmonella pathogenicity island (SPI)-2 type III secretion system, leading to increased translocation of the SPI-2 effector SteE, which is responsible for driving M2 polarization. Overall, these findings suggest that lactate promotes Salmonella intracellular replication and systemic infection via driving macrophage M2 polarization and highlight the complex interactions between Salmonella and macrophages. IMPORTANCE The important enteropathogen Salmonella can cause lethal systemic infection via survival and replication in host macrophages. Lactate represents an abundant intracellular metabolite during bacterial infection, which can also induce macrophage M2 polarization. In this study, we found that macrophage-derived lactate promotes the intracellular replication and systemic infection of Salmonella. During Salmonella infection, lactate via the Salmonella type III secretion system effector SteE promotes macrophage M2 polarization, and the induction of macrophage M2 polarization by lactate is responsible for lactate-mediated Salmonella growth promotion. This study highlights the complex interactions between Salmonella and macrophages and provides an additional perspective on host-pathogen crosstalk at the metabolic interface.
    Keywords:  Salmonella; infection; lactate; macrophage polarization; macrophages
    DOI:  https://doi.org/10.1128/spectrum.02253-23
  13. Front Cell Infect Microbiol. 2023 ;13 1245874
    The great divide: rhamnolipids mediate separation between P. aeruginosa and S. aureus.
    Jean-Louis Bru, Summer J Kasallis, Rendell Chang, Quantum Zhuo, Jacqueline Nguyen, Phillip Pham, Elizabeth Warren, Katrine Whiteson, Nina Molin Høyland-Kroghsbo, Dominique H Limoli, Albert Siryaporn.
      The interactions between bacterial species during infection can have significant impacts on pathogenesis. Pseudomonas aeruginosa and Staphylococcus aureus are opportunistic bacterial pathogens that can co-infect hosts and cause serious illness. The factors that dictate whether one species outcompetes the other or whether the two species coexist are not fully understood. We investigated the role of surfactants in the interactions between these two species on a surface that enables P. aeruginosa to swarm. We found that P. aeruginosa swarms are repelled by colonies of clinical S. aureus isolates, creating physical separation between the two strains. This effect was abolished in mutants of S. aureus that were defective in the production of phenol-soluble modulins (PSMs), which form amyloid fibrils around wild-type S. aureus colonies. We investigated the mechanism that establishes physical separation between the two species using Imaging of Reflected Illuminated Structures (IRIS), which is a non-invasive imaging method that tracks the flow of surfactants produced by P. aeruginosa. We found that PSMs produced by S. aureus deflected the surfactant flow, which in turn, altered the direction of P. aeruginosa swarms. These findings show that rhamnolipids mediate physical separation between P. aeruginosa and S. aureus, which could facilitate coexistence between these species. Additionally, we found that a number of molecules repelled P. aeruginosa swarms, consistent with a surfactant deflection mechanism. These include Bacillus subtilis surfactant, the fatty acids oleic acid and linoleic acid, and the synthetic lubricant polydimethylsiloxane. Lung surfactant repelled P. aeruginosa swarms and inhibited swarm expansion altogether at higher concentration. Our results suggest that surfactant interactions could have major impacts on bacteria-bacteria and bacteria-host relationships. In addition, our findings uncover a mechanism responsible for P. aeruginosa swarm development that does not rely solely on sensing but instead is based on the flow of surfactant.
    Keywords:  biofilms; cystic fibrosis; lung surfactant; rhamnolipids; structured illumination; surfactant flow; swarm repulsion; tendril organization
    DOI:  https://doi.org/10.3389/fcimb.2023.1245874
  14. bioRxiv. 2023 Sep 22. pii: 2023.09.21.558814. [Epub ahead of print]
    Intestinal microbiota programming of alveolar macrophages influences severity of respiratory viral infection.
    Vu L Ngo, Carolin M Lieber, Hae-Ji Kang, Kaori Sakamoto, Michal Kuczma, Richard K Plemper, Andrew T Gewirtz.
      Investigating the influence of intestinal microbiota composition on respiratory viral infection (RVI) revealed that segmented filamentous bacteria (SFB), naturally acquired or exogenously administered, protected mice against influenza virus (IAV) infection, as assessed by viral titers, histopathology, and clinical disease features. Such protection, which also applied to RSV and SARS-CoV-2, was independent of interferon and adaptive immunity but required basally resident alveolar macrophages (AM), which, in SFB-negative mice, were quickly depleted as RVI progressed. Examination of AM from SFB-colonized mice revealed that they were intrinsically altered to resist IAV-induced depletion and inflammatory signaling. Yet, AM from SFB-colonized mice were not quiescent. Rather, they directly disabled IAV via enhanced complement production and phagocytosis. Transplant of SFB-transformed AM into SFB-free hosts recapitulated SFB-mediated protection against IAV mechanistically linking intestinal microbiota, AM phenotype, and RVI severity.One sentence summary: Intestinal segmented filamentous bacteria reprogram alveolar macrophages enabling their host to withstand respiratory viruses.
    DOI:  https://doi.org/10.1101/2023.09.21.558814
  15. J Allergy Clin Immunol Glob. 2023 Nov;2(4): 100163
    Short-chain fatty acids ameliorate allergic airway inflammation via sequential induction of PMN-MDSCs and Treg cells.
    Min-Ting Huang, Chiao-Juno Chiu, Ching-Yi Tsai, Yue-Ru Lee, Wei-Liang Liu, Hsiao-Li Chuang, Miao-Tzu Huang.
      Background: Reinforcement of the immune-regulatory pathway is a feasible strategy for prevention and therapy of allergic asthma. The short-chain fatty acids (SCFAs) acetate, propionate, and butyrate are pleiotropic microbial fermentation products known to induce regulatory T (Treg) cells and exert an immune-regulatory effect. The cellular mechanism underlying SCFA immune regulation in asthma is not fully understood.Objective: We investigated the role of myeloid-derived suppressor cells (MDSCs) and Treg cells, the immune-regulatory cells of innate and adaptive origin, respectively, in SCFA-elicited protection against allergic airway inflammation.
    Methods: BALB/c mice were given SCFA-containing drinking water before being rendered asthmatic in response to ovalbumen. When indicated, mice were given a GR1-depleting antibody to investigate the function of MDSCs in allergic inflammation of the airways. MDSCs were sorted to examine their immunosuppressive function and interaction with T cells.
    Results: The mice receiving SCFAs developed less severe asthma that was accompanied by expansion of PMN-MDSCs and Treg cells. Mice depleted of PMN-MDSCs exhibited aggravated asthma, and the protective effect of SCFAs was abrogated after PMN-MDSC depletion. SCFAs were able to directly induce T-cell differentiation toward Treg cells. Additionally, we found that PMN-MDSCs enhanced Treg cell expansion in a cell contact-dependent manner. Whilst membrane-bound TGF-β has been shown to induce Treg cell differentiation, we found that MDSCs upregulated surface expression of TGF-β after coculture with T-cells and that MDSC-induced Treg cell differentiation was partially inhibited by TGF-β blockage.
    Conclusions: Although previous studies revealed Treg cells as the effector mechanism of SCFA immune regulation, we found that SCFAs ameliorate allergic airway inflammation by relaying immune regulation, with sequential induction of PMN-MDSCs and Treg cells.
    Keywords:  Asthma; MDSCs; SCFAs; Treg cells; microbiota; myeloid-derived suppressor cells; short-chain fatty acids
    DOI:  https://doi.org/10.1016/j.jacig.2023.100163
  16. J Cell Biol. 2023 Dec 04. pii: e202303066. [Epub ahead of print]222(12):
    Peroxisomal ROS control cytosolic Mycobacterium tuberculosis replication in human macrophages.
    Enrica Pellegrino, Beren Aylan, Claudio Bussi, Antony Fearns, Elliott M Bernard, Natalia Athanasiadi, Pierre Santucci, Laure Botella, Maximiliano G Gutierrez.
      Peroxisomes are organelles involved in many metabolic processes including lipid metabolism, reactive oxygen species (ROS) turnover, and antimicrobial immune responses. However, the cellular mechanisms by which peroxisomes contribute to bacterial elimination in macrophages remain elusive. Here, we investigated peroxisome function in iPSC-derived human macrophages (iPSDM) during infection with Mycobacterium tuberculosis (Mtb). We discovered that Mtb-triggered peroxisome biogenesis requires the ESX-1 type 7 secretion system, critical for cytosolic access. iPSDM lacking peroxisomes were permissive to Mtb wild-type (WT) replication but were able to restrict an Mtb mutant missing functional ESX-1, suggesting a role for peroxisomes in the control of cytosolic but not phagosomal Mtb. Using genetically encoded localization-dependent ROS probes, we found peroxisomes increased ROS levels during Mtb WT infection. Thus, human macrophages respond to the infection by increasing peroxisomes that generate ROS primarily to restrict cytosolic Mtb. Our data uncover a peroxisome-controlled, ROS-mediated mechanism that contributes to the restriction of cytosolic bacteria.
    DOI:  https://doi.org/10.1083/jcb.202303066
  17. J Leukoc Biol. 2023 Oct 04. pii: qiad120. [Epub ahead of print]
    Bacteria- and Fungus-derived PAMPs Induce Innate Immune Memory via Similar Functional, Metabolic and Transcriptional Adaptations.
    Margaret A McBride, Cody L Stothers, Benjamin A Fensterheim, Katherine R Caja, Allison M Owen, Antonio Hernandez, Julia K Bohannon, Naeem K Patil, Sabah Ali, Sujata Dalal, Mohsin Rahim, Irina A Trenary, Jamey D Young, David L Williams, Edward R Sherwood.
      Exposure to pathogen-associated molecular patterns (PAMPs) induces an augmented, broad-spectrum antimicrobial response to subsequent infection, a phenomenon termed innate immune memory. This study examined the effects of treatment with β-glucan, a fungus-derived Dectin-1 ligand, or monophosphoryl lipid A (MPLA), a bacteria-derived TLR4 ligand, on innate immune memory with a focus on identifying common cellular and molecular pathways activated by these diverse PAMPs. Treatment with either PAMP prepared the innate immune system to respond more robustly to Pseudomonas aeruginosa infection in vivo by facilitating mobilization of innate leukocytes into blood, recruitment of leukocytes to the site of infection, augmentation of microbial clearance and attenuation of cytokine production. Examination of macrophages ex vivo showed amplification of metabolism, phagocytosis, and respiratory burst after treatment with either agent, although MPLA more robustly augmented these activities and more effectively facilitated killing of bacteria. Both agents activated gene expression pathways in macrophages that control inflammation, antimicrobial functions and protein synthesis and suppressed pathways regulating cell division. β-glucan treatment minimally altered macrophage differential gene expression in response to LPS challenge whereas MPLA attenuated the magnitude of the LPS-induced transcriptional response, especially cytokine gene expression. These results show that β-glucan and MPLA similarly augment the innate response to infection in vivo. Yet, MPLA more potently induces alterations in macrophage metabolism, antimicrobial functions, gene transcription and the response to LPS.
    Keywords:  Innate Immune Memory; Macrophages; Monophosphoryl Lipid A; β-glucan
    DOI:  https://doi.org/10.1093/jleuko/qiad120
  18. Sci Rep. 2023 10 03. 13(1): 16622
    Distinctive features of the oropharyngeal microbiome in Inuit of Nunavik and correlations of mild to moderate bronchial obstruction with dysbiosis.
    Mathilde Flahaut, Philippe Leprohon, Nguyen Phuong Pham, Hélène Gingras, Jean Bourbeau, Barbara Papadopoulou, François Maltais, Marc Ouellette.
      Inuit of Nunavik are coping with living conditions that can influence respiratory health. Our objective was to investigate associations between respiratory health in Inuit communities and their airway microbiome. Oropharyngeal samples were collected during the Qanuilirpitaa? 2017 Inuit Health Survey and subjected to metagenomic analyses. Participants were assigned to a bronchial obstruction group or a control group based on their clinical history and their pulmonary function, as monitored by spirometry. The Inuit microbiota composition was found to be distinct from other studied populations. Within the Inuit microbiota, differences in diversity measures tend to distinguish the two groups. Bacterial taxa found to be more abundant in the control group included candidate probiotic strains, while those enriched in the bronchial obstruction group included opportunistic pathogens. Crossing taxa affiliation method and machine learning consolidated our finding of distinct core microbiomes between the two groups. More microbial metabolic pathways were enriched in the control participants and these were often involved in vitamin and anti-inflammatory metabolism, while a link could be established between the enriched pathways in the disease group and inflammation. Overall, our results suggest a link between microbial abundance, interactions and metabolic activities and respiratory health in the Inuit population.
    DOI:  https://doi.org/10.1038/s41598-023-43821-4
  19. J Leukoc Biol. 2023 Sep 30. pii: qiad118. [Epub ahead of print]
    The effect of leptin on trained innate immunity and on systemic inflammation in subjects with obesity.
    Daniela Flores Gomez, Siroon Bekkering, Rob Ter Horst, Benjamin Cossins, Inge C L van den Munckhof, Joost H W Rutten, Leo A B Joosten, Mihai G Netea, Niels P Riksen.
      Leptin is associated with cardiometabolic complications of obesity, such as metabolic syndrome and atherosclerosis. In obese men, the presence of metabolic syndrome is associated with higher circulating leptin and interleukin-6 concentrations, and increased monocyte cytokine production capacity. Here we investigated the effects of leptin on monocyte function and systemic inflammatory markers in obese individuals. We specifically explored whether leptin can induce long-term changes in innate immune function by inducing innate immune memory (also called trained immunity). We exposed human primary monocytes for 24 hours to relevant leptin concentrations in vitro and measured cytokine production. In addition, after removing leptin, we incubated monocytes for 5 days in culture medium, and we restimulated them on day 6 to assess cytokine production capacity, phagocytosis and foam cell formation. Direct stimulation with leptin did not induce cytokine production, but exposure to 50 ng/ml leptin augmented LPS- and R848-induced tumor necrosis factor (TNF-α) production after 1 week. In a separate in vivo study in a cohort of 302 obese subjects (BMI>27, 55-81 years), we measured circulating leptin, inflammatory markers, and cytokine production upon ex-vivo stimulation of isolated peripheral blood mononuclear cells. Circulating leptin concentrations positively correlated with circulating IL-1β and IL-6, which was more pronounced in men than in women. Four single nucleotide polymorphisms in the leptin gene influenced circulating IL-6 concentrations in men, suggesting a direct effect of leptin on IL-6. In conclusion, in vitro, leptin does not directly stimulate monocytes to produce cytokines, yet induces long-term monocyte hyperresponsiveness, i.e. trained immunity. In obese subjects, leptin is associated with circulating IL-6 in a sex-dependent manner. The underlying mechanisms of the sex-specific effect of leptin on innate immune cells remain to be further investigated.
    Keywords:  Adipokines; atherosclerosis; cytokines; metabolic syndrome
    DOI:  https://doi.org/10.1093/jleuko/qiad118
  20. J Biol Chem. 2023 Oct 04. pii: S0021-9258(23)02349-9. [Epub ahead of print] 105321
    Unlatching of the stem domains in the Staphylococcus aureus pore-forming leukocidin LukAB influences toxin oligomerization.
    Juliana K Ilmain, Sofya S Perelman, Maria C Panepinto, Irnov Irnov, Nicolas Coudray, Nora Samhadaneh, Alejandro Pironti, Beatrix Ueberheide, Damian C Ekiert, Gira Bhabha, Victor J Torres.
      Staphylococcus aureus (S. aureus) is a serious global pathogen that causes a diverse range of invasive diseases. S. aureus utilizes a family of pore-forming toxins, known as bi-component leukocidins, to evade the host immune response and promote infection. Among these is LukAB (leukocidin A/leukocidin B), a toxin that assembles into an octameric β-barrel pore in the target cell membrane, resulting in host cell death. The established cellular receptor for LukAB is CD11b of the Mac-1 complex. Here, we show that hydrogen voltage gated channel 1 (HVCN1) is also required for the cytotoxicity of all major LukAB variants. We demonstrate that while each receptor is sufficient to recruit LukAB to the plasma membrane, both receptors are required for maximal lytic activity. Why LukAB requires two receptors, and how each of these receptors contributes to pore-formation remains unknown. To begin to resolve this, we performed an alanine scanning mutagenesis screen to identify mutations that allow LukAB to maintain cytotoxicity without CD11b. We discovered thirty mutations primarily localized in the stem domains of LukA and LukB that enable LukAB to exhibit full cytotoxicity in the absence of CD11b. Using crosslinking, electron microscopy and hydroxyl radical protein footprinting, we show these mutations increase the solvent accessibility of the stem domain, priming LukAB for oligomerization. Together, our data support a model in which CD11b binding unlatches the membrane penetrating stem domains of LukAB, and this change in flexibility promotes toxin oligomerization.
    Keywords:  Staphylococcus aureus (S. aureus); bacterial toxin; high-throughput screening; oligomerization; receptor
    DOI:  https://doi.org/10.1016/j.jbc.2023.105321
  21. Philos Trans R Soc Lond B Biol Sci. 2023 Nov 20. 378(1890): 20230042
    Peptidylarginine deiminase 4 and ADAMTS13 activity in Staphylococcus aureus bacteraemia.
    Caroline P Martens, Marijke Peetermans, Thomas Vanassche, Peter Verhamme, Marc Jacquemin, Kimberly Martinod.
      Staphylococcus aureus infection is associated with increased levels of neutrophil extracellular traps (NETs) and von Willebrand factor (VWF), and with reduced activity of ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13). Peptidylarginine deiminase 4 (PAD4) contributes to NET formation and inactivates ADAMTS13 in vitro. The role of PADs in the dynamics of NETs, VWF and ADAMTS13 has not yet been studied. We thus aimed to assess the longitudinal evolution of NETs, PADs, VWF and ADAMTS13 activity in S. aureus infection. Plasma samples from S. aureus bacteraemia patients were longitudinally collected and analysed for NETs, PAD4/PAD2, VWF and ADAMTS13 activity. Correlation analyses with clinical data were performed. Recombinant PAD4 and S. aureus were assessed in vitro for their potential to modulate ADAMTS13 activity. Sixty-seven patients were included. Plasma levels of NETs, VWF, PAD4 and PAD2 were increased and ADAMTS13 activity was decreased. Levels of PADs were negatively correlated with ADAMTS13 activity. NETs were positively correlated with PADs, and negatively with ADAMTS13 activity. In vitro, recombinant PAD4 but not S. aureus reduced ADAMTS13 activity in plasma. Levels of PAD4 and PAD2 correlate with reduced ADAMTS13 activity, with neutrophils as the likely source of PAD activity in S. aureus bacteraemia. This article is part of the Theo Murphy meeting issue 'The virtues and vices of protein citrullination'.
    Keywords:  ADAMTS13; Staphylococcus aureus; neutrophil extracellular traps; peptidylarginine deiminase 4; von Willebrand factor
    DOI:  https://doi.org/10.1098/rstb.2023.0042
  22. mBio. 2023 Oct 05. e0134923
    Clinical Staphylococcus aureus inhibits human T-cell activity through interaction with the PD-1 receptor.
    Maiken Mellergaard, Sarah Line Skovbakke, Stine Dam Jepsen, Nafsika Panagiotopoulou, Amalie Bøge Rud Hansen, Weihua Tian, Astrid Lund, Rikke Illum Høgh, Sofie Hedlund Møller, Romain Guérillot, Ashleigh S Hayes, Lise Tornvig Erikstrup, Lars Andresen, Anton Y Peleg, Anders Rhod Larsen, Timothy P Stinear, Aase Handberg, Christian Erikstrup, Benjamin P Howden, Steffen Goletz, Dorte Frees, Søren Skov.
      Staphylococcus aureus (S. aureus) represents a major clinical challenge due to its explicit capacity to select mutations that increase antibiotic resistance and immune evasion. However, the molecular mechanisms are poorly defined, especially for adaptive immunity. Cancer immunotherapy targeting programmed cell death protein 1 (PD-1) enhances T-cell activity and is emerging for the treatment of certain viral infections, while its potential against bacterial infections remains elusive. We show that an S. aureus clpP mutant, selected during clinical antibiotic therapy, inhibits T-cell activity by directly interacting with PD-1 on human T cells. Specificity of the interaction was confirmed using recombinant PD-1, as well as PD-1 overexpressing and knock out cells. Moreover, the PD-1-binding S. aureus inhibited intracellular calcium mobilization, T-cell proliferation, CD25 expression, and IL-2 secretion, while the key effects were alleviated by antibody-mediated PD-1 blockade using an engineered IgG1-based anti-PD-1 antibody. Our results suggest that clpP mutant S. aureus directly targets PD-1 to evade immune activation and that therapeutic targeting of PD-1 may be used against certain staphylococcal infections. IMPORTANCE Therapies that target and aid the host immune defense to repel cancer cells or invading pathogens are rapidly emerging. Antibiotic resistance is among the largest threats to human health globally. Staphylococcus aureus (S. aureus) is the most common bacterial infection, and it poses a challenge to the healthcare system due to its significant ability to develop resistance toward current available therapies. In long-term infections, S. aureus further adapt to avoid clearance by the host immune defense. In this study, we discover a new interaction that allows S. aureus to avoid elimination by the immune system, which likely supports its persistence in the host. Moreover, we find that blocking the specific receptor (PD-1) using antibodies significantly relieves the S. aureus-imposed inhibition. Our findings suggest that therapeutically targeting PD-1 is a possible future strategy for treating certain antibiotic-resistant staphylococcal infections.
    Keywords:  ClpP mutation; T cells; adaptive immunity; clinical Staphylococcus aureus; immune evasion
    DOI:  https://doi.org/10.1128/mbio.01349-23
  23. J Clin Invest. 2023 10 02. pii: e170501. [Epub ahead of print]133(19):
    Alveolar macrophages in tissue homeostasis, inflammation, and infection: evolving concepts of therapeutic targeting.
    Christina Malainou, Shifaa M Abdin, Nico Lachmann, Ulrich Matt, Susanne Herold.
      Alveolar macrophages (AMs) are the sentinel cells of the alveolar space, maintaining homeostasis, fending off pathogens, and controlling lung inflammation. During acute lung injury, AMs orchestrate the initiation and resolution of inflammation in order to ultimately restore homeostasis. This central role in acute lung inflammation makes AMs attractive targets for therapeutic interventions. Single-cell RNA-Seq and spatial omics approaches, together with methodological advances such as the generation of human macrophages from pluripotent stem cells, have increased understanding of the ontogeny, function, and plasticity of AMs during infectious and sterile lung inflammation, which could move the field closer to clinical application. However, proresolution phenotypes might conflict with proinflammatory and antibacterial responses. Therefore, therapeutic targeting of AMs at vulnerable time points over the course of infectious lung injury might harbor the risk of serious side effects, such as loss of antibacterial host defense capacity. Thus, the identification of key signaling hubs that determine functional fate decisions in AMs is of the utmost importance to harness their therapeutic potential.
    DOI:  https://doi.org/10.1172/JCI170501
  24. Nat Commun. 2023 10 02. 14(1): 5818
    NAD+ metabolism is a key modulator of bacterial respiratory epithelial infections.
    Björn Klabunde, André Wesener, Wilhelm Bertrams, Isabell Beinborn, Nicole Paczia, Kristin Surmann, Sascha Blankenburg, Jochen Wilhelm, Javier Serrania, Kèvin Knoops, Eslam M Elsayed, Katrin Laakmann, Anna Lena Jung, Andreas Kirschbaum, Sven Hammerschmidt, Belal Alshaar, Nicolas Gisch, Mobarak Abu Mraheil, Anke Becker, Uwe Völker, Evelyn Vollmeister, Birke J Benedikter, Bernd Schmeck.
      Lower respiratory tract infections caused by Streptococcus pneumoniae (Spn) are a leading cause of death globally. Here we investigate the bronchial epithelial cellular response to Spn infection on a transcriptomic, proteomic and metabolic level. We found the NAD+ salvage pathway to be dysregulated upon infection in a cell line model, primary human lung tissue and in vivo in rodents, leading to a reduced production of NAD+. Knockdown of NAD+ salvage enzymes (NAMPT, NMNAT1) increased bacterial replication. NAD+ treatment of Spn inhibited its growth while growth of other respiratory pathogens improved. Boosting NAD+ production increased NAD+ levels in immortalized and primary cells and decreased bacterial replication upon infection. NAD+ treatment of Spn dysregulated the bacterial metabolism and reduced intrabacterial ATP. Enhancing the bacterial ATP metabolism abolished the antibacterial effect of NAD+. Thus, we identified the NAD+ salvage pathway as an antibacterial pathway in Spn infections, predicting an antibacterial mechanism of NAD+.
    DOI:  https://doi.org/10.1038/s41467-023-41372-w
  25. J Innate Immun. 2023 Oct 05.
    Mesenchymal Stromal Cells Facilitate Neutrophil Trained Immunity by Reprogramming Hematopoietic Stem Cells.
    Julie Ng, Anna E Marneth, Alec Griffith, Daniel Younger, Sailaja Ghanta, Alan Jiao, Gareth Willis, Junwen Han, Jewel Imani, Bailin Niu, Joshua W Keegan, Brandon Hancock, Fei Guo, Yang Shi, Mark A Perrella, James A Lederer.
      Novel therapeutics are urgently needed to prevent opportunistic infections in immunocompromised individuals undergoing cancer treatments or other immune suppressive therapies. Trained immunity is a promising strategy to reduce this burden of disease. We previously demonstrated that mesenchymal stromal cells (MSCs) preconditioned with a class A CpG oligodeoxynucleotide (CpG-ODN), a Toll-like receptor 9 (TLR9) agonist, can augment emergency granulopoiesis in a murine model of neutropenic sepsis. Here, we used a chimeric mouse model to demonstrate that MSCs secrete paracrine factors that act on lineage negative c-kit+ hematopoietic stem cells (HSCs), leaving them 'poised' to enhance emergency granulopoiesis months after transplantation. Chimeric mice developed from HSCs exposed to conditioned media from MSCs and CpG-ODN preconditioned MSCs showed significantly higher bacterial clearance and increased neutrophil granulopoiesis following lung infection than control mice. By CUT&RUN chromatin sequencing and cytometry by time of flight (CyTOF) approaches, we identified that MSC conditioned media leaves H3K4me3 histone marks in HSCs at genes involved in myelopoiesis and in signaling persistence by the mTOR pathway. Both soluble factors and extracellular vesicles (EV) from MSCs mediated these effects on HSCs and proteomic analysis by mass spectrometry revealed soluble calreticulin as a potential mediator. In summary, this study demonstrates that trained immunity can be mediated by paracrine factors from MSCs to induce neutrophil trained immunity by reprogramming HSCs for long-lasting functional changes in neutrophil mediated anti-microbial immunity.
    DOI:  https://doi.org/10.1159/000533732
  26. Front Microbiol. 2023 ;14 1269843
    The oxidative stress response of Streptococcus pneumoniae: its contribution to both extracellular and intracellular survival.
    Mirelys Hernandez-Morfa, Nadia B Olivero, Victoria E Zappia, German E Piñas, Nicolas M Reinoso-Vizcaino, Melina B Cian, Mariana Nuñez-Fernandez, Paulo R Cortes, Jose Echenique.
      Streptococcus pneumoniae is a gram-positive, aerotolerant bacterium that naturally colonizes the human nasopharynx, but also causes invasive infections and is a major cause of morbidity and mortality worldwide. This pathogen produces high levels of H2O2 to eliminate other microorganisms that belong to the microbiota of the respiratory tract. However, it also induces an oxidative stress response to survive under this stressful condition. Furthermore, this self-defense mechanism is advantageous in tolerating oxidative stress imposed by the host's immune response. This review provides a comprehensive overview of the strategies employed by the pneumococcus to survive oxidative stress. These strategies encompass the utilization of H2O2 scavengers and thioredoxins, the adaptive response to antimicrobial host oxidants, the regulation of manganese and iron homeostasis, and the intricate regulatory networks that control the stress response. Here, we have also summarized less explored aspects such as the involvement of reparation systems and polyamine metabolism. A particular emphasis is put on the role of the oxidative stress response during the transient intracellular life of Streptococcus pneumoniae, including coinfection with influenza A and the induction of antibiotic persistence in host cells.
    Keywords:  Streptococcus pneumoniae; fluoroquinolones; immune cells; influenza A; intracellular survival; oxidative stress; persistence; two-component systems
    DOI:  https://doi.org/10.3389/fmicb.2023.1269843
  27. J Allergy Clin Immunol Glob. 2023 Nov;2(4): 100134
    Chronic rhinosinusitis with nasal polyps and allergic rhinitis as different multimorbid treatable traits in asthma.
    José Antonio Castillo, Vicente Plaza, Gustavo Rodrigo, Berta Juliá, César Picado, Cristina Fernández, Joaquim Mullol.
      Background: Respiratory multimorbidities are linked to asthma, such as allergic rhinitis (AR) with early allergic asthma and chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) with late nonallergic asthma.Objective: Our aim was to investigate the association of asthma severity and control with specific upper airway phenotypes.
    Method: Patients with asthma were prospectively recruited from 23 pulmonology and ear, nose, and throat clinics. Asthma severity and control, as well as upper airway comorbidities (AR and non-AR [NAR], CRSwNP, and CRS without nasal polyps [CRSsNP]) were assessed according to international consensus guidelines definitions.
    Results: A total of 492 asthmatic patients were included. Half of the asthmatic patients (49.6%) had associated rhinitis (37.0% had AR and 12.6% had NAR) and 36.2% had CRS (16.7% had CRSsNP and 19.5% had CRSwNP), whereas 14.2% had no sinonasal symptoms. Most cases of AR (78%) and NAR (84%) were present in patients with mild-to-moderate asthma, whereas CRSwNP was more frequent in patients with severe asthma (35% [P < .001]), mainly nonatopic asthma (44% [P < .001]). Patients with severe asthma with CRSwNP had worse asthma control, which was correlated (r = 0.249 [P = .034]) with sinus occupancy. Multiple logistic regression analysis showed that late-onset asthma, intolerance of aspirin and/or nonsteroidal anti-inflammatory drugs, and CRSwNP were independently associated with severe asthma.
    Conclusion: Severe asthma is associated with CRSwNP, with sinus occupancy affecting asthma control. This study has identified 2 main different upper airway treatable traits, AR and CRSwNP, which need further evaluation to improve management and control of patients with asthma.
    Keywords:  Asthma; allergic rhinitis; asthma control; asthma severity; chronic rhinosinusitis with nasal polyps; united airway disease
    DOI:  https://doi.org/10.1016/j.jacig.2023.100134
  28. J Dent Sci. 2023 Oct;18(4): 1630-1637
    Preparation of human primary macrophages to study the polarization from monocyte-derived macrophages to pro- or anti-inflammatory macrophages at biomaterial interface in vitro.
    Ludovica Parisi, Massimiliano Giovanni Bianchi, Benedetta Ghezzi, Eleonora Maurizi, Guido Maria Macaluso, Ovidio Bussolati, Simone Lumetti.
      Background/purpose: Testing of dental materials when in contact with innate immune cells has been so far hindered by the lack of proper in vitro models. Human primary monocyte-derived macrophages (MDMs) would be an excellent option to this aim. However, the inability to detach them from the tissue culture plates contrast the possibility to culture them on biomaterials. The goal of the present work is to present and validate an innovative protocol to obtain MDMs from peripheral blood monocytes, and to reseed them in contact with biomaterials without altering their viability and phenotype.Materials and methods: We differentiated MDMs on ultra-low attachment tissue culture plastics and recovered them with specific detachment solution in order to be reseeded on a secondary substrate. Therefore, using biological assays (RT-PCR, Western blot, and immunofluorescence) we compared their phenotype to MDMs differentiated on standard culture plates.
    Results: Transferred MDMs keep their differentiated M0 resting state, as well as the ability to be polarized into M1 (pro-inflammatory) or M2 (anti-inflammatory) macrophages.
    Conclusion: These data provide the dental material research community the unprecedented possibility to investigate the immunomodulatory properties of biomaterials for dental application.
    Keywords:  Biocompatible materials; Bone substitutes; Dental implants; Human; Macrophage inflammation; Macrophages
    DOI:  https://doi.org/10.1016/j.jds.2023.01.020
  29. Cell Metab. 2023 Oct 03. pii: S1550-4131(23)00332-7. [Epub ahead of print]35(10): 1767-1781.e6
    Ketogenesis promotes tolerance to Pseudomonas aeruginosa pulmonary infection.
    Kira L Tomlinson, Ying-Tsun Chen, Alex Junker, AndreaCarola Urso, Tania Wong Fok Lung, Danielle Ahn, Casey E Hofstaedter, Swikrity U Baskota, Robert K Ernst, Alice Prince, Sebastián A Riquelme.
      Pseudomonas aeruginosa is a common cause of pulmonary infection. As a Gram-negative pathogen, it can initiate a brisk and highly destructive inflammatory response; however, most hosts become tolerant to the bacterial burden, developing chronic infection. Using a murine model of pneumonia, we demonstrate that this shift from inflammation to disease tolerance is promoted by ketogenesis. In response to pulmonary infection, ketone bodies are generated in the liver and circulate to the lungs where they impose selection for P. aeruginosa strains unable to display surface lipopolysaccharide (LPS). Such keto-adapted LPS strains fail to activate glycolysis and tissue-damaging cytokines and, instead, facilitate mitochondrial catabolism of fats and oxidative phosphorylation (OXPHOS), which maintains airway homeostasis. Within the lung, P. aeruginosa exploits the host immunometabolite itaconate to further stimulate ketogenesis. This environment enables host-P. aeruginosa coexistence, supporting both pathoadaptive changes in the bacteria and the maintenance of respiratory integrity via OXPHOS.
    Keywords:  OXPHOS; Pseudomonas aeruginosa; bioenergetics; disease tolerance; infection; inflammation; itaconate; ketogenesis; ketogenic diet; pneumonia
    DOI:  https://doi.org/10.1016/j.cmet.2023.09.001
  30. Clin Transplant. 2023 Oct 03. e15152
    The role of lung microbiota in primary graft dysfunction in lung transplant recipients.
    Yuhan Wu, Linna Huang, Min Li, Xiaoyang Cui, Qingyuan Zhan, Chen Wang.
      BACKGROUND: Recent studies have shown that the lung microbiota is altered in critically ill patients and predicts clinical outcomes. Primary graft dysfunction (PGD) is a common complication and a leading cause of death within 1 month of lung transplantation, but the clinical significance of changes in the lung bacterial community during PGD is unclear. The aim of this study was to determine the contribution of the lung microbiota to the development and course of severe PGD.METHODS: We conducted a retrospective study to characterize the lung microbiota of 32 lung transplant patients with combined PGD using next-generation sequencing of bronchoalveolar lavage samples. The relationship between lung flora dysbiosis and lung immunity in PGD was assessed by quantification of alveolar cytokines. The contribution of microbiota characteristics to patient outcomes was assessed by estimating overall survival.
    RESULTS: Patients diagnosed with PGD grade 3 showed a reduction in alpha diversity, driven by a significant increase in the abundance of the genera Modestobacter, Scardovia and Selenomonas, and a reduction in the proportion of the genera Klebsiella and Oribacterium. Alpha diversity of the lung microbiota in PGD3 patients was negatively correlated with BALF interleukin (IL)-2 (r = -.752, p < .05). In addition, bacterial diversity in the lung microbiota of non-survivors was lower than that of survivors (p = .041).
    CONCLUSIONS: There is variation in the lung microbiota of PGD grade 3 patients and dysbiosis of the lung microbiota is associated with lung immunity. The lung microbiota has potential in the diagnosis and treatment of PGD grade 3.
    Keywords:  lung microbiota; lung transplantation; metagenomic next-generation sequencing; primary graft dysfunction
    DOI:  https://doi.org/10.1111/ctr.15152
  31. Trends Endocrinol Metab. 2023 Sep 30. pii: S1043-2760(23)00192-3. [Epub ahead of print]
    Carbon metabolism in the regulation of macrophage functions.
    Zhending Gan, Muyang Zhao, Yaoyao Xia, Yuqi Yan, Wenkai Ren.
      Carbon metabolism, including one-carbon (1C) metabolism and central carbon metabolism (CCM), provides energy for the cell and generates metabolites with signaling activities. The regulation of macrophage polarization involves complex signals and includes an epigenetic level. Epigenetic modifications through changes in carbon metabolism allow macrophages to respond in a timely manner to their environment and adapt to metabolic demands during macrophage polarization. Here we summarize the current understanding of the crosstalk between carbon metabolism and epigenetic modifications in macrophages under physiological conditions and in the tumor microenvironment (TME) and provide targets and further directions for macrophage-associated diseases.
    Keywords:  central carbon metabolism; epigenetic modification; macrophage; one-carbon metabolism
    DOI:  https://doi.org/10.1016/j.tem.2023.09.003
  32. PLoS One. 2023 ;18(10): e0292368
    Characterization of 3D organotypic epithelial tissues reveals tonsil-specific differences in tonic interferon signaling.
    Robert Jackson, Esha V Rajadhyaksha, Reid S Loeffler, Caitlyn E Flores, Koenraad Van Doorslaer.
      Three-dimensional (3D) culturing techniques can recapitulate the stratified nature of multicellular epithelial tissues. Organotypic 3D epithelial tissue culture methods have several applications, including the study of tissue development and function, drug discovery and toxicity testing, host-pathogen interactions, and the development of tissue-engineered constructs for use in regenerative medicine. We grew 3D organotypic epithelial tissues from foreskin, cervix, and tonsil-derived primary cells and characterized the transcriptome of these in vitro tissue equivalents. Using the same 3D culturing method, all three tissues yielded stratified squamous epithelium, validated histologically using basal and superficial epithelial cell markers. The goal of this study was to use RNA-seq to compare gene expression patterns in these three types of epithelial tissues to gain a better understanding of the molecular mechanisms underlying their function and identify potential therapeutic targets for various diseases. Functional profiling by over-representation and gene set enrichment analysis revealed tissue-specific differences: i.e., cutaneous homeostasis and lipid metabolism in foreskin, extracellular matrix remodeling in cervix, and baseline innate immune differences in tonsil. Specifically, tonsillar epithelia may play an active role in shaping the immune microenvironment of the tonsil balancing inflammation and immune responses in the face of constant exposure to microbial insults. Overall, these data serve as a resource, with gene sets made available for the research community to explore, and as a foundation for understanding the epithelial heterogeneity and how it may impact their in vitro use. An online resource is available to investigate these data (https://viz.datascience.arizona.edu/3DEpiEx/).
    DOI:  https://doi.org/10.1371/journal.pone.0292368
  33. Clin Immunol. 2023 Sep 26. pii: S1521-6616(23)00554-5. [Epub ahead of print]256 109791
    The multi-omics single-cell landscape of sinus mucosa in uncontrolled severe chronic rhinosinusitis with nasal polyps.
    Zhaofeng Xu, Yanran Huang, Tim Meese, Sharon Van Nevel, Gabriele Holtappels, Stijn Vanhee, Barbara M Bröker, Zhengqi Li, Ellen de Meester, Natalie De Ruyck, Thibaut Van Zele, Philip Gevaert, Filip Van Nieuwerburgh, Luo Zhang, Mohamed H Shamji, Weiping Wen, Nan Zhang, Claus Bachert.
      Uncontrolled severe chronic rhinosinusitis with nasal polyps (CRSwNP) is associated with elevated levels of type 2 inflammatory cytokines and raised immunoglobulin concentrations in nasal polyp tissue. By using single-cell RNA sequencing, transcriptomics, surface proteomics, and T cell and B cell receptor sequencing, we found the predominant cell types in nasal polyps were shifted from epithelial and mesenchymal cells to inflammatory cells compared to nasal mucosa from healthy controls. Broad expansions of CD4 T effector memory cells, CD4 tissue-resident memory T cells, CD8 T effector memory cells and all subtypes of B cells in nasal polyp tissues. The T and B cell receptor repertoires were skewed in NP. This study highlights the deviated immune response and remodeling mechanisms that contribute to the pathogenesis of uncontrolled severe CRSwNP. CLINICAL IMPLICATIONS: We identified differences in the cellular compositions, transcriptomes, proteomes, and deviations in the immune profiles of T cell and B cell receptors as well as alterations in the intercellular communications in uncontrolled severe CRSwNP patients versus healthy controls, which might help to define potential therapeutic targets in the future.
    Keywords:  Chronic rhinosinusitis with nasal polyps; Immune profiles; Tissue remodeling; Type 2 immune responses; scRNA-seq
    DOI:  https://doi.org/10.1016/j.clim.2023.109791
  34. Annu Rev Pathol. 2023 Oct 03.
    Control of Cell Death in Health and Disease.
    Nobuhiko Kayagaki, Joshua D Webster, Kim Newton.
      Apoptosis, necroptosis, and pyroptosis are genetically programmed cell death mechanisms that eliminate obsolete, damaged, infected, and self-reactive cells. Apoptosis fragments cells in a manner that limits immune cell activation, whereas the lytic death programs of necroptosis and pyroptosis release proinflammatory intracellular contents. Apoptosis fine-tunes tissue architecture during mammalian development, promotes tissue homeostasis, and is crucial for averting cancer and autoimmunity. All three cell death mechanisms are deployed to thwart the spread of pathogens. Disabling regulators of cell death signaling in mice has revealed how excessive cell death can fuel acute or chronic inflammation. Here we review strategies for modulating cell death in the context of disease. For example, BCL-2 inhibitor venetoclax, an inducer of apoptosis, is approved for the treatment of certain hematologic malignancies. By contrast, inhibition of RIPK1, NLRP3, GSDMD, or NINJ1 to limit proinflammatory cell death and/or the release of large proinflammatory molecules from dying cells may benefit patients with inflammatory diseases. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 19 is January 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-pathmechdis-051022-014433
  35. Front Microbiol. 2023 ;14 1260543
    Diverse roles of lung macrophages in the immune response to influenza A virus.
    Haoning Li, Aoxue Wang, Yuying Zhang, Fanhua Wei.
      Influenza viruses are one of the major causes of human respiratory infections and the newly emerging and re-emerging strains of influenza virus are the cause of seasonal epidemics and occasional pandemics, resulting in a huge threat to global public health systems. As one of the early immune cells can rapidly recognize and respond to influenza viruses in the respiratory, lung macrophages play an important role in controlling the severity of influenza disease by limiting viral replication, modulating the local inflammatory response, and initiating subsequent adaptive immune responses. However, influenza virus reproduction in macrophages is both strain- and macrophage type-dependent, and ineffective replication of some viral strains in mouse macrophages has been observed. This review discusses the function of lung macrophages in influenza virus infection in order to better understand the pathogenesis of the influenza virus.
    Keywords:  antiviral; immune response; inflammation; influenza virus; macrophage
    DOI:  https://doi.org/10.3389/fmicb.2023.1260543
  36. FASEB J. 2023 Nov;37(11): e23216
    Aberrant glucose metabolism underlies impaired macrophage differentiation in glycogen storage disease type Ib.
    Yuyeon Jang, Tae Sub Park, Byung-Chul Park, Young Mok Lee, Tae-Hwe Heo, Hyun Sik Jun.
      Glycogen storage disease type Ib (GSD-Ib) is an autosomal recessive disorder caused by a deficiency in the glucose-6-phosphate (G6P) transporter (G6PT) that is responsible for transporting G6P into the endoplasmic reticulum. GSD-Ib is characterized by disturbances in glucose homeostasis, neutropenia, and neutrophil dysfunction. Although some studies have explored neutrophils abnormalities in GSD-Ib, investigations regarding monocytes/macrophages remain limited so far. In this study, we examined the impact of G6PT deficiency on monocyte-to-macrophage differentiation using bone marrow-derived monocytes from G6pt-/- mice as well as G6PT-deficient human THP-1 monocytes. Our findings revealed that G6PT-deficient monocytes exhibited immature differentiation into macrophages. Notably, the impaired differentiation observed in G6PT-deficient monocytes seemed to be associated with abnormal glucose metabolism, characterized by enhanced glucose consumption through glycolysis, even under quiescent conditions with oxidative phosphorylation. Furthermore, we observed a reduced secretion of inflammatory cytokines in G6PT-deficient THP-1 monocytes during the inflammatory response, despite their elevated glucose consumption. In conclusion, this study sheds light on the significance of G6PT in monocyte-to-macrophage differentiation and underscores its importance in maintaining glucose homeostasis and supporting immune response in GSD-Ib. These findings may contribute to a better understanding of the pathogenesis of GSD-Ib and potentially pave the way for the development of targeted therapeutic interventions.
    Keywords:  differentiation; glucose metabolism; glucose-6-phosphate transporter; macrophages; metabolic reprogramming; monocytes
    DOI:  https://doi.org/10.1096/fj.202300592RR
  37. Front Immunol. 2023 ;14 1269015
    Learning from the microbes: exploiting the microbiome to enforce T cell immunotherapy.
    Sarah Staudt, Kai Ziegler-Martin, Alexander Visekruna, John Slingerland, Roni Shouval, Michael Hudecek, Marcel van den Brink, Maik Luu.
      The opportunities genetic engineering has created in the field of adoptive cellular therapy for cancer are accelerating the development of novel treatment strategies using chimeric antigen receptor (CAR) and T cell receptor (TCR) T cells. The great success in the context of hematologic malignancies has made especially CAR T cell therapy a promising approach capable of achieving long-lasting remission. However, the causalities involved in mediating resistance to treatment or relapse are still barely investigated. Research on T cell exhaustion and dysfunction has drawn attention to host-derived factors that define both the immune and tumor microenvironment (TME) crucially influencing efficacy and toxicity of cellular immunotherapy. The microbiome, as one of the most complex host factors, has become a central topic of investigations due to its ability to impact on health and disease. Recent findings support the hypothesis that commensal bacteria and particularly microbiota-derived metabolites educate and modulate host immunity and TME, thereby contributing to the response to cancer immunotherapy. Hence, the composition of microbial strains as well as their soluble messengers are considered to have predictive value regarding CAR T cell efficacy and toxicity. The diversity of mechanisms underlying both beneficial and detrimental effects of microbiota comprise various epigenetic, metabolic and signaling-related pathways that have the potential to be exploited for the improvement of CAR T cell function. In this review, we will discuss the recent findings in the field of microbiome-cancer interaction, especially with respect to new trajectories that commensal factors can offer to advance cellular immunotherapy.
    Keywords:  CAR T cell; cancer immune cell therapy; immunology; immunotherapy; microbiome
    DOI:  https://doi.org/10.3389/fimmu.2023.1269015
  38. Arthritis Rheumatol. 2023 Oct 06.
    α-ketoglutarate-dependent KDM6 histone demethylases regulate Interferon Stimulated Gene expression in Lupus.
    Erica N Montano, Moumita Bose, Lihong Huo, Gantsetseg Tumurkhuu, Gabriela De Los Santos, Brianna Simental, Aleksandr B Stotland, Janet Wei, C Noel Bairey Merz, Jo Suda, Gislaine Martins, Sarfaraz Lalani, Kate Lawrenson, Yizhou Wang, Sarah Parker, Swamy Venuturupalli, Mariko Ishimori, Daniel J Wallace, Caroline A Jefferies.
      OBJECTIVE: Investigate the hypothesis that interferon (IFN) stimulated gene (ISG) expression in systemic lupus erythematosus (SLE) monocytes is linked to changes in metabolic reprogramming and epigenetic regulation of ISG expression.METHODS: Monocytes from healthy volunteers and SLE patients at baseline or following IFNα treatment were analyzed by extracellular flux analysis, proteomics, metabolomics, chromatin immunoprecipitation and gene expression. The histone demethylases KDM6A/B were inhibited using GSK-J4. GSK-J4 was tested in pristane and resiquimod (R848) models of IFN-driven SLE.
    RESULTS: SLE monocytes had enhanced rates of glycolysis and oxidative phosphorylation compared to healthy control (HC) monocytes, as well as increased levels of isocitrate dehydrogenase (IDH2) and its product, α-ketoglutarate (α-KG). As α-KG is a required cofactor for histone demethylases KDM6A and KDM6B, we hypothesized that IFNα may be driving 'trained immune' responses through altering histone methylation. IFNα priming (day 1) resulted in a sustained increase in the expression of ISGs in primed cells (day 5) and enhanced expression on restimulation with IFNα. Importantly decreased H3K27 trimethylation was observed at the promoters of ISGs following IFNα priming. Finally, GSK-J4 (KDM6A/B inhibitor) resulted in decreased ISG expression in SLE patient monocytes, as well as reduced autoantibody production, ISG expression and kidney pathology in R848-treated Balb/c mice.
    CONCLUSION: Our study suggests chronic IFNα exposure alters epigenetic regulation of ISG expression in SLE monocytes via changes in immunometabolism, a mechanism reflecting trained immunity to type I IFN. Importantly, it opens the possibility that targeting histone modifying enzymes such as KDM6A/B may reduce IFN responses in SLE.
    DOI:  https://doi.org/10.1002/art.42724
  39. mSystems. 2023 Oct 03. e0073023
    Use of single-cell technology to improve our understanding of the role of TLR2 in macrophage-Mycobacterium tuberculosis interaction.
    Alexandre Gouzy.
      The interaction between Mycobacterium tuberculosis, the agent of tuberculosis (TB), and its host cell, the macrophage, is multifaceted, dynamic, and involves multiple molecular partners. A better understanding of this interaction could help researchers manipulate the immune system in order to design host-targeted immunotherapies and/or develop a novel vaccine protecting better adults against TB. Jani and coworkers studied the role of the macrophage receptor TLR2 in the response to M. tuberculosis using single-cell technologies (C. Jani, S. L. Solomon, J. M. Peters, and S. C. Pringle, et al., mSystems, https://doi.org/10.1128/msystems.00052-23, 2023). This work addresses the multiple challenges associated with such studies and shows how informative single-cell analysis can be for the study of heterogeneous and complex host-pathogen interactions.
    Keywords:  Mycobacterium tuberculosis; TLR2; macrophage; single-cell RNA sequencing
    DOI:  https://doi.org/10.1128/msystems.00730-23
  40. J Allergy Clin Immunol. 2023 Sep 28. pii: S0091-6749(23)01201-0. [Epub ahead of print]
    HIF-1α activates NLRP3 inflammasome to regulate epithelial differentiation in chronic rhinosinusitis.
    Bing Zhong, Silu Sun, Kai Sen Tan, Hsiao Hui Ong, Jintao Du, Feng Liu, Yafeng Liu, Shixi Liu, Luo Ba, Jing Li, De Yun Wang, Jing Liu.
      BACKGROUND: Chronic rhinosinusitis (CRS) is an upper airway inflammation disease which is associated with hypoxia-mediated inflammation. The effect of Hypoxia-inducible factor-1(HIF-1)α on NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation in the pathogenesis of sinonasal mucosa is unclear.OBJECTIVE: To investigate the effect and mechanism of HIF-1α on NLRP3 inflammasome activation in the human nasal epithelial cells (hNECs).
    METHODS: We measured the expression levels of HIF-1α and NLRP3 inflammasome in nasal biopsies and hNECs derived from negative controls (NC, healthy) and patients with CRS with and without nasal polyps, and further analyzed the specific mechanism of HIF-1α regulation of NLRP3 inflammasome and its effect on the differentiation of hNECs.
    RESULTS: Increased both mRNA and protein expression levels of HIF-1α and NLRP3 inflammasome were shown in all CRS tissue biopsies. HIF-1α was able to enhance the expression of phosphorylated NLRP3 (S295) in both HEK293T cells and hNECs, and promoted the recruitment of caspase-1 and the apoptotic speck-like protein containing a caspase recruitment domain (ASC) by NLRP3. HIF-1α could also improve the stability of NLRP3 by preventing NLRP3 degradation caused by hypoxia-mediated inflammation. In addition, HIF-1α could also increase the expression of Mucin5AC and decrease the expression of α-Tubulin by promoting the activation of NLRP3 inflammasome in hNECs. It is worth mentioning that HIF-1α could directly promote the expression of P63 in hNECs too.
    CONCLUSION: Our study demonstrated that HIF-1α could potentially induce cilia loss and enhance the proliferation of goblet cells, possibly mediated by the regulation of NLRP3 phosphorylation in CRS inflammation.
    Keywords:  Chronic rhinosinusitis; NOD-like receptor family; Nasal epithelial cells; differentiation; hypoxia-inducible factor-1α; phosphorylation; pyrin domain containing 3
    DOI:  https://doi.org/10.1016/j.jaci.2023.09.020
  41. Free Radic Biol Med. 2023 Oct 02. pii: S0891-5849(23)00656-1. [Epub ahead of print]
    Staphylococcus aureus adapts to the immunometabolite itaconic acid by inducing acid and oxidative stress responses including S-bacillithiolations and S-itaconations.
    Vu Van Loi, Tobias Busche, Benno Kuropka, Susanne Müller, Karen Methling, Michael Lalk, Jörn Kalinowski, Haike Antelmann.
      Staphylococcus aureus is a major pathogen, which has to defend against reactive oxygen and electrophilic species encountered during infections. Activated macrophages produce the immunometabolite itaconate as potent electrophile and antimicrobial upon pathogen infection. In this work, we used transcriptomics, metabolomics and shotgun redox proteomics to investigate the specific stress responses, metabolic changes and redox modifications caused by sublethal concentrations of itaconic acid in S. aureus. In the RNA-seq transcriptome, itaconic acid caused the induction of the GlnR, KdpDE, CidR, SigB, GraRS, PerR, CtsR and HrcA regulons and the urease-encoding operon, revealing an acid and oxidative stress response and impaired proteostasis. Neutralization using external urea as ammonium source improved the growth and decreased the expression of the glutamine synthetase-controlling GlnR regulon, indicating that S. aureus experienced ammonium starvation upon itaconic acid stress. In the extracellular metabolome, the amounts of acetate and formate were decreased, while secretion of pyruvate and the neutral product acetoin were strongly enhanced to avoid intracellular acidification. Exposure to itaconic acid affected the amino acid uptake and metabolism as revealed by the strong intracellular accumulation of lysine, threonine, histidine, aspartate, alanine, valine, leucine, isoleucine, cysteine and methionine. In the proteome, itaconic acid caused widespread S-bacillithiolation and S-itaconation of redox-sensitive antioxidant and metabolic enzymes, ribosomal proteins and translation factors in S. aureus, supporting its oxidative and electrophilic mode of action in S. aureus. In phenotype analyses, the catalase KatA, the low molecular weight thiol bacillithiol and the urease provided protection against itaconic acid-induced oxidative and acid stress in S. aureus. Altogether, our results revealed that under physiological infection conditions, such as in the acidic phagolysome, itaconic acid is a highly effective antimicrobial against multi-resistant S. aureus isolates, which acts as weak acid causing an acid, oxidative and electrophilic stress response, leading to S-bacillithiolation and itaconation.
    Keywords:  Itaconation; Itaconic acid; Metabolome; S-bacillithiolation; Staphylococcus aureus; Transcriptome
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.09.031
  42. Vet Res. 2023 Oct 03. 54(1): 87
    The impact of helminth-induced immunity on infection with bacteria or viruses.
    Hong Chen, Zengguo Cao, Mingyuan Liu, Michael S Diamond, Xuemin Jin.
      Different human and animal pathogens trigger distinct immune responses in their hosts. The infection of bacteria or viruses can trigger type I pro-inflammatory immune responses (e.g., IFN-γ, TNF-α, TH1 cells), whereas infection by helminths typically elicits a type II host resistance and tolerizing immune response (e.g., IL-4, IL-5, IL-13, TH2 cells). In some respects, the type I and II immune responses induced by these different classes of pathogens are antagonistic. Indeed, recent studies indicate that infection by helminths differentially shapes the response and outcome of subsequent infection by viruses and bacteria. In this review, we summarize the current knowledge on how helminth infections influence concurrent or subsequent microbial infections and also discuss the implications for helminth-mediated immunity on the outcome of SARS-CoV-2 disease.
    Keywords:  Helminth; SARS-CoV-2; co-infection; type 2 immune response; viruses and bacteria
    DOI:  https://doi.org/10.1186/s13567-023-01216-3
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