bims-bac4me Biomed News
on Microbiome and trained immunity
Issue of 2024–01–07
forty-nine papers selected by
Chun-Chi Chang, University Hospital Zurich
  1. Temperature influences commensal-pathogen dynamics in a nasal epithelial cell co-culture model.
  2. Macrophages control pathological interferon responses during viral respiratory infection.
  3. Metabolic diversity of human macrophages: potential influence on Staphylococcus aureus intracellular survival.
  4. The Staphylococcus aureus CamS lipoprotein is a repressor of toxin production that shapes host-pathogen interaction.
  5. Interplay between Staphylococcus aureus and the vaginal microbiota.
  6. A bacterial pigment provides cross-species protection from H2O2- and neutrophil-mediated killing.
  7. Pathogen-driven nucleotide overload triggers mitochondria-centered cell death in phagocytes.
  8. Understanding staphylococcus aureus internalization and induction of antimicrobial tolerance.
  9. Ectopic expression of C-type lectin Mincle renders mice susceptible to staphylococcal pneumonia.
  10. Symbiotic Synergy from Sponges to Humans: Microflora-Host Harmony Is Crucial for Ensuring Survival and Shielding against Invading Pathogens.
  11. BBQ methods: Streamlined workflows for Bacterial Burden Quantification in infected cells by confocal microscopy.
  12. Controlling TRM differentiation.
  13. Rice-derived arabinoxylan fibers are particle size-dependent inducers of trained immunity in a human macrophage-intestinal epithelial cell co-culture model.
  14. Inflammasomes as regulators of mechano-immunity.
  15. Granulocyte macrophage colony stimulating factor exerts dominant effects over macrophage colony stimulating factor during macrophage differentiation in vitro to induce an inflammatory phenotype.
  16. The biochemical pathways of apoptotic, necroptotic, pyroptotic, and ferroptotic cell death.
  17. TRAM deletion attenuates monocyte exhaustion and alleviates sepsis severity.
  18. TLR2 regulates Moraxella catarrhalis adhesion to and invasion into alveolar epithelial cells and mediates inflammatory responses.
  19. Contribution of circulating monocytes in maintaining homeostasis of resident macrophages in postnatal and young adult mouse cochlea.
  20. Endogenous blocking of TLR2 along with TNF-α and IL-1β ameliorates the severity of the S. aureus arthritis via modulating STAT3/SOCS3 expressions in tissue resident macrophages.
  21. Neutrophil-plasmacytoid dendritic cell interaction leads to production of type I IFN in response to Mycobacterium tuberculosis.
  22. Microbial transmission in the social microbiome and host health and disease.
  23. Airway epithelial cell identity and plasticity are constrained by Sox2 during lung homeostasis, tissue regeneration, and in human disease.
  24. Human and mouse peritoneal macrophages and dendritic cells compared.
  25. Soluble CD83 modulates human-monocyte-derived macrophages toward alternative phenotype, function, and metabolism.
  26. The antibiotic resistance reservoir of the lung microbiome expands with age in a population of critically ill patients.
  27. Borrelia burgdorferi initiates early transcriptional re-programming in macrophages that supports long-term suppression of inflammation.
  28. Pyroptotic Macrophage-Derived Microvesicles Accelerate Formation of Neutrophil Extracellular Traps via GSDMD-N-expressing Mitochondrial Transfer during Sepsis.
  29. VISTA promotes the metabolism and differentiation of myeloid-derived suppressor cells by STAT3 and polyamine-dependent mechanisms.
  30. Polysaccharide of Asparagus cochinchinensis (Lour.) Merr regulates macrophage immune response and epigenetic memory through TLR4-JNK/p38/ERK signaling pathway and histone modification.
  31. Modelling bronchial epithelial-fibroblast cross-talk in idiopathic pulmonary fibrosis (IPF) using a human-derived in vitro air liquid interface (ALI) culture.
  32. Candida albicans extracellular vesicles trigger type I IFN signalling via cGAS and STING.
  33. Multi-omic approaches for host-microbiome data integration.
  34. CRISPR-Cas-based identification of a sialylated human milk oligosaccharides utilization cluster in the infant gut commensal Bacteroides dorei.
  35. Intestinal Bacteroides modulates inflammation, systemic cytokines, and microbial ecology via propionate in a mouse model of cystic fibrosis.
  36. Targeting myeloid cells for cancer immunotherapy: Siglec-7/9/10/15 and their ligands.
  37. Ink-spiring innovations: 3D bioprinting skin models for disease discovery.
  38. Restoring the epigenetic landscape of lung microbiome: potential therapeutic approach for chronic respiratory diseases.
  39. Metabolic reprogramming in skin wound healing.
  40. Human apical-out nasal organoids reveal an essential role of matrix metalloproteinases in airway epithelial differentiation.
  41. ROS-induced metabolic reprogramming to one-carbon metabolism and S-adenosylmethionine-mediated epigenetic modification in IL-10-producing B cells for the resolution of pneumonia.
  42. Histone lactylation couples cellular metabolism with developmental gene regulatory networks.
  43. Pyroptosis in microbial infectious diseases.
  44. BCG vaccination-induced acquired control of mycobacterial growth differs from growth control preexisting to BCG vaccination.
  45. Systemic neutrophils are triggered by respiratory Bacillus Calmette- Guérin and mediate pulmonary mycobacterial clearance in synergy with the triggering receptor expressed on myeloid cells 1.
  46. Circulating NK cells establish tissue residency upon acute infection of skin and mediate accelerated effector responses to secondary infection.
  47. BCG-mediated viral protection goes biphasic.
  48. Innate immune and proinflammatory signals activate the Hippo pathway via a Tak1-STRIPAK-Tao axis.
  49. Phage Paride can kill dormant, antibiotic-tolerant cells of Pseudomonas aeruginosa by direct lytic replication.
  1. mSphere. 2024 Jan 05. e0058923
    Temperature influences commensal-pathogen dynamics in a nasal epithelial cell co-culture model.
    Joshua T Huffines, RaNashia L Boone, Megan R Kiedrowski.
       IMPORTANCE: Chronic rhinosinusitis is a complex inflammatory disease with a significant healthcare burden. Although presence of S. aureus and microbial dysbiosis are considered mediators of inflammation in CRS, no studies have examined the influence of temperature on S. aureus interactions with the nasal epithelium and the dominant genus of the healthy URT, Corynebacterium. Interactions between Corynebacterium species and S. aureus have been documented in several studies, but none to date have examined how environmental changes in the URT may alter their interactions with the epithelium or each other. This study utilizes a polarized epithelial cell culture model at air-liquid interface to study the colonization and spatial dynamics of S. aureus and clinical isolates of Corynebacterium from people with CRS to characterize the role temperature has in single- and dual-species dynamics on the nasal epithelium.
    Keywords:  bacterial persistence; chronic rhinosinusitis; commensal; microbial ecology; pathobiont; temperature; upper respiratory tract
    DOI:  https://doi.org/10.1128/msphere.00589-23
  2. bioRxiv. 2023 Dec 17. pii: 2023.12.16.572019. [Epub ahead of print]
    Macrophages control pathological interferon responses during viral respiratory infection.
    Daisy A Hoagland, Patricia Rodríguez-Morales, Alexander O Mann, Shuang Yu, Alicia Lai, Alan Baez Vazquez, Scott D Pope, Jaechul Lim, Shun Li, Xian Zhang, Ming O Li, Ruslan Medzhitov, Ruth A Franklin.
      Antiviral immune mediators, including interferons and their downstream effectors, are critical for host defense yet can become detrimental when uncontrolled. Here, we identify a macrophage-mediated anti-inflammatory mechanism that limits type I interferon (IFN-I) responses. Specifically, we found that cellular stress and pathogen recognition induce Oncostatin M (OSM) production by macrophages. OSM-deficient mice succumbed to challenge with influenza or a viral mimic due to heightened IFN-I activation. Macrophage-derived OSM restricted excessive IFN-I production by lung epithelial cells following viral stimulation. Furthermore, reconstitution of OSM in the respiratory tract was sufficient to protect mice lacking macrophage-derived OSM against morbidity, indicating the importance of local OSM production. This work reveals a host strategy to dampen inflammation in the lung through the negative regulation of IFN-I by macrophages.
    One-Sentence Summary: Type I interferons induced by viral stimuli are negatively regulated by macrophage-derived Oncostatin M.
    DOI:  https://doi.org/10.1101/2023.12.16.572019
  3. Infect Immun. 2024 Jan 05. e0047423
    Metabolic diversity of human macrophages: potential influence on Staphylococcus aureus intracellular survival.
    Blake P Bertrand, Dhananjay Shinde, Vinai C Thomas, Marvin Whiteley, Carolyn B Ibberson, Tammy Kielian.
       IMPORTANCE: One mechanism that Staphylococcus aureus biofilm elicits in the host to facilitate infection persistence is the production of the anti-inflammatory cytokine interleukin-10 (IL-10). Here, we show that exposure of human monocyte-derived macrophages (HMDMs) to IL-10 promotes S. aureus biofilm formation and programs intracellular bacteria to favor catabolic pathways. Examination of intracellular metabolites in HMDMs revealed heterogeneity between donors that may explain the observed variability in essential genes for S. aureus survival based on nutrient availability for bacteria within the intracellular compartment. Collectively, these studies provide novel insights into how IL-10 polarization affects S. aureus intracellular survival in HMDMs and the importance of considering macrophage heterogeneity between human donors as a variable when examining effector mechanisms.
    Keywords:  S. aureus; intracellular survival; macrophage; metabolism; transposon sequencing
    DOI:  https://doi.org/10.1128/iai.00474-23
  4. PLoS Biol. 2024 Jan;22(1): e3002451
    The Staphylococcus aureus CamS lipoprotein is a repressor of toxin production that shapes host-pathogen interaction.
    Katrin Schilcher, Morgan M Severn, Christian Jenul, Young-Saeng C Avina, Rebecca A Keogh, Alexander R Horswill.
      Lipoproteins of the opportunistic pathogen Staphylococcus aureus play a crucial role in various cellular processes and host interactions. Consisting of a protein and a lipid moiety, they support nutrient acquisition and anchor the protein to the bacterial membrane. Recently, we identified several processed and secreted small linear peptides that derive from the secretion signal sequence of S. aureus lipoproteins. Here, we show, for the first time, that the protein moiety of the S. aureus lipoprotein CamS has a biological role that is distinct from its associated linear peptide staph-cAM373. The small peptide was shown to be involved in interspecies horizontal gene transfer, the primary mechanism for the dissemination of antibiotic resistance among bacteria. We provide evidence that the CamS protein moiety is a potent repressor of cytotoxins, such as α-toxin and leukocidins. The CamS-mediated suppression of toxin transcription was reflected by altered disease severity in in vivo infection models involving skin and soft tissue, as well as bloodstream infections. Collectively, we have uncovered the role of the protein moiety of the staphylococcal lipoprotein CamS as a previously uncharacterized repressor of S. aureus toxin production, which consequently regulates virulence and disease outcomes. Notably, the camS gene is conserved in S. aureus, and we also demonstrated the muted transcriptional response of cytotoxins in 2 different S. aureus lineages. Our findings provide the first evidence of distinct biological functions of the protein moiety and its associated linear peptide for a specific lipoprotein. Therefore, lipoproteins in S. aureus consist of 3 functional components: a lipid moiety, a protein moiety, and a small linear peptide, with putative different biological roles that might not only determine the outcome of host-pathogen interactions but also drive the acquisition of antibiotic resistance determinants.
    DOI:  https://doi.org/10.1371/journal.pbio.3002451
  5. Trends Microbiol. 2024 Jan 04. pii: S0966-842X(23)00340-2. [Epub ahead of print]
    Interplay between Staphylococcus aureus and the vaginal microbiota.
    Carla S Maduta, Stephen W Tuffs, John K McCormick, Karine Dufresne.
      Staphylococcus aureus is a proficient colonizer and opportunistic pathogen which can lead to vaginal dysbiosis, aerobic vaginitis, or life-threatening menstrual toxic shock syndrome. Here we explore the complex but underappreciated interactions that S. aureus may impose on the vaginal environment leading to additional disease outcomes.
    Keywords:  Staphylococcus aureus; aerobic vaginitis; mTSS; menstrual cycle; microbiota; vaginal tract
    DOI:  https://doi.org/10.1016/j.tim.2023.12.005
  6. Proc Natl Acad Sci U S A. 2024 Jan 09. 121(2): e2312334121
    A bacterial pigment provides cross-species protection from H2O2- and neutrophil-mediated killing.
    Yiwei Liu, Eleanor A McQuillen, Pranav S J B Rana, Erin S Gloag, Matthew R Parsek, Daniel J Wozniak.
      Bacterial infections are often polymicrobial. Pseudomonas aeruginosa and Staphylococcus aureus cause chronic co-infections, which are more problematic than mono-species infections. Understanding the mechanisms of their interactions is crucial for treating co-infections. Staphyloxanthin (STX), a yellow pigment synthesized by the S. aureus crt operon, promotes S. aureus resistance to oxidative stress and neutrophil-mediated killing. We found that STX production by S. aureus, either as surface-grown macrocolonies or planktonic cultures, was elevated when exposed to the P. aeruginosa exoproduct, 2-heptyl-4-hydroxyquinoline N-oxide (HQNO). This was observed with both mucoid and non-mucoid P. aeruginosa strains. The induction phenotype was found in a majority of P. aeruginosa and S. aureus clinical isolates examined. When subjected to hydrogen peroxide or human neutrophils, P. aeruginosa survival was significantly higher when mixed with wild-type (WT) S. aureus, compared to P. aeruginosa alone or with an S. aureus crt mutant deficient in STX production. In a murine wound model, co-infection with WT S. aureus, but not the STX-deficient mutant, enhanced P. aeruginosa burden and disease compared to mono-infection. In conclusion, we identified a role for P. aeruginosa HQNO mediating polymicrobial interactions with S. aureus by inducing STX production, which consequently promotes resistance to the innate immune effectors H2O2 and neutrophils. These results further our understanding of how different bacterial species cooperatively cause co-infections.
    Keywords:  Pseudomonas aeruginosa; Staphylococcus aureus; Staphyloxanthin; innate immunity; polymicrobial
    DOI:  https://doi.org/10.1073/pnas.2312334121
  7. PLoS Pathog. 2023 Dec;19(12): e1011892
    Pathogen-driven nucleotide overload triggers mitochondria-centered cell death in phagocytes.
    Nicoletta Schwermann, Rita Haller, Sebastian Koch, Guntram A Grassl, Volker Winstel.
      Staphylococcus aureus is a dangerous pathogen that evolved refined immuno-evasive strategies to antagonize host immune responses. This involves the biogenesis of death-effector deoxyribonucleosides, which kill infectious foci-penetrating macrophages. However, the exact mechanisms whereby staphylococcal death-effector deoxyribonucleosides and coupled imbalances of intracellular deoxyribonucleotide species provoke immune cell death remain elusive. Here, we report that S. aureus systematically promotes an overload of deoxyribonucleotides to trigger mitochondrial rupture in macrophages, a fatal event that induces assembly of the caspase-9-processing apoptosome and subsequent activation of the intrinsic pathway of apoptosis. Remarkably, genetic disruption of this cascade not only helps macrophages coping with death-effector deoxyribonucleoside-mediated cytotoxicity but also enhances their infiltration into abscesses thereby ameliorating pathogen control and infectious disease outcomes in laboratory animals. Combined with the discovery of protective alleles in human CASP9, these data highlight the role of mitochondria-centered apoptosis during S. aureus infection and suggest that gene polymorphisms may shape human susceptibility toward a predominant pathogen.
    DOI:  https://doi.org/10.1371/journal.ppat.1011892
  8. Expert Rev Anti Infect Ther. 2024 Jan 05.
    Understanding staphylococcus aureus internalization and induction of antimicrobial tolerance.
    Frédéric Goormaghtigh, Françoise Van Bambeke.
       INTRODUCTION: Staphylococcus aureus, a human commensal, is also one of the most common and serious pathogens for humans. In recent years, its capacity to survive and replicate in phagocytic and non-phagocytic cells has been largely demonstrated. In these intracellular niches, bacteria are shielded from the immune response and antibiotics, turning host cells into long-term infectious reservoirs. Moreover, neutrophils carry intracellular bacteria in the bloodstream, leading to systemic spreading of the disease. Despite the serious threat posed by intracellular S. aureus to human health, the molecular mechanisms behind its intracellular survival and subsequent antibiotic treatment failure remain elusive.
    AREA COVERED: We give an overview of the killing mechanisms of phagocytes and of the impressive arsenal of virulence factors, toxins and stress responses deployed by S. aureus as a response. We then discuss the different barriers to antibiotic activity in this intracellular niche and finally describe innovative strategies to target intracellular persisting reservoirs.
    EXPERT OPINION: Intracellular niches represent a challenge in terms of diagnostic and treatment. Further research using ad-hoc in-vivo models and single cell approaches are needed to better understand the molecular mechanisms underlying intracellular survival and tolerance to antibiotics in order to identify strategies to eliminate these persistent bacteria.
    Keywords:  Antibiotic tolerance; Bacterial persistence; Chronic infections; Host-pathogen interactions; Intracellular pathogen; Intracellular survival; Persistent infections; Small colony variants; Staphylococcus aureus; reactive oxygen species
    DOI:  https://doi.org/10.1080/14787210.2024.2303018
  9. J Infect Dis. 2023 Dec 30. pii: jiad608. [Epub ahead of print]
    Ectopic expression of C-type lectin Mincle renders mice susceptible to staphylococcal pneumonia.
    Femke D Hollwedel, Regina Maus, Jennifer Stolper, Satoru Iwai, Hayato Kasai, Silva Holtfreter, Andreas Pich, Lavinia Neubert, Tobias Welte, Sho Yamasaki, Ulrich A Maus.
      Staphylococcus aureus is a prevalent pathogen in pneumonia and harbors glycolipids which may serve as molecular patterns in Mincle (Macrophage inducible C-type lectin) dependent pathogen recognition. We examined the role of Mincle in lung defense against S. aureus in WT, Mincle KO and Mincle transgenic (tg) mice. Two glycolipids, glucosyl-diacylglycerol (Glc-DAG) and diglucosyl-diacylglycerol (Glc2-DAG) were purified, of which only Glc-DAG triggered Mincle reporter cell activation and professional phagocyte responses. Proteomic profiling revealed that Glc2-DAG blocked Glc-DAG-induced cytokine responses, thereby acting as inhibitor of Glc-DAG/Mincle-signaling. WT mice responded to S. aureus with a similar lung pathology as Mincle KO mice, most likely due to Glc2-DAG-dependent inhibition of Glc-DAG/Mincle-signaling. In contrast, ectopic Mincle expression caused severe lung pathology in S. aureus-infected mice characterized by bacterial outgrowth and fatal pneumonia. Collectively, Glc2-DAG inhibits Glc-DAG/Mincle-dependent responses in WT mice, whereas sustained Mincle expression overrides Glc2-DAG-mediated inhibitory effects, conferring increased host susceptibility to S. aureus.
    Keywords:   S. aureus ; Glc-DAG; Mincle; glycolipid; lung; pattern recognition
    DOI:  https://doi.org/10.1093/infdis/jiad608
  10. ACS Infect Dis. 2024 Jan 03.
    Symbiotic Synergy from Sponges to Humans: Microflora-Host Harmony Is Crucial for Ensuring Survival and Shielding against Invading Pathogens.
    Dipasree Hajra, Nikhita Kirthivasan, Dipshikha Chakravortty.
      Gut microbiota plays several roles in the host organism's metabolism and physiology. This phenomenon holds across different species from different kingdoms and classes. Different species across various classes engage in continuous crosstalk via various mechanisms with their gut microbiota, ensuring homeostasis of the host. In this Review, the diversity of the microflora, the development of the microflora in the host, its regulations by the host, and its functional implications on the host, especially in the context of dysbiosis, are discussed across different organisms from sponges to humans. Overall, our review aims to address the indispensable nature of the microbiome in the host's survival, fitness, and protection against invading pathogens.
    Keywords:  Gut microbiota; composition; development; dysbiosis; host homeostasis; immunity; regulation
    DOI:  https://doi.org/10.1021/acsinfecdis.3c00554
  11. Biol Open. 2023 Dec 21. pii: bio.060189. [Epub ahead of print]
    BBQ methods: Streamlined workflows for Bacterial Burden Quantification in infected cells by confocal microscopy.
    Jacques Augenstreich, Michael Shuster, Yongqiang Fan, Zhihui Lyu, Jiqiang Ling, Volker Briken.
      Accurate quantification of bacterial burden within macrophages, termed Bacterial Burden Quantification (BBQ), is crucial for understanding host-pathogen interactions. Various methods have been employed, each with strengths and weaknesses. This article addresses limitations in existing techniques and introduces two novel automated methods for BBQ within macrophages based on confocal microscopy data analysis. The first method refines total fluorescence quantification by incorporating filtering steps to exclude uninfected cells, while the second method calculates total bacterial volume per cell to mitigate potential biases in fluorescence-based readouts. These workflows utilize PyImageJ and Cellpose software, providing reliable, unbiased, and rapid quantification of bacterial load. The proposed workflows were validated using Salmonella enterica serovar Typhimurium and Mycobacterium tuberculosis models, demonstrating their effectiveness in accurately assessing bacterial burden. These automated workflows offer valuable tools for studying bacterial interactions within host cells and provide insights for various research applications.
    Keywords:  Bio-image analysis; Confocal microscopy; Host-pathogen interaction
    DOI:  https://doi.org/10.1242/bio.060189
  12. Nat Immunol. 2024 Jan;25(1): 3
    Controlling TRM differentiation.
    Nicholas J Bernard.
      
    DOI:  https://doi.org/10.1038/s41590-023-01728-2
  13. Curr Res Food Sci. 2024 ;8 100666
    Rice-derived arabinoxylan fibers are particle size-dependent inducers of trained immunity in a human macrophage-intestinal epithelial cell co-culture model.
    Bart G J Moerings, Suzanne Abbring, Monic M M Tomassen, Henk A Schols, Renger F Witkamp, Klaske van Norren, Coen Govers, Jeroen van Bergenhenegouwen, Jurriaan J Mes.
      Arabinoxylans have been identified for a wide range of purported health-promoting applications, primarily attributed to its immunomodulatory effects. Previously, we have reported the ability of arabinoxylans to induce non-specific memory in innate immune cells, commonly referred to as "trained innate immunity". In the present study, we investigated the effect of particle size on innate immune training and resilience in primary human macrophages as well as in a more physiologically relevant macrophage-intestinal epithelial cell co-culture model. We demonstrated that smaller (>45 & < 90 μm) compared to larger (>90 μm) particle size fractions of rice bran-derived arabinoxylan preparations have a higher enhancing effect on training and resilience in both models. Smaller particle size fractions elevated TNF-α production in primary macrophages and enhanced Dectin-1 receptor activation in reporter cell lines compared to larger particles. Responses were arabinoxylan source specific as only the rice-derived arabinoxylans showed these immune-supportive effects. This particle size-dependent induction of trained immunity was confirmed in the established co-culture model. These findings demonstrate the influence of particle size on the immunomodulatory potential of arabinoxylans, provide further insight into the structure-activity relationship, and offer new opportunities to optimize the immune-enhancing effects of these dietary fibers.
    Keywords:  Arabinoxylan; Co-culture model; Dectin-1; Particle size; Trained immunity
    DOI:  https://doi.org/10.1016/j.crfs.2023.100666
  14. EMBO Rep. 2023 Dec 15.
    Inflammasomes as regulators of mechano-immunity.
    Jelena S Bezbradica, Clare E Bryant.
      Mechano-immunity, the intersection between cellular or tissue mechanics and immune cell function, is emerging as an important factor in many inflammatory diseases. Mechano-sensing defines how cells detect mechanical changes in their environment. Mechano-response defines how cells adapt to such changes, e.g. form synapses, signal or migrate. Inflammasomes are intracellular immune sensors that detect changes in tissue and cell homoeostasis during infection or injury. We and others recently found that mechano-sensing of tissue topology (swollen tissue), topography (presence and distribution of foreign solid implant) or biomechanics (stiffness), alters inflammasome activity. Once activated, inflammasomes induce the secretion of inflammatory cytokines, but also change cellular mechanical properties, which influence how cells move, change their shape, and interact with other cells. When overactive, inflammasomes lead to chronic inflammation. This clearly places inflammasomes as important players in mechano-immunity. Here, we discuss a model whereby inflammasomes integrate pathogen- and tissue-injury signals, with changes in tissue mechanics, to shape the downstream inflammatory responses and allow cell and tissue mechano-adaptation. We will review the emerging evidence that supports this model.
    Keywords:  Foreign Body Reaction; Inflammasomes; Macrophages; Mechano-Responses; Mechano-Sensing
    DOI:  https://doi.org/10.1038/s44319-023-00008-2
  15. Inflamm Res. 2023 Dec 30.
    Granulocyte macrophage colony stimulating factor exerts dominant effects over macrophage colony stimulating factor during macrophage differentiation in vitro to induce an inflammatory phenotype.
    Maria Petrina, Torki Alothaimeen, Nasry Zane Bouzeineddine, Evan Trus, Andra Banete, Katrina Gee, Sameh Basta.
       BACKGROUND: Macrophages (Mφ) can exist along a spectrum of phenotypes that include pro-inflammatory (M1) or anti-inflammatory (M2) immune cells. Mφ colony stimulating factor (M-CSF) and granulocyte Mφ colony stimulating factor (GM-CSF) are cytokines important in hematopoiesis, polarization and activation of Mφ.
    METHODS AND RESULTS: To gain a greater understanding of the relationship between GM-CSF and M-CSF, we investigated an in vitro model of differentiation to determine if GM-CSF and M-CSF can antagonize each other, in terms of Mφ phenotype and functions. We determined that Mφ cultured in mixed M-CSF: GM-CSF ratios exhibit M1-like GM-CSF-treated macrophage phenotype when the ratios of the two cytokines are 1:1 in culture. Moreover, GM-CSF is dominant over M-CSF in influencing Mφ production of proinflammatory cytokines such as IL-6, TNFα, and IL-12p40, and the anti-inflammatory cytokine IL-10.
    CONCLUSIONS: Our data established that GM-CSF is more dominant over M-CSF, triggering the Mφ to become pro-inflammatory cells. These findings provide insight into how GM-CSF can influence Mφ activation with implications in inflammatory diseases where the Mφ status can play a significant role in supporting the inflammatory conditions.
    Keywords:  Cytokines; GM-CSF; Inflammation; M-CSF; Nitric oxide; Polarization
    DOI:  https://doi.org/10.1007/s00011-023-01834-9
  16. Mol Cell. 2024 Jan 04. pii: S1097-2765(23)01017-1. [Epub ahead of print]84(1): 170-179
    The biochemical pathways of apoptotic, necroptotic, pyroptotic, and ferroptotic cell death.
    Youwei Ai, Yutong Meng, Bo Yan, Qinyi Zhou, Xiaodong Wang.
      Apoptosis, the first regulated form of cell death discovered in mammalian cells, is executed by caspase-3/7, which are dormant in living cells but become activated by upstream caspase-8 or caspase-9 in responding to extracellular cytokines or intracellular stress signals, respectively. The same cell death-inducing cytokines also cause necroptosis when caspase-8 is inhibited, resulting in the activation of receptor-interacting protein kinase 3 (RIPK3), which phosphorylates pseudokinase MLKL to trigger its oligomerization and membrane-disrupting activity. Caspase-1/4/5/11, known as inflammatory caspases, instead induce pyroptosis by cleaving gasdermin D, whose caspase-cleaved N terminus forms pores on the plasma membrane. The membrane protein NINJ1 amplifies the extent of membrane rupture initiated by gasdermin D. Additionally, disturbance of peroxidation of polyunsaturated fatty acid tails of membrane phospholipids triggers ferroptosis, an iron-dependent and caspases-independent necrotic death. This review will discuss how these regulated cell death pathways act individually and interconnectively in particular cell types to carry out specific physiological and pathological functions.
    Keywords:  apoptosis; ferroptosis; necroptosis; pyroptosis; regulated cell death
    DOI:  https://doi.org/10.1016/j.molcel.2023.11.040
  17. Front Immunol. 2023 ;14 1297329
    TRAM deletion attenuates monocyte exhaustion and alleviates sepsis severity.
    Jing Wang, Yajun Wu, RuiCi Lin, Yao Zhang, Liwu Li.
      Monocyte exhaustion characterized by immune-suppressive features can develop during sepsis and contribute to adverse patient outcomes. However, molecular mechanisms responsible for the establishment of immune-suppressive monocytes with reduced expression of immune-enhancing mediators such as CD86 during sepsis are not well understood. In this study, we identified that the TLR4 intracellular adaptor TRAM plays a key role in mediating the sustained reduction of CD86 expression on exhausted monocytes and generating an immune-suppressive monocyte state. TRAM contributes to the prolonged suppression of CD86 through inducing TAX1BP1 as well as SARM1, collectively inhibiting Akt and NFκB. TRAM deficient mice are protected from cecal slurry-induced experimental sepsis and retain immune-competent monocytes with CD86 expression. Our data reveal a key molecular circuitry responsible for monocyte exhaustion and provide a viable target for rejuvenating functional monocytes and treating sepsis.
    Keywords:  TRAM; intervention; monocyte exhaustion; sepsis; signaling
    DOI:  https://doi.org/10.3389/fimmu.2023.1297329
  18. Virulence. 2024 Dec;15(1): 2298548
    TLR2 regulates Moraxella catarrhalis adhesion to and invasion into alveolar epithelial cells and mediates inflammatory responses.
    Rui Ding, Jinhan Yu, Weixin Ke, Lijun Du, Guixue Cheng, Siqi Hu, Yingchun Xu, Yali Liu.
      Moraxella catarrhalis is a major cause of chronic obstructive pulmonary disease. Toll-like receptor 2 (TLR2) plays an important role in the inflammatory response in host respiratory epithelial cells. M. catarrhalis induces an inflammatory immune response in respiratory epithelial cells that is mostly dependent on TLR2. However, the mechanisms by which this pathogen adheres to and invades the respiratory epithelium are not well understood. The present study aimed to reveal the role of TLR2 in M. catarrhalis adhesion to and invasion into alveolar epithelial cells, using molecular techniques. Pretreatment with the TLR2 inhibitor TLR2-IN-C29 enhanced M. catarrhalis adhesion to A549 cells but reduced its invasion, whereas the agonist Pam3CSK4 reduced both M. catarrhalis adhesion and invasion into A549 cells. Similarly, M. catarrhalis 73-OR strain adhesion and invasion were significantly reduced in TLR2-/- A549 cells. Moreover, the lung clearance rate of the 73-OR strain was significantly higher in TLR2-/- C57/BL6J mice than in wild-type (WT) mice. Histological analysis showed that inflammatory responses were milder in TLR2-/- C57/BL6J mice than in WT mice, which was confirmed by a decrease in cytokine levels in TLR2-/- C57/BL6J mice. Overall, these results indicate that TLR2 promoted M. catarrhalis adhesion and invasion of A549 cells and lung tissues and mediated inflammatory responses in infected lungs. This study provides important insights into the development of potential therapeutic strategies against M. catarrhalis and TLR2-induced inflammatory responses.
    Keywords:  Moraxella catarrhalis; adhesion; alveolar epithelial cells; invasion; toll-like receptor 2
    DOI:  https://doi.org/10.1080/21505594.2023.2298548
  19. Sci Rep. 2024 01 02. 14(1): 62
    Contribution of circulating monocytes in maintaining homeostasis of resident macrophages in postnatal and young adult mouse cochlea.
    Toru Miwa, Gowshika Rengasamy, Zhaoyuan Liu, Florent Ginhoux, Takayuki Okano.
      The percentage of macrophage subpopulations based on their origins in the adult cochlea remains unclear. This study aimed to elucidate the origins of cochlear macrophages during the onset phase and development of auditory function. We used three types of mice: wildtype ICR mice, colony-stimulating factor 1 receptor (Csf1r)-deficient mice, and Ms4a3Cre-Rosa tdTomato (Ms4a3tdT) transgenic mice. Macrophages were labeled with ionized calcium-binding adapter molecule 1 (Iba1), which is specific to more mature macrophages, and CD11b, which is specific to monocyte lineage. We investigated the spatial and temporal distribution patterns of resident macrophages in the cochlea during the postnatal and early adult stages. During the adult stages, the rate of monocytes recruited from the systemic circulation increased; moreover, Iba1+/CD11b- cochlear macrophages gradually decreased with age. Fate mapping of monocytes using Ms4a3tdT transgenic mice revealed an increased proportion of bone marrow-derived cochlear macrophages in the adult stage. Contrastingly, the proportion of yolk sac- and fetal liver-derived tissue-resident macrophages decreased steadily with age. This heterogeneity could be attributed to differences in environmental niches within the tissue or at the sub-tissue levels. Future studies should investigate the role of cochlear macrophages in homeostasis, inflammation, and other diseases, including infection, autoimmune, and metabolic diseases.
    DOI:  https://doi.org/10.1038/s41598-023-50634-y
  20. Microb Pathog. 2023 Dec 30. pii: S0882-4010(23)00551-X. [Epub ahead of print]187 106518
    Endogenous blocking of TLR2 along with TNF-α and IL-1β ameliorates the severity of the S. aureus arthritis via modulating STAT3/SOCS3 expressions in tissue resident macrophages.
    Rituparna Ghosh, Biswadev Bishayi.
      In vivo studies identifying a role of TLR2 in septic arthritis models are lacking. TNF-α played as the most important proinflammatory cytokine, and connected directly to the pathogenesis of bacterial arthritis. IL-1β is another central mediator cytokine in arthritis. It is therefore reasonable to question the role of neutralization of endogenous TNF-α and IL-1β along with TLR2 and associated downstream signaling as crucial mediators in the S. aureus -induced inflammatory arthritis. In reaction to an injury or a pathogen encounter, innate immune cells serve as the initial line of defense. TLR2 mediated entry of S. aureus into macrophage cells initiates an array of inflammatory cascades. After macrophage cell gets activated at the site inflammation, they generate elevated number of cytokines which includes TNF-α, IL-1β. This cytokines signals through STAT1/STAT3 mediated pathways. Thus, aim of this study was to discover how This bone damage could be altered by altering the STAT/STAT3/SOCS3 ratio by blocking TLR2, a particular S. aureus binding site, in conjunction with the use of IL-1 and TNF- antibodies for neutralizing endogenous IL-1β and TNF-α. Additionally, the role of local macrophages in therapy of arthritis was investigated in synovial and Splenic tissue. To comprehend the inflammatory milieu within the system, ROS and other antioxidant enzymes, along with the expression of mTOR in macrophage cells, were also taken into consideration. The detrimental impact of bacterial burden on synovial joints was reduced by simultaneously inhibiting TLR2, TNF-α, and IL-1β. Lowered IFN-γ decreases its sensitivity to STAT1 and lowered IL-6 reduces STAT3 expressions. Whereas, elevated IL-10 enhances SOSC3 expression, which thereby able to limits STAT1/STAT3 inter-conversion. As a result, NF-κB activity was downregulated.
    Keywords:  IL-1β; Macrophage; SOS3; STAT1/STAT3; TLR2; TNF-α
    DOI:  https://doi.org/10.1016/j.micpath.2023.106518
  21. Eur J Immunol. 2023 Dec 31. e2350666
    Neutrophil-plasmacytoid dendritic cell interaction leads to production of type I IFN in response to Mycobacterium tuberculosis.
    Angela M Lee, Paôline Laurent, Carl F Nathan, Franck J Barrat.
      Mycobacterium tuberculosis (Mtb) can cause a latent infection that sometimes progresses to clinically active tuberculosis (TB). Type I interferons (IFN-I) have been implicated in initiating the progression from latency to active TB, in part because IFN-I stimulated genes are the earliest genes to be upregulated in patients as they advance to active TB. Plasmacytoid dendritic cells (pDCs) are major producers of IFN-I during viral infections and in response to autoimmune-induced neutrophil extracellular traps. pDCs have also been suggested to be the major producers of IFN-I during Mtb infection of mice and nonhuman primates, but direct evidence has been lacking. Here, we found that Mtb did not stimulate isolated human pDCs to produce IFN-I, but human neutrophils infected with Mtb-activated co-cultured pDCs to do so. Mtb-infected neutrophils produced neutrophil extracellular traps, whose exposed DNA is a well-known mechanism to activate pDCs to secrete IFN-I. We conclude that pDCs contribute to the IFN-I response during Mtb infection by interacting with infected neutrophils which may then promote Mtb pathogenesis.
    Keywords:  Interferon; Mycobacterium; Neutrophil; Plasmacytoid dendritic cell; Tuberculosis
    DOI:  https://doi.org/10.1002/eji.202350666
  22. Cell. 2024 Jan 04. pii: S0092-8674(23)01346-6. [Epub ahead of print]187(1): 17-43
    Microbial transmission in the social microbiome and host health and disease.
    Amar Sarkar, Cameron J A McInroy, Siobhán Harty, Aura Raulo, Neil G O Ibata, Mireia Valles-Colomer, Katerina V-A Johnson, Ilana L Brito, Joseph Henrich, Elizabeth A Archie, Luis B Barreiro, Francesca S Gazzaniga, B Brett Finlay, Eugene V Koonin, Rachel N Carmody, Andrew H Moeller.
      Although social interactions are known to drive pathogen transmission, the contributions of socially transmissible host-associated mutualists and commensals to host health and disease remain poorly explored. We use the concept of the social microbiome-the microbial metacommunity of a social network of hosts-to analyze the implications of social microbial transmission for host health and disease. We investigate the contributions of socially transmissible microbes to both eco-evolutionary microbiome community processes (colonization resistance, the evolution of virulence, and reactions to ecological disturbance) and microbial transmission-based processes (transmission of microbes with metabolic and immune effects, inter-specific transmission, transmission of antibiotic-resistant microbes, and transmission of viruses). We consider the implications of social microbial transmission for communicable and non-communicable diseases and evaluate the importance of a socially transmissible component underlying canonically non-communicable diseases. The social transmission of mutualists and commensals may play a significant, under-appreciated role in the social determinants of health and may act as a hidden force in social evolution.
    Keywords:  antibiotic resistance; antibiotics; communicable diseases; immunity; microbial transmission; microbiota; non-communicable diseases; social determinants of health; social evolution; social networks; social transmission; social virome
    DOI:  https://doi.org/10.1016/j.cell.2023.12.014
  23. NPJ Regen Med. 2024 Jan 05. 9(1): 2
    Airway epithelial cell identity and plasticity are constrained by Sox2 during lung homeostasis, tissue regeneration, and in human disease.
    Kazushige Shiraishi, Michael P Morley, Dakota L Jones, Gan Zhao, Aaron I Weiner, Maria C Basil, Edward Cantu, Laura T Ferguson, Michele Oyster, Apoorva Babu, Yun Ying, Su Zhou, Shanru Li, Andrew E Vaughan, Edward E Morrisey.
      Maintenance of the cellular boundary between airway and alveolar compartments during homeostasis and after injury is essential to prohibit pathological plasticity which can reduce respiratory function. Lung injury and disease can induce either functional alveolar epithelial regeneration or dysplastic formation of keratinized epithelium which does not efficiently contribute to gas exchange. Here we show that Sox2 preserves airway cell identity and prevents fate changes into either functional alveolar tissue or pathological keratinization following lung injury. Loss of Sox2 in airway epithelium leads to a loss of airway epithelial identity with a commensurate gain in alveolar and basal cell identity, in part due to activation of Wnt signaling in secretory cells and increased Trp63 expression in intrapulmonary basal-like progenitors. In idiopathic pulmonary fibrosis, loss of SOX2 expression correlates with increased WNT signaling activity in dysplastic keratinized epithelium. SOX2-deficient dysplastic epithelial cells are also observed in COVID-19 damaged lungs. Thus, Sox2 provides a molecular barrier that suppresses airway epithelial plasticity to prevent acquisition of alveolar or basal cell identity after injury and help guide proper epithelial fate and regeneration.
    DOI:  https://doi.org/10.1038/s41536-023-00344-w
  24. Nat Immunol. 2024 Jan;25(1): 17-18
    Human and mouse peritoneal macrophages and dendritic cells compared.
      
    DOI:  https://doi.org/10.1038/s41590-023-01709-5
  25. Front Immunol. 2023 ;14 1293828
    Soluble CD83 modulates human-monocyte-derived macrophages toward alternative phenotype, function, and metabolism.
    Katrin Peckert-Maier, Andreas B Wild, Laura Sprißler, Maximilian Fuchs, Philipp Beck, Jean-Philippe Auger, Pia Sinner, Astrid Strack, Petra Mühl-Zürbes, Ntilek Ramadan, Meik Kunz, Gerhard Krönke, Lena Stich, Alexander Steinkasserer, Dmytro Royzman.
      Alterations in macrophage (Mφ) polarization, function, and metabolic signature can foster development of chronic diseases, such as autoimmunity or fibrotic tissue remodeling. Thus, identification of novel therapeutic agents that modulate human Mφ biology is crucial for treatment of such conditions. Herein, we demonstrate that the soluble CD83 (sCD83) protein induces pro-resolving features in human monocyte-derived Mφ biology. We show that sCD83 strikingly increases the expression of inhibitory molecules including ILT-2 (immunoglobulin-like transcript 2), ILT-4, ILT-5, and CD163, whereas activation markers, such as MHC-II and MSR-1, were significantly downregulated. This goes along with a decreased capacity to stimulate alloreactive T cells in mixed lymphocyte reaction (MLR) assays. Bulk RNA sequencing and pathway analyses revealed that sCD83 downregulates pathways associated with pro-inflammatory, classically activated Mφ (CAM) differentiation including HIF-1A, IL-6, and cytokine storm, whereas pathways related to alternative Mφ activation and liver X receptor were significantly induced. By using the LXR pathway antagonist GSK2033, we show that transcription of specific genes (e.g., PPARG, ABCA1, ABCG1, CD36) induced by sCD83 is dependent on LXR activation. In summary, we herein reveal for the first time mechanistic insights into the modulation of human Mφ biology by sCD83, which is a further crucial preclinical study for the establishment of sCD83 as a new therapeutical agent to treat inflammatory conditions.
    Keywords:  LXR pathway; alternative activation; checkpoint molecule; human-monocyte-derived macrophages; soluble CD83
    DOI:  https://doi.org/10.3389/fimmu.2023.1293828
  26. Nat Commun. 2024 Jan 02. 15(1): 92
    The antibiotic resistance reservoir of the lung microbiome expands with age in a population of critically ill patients.
    Victoria T Chu, Alexandra Tsitsiklis, Eran Mick, Lilliam Ambroggio, Katrina L Kalantar, Abigail Glascock, Christina M Osborne, Brandie D Wagner, Michael A Matthay, Joseph L DeRisi, Carolyn S Calfee, Peter M Mourani, Charles R Langelier.
      Antimicrobial resistant lower respiratory tract infections are an increasing public health threat and an important cause of global mortality. The lung microbiome can influence susceptibility of respiratory tract infections and represents an important reservoir for exchange of antimicrobial resistance genes. Studies of the gut microbiome have found an association between age and increasing antimicrobial resistance gene burden, however, corollary studies in the lung microbiome remain absent. We performed an observational study of children and adults with acute respiratory failure admitted to the intensive care unit. From tracheal aspirate RNA sequencing data, we evaluated age-related differences in detectable antimicrobial resistance gene expression in the lung microbiome. Using a multivariable logistic regression model, we find that detection of antimicrobial resistance gene expression was significantly higher in adults compared with children after adjusting for demographic and clinical characteristics. This association remained significant after additionally adjusting for lung bacterial microbiome characteristics, and when modeling age as a continuous variable. The proportion of adults expressing beta-lactam, aminoglycoside, and tetracycline antimicrobial resistance genes was higher compared to children. Together, these findings shape our understanding of the lung resistome in critically ill patients across the lifespan, which may have implications for clinical management and global public health.
    DOI:  https://doi.org/10.1038/s41467-023-44353-1
  27. PLoS Pathog. 2023 Dec 29. 19(12): e1011886
    Borrelia burgdorferi initiates early transcriptional re-programming in macrophages that supports long-term suppression of inflammation.
    Tanja Petnicki-Ocwieja, Julie E McCarthy, Urmila Powale, P Kent Langston, Jennifer D Helble, Linden T Hu.
      Borrelia burgdorferi (Bb), the causative agent of Lyme disease, establishes a long-term infection and leads to disease manifestations that are the result of host immune responses to the pathogen. Inflammatory manifestations resolve spontaneously despite continued bacterial presence, suggesting inflammatory cells become less responsive over time. This is mimicked by in vitro repeated stimulations, resulting in tolerance, a phenotypic subset of innate immune memory. We performed comparative transcriptional analysis of macrophages in acute and memory states and identified sets of Tolerized, Hyper-Induced, Secondary-Induced and Hyper-Suppressed genes resulting from memory induction, revealing previously unexplored networks of genes affected by cellular re-programming. Tolerized gene families included inflammatory mediators and interferon related genes as would be predicted by the attenuation of inflammation over time. To better understand how cells mediate inflammatory hypo-responsiveness, we focused on genes that could mediate maintenance of suppression, such as Hyper-Induced genes which are up-regulated in memory states. These genes were notably enriched in stress pathways regulated by anti-inflammatory modulators. We examined one of the most highly expressed negative regulators of immune pathways during primary stimulation, Aconitate decarboxylase 1 (Acod1), and tested its effects during in vivo infection with Bb. As predicted by our in vitro model, we show its inflammation-suppressive downstream effects are sustained during in vivo long-term infection with Bb, with a specific role in Lyme carditis.
    DOI:  https://doi.org/10.1371/journal.ppat.1011886
  28. Int J Biol Sci. 2024 ;20(2): 733-750
    Pyroptotic Macrophage-Derived Microvesicles Accelerate Formation of Neutrophil Extracellular Traps via GSDMD-N-expressing Mitochondrial Transfer during Sepsis.
    Liangjian Kuang, Yongjian Wu, Jingxian Shu, Jingwen Yang, Haibo Zhou, Xi Huang.
      Macrophage pyroptosis and neutrophil extracellular traps (NETs) play a critical role in sepsis pathophysiology; however, the role of macrophage pyroptosis in the regulation of NETs formation during sepsis is unknown. Here, we showed that macrophages transfer mitochondria to neutrophils through microvesicles following pyroptosis; this process induces mitochondrial dysfunction and triggers the induction of NETs formation through mitochondrial reactive oxygen species (mtROS)/Gasdermin D (GSDMD) axis. These pyroptotic macrophage-derived microvesicles can induce tissues damage, coagulation, and NETs formation in vivo. Disulfiram partly inhibits these effects in a mouse model of sepsis. Pyroptotic macrophage-derived microvesicles induce NETs formation through mitochondrial transfer, both in vitro and in vivo. Microvesicles-mediated NETs formation depends on the presence of GSDMD-N-expressing mitochondria in the microvesicles. This study elucidates a microvesicles-based pathway for NETs formation during sepsis and proposes a microvesicles-based intervention measure for sepsis management.
    Keywords:  Pyroptosis; microvesicles; mitochondrial transfer; neutrophil extracellular traps; sepsis
    DOI:  https://doi.org/10.7150/ijbs.87646
  29. Cell Rep. 2024 Jan 03. pii: S2211-1247(23)01672-8. [Epub ahead of print]43(1): 113661
    VISTA promotes the metabolism and differentiation of myeloid-derived suppressor cells by STAT3 and polyamine-dependent mechanisms.
    Keman Zhang, Amin Zakeri, Tyler Alban, Juan Dong, Hieu M Ta, Ajay H Zalavadia, Andrelie Branicky, Haoxin Zhao, Ivan Juric, Hanna Husich, Prerana B Parthasarathy, Amit Rupani, Judy A Drazba, Abhishek A Chakraborty, Stanley Ching-Cheng Huang, Timothy Chan, Stefanie Avril, Li Lily Wang.
      Myeloid-derived suppressor cells (MDSCs) impair antitumor immune responses. Identifying regulatory circuits during MDSC development may bring new opportunities for therapeutic interventions. We report that the V-domain suppressor of T cell activation (VISTA) functions as a key enabler of MDSC differentiation. VISTA deficiency reduced STAT3 activation and STAT3-dependent production of polyamines, which causally impaired mitochondrial respiration and MDSC expansion. In both mixed bone marrow (BM) chimera mice and myeloid-specific VISTA conditional knockout mice, VISTA deficiency significantly reduced tumor-associated MDSCs but expanded monocyte-derived dendritic cells (DCs) and enhanced T cell-mediated tumor control. Correlated expression of VISTA and arginase-1 (ARG1), a key enzyme supporting polyamine biosynthesis, was observed in multiple human cancer types. In human endometrial cancer, co-expression of VISTA and ARG1 on tumor-associated myeloid cells is associated with poor survival. Taken together, these findings unveil the VISTA/polyamine axis as a central regulator of MDSC differentiation and warrant therapeutically targeting this axis for cancer immunotherapy.
    Keywords:  CP: Cancer; CP: Immunology; GM-CSF; IL-6; MDSC differentiation; STAT3; VISTA; mitochondrial function; myeloid-derived suppressor cells; polyamine; tumor-associated myeloid cells
    DOI:  https://doi.org/10.1016/j.celrep.2023.113661
  30. Phytomedicine. 2023 Dec 17. pii: S0944-7113(23)00652-9. [Epub ahead of print]124 155294
    Polysaccharide of Asparagus cochinchinensis (Lour.) Merr regulates macrophage immune response and epigenetic memory through TLR4-JNK/p38/ERK signaling pathway and histone modification.
    Xiao-Dong Xie, Min Tang, Shou-Li Yi, Ying He, Si-Yu Chen, Yi Zhao, Qi Chen, Mi-Xia Cao, Mei-Ling Yu, Ying-Yi Wei, Wei-Hua Yu, Ting-Jun Hu.
       BACKGROUND: Innate immune memory of macrophages is closely linked to histone modifications. While various studies have demonstrated that the polysaccharide of Asparagus cochinchinensis (Lour.) Merr (ACMP), extracted through alcohol-alkali extraction, enhances macrophages' non-specific immune function; no literature currently addresses whether ACMP's regulatory effect is related to innate immune memory and histone modification.
    PURPOSE: This study aims to investigate if ACMP induces innate immune memory emergence in macrophages via pattern recognition receptor (PRR).
    STUDY DESIGN: After co-incubating different doses of ACMP with RAW264.7 cells and BMDM cells, we observed changes in signaling pathways related to PRR and assessed the presence of innate immune memory phenomenon in the cells.
    METHODS: We observed the morphological characteristics of the ACMP using a scanning electron microscope, infrared spectrum, and HPLC pre-column derivatization method. We used q-PCR, Western blot, RNA-seq, and CUT&Tag-seq methods to examine ACMP's regulation of macrophage immune response and innate immune memory and explored its specific mechanism.
    RESULTS: ACMP, primarily composed of Man, GlcN, Rha, Fuc, GalA, Xyl, Glc, Gal, Ara, and, exhibited a molar ratio of each monosaccharide (1.41: 0.35: 0.49: 0.18: 1.00: 97.12: 0.36: 3.58: 1.14). ACMP regulated immunological function in macrophages through the TLR4-MAPK-JNK/p38/ERK pathway. ACMP induced elevated levels of chromosomal H3K4me1, enhancing TNF-α, IL-1β, and other genes' responsiveness, allowing macrophages to develop innate immune memory to ACMP stimulation.
    CONCLUSION: This study first time demonstrates that ACMP regulates immunological function through the TLR4-MAPK-JNK/ERK/p38 signaling pathway, distinct from prior reports. ACMP induces innate immune memory in macrophages in response to its immune stimulation by promoting increased H3K4me1 on chromosomes. This mechanism may be crucial in how plant polysaccharides regulate macrophages and the body's immune function.
    Keywords:  Asparagus cochinchinensis (lour.) Merr; H3K4me1; Innate immune memory; TLR4
    DOI:  https://doi.org/10.1016/j.phymed.2023.155294
  31. Sci Rep. 2024 01 02. 14(1): 240
    Modelling bronchial epithelial-fibroblast cross-talk in idiopathic pulmonary fibrosis (IPF) using a human-derived in vitro air liquid interface (ALI) culture.
    Sarah L Barron, Owen Wyatt, Andy O'Connor, David Mansfield, E Suzanne Cohen, Tomasz M Witkos, Sam Strickson, Róisín M Owens.
      Idiopathic Pulmonary Fibrosis (IPF) is a devastating form of respiratory disease with a life expectancy of 3-4 years. Inflammation, epithelial injury and myofibroblast proliferation have been implicated in disease initiation and, recently, epithelial-fibroblastic crosstalk has been identified as a central driver. However, the ability to interrogate this crosstalk is limited due to the absence of in vitro models that mimic physiological conditions. To investigate IPF dysregulated cross-talk, primary normal human bronchial epithelial (NHBE) cells and primary normal human lung fibroblasts (NHLF) or diseased human lung fibroblasts (DHLF) from IPF patients, were co-cultured in direct contact at the air-liquid interface (ALI). Intercellular crosstalk was assessed by comparing cellular phenotypes of co-cultures to respective monocultures, through optical, biomolecular and electrical methods. A co-culture-dependent decrease in epithelium thickness, basal cell mRNA (P63, KRT5) and an increase in transepithelial electrical resistance (TEER) was observed. This effect was significantly enhanced in DHLF co-cultures and lead to the induction of epithelial to mesenchymal transition (EMT) and increased mRNA expression of TGFβ-2, ZO-1 and DN12. When stimulated with exogenous TGFβ, NHBE and NHLF monocultures showed a significant upregulation of EMT (COL1A1, FN1, VIM, ASMA) and senescence (P21) markers, respectively. In contrast, direct NHLF/NHBE co-culture indicated a protective role of epithelial-fibroblastic cross-talk against TGFβ-induced EMT, fibroblast-to-myofibroblast transition (FMT) and inflammatory cytokine release (IL-6, IL-8, IL-13, IL-1β, TNF-α). DHLF co-cultures showed no significant phenotypic transition upon stimulation, likely due to the constitutively high expression of TGFβ isoforms prior to any exogenous stimulation. The model developed provides an alternative method to generate IPF-related bronchial epithelial phenotypes in vitro, through the direct co-culture of human lung fibroblasts with NHBEs. These findings highlight the importance of fibroblast TGFβ signaling in EMT but that monocultures give rise to differential responses compared to co-cultures, when exposed to this pro-inflammatory stimulus. This holds implications for any translation conclusions drawn from monoculture studies and is an important step in development of more biomimetic models of IPF. In summary, we believe this in vitro system to study fibroblast-epithelial crosstalk, within the context of IPF, provides a platform which will aid in the identification and validation of novel targets.
    DOI:  https://doi.org/10.1038/s41598-023-50618-y
  32. Nat Microbiol. 2024 Jan;9(1): 95-107
    Candida albicans extracellular vesicles trigger type I IFN signalling via cGAS and STING.
    Hannah Brown Harding, Geneva N Kwaku, Christopher M Reardon, Nida S Khan, Daniel Zamith-Miranda, Robert Zarnowski, Jenny M Tam, Collins K Bohaen, Lauren Richey, Kenta Mosallanejad, Arianne J Crossen, Jennifer L Reedy, Rebecca A Ward, Diego A Vargas-Blanco, Kyle J Basham, Roby P Bhattacharyya, Jeniel E Nett, Michael K Mansour, Frank L van de Veerdonk, Vinod Kumar, Jonathan C Kagan, David R Andes, Joshua D Nosanchuk, Jatin M Vyas.
      The host type I interferon (IFN) pathway is a major signature of inflammation induced by the human fungal pathogen, Candida albicans. However, the molecular mechanism for activating this pathway in the host defence against C. albicans remains unknown. Here we reveal that mice lacking cyclic GMP-AMP synthase (cGAS)-stimulator of IFN genes (STING) pathway components had improved survival following an intravenous challenge by C. albicans. Biofilm-associated C. albicans DNA packaged in extracellular vesicles triggers the cGAS-STING pathway as determined by induction of interferon-stimulated genes, IFNβ production, and phosphorylation of IFN regulatory factor 3 and TANK-binding kinase 1. Extracellular vesicle-induced activation of type I IFNs was independent of the Dectin-1/Card9 pathway and did not require toll-like receptor 9. Single nucleotide polymorphisms in cGAS and STING potently altered inflammatory cytokine production in human monocytes challenged by C. albicans. These studies provide insights into the early innate immune response induced by a clinically significant fungal pathogen.
    DOI:  https://doi.org/10.1038/s41564-023-01546-0
  33. Gut Microbes. 2024 Jan-Dec;16(1):16(1): 2297860
    Multi-omic approaches for host-microbiome data integration.
    Ashwin Chetty, Ran Blekhman.
      The gut microbiome interacts with the host through complex networks that affect physiology and health outcomes. It is becoming clear that these interactions can be measured across many different omics layers, including the genome, transcriptome, epigenome, metabolome, and proteome, among others. Multi-omic studies of the microbiome can provide insight into the mechanisms underlying host-microbe interactions. As more omics layers are considered, increasingly sophisticated statistical methods are required to integrate them. In this review, we provide an overview of approaches currently used to characterize multi-omic interactions between host and microbiome data. While a large number of studies have generated a deeper understanding of host-microbiome interactions, there is still a need for standardization across approaches. Furthermore, microbiome studies would also benefit from the collection and curation of large, publicly available multi-omics datasets.
    Keywords:  Multiomics; analysis; disease; host-microbiome interactions; inference; microbiome; network
    DOI:  https://doi.org/10.1080/19490976.2023.2297860
  34. Nat Commun. 2024 Jan 02. 15(1): 105
    CRISPR-Cas-based identification of a sialylated human milk oligosaccharides utilization cluster in the infant gut commensal Bacteroides dorei.
    Sivan Kijner, Dena Ennis, Shimrit Shmorak, Anat Florentin, Moran Yassour.
      The infant gut microbiome is impacted by early-life feeding, as human milk oligosaccharides (HMOs) found in breastmilk cannot be digested by infants and serve as nutrients for their gut bacteria. While the vast majority of HMO-utilization research has focused on Bifidobacterium species, recent studies have suggested additional HMO-utilizers, mostly Bacteroides, yet their utilization mechanism is poorly characterized. Here, we investigate Bacteroides dorei isolates from breastfed-infants and identify that polysaccharide utilization locus (PUL) 33 enables B. dorei to utilize sialylated HMOs. We perform transcriptional profiling and identity upregulated genes when growing on sialylated HMOs. Using CRISPR-Cas12 to knock-out four PUL33 genes, combined with complementation assays, we identify GH33 as the critical gene in PUL33 for sialylated HMO-utilization. This demonstration of an HMO-utilization system by Bacteroides species isolated from infants opens the way to further characterization of additional such systems, to better understand HMO-utilization in the infant gut.
    DOI:  https://doi.org/10.1038/s41467-023-44437-y
  35. mBio. 2024 Jan 05. e0314423
    Intestinal Bacteroides modulates inflammation, systemic cytokines, and microbial ecology via propionate in a mouse model of cystic fibrosis.
    Courtney E Price, Rebecca A Valls, Alexis R Ramsey, Nicole A Loeven, Jane T Jones, Kaitlyn E Barrack, Joseph D Schwartzman, Darlene B Royce, Robert A Cramer, Juliette C Madan, Benjamin D Ross, James Bliska, George A O'Toole.
       IMPORTANCE: The composition of the gut microbiome in persons with CF is correlated with lung health outcomes, a phenomenon referred to as the gut-lung axis. Here, we demonstrate that the intestinal microbe Bacteroides decreases inflammation through the production of the short-chain fatty acid propionate. Supplementing the levels of Bacteroides in an animal model of CF is associated with reduced systemic inflammation and reduction in the relative abundance of the opportunistically pathogenic group Escherichia/Shigella in the gut. Taken together, these data demonstrate a key role for Bacteroides and microbially produced propionate in modulating inflammation, gut microbial ecology, and the gut-lung axis in cystic fibrosis. These data support the role of Bacteroides as a potential probiotic in CF.
    Keywords:  SCFA; cystic fibrosis; gut; inflammation; probiotic; propionate
    DOI:  https://doi.org/10.1128/mbio.03144-23
  36. Trends Cancer. 2023 Dec 29. pii: S2405-8033(23)00240-6. [Epub ahead of print]
    Targeting myeloid cells for cancer immunotherapy: Siglec-7/9/10/15 and their ligands.
    Kelly Boelaars, Yvette van Kooyk.
      Advances in immunotherapy have revolutionized cancer treatment, yet many patients do not show clinical responses. While most immunotherapies target T cells, myeloid cells are the most abundant cell type in solid tumors and are key orchestrators of the immunosuppressive tumor microenvironment (TME), hampering effective T cell responses. Therefore, unraveling the immune suppressive pathways within myeloid cells could unveil new avenues for cancer immunotherapy. Over the past decade, Siglec receptors and their ligand, sialic acids, have emerged as a novel immune checkpoint on myeloid cells. In this review, we highlight key findings on how sialic acids modify immunity in the TME through engagement of Siglec-7/9/10/15 expressed on myeloid cells, and how the sialic acid-Siglec axis can be targeted for future cancer immunotherapies.
    Keywords:  Siglecs; cancer immunology; glyco-immune checkpoints; myeloid cells; sialylation
    DOI:  https://doi.org/10.1016/j.trecan.2023.11.009
  37. Regen Med. 2024 Jan 05.
    Ink-spiring innovations: 3D bioprinting skin models for disease discovery.
    Rafaela Mayumi Simoes Torigoe, Alexander Revzin, Andrew Badley, Saranya Wyles.
      Tweetable abstract Inflammatory skin diseases account for most chronic skin conditions. 3D bioprinting is an exciting technology that can revolutionize the understanding and approach to treatment of atopic dermatitis and graft-versus-host disease.
    Keywords:  atopic dermatitis; bioprinting; graft-versus-host disease; human skin equivalent; skin and wound care; skin disease
    DOI:  https://doi.org/10.2217/rme-2023-0216
  38. BMC Pulm Med. 2024 Jan 02. 24(1): 2
    Restoring the epigenetic landscape of lung microbiome: potential therapeutic approach for chronic respiratory diseases.
    Azadeh KavianFar, Hamidreza Taherkhani, Ali Ahmadi, Mahdieh Salimi, Hossein Lanjanian, Ali Masoudi-Nejad.
       BACKGROUND: Chronic respiratory diseases, such as chronic obstructive pulmonary disease (COPD) and bronchiectasis, present significant threats to global health. Recent studies have revealed the crucial role of the lung microbiome in the development of these diseases. Pathogens have evolved complex strategies to evade the immune response, with the manipulation of host cellular epigenetic mechanisms playing a pivotal role. There is existing evidence regarding the effects of Pseudomonas on epigenetic modifications and their association with pulmonary diseases. Therefore, this study aims to directly assess the connection between Pseudomonas abundance and chronic respiratory diseases. We hope that our findings will shed light on the molecular mechanisms behind lung pathogen infections.
    METHODS: We analyzed data from 366 participants, including individuals with COPD, acute exacerbations of COPD (AECOPD), bronchiectasis, and healthy individuals. Previous studies have given limited attention to the impact of Pseudomonas on these groups and their comparison with healthy individuals. Two independent datasets from different ethnic backgrounds were used for external validation. Each dataset separately analyzed bacteria at the genus level.
    RESULTS: The study reveals that Pseudomonas, a bacterium, was consistently found in high concentrations in all chronic lung disease datasets but it was present in very low abundance in the healthy datasets. This suggests that Pseudomonas may influence cellular mechanisms through epigenetics, contributing to the development and progression of chronic respiratory diseases.
    CONCLUSIONS: This study emphasizes the importance of understanding the relationship between the lung microbiome, epigenetics, and the onset of chronic pulmonary disease. Enhanced recognition of molecular mechanisms and the impact of the microbiome on cellular functions, along with a better understanding of these concepts, can lead to improved diagnosis and treatment.
    Keywords:  Chronic respiratory diseases; Epigenetic; Lung microbiome; Pseudomonas
    DOI:  https://doi.org/10.1186/s12890-023-02789-7
  39. Burns Trauma. 2024 ;12 tkad047
    Metabolic reprogramming in skin wound healing.
    Zitong Wang, Feng Zhao, Chengcheng Xu, Qiqi Zhang, Haiyue Ren, Xing Huang, Cai He, Jiajie Ma, Zhe Wang.
      Metabolic reprogramming refers to the ability of a cell to alter its metabolism in response to different stimuli and forms of pressure. It helps cells resist external stress and provides them with new functions. Skin wound healing involves the metabolic reprogramming of nutrients, such as glucose, lipids, and amino acids, which play vital roles in the proliferation, differentiation, and migration of multiple cell types. During the glucose metabolic process in wounds, glucose transporters and key enzymes cause elevated metabolite levels. Glucose-mediated oxidative stress drives the proinflammatory response and promotes wound healing. Reprogramming lipid metabolism increases the number of fibroblasts and decreases the number of macrophages. It enhances local neovascularization and improves fibrin stability to promote extracellular matrix remodelling, accelerates wound healing, and reduces scar formation. Reprogramming amino acid metabolism affects wound re-epithelialization, collagen deposition, and angiogenesis. However, comprehensive reviews on the role of metabolic reprogramming in skin wound healing are lacking. Therefore, we have systematically reviewed the metabolic reprogramming of glucose, lipids, and amino acids during skin wound healing. Notably, we identified their targets with potential therapeutic value and elucidated their mechanisms of action.
    Keywords:  Metabolic reprogramming; Molecular mechanism; Skin; Therapeutic potential; Wound healing
    DOI:  https://doi.org/10.1093/burnst/tkad047
  40. Nat Commun. 2024 Jan 02. 15(1): 143
    Human apical-out nasal organoids reveal an essential role of matrix metalloproteinases in airway epithelial differentiation.
    Liyue Li, Linyi Jiao, Danni Feng, Yizhang Yuan, Xiaoqian Yang, Jian Li, Dong Jiang, Hexin Chen, Qingxiang Meng, Ruchong Chen, Bixing Fang, Xuenong Zou, Zhenhua Luo, Xiaoyan Ye, Yue Hong, Chun Liu, Chunwei Li.
      Extracellular matrix (ECM) assembly/disassembly is a critical regulator for airway epithelial development and remodeling. Airway organoid is widely used in respiratory research, yet there is limited study to indicate the roles and mechanisms of ECM organization in epithelial growth and differentiation by using in vitro organoid system. Moreover, most of current Matrigel-based airway organoids are in basal-out orientation where accessing the apical surface is challenging. We present a human apical-out airway organoid using a biochemically defined hybrid hydrogel system. During human nasal epithelial progenitor cells (hNEPCs) differentiation, the gel gradually degrade, leading to the organoid apical surfaces facing outward. The expression and activity of ECM-degrading enzymes, matrix metalloproteinases (MMP7, MMP9, MMP10 and MMP13) increases during organoid differentiation, where inhibition of MMPs significantly suppresses the normal ciliation, resulting in increased goblet cell proportion. Moreover, a decrease of MMPs is found in goblet cell hyperplastic epithelium in inflammatory mucosa. This system reveals essential roles of epithelial-derived MMPs on epithelial cell fate determination, and provides an applicable platform enabling further study for ECM in regulating airway development in health and diseases.
    DOI:  https://doi.org/10.1038/s41467-023-44488-1
  41. Cell Mol Immunol. 2024 Jan 04.
    ROS-induced metabolic reprogramming to one-carbon metabolism and S-adenosylmethionine-mediated epigenetic modification in IL-10-producing B cells for the resolution of pneumonia.
    Sujin Lee, Tae Jin Kim.
      
    DOI:  https://doi.org/10.1038/s41423-023-01117-7
  42. Nat Commun. 2024 Jan 02. 15(1): 90
    Histone lactylation couples cellular metabolism with developmental gene regulatory networks.
    Fjodor Merkuri, Megan Rothstein, Marcos Simoes-Costa.
      Embryonic cells exhibit diverse metabolic states. Recent studies have demonstrated that metabolic reprogramming drives changes in cell identity by affecting gene expression. However, the connection between cellular metabolism and gene expression remains poorly understood. Here we report that glycolysis-regulated histone lactylation couples the metabolic state of embryonic cells with chromatin organization and gene regulatory network (GRN) activation. We found that lactylation marks genomic regions of glycolytic embryonic tissues, like the neural crest (NC) and pre-somitic mesoderm. Histone lactylation occurs in the loci of NC genes as these cells upregulate glycolysis. This process promotes the accessibility of active enhancers and the deployment of the NC GRN. Reducing the deposition of the mark by targeting LDHA/B leads to the downregulation of NC genes and the impairment of cell migration. The deposition of lactyl-CoA on histones at NC enhancers is supported by a mechanism that involves transcription factors SOX9 and YAP/TEAD. These findings define an epigenetic mechanism that integrates cellular metabolism with the GRNs that orchestrate embryonic development.
    DOI:  https://doi.org/10.1038/s41467-023-44121-1
  43. Mol Biol Rep. 2023 Dec 29. 51(1): 42
    Pyroptosis in microbial infectious diseases.
    Cui Xiao, Saihong Cao, Yunfei Li, Yuchen Luo, Jian Liu, Yuyu Chen, Qinqin Bai, Lili Chen.
      Pyroptosis is a gasdermins-mediated programmed cell death that plays an essential role in immune regulation, and its role in autoimmune disease and cancer has been studied extensively. Increasing evidence shows that various microbial infections can lead to pyroptosis, associated with the occurrence and development of microbial infectious diseases. This study reviews the recent advances in pyroptosis in microbial infection, including bacterial, viral, and fungal infections. We also explore potential therapeutic strategies for treating microbial infection-related diseases by targeting pyroptosis.
    Keywords:  Caspases; Gasdermins; Inflammasomes; Microbial infections; Pyroptosis; Therapeutic strategies
    DOI:  https://doi.org/10.1007/s11033-023-09078-w
  44. Nat Commun. 2024 Jan 02. 15(1): 114
    BCG vaccination-induced acquired control of mycobacterial growth differs from growth control preexisting to BCG vaccination.
    Krista E van Meijgaarden, Wenchao Li, Simone J C F M Moorlag, Valerie A C M Koeken, Hans J P M Koenen, Leo A B Joosten, Annapurna Vyakarnam, Asma Ahmed, Srabanti Rakshit, Vasista Adiga, Tom H M Ottenhoff, Yang Li, Mihai G Netea, Simone A Joosten.
      Bacillus Calmette-Guèrin - vaccination induces not only protection in infants and young children against severe forms of tuberculosis, but also against non-tuberculosis related all-cause mortality. To delineate different factors influencing mycobacterial growth control, here we first investigate the effects of BCG-vaccination in healthy Dutch adults. About a quarter of individuals already control BCG-growth prior to vaccination, whereas a quarter of the vaccinees acquires the capacity to control BCG upon vaccination. This leaves half of the population incapable to control BCG-growth. Single cell RNA sequencing identifies multiple processes associated with mycobacterial growth control. These data suggest (i) that already controllers employ different mechanisms to control BCG-growth than acquired controllers, and (ii) that half of the individuals fail to develop measurable growth control irrespective of BCG-vaccination. These results shed important new light on the variable immune responses to mycobacteria in humans and may impact on improved vaccination against tuberculosis and other diseases.
    DOI:  https://doi.org/10.1038/s41467-023-44252-5
  45. Microb Pathog. 2024 Jan 02. pii: S0882-4010(24)00002-0. [Epub ahead of print] 106535
    Systemic neutrophils are triggered by respiratory Bacillus Calmette- Guérin and mediate pulmonary mycobacterial clearance in synergy with the triggering receptor expressed on myeloid cells 1.
    Pei Li, Rui Wang, Wen-Qi Dong, Gao-Yan Wang, An-Ding Zhang, Huan-Chun Chen, Chen Tan.
      Tuberculosis remains a threat to public health. The only approved vaccine, Bacillus Calmette-Guérin (BCG), is administered intradermally and provides limited protection, and its effect on innate immunity via the respiratory route has not been fully elucidated. A mouse model with genetically depleted TREM1 and seven-color flow cytometry staining were used to characterize the comprehensive immune response induced by respiratory BCG, through evaluating organ bacterial loads, lung histopathology, and lung immunohistochemistry. During respiratory BCG infection, the murine lungs displayed effective bacterial clearance. Notably, marked differences in neutrophils were observed between thymus and bone marrow cells, characterized by a significant increase in the expression of the triggering receptor expressed on myeloid cells 1 (TREM1). Subsequently, upon depletion of TREM1, a reduction in pulmonary neutrophils was observed, which further exacerbated bacterial loads and resulted in worsened pathology following respiratory BCG infection. In summary, up-regulated expression of TREM1 in rapidly increasing circulating neutrophil by pulmonary BCG is required for an efficient host response to BCG infection, and suggests the important role of TREM1 in neutrophil-related pulmonary bacteria clearance and pathology.
    Keywords:  Animal infection; Bacillus Calmette-Guérin; Innate immunity; Neutrophils; The triggering receptor expressed on myeloid cells 1 (TREM1)
    DOI:  https://doi.org/10.1016/j.micpath.2024.106535
  46. Immunity. 2023 Dec 22. pii: S1074-7613(23)00500-9. [Epub ahead of print]
    Circulating NK cells establish tissue residency upon acute infection of skin and mediate accelerated effector responses to secondary infection.
    Tommaso Torcellan, Christin Friedrich, Rémi Doucet-Ladevèze, Thomas Ossner, Virgínia Visaconill Solé, Sofie Riedmann, Milas Ugur, Fabian Imdahl, Stephan P Rosshart, Sebastian J Arnold, Mercedes Gomez de Agüero, Nicola Gagliani, Richard A Flavell, Simone Backes, Wolfgang Kastenmüller, Georg Gasteiger.
      Natural killer (NK) cells are present in the circulation and can also be found residing in tissues, and these populations exhibit distinct developmental requirements and are thought to differ in terms of ontogeny. Here, we investigate whether circulating conventional NK (cNK) cells can develop into long-lived tissue-resident NK (trNK) cells following acute infections. We found that viral and bacterial infections of the skin triggered the recruitment of cNK cells and their differentiation into Tcf1hiCD69hi trNK cells that share transcriptional similarity with CD56brightTCF1hi NK cells in human tissues. Skin trNK cells arose from interferon (IFN)-γ-producing effector cells and required restricted expression of the transcriptional regulator Blimp1 to optimize Tcf1-dependent trNK cell formation. Upon secondary infection, trNK cells rapidly gained effector function and mediated an accelerated NK cell response. Thus, cNK cells redistribute and permanently position at sites of previous infection via a mechanism promoting tissue residency that is distinct from Hobit-dependent developmental paths of NK cells and ILC1 seeding tissues during ontogeny.
    Keywords:  Staphylococcus aureus; infection; innate immune memory; innate lymphoid cells; natural killer cells; tissue immunity; tissue-resident lymphocytes; trained immunity; vaccination; vaccinia virus
    DOI:  https://doi.org/10.1016/j.immuni.2023.11.018
  47. Nat Immunol. 2024 Jan;25(1): 13-14
    BCG-mediated viral protection goes biphasic.
    Maria Rescigno.
      
    DOI:  https://doi.org/10.1038/s41590-023-01713-9
  48. Nat Commun. 2024 Jan 02. 15(1): 145
    Innate immune and proinflammatory signals activate the Hippo pathway via a Tak1-STRIPAK-Tao axis.
    Yinan Yang, Huijing Zhou, Xiawei Huang, Chengfang Wu, Kewei Zheng, Jingrong Deng, Yonggang Zheng, Jiahui Wang, Xiaofeng Chi, Xianjue Ma, Huimin Pan, Rui Shen, Duojia Pan, Bo Liu.
      The Hippo pathway controls developmental, homeostatic and regenerative tissue growth, and is frequently dysregulated in various diseases. Although this pathway can be activated by innate immune/inflammatory stimuli, the underlying mechanism is not fully understood. Here, we identify a conserved signaling cascade that leads to Hippo pathway activation by innate immune/inflammatory signals. We show that Tak1, a key kinase in innate immune/inflammatory signaling, activates the Hippo pathway by inducing the lysosomal degradation of Cka, an essential subunit of the STRIPAK PP2A complex that suppresses Hippo signaling. Suppression of STRIPAK results in the activation of Hippo pathway through Tao-Hpo signaling. We further show that Tak1-mediated Hippo signaling is involved in processes ranging from cell death to phagocytosis and innate immune memory. Our findings thus reveal a molecular connection between innate immune/inflammatory signaling and the evolutionally conserved Hippo pathway, thus contributing to our understanding of infectious, inflammatory and malignant diseases.
    DOI:  https://doi.org/10.1038/s41467-023-44542-y
  49. Nat Commun. 2024 Jan 02. 15(1): 175
    Phage Paride can kill dormant, antibiotic-tolerant cells of Pseudomonas aeruginosa by direct lytic replication.
    Enea Maffei, Anne-Kathrin Woischnig, Marco R Burkolter, Yannik Heyer, Dorentina Humolli, Nicole Thürkauf, Thomas Bock, Alexander Schmidt, Pablo Manfredi, Adrian Egli, Nina Khanna, Urs Jenal, Alexander Harms.
      Bacteriophages are ubiquitous viral predators that have primarily been studied using fast-growing laboratory cultures of their bacterial hosts. However, microbial life in nature is mostly in a slow- or non-growing, dormant state. Here, we show that diverse phages can infect deep-dormant bacteria and suspend their replication until the host resuscitates ("hibernation"). However, a newly isolated Pseudomonas aeruginosa phage, named Paride, can directly replicate and induce the lysis of deep-dormant hosts. While non-growing bacteria are notoriously tolerant to antibiotic drugs, the combination with Paride enables the carbapenem meropenem to eradicate deep-dormant cultures in vitro and to reduce a resilient bacterial infection of a tissue cage implant in mice. Our work might inspire new treatments for persistent bacterial infections and, more broadly, highlights two viral strategies to infect dormant bacteria (hibernation and direct replication) that will guide future studies on phage-host interactions.
    DOI:  https://doi.org/10.1038/s41467-023-44157-3
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