bims-bac4me 2024-11-17 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2024–11–17
38 papers selected by
Chun-Chi Chang, Universitäts Spital Zürich

Interleukin-10 inhibits important components of trained immunity in human monocytes.
Mycobacterium tuberculosis Antigen Rv1471 Induces Innate Immune Memory and Adaptive Immunity against Infection.
Interleukin-1β induces trained innate immunity in human hematopoietic progenitor cells in vitro.
Single-cell transcriptomics unveils skin cell specific antifungal immune responses and IL-1Ra- IL-1R immune evasion strategies of emerging fungal pathogen Candida auris.
Human microbiota peptides: important roles in human health.
Hypoxia-reduced YAP phosphorylation enhances expression of Mucin5AC in nasal epithelial cells of chronic rhinosinusitis with nasal polyps.
Early-life Upper Airway Microbiota are Associated with Decreased Lower Respiratory Tract Infections.
Post-translational toxin modification by lactate controls Staphylococcus aureus virulence.
The Heterogeneity, Parallel and Divergence of Alveolar Macrophages in Humans and Mice.
Fibroblast growth factor 10 alleviates LPS-induced acute lung injury by promoting recruited macrophage M2 polarization.
Experimental models of antibiotic exposure and atopic disease.
Perturbations in the skin microbiome of infantile and adult seborrheic dermatitis and new treatment options based on restoring a healthy skin microbiome.
Microbial metabolism disrupts cytokine activity to impact host immune response.
The Impact of NO2 on Epithelial Barrier Integrity of a Primary Cell-Based Air-Liquid Interface Model of the Nasal Respiratory Epithelium.
Chemical genetic approaches to dissect microbiota mechanisms in health and disease.
Sialylated IgG induces the transcription factor REST in alveolar macrophages to protect against lung inflammation and severe influenza disease.
Metabolic pathways fueling the suppressive activity of myeloid-derived suppressor cells.
Trained immunity in the bone marrow: Hub of autoimmunity.
Tetrandrine Alleviates Pulmonary Fibrosis by Modulating Lung Microbiota-Derived Metabolism and Ameliorating Alveolar Epithelial Cell Senescence.
Inhibiting lipid droplet biogenesis enhances host protection against hypervirulent Klebsiella pneumoniae infections.
Esculetin rebalances M1/M2 macrophage polarization to treat sepsis-induced acute lung injury through regulating metabolic reprogramming.
Histone H1 kills MRSA.
Microbiota-induced alteration of kynurenine metabolism in macrophages drives formation of creeping fat in Crohn's disease.
Lactate-mediated lactylation in human health and diseases: Progress and remaining challenges.
Single-Cell RNA Sequencing Reveals Monocyte-Derived Interstitial Macrophages with a Pro-Fibrotic Phenotype in Bleomycin-Induced Pulmonary Fibrosis.
System-level integrative omics analysis to identify the virus-host immunometabolic footprint during infection.
Therapeutic Modulation of the Microbiome in Oncology: Current Trends and Future Directions.
Label-free biosensor assay decodes the dynamics of Toll-like receptor signaling.
PPARα exacerbates Salmonella Typhimurium infection by modulating the immunometabolism and macrophage polarization.
Hops bitter β-acids have antibacterial effects against sinonasal Staphylococcus aureus but also induce sinonasal cilia and mitochondrial dysfunction.
A two-way relationship between histone acetylation and metabolism.
The battle against antimicrobial resistance is more important now than ever: time to educate, advocate and act.
Lifestyle Medicine and the Microbiome: Holistic Prevention and Treatment.
I don't know about you, but I'm feeling IL-22.
A model of proximate protection against pathogenic infection through shared immunity.
Cannabinoid Receptor type 2 agonist GP1a attenuates macrophage activation induced by M. bovis-BCG by inhibiting NF-ĸB signaling.
Ferroptosis as a new tool for tumor suppression through lipid peroxidation.
Epigenetic Mechanisms Induced by Mycobacterium tuberculosis to Promote Its Survival in the Host.

J Leukoc Biol. 2024 Nov 12. pii: qiae240. [Epub ahead of print]

Interleukin-10 inhibits important components of trained immunity in human monocytes.

Rutger J Röring, Flavia Scognamiglio, Lisanne C de Jong, Laszlo A Groh, Vasiliki Matzaraki, Valerie A C M Koeken, Leo A B Joosten, Athanasios Ziogas, Mihai G Netea.

  Trained immunity induces antigen-agnostic enhancement of host defense and protection against secondary infections, but inappropriate activation can contribute to the pathophysiology of inflammatory diseases. Tight regulation of trained immunity is therefore needed to avoid pathology, but little is known about the endogenous processes that modulate it. Here, we investigated the potential of IL-10, a prototypical anti-inflammatory cytokine, to inhibit trained immunity. IL-10 induced tolerance and inhibited trained immunity in primary human monocytes at both functional and transcriptional levels. Inhibition of STAT3, a signaling route that mediates IL-10 signals, induced trained immunity. IL-10 downregulated glycolytic and oxidative metabolism in monocytes, but did not impact the metabolic effects of β-glucan-induced trained immunity. Furthermore, IL-10 prevented increased ROS production in BCG-induced training, but did not influence phagocytosis upregulation. In a cohort study of healthy volunteers vaccinated with BCG, genetic variants that influenced IL-10 or its receptor modulated BCG-induced trained immunity. Furthermore, circulating IL-10 concentrations were negatively correlated with induction of trained immunity after BCG vaccination in a sex-specific manner. In conclusion, IL-10 inhibited several, albeit not all, immunological functions amplified after induction of trained immunity. Follow-up studies should explore the precise molecular mechanism that mediate the effects of IL-10 on trained immunity. Addressing these knowledge gaps is an important step towards optimizing IL-10's potential as a therapeutic target in diseases characterized by inappropriate induction of trained immunity.

Keywords:  IL-10; cytokines; tolerance; trained immunity

DOI:  https://doi.org/10.1093/jleuko/qiae240
J Infect Dis. 2024 Nov 14. pii: jiae572. [Epub ahead of print]

Mycobacterium tuberculosis Antigen Rv1471 Induces Innate Immune Memory and Adaptive Immunity against Infection.

Xuejiao Huang, Juan Wu, Jinchuan Xu, Huiling Wang, Zhenyan Chen, Xiao-Yong Fan, Zhidong Hu.

  Protein subunit vaccines form a key pipeline for developing novel tuberculosis (TB) vaccines. Mycobacterium tuberculosis (Mtb) contains approximately 4000 individual proteins. However, only approximately 100 have been evaluated as antigens in the clinical and preclinical stages of vaccine development. Trained immunity-targeting vaccines induce innate immune memory against heterologous infections and enhance antigen-specific adaptive immune responses. However, no trained immunity-targeting subunit TB vaccine has been reported yet. This study tested Rv1471, a thioredoxin secreted by Mtb, as a candidate TB vaccine antigen due to its capacity to stimulate mouse bone marrow-derived macrophages (BMDMs). Rv1471 induced functional and phenotypic maturation of BMDMs in vitro, reflected by the increased production of inflammatory cytokines and surface expression of co-stimulatory molecules. Transcription analysis of Rv1471-trained BMDMs indicated that innate immune memory was activated through pathways of Akt-mTOR-HIF-1α and aerobic glycolysis. Rv1471 also enhanced innate immune memory responses and protection against intracellular infections of different mycobacteria. In a murine model of TB, immunization with Rv1471 formulated with liposomal DDA/MPLA adjuvant produced robust antigen-specific multi-functional CD4+ and CD8+ T-cell immune responses and had substantial protective efficacy against Mtb challenge. Analysis of recall immunity showed that the Rv1471 subunit vaccine triggered robust T-cell immunity post Mtb infection. These findings support the development of an innate immune memory-targeting subunit TB vaccine to increase TB vaccine efficacy.

Keywords:   Mycobacterium tuberculosis ; Rv1471; innate immune memory; subunit vaccine; trained immunity

DOI:  https://doi.org/10.1093/infdis/jiae572
Stem Cell Reports. 2024 Sep 25. pii: S2213-6711(24)00266-2. [Epub ahead of print]

Interleukin-1β induces trained innate immunity in human hematopoietic progenitor cells in vitro.

Daniela Flores-Gomez, Willemijn Hobo, Diede van Ens, Elise L Kessler, Boris Novakovic, Nicolaas P M Schaap, Wim H C Rijnen, Leo A B Joosten, Mihai G Netea, Niels P Riksen, Siroon Bekkering.

  Innate immune cells can develop a long-lasting hyperresponsive phenotype, termed trained immunity, mediated by epigenetic and metabolic reprogramming. In mice, exposure to Bacille Calmette-Guérin (BCG), β-glucan, or Western diet induces trained immunity by reprogramming hematopoietic progenitor cells (HPCs), through interleukin-1β (IL-1β) signaling in the bone marrow (BM). We investigated whether IL-1β induces trained immunity in primary human BM-derived HPCs in vitro. We exposed human BM-derived HPCs to IL-1β for 4 h. HPCs were expanded and differentiated into monocytes followed by functional and transcriptomic characterization. IL-1β-exposed HPCs showed higher granulocyte-macrophage colony-forming units. The monocyte offspring produced more tumor necrosis factor (TNF) and IL-1β after restimulation with lipopolysaccharide (LPS) and Pam3Cys and is metabolically more active. Transcriptomic analysis showed upregulation of key atherogenic and inflammatory pathways. In conclusion, brief exposure of human BM-derived HPCs to IL-1β in vitro induces a trained immunity phenotype.

Keywords:  IL-1β; bone marrow; hematopoietic progenitor cells; macrophages; monocytes; trained immunity

DOI:  https://doi.org/10.1016/j.stemcr.2024.09.004
PLoS Pathog. 2024 Nov 13. 20(11): e1012699

Single-cell transcriptomics unveils skin cell specific antifungal immune responses and IL-1Ra- IL-1R immune evasion strategies of emerging fungal pathogen Candida auris.

Abishek Balakumar, Diprasom Das, Abhishek Datta, Abtar Mishra, Garrett Bryak, Shrihari M Ganesh, Mihai G Netea, Vinod Kumar, Michail S Lionakis, Devender Arora, Jyothi Thimmapuram, Shankar Thangamani.

Candida auris is an emerging multidrug-resistant fungal pathogen that preferentially colonizes and persists in skin tissue, yet the host immune factors that regulate the skin colonization of C. auris in vivo are unknown. In this study, we employed unbiased single-cell transcriptomics of murine skin infected with C. auris to understand the cell type-specific immune response to C. auris. C. auris skin infection results in the accumulation of immune cells such as neutrophils, inflammatory monocytes, macrophages, dendritic cells, T cells, and NK cells at the site of infection. We identified fibroblasts as a major non-immune cell accumulated in the C. auris infected skin tissue. The comprehensive single-cell profiling revealed the transcriptomic signatures in cytokines, chemokines, host receptors (TLRs, C-type lectin receptors, NOD receptors), antimicrobial peptides, and immune signaling pathways in individual immune and non-immune cells during C. auris skin infection. Our analysis revealed that C. auris infection upregulates the expression of the IL-1RN gene (encoding IL-1R antagonist protein) in different cell types. We found IL-1Ra produced by macrophages during C. auris skin infection decreases the killing activity of neutrophils. Furthermore, C. auris uses a unique cell wall mannan outer layer to evade IL-1R-signaling mediated host defense. Collectively, our single-cell RNA seq profiling identified the transcriptomic signatures in immune and non-immune cells during C. auris skin infection. Our results demonstrate the IL-1Ra and IL-1R-mediated immune evasion mechanisms employed by C. auris to persist in the skin. These results enhance our understanding of host defense and immune evasion mechanisms during C. auris skin infection and identify potential targets for novel antifungal therapeutics.

DOI: https://doi.org/10.1371/journal.ppat.1012699
Nat Prod Rep. 2024 Nov 15.

Human microbiota peptides: important roles in human health.

Abdul Bari Shah, Sang Hee Shim.

Covering: 1974 to 2024Human microbiota consist of a diverse array of microorganisms, such as bacteria, Eukarya, archaea, and viruses, which populate various parts of the human body and live in a cooperatively beneficial relationship with the host. They play a crucial role in supporting the functional balance of the microbiome. The coevolutionary progression has led to the development of specialized metabolites that have the potential to substitute traditional antibiotics in combating global health challenges. Although there has been a lot of research on the human microbiota, there is a considerable lack of understanding regarding the wide range of peptides that these microbial populations produce. Particularly noteworthy are the antibiotics that are uniquely produced by the human microbiome, especially by bacteria, to protect against invasive infections. This review seeks to fill this knowledge gap by providing a thorough understanding of various peptides, along with their in-depth biological importance in terms of human disorders. Advancements in genomics and the understanding of molecular mechanisms that control the interactions between microbiota and hosts have made it easier to find peptides that come from the human microbiome. We hope that this review will serve as a basis for developing new therapeutic approaches and personalized healthcare strategies. Additionally, it emphasizes the significance of these microbiota in the field of natural product discovery and development.

DOI: https://doi.org/10.1039/d4np00042k
Allergy. 2024 Nov 13.

Hypoxia-reduced YAP phosphorylation enhances expression of Mucin5AC in nasal epithelial cells of chronic rhinosinusitis with nasal polyps.

Bing Zhong, Jing Liu, Hsiao Hui Ong, Jintao Du, Feng Liu, Yafeng Liu, Luo Ba, Silu Sun, De Yun Wang.

   BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is an upper respiratory disease characterized by persistent inflammation of the nasal mucosa. However, the mechanism of abnormal Mucin5AC expression by CRSwNP epithelial cells is not fully understood.
OBJECTIVE: We investigated the potential role of yes-associated protein (YAP) underlying the mechanism of excessive epithelial Mucin5AC expression in CRSwNP in a hypoxic model.
METHODS: Tissue biopsies of CRSwNP (n = 60), chronic rhinosinusitis without nasal polyps (CRSsNP) (n = 9) and healthy controls (n = 30) were investigated together with a well-established hypoxic model of primary human nasal epithelial cells (hNECs). The expression levels of hypoxia inducible factor (HIF)-1α and YAP, and the effect of the signaling axis on mucus secretion in hNECs were analyzed.
RESULTS: We observed a significant elevated expression levels of YAP in patients with CRSwNP and CRSsNP compared to controls. In addition, HIF-1α expression of CRSwNP was higher than that of control group. Under hypoxic conditions, HIF-1α was found to regulate the upregulation of YAP in hNECs. Further investigations revealed that HIF-1α facilitated the activation and nuclear localization of active-YAP by reducing the phosphorylation of YAP. This mechanism appeared to be linked to HIF-1α-mediated inhibition of LATS 1 phosphorylation and subsequent YAP degradation. HIF-1α was shown to promote the expression of P63 and the levels of Mucin5AC in hNECs by enhancing YAP activation.
CONCLUSION: Our findings indicated that hypoxia enhances YAP activation by decreasing p-LATS 1 and YAP phosphorylation. This has the potential to impact on the proliferation of basal cells and the differentiation of goblet cells in CRSwNP, ultimately leading to a pathological condition characterized by excessive Mucin5AC expression.

Keywords:  Mucin5AC; chronic rhinosinusitis with nasal polyps; epithelium; hypoxia‐inducible factor‐1α; yes‐associated protein

DOI:  https://doi.org/10.1111/all.16394
J Allergy Clin Immunol. 2024 Nov 13. pii: S0091-6749(24)01189-8. [Epub ahead of print]

Early-life Upper Airway Microbiota are Associated with Decreased Lower Respiratory Tract Infections.

Susan Zelasko, Mary Hannah Swaney, Shelby Sandstrom, Kristine E Lee, Jonah Dixon, Colleen Riley, Lauren Watson, Jared J Godfrey, Naomi Ledrowski, Federico Rey, Nasia Safdar, Christine M Seroogy, James E Gern, Lindsay Kalan, Cameron Currie.

  Microbial interactions mediating colonization resistance play key roles within the human microbiome, shaping susceptibility to infection from birth. To gain insight into microbiome-mediated defenses and respiratory pathogen colonization dynamics, we sequenced and analyzed nasal (n=229) and oral (n=210) microbiomes with associated health/environmental data from our Wisconsin Infant Study Cohort at age 24-months. Participants with early-life lower respiratory tract infection (LRTI) were more likely to be formula-fed, attend daycare, and experience wheezing. Shotgun metagenomic sequencing with detection of viral and bacterial respiratory pathogens revealed nasal microbiome composition to associate with prior LRTI - namely lower alpha diversity, depletion of Prevotella, and enrichment of Moraxella catarrhalis including drug-resistant strains. Prevotella originating from healthy microbiomes had higher biosynthetic gene cluster abundance and exhibited contact-independent inhibition of M. catarrhalis, suggesting interbacterial competition impacts nasal pathogen colonization. This work advances understanding of protective host-microbial interactions occurring in airway microbiomes that alter infection susceptibility in early-life.

Keywords:  Moraxella catarrhalis; Nasal microbiome; Prevotella; asthma; children; oral microbiome; pediatric; pneumonia; respiratory tract infection; wheezing

DOI:  https://doi.org/10.1016/j.jaci.2024.11.008
Nat Commun. 2024 Nov 13. 15(1): 9835

Post-translational toxin modification by lactate controls Staphylococcus aureus virulence.

Yanan Wang, Yanfeng Liu, Guoxiu Xiang, Ying Jian, Ziyu Yang, Tianchi Chen, Xiaowei Ma, Na Zhao, Yingxin Dai, Yan Lv, Hua Wang, Lei He, Bisheng Shi, Qian Liu, Yao Liu, Michael Otto, Min Li.

Diverse post-translational modifications have been shown to play important roles in regulating protein function in eukaryotes. By contrast, the roles of post-translational modifications in bacteria are not so well understood, particularly as they relate to pathogenesis. Here, we demonstrate post-translational protein modification by covalent addition of lactate to lysine residues (lactylation) in the human pathogen Staphylococcus aureus. Lactylation is dependent on lactate concentration and specifically affects alpha-toxin, in which a single lactylated lysine is required for full activity and virulence in infection models. Given that lactate levels typically increase during infection, our results suggest that the pathogen can use protein lactylation as a mechanism to increase toxin-mediated virulence during infection.

DOI: https://doi.org/10.1038/s41467-024-53979-8
Am J Respir Cell Mol Biol. 2024 Nov 13.

The Heterogeneity, Parallel and Divergence of Alveolar Macrophages in Humans and Mice.

Xin Li, Claudia V Jakubzick.



Keywords:  alveolar macrophages; cross-species analysis; heterogeneity; macrophage subsets; scRNA-seq

DOI:  https://doi.org/10.1165/rcmb.2024-0315LE
Inflammation. 2024 Nov 14.

Fibroblast growth factor 10 alleviates LPS-induced acute lung injury by promoting recruited macrophage M2 polarization.

Nana Feng, Yufan Li, Fengxia Guo, Juan Song, Lu Wang, Miao Li, Kaijing Gao, Xiaocen Wang, Dejie Chu, Yuanlin Song, Linlin Wang.

  Acute lung injury (ALI) is characterized by damage to the alveoli and an overabundance of inflammation. Representing a serious inflammatory condition, ALI lacks a precise treatment approach. Despite the recognized benefit impacts of Fibroblast growth factor-10 (FGF10) on ALI, the underlying mechanisms remain unelucidated. To study the role of FGF10 in ALI, C57BL/6 J mice were intratracheally injected with 5 mg/kg Lipopolysaccharide (LPS) with FGF10 (5 mg/kg) or an equal volume of PBS. Inflammatory factors were quantified in bronchoalveolar lavage fluid (BALF) and plasma using ELISA. RNA sequencing of F4/80+Ly6G- macrophages in BALF explored changes in macrophage phenotype and potential mechanisms. Macrophage polarization in BALF was assessed using qRT-PCR, flow cytometry, and Western blot analysis. In vitro, a Transwell co-culture of mouse lung epithelial cells (MLE12) and bone marrow macrophages (BMDM) validated the role of FGF10 in modulating LPS-induced macrophage phenotypic changes. FGF10 ameliorated LPS-induced ALI by diminishing pro-inflammatory factors (IL-1β, TNF-α, and IL-6) and the neutrophil accumulation in BALF. FGF10 also increased the levels of anti-inflammatory factor IL-10. The FGF10 intervention group exhibited enhanced gene expression of macrophage arginine biosynthesis marker (ARG1), and expression of M2-type marker CD206 in monocytes and macrophages. In addition, phosphorylated STAT3 expression increased in isolated monocyte-derived macrophages. Experiments in vitro confirmed that FGF10 could elevate macrophage M2 marker ARG1 expression through the JAK2/STAT3 pathway. FGF10 ameliorates acute LPS-induced lung injury by modulating the polarization of monocyte-derived macrophages recruited in the alveolar space to the M2 type.

Keywords:  ARG1; Acute lung injury; Fibroblast Growth Factor 10; Macrophage

DOI:  https://doi.org/10.1007/s10753-024-02158-4
Front Allergy. 2024 ;5 1455438

Experimental models of antibiotic exposure and atopic disease.

Katherine Donald, B Brett Finlay.

  In addition to numerous clinical studies, research using experimental models have contributed extensive evidence to the link between antibiotic exposure and atopic disease. A number of mouse models of allergy have been developed and used to uncover the specific effects of various microbiota members and perturbations on allergy development. Studies in mice that lack microbes entirely have also demonstrated the various components of the immune system that require microbial exposure. The importance of the early-life period and the mechanisms by which atopy "protective" species identified in human cohorts promote immune development have been elucidated in mice. Finally, non-animal models involving human-derived cells shed light on specific effects of bacteria on human epithelial and immune responses. When considered alongside clinical cohort studies, experimental model systems have provided crucial evidence for the link between the neonatal gut microbiota and allergic disease, immensely supporting the stewardship of antibiotic administration in infants. The following review aims to describe the range of experimental models used for studying factors that affect the relationship between the gut microbiota and allergic disease and summarize key findings that have come from research in animal and in vitro models.

Keywords:  allergies; animal models; antibiotics – immune effect; atopy & microbiome; cell culture models; gut microbiota

DOI:  https://doi.org/10.3389/falgy.2024.1455438
Int J Dermatol. 2024 Nov 11.

Perturbations in the skin microbiome of infantile and adult seborrheic dermatitis and new treatment options based on restoring a healthy skin microbiome.

Akira Vorapreechapanich, Arsa Thammahong, Tanittha Chatsuwan, Steven W Edwards, Chanat Kumtornrut, Karaked Chantawarangul, Susheera Chatproedprai, Siriwan Wananukul, Direkrit Chiewchengchol.

  Seborrheic dermatitis (SD) is a common, multifaceted skin condition, but its undefined etiology hampers the development of effective therapeutic strategies. In this review, we describe the intricate relationship between the skin microbiome and the pathogenesis of SD, focusing on the complex interplay between three major groups of organisms that can either induce inflammation (Malassezia spp., Staphylococcus aureus) or else promote healthy skin (Propionibacterium spp.). We describe how the disequilibrium of these microorganisms in the skin microbiome can develop skin inflammation in SD patients. Understanding these complex interactions of the skin microbiome has led to development of novel probiotics (e.g., Vitreoscilla spp. and Lactobacillus spp.) to restore normal skin physiology in SD. There are also differences in the skin microbiomes of healthy and SD infant and adult patients that impact pathogenesis and prompt different management strategies. A deeper understanding of the skin microbiome and its dynamic interactions will provide valuable insights into the pathogenesis of SD and prompt further development of targeted probiotic treatments to restore the balance of the skin microbiome in SD patients.

Keywords:  Cutibacterium; Malassezia; Staphylococcus; infantile seborrheic dermatitis; probiotics; seborrheic dermatitis; skin microbiome

DOI:  https://doi.org/10.1111/ijd.17568
Proc Natl Acad Sci U S A. 2024 Nov 12. 121(46): e2405719121

Microbial metabolism disrupts cytokine activity to impact host immune response.

Eleanor K P Marshall, Catarina Nunes, Sophie Burbaud, Crystal M Vincent, Natalie O Munroe, Carolina J Simoes da Silva, Ashima Wadhawan, William H Pearson, Jasper Sangen, Lucas Boeck, R Andres Floto, Marc S Dionne.

  Host-pathogen interactions are shaped by the metabolic status of both the host and pathogen. The host must regulate metabolism to fuel the immune response, while the pathogen must extract metabolic resources from the host to enable its own survival. In this study, we focus on the metabolic interactions of Mycobacterium abscessus with Drosophila melanogaster. We identify MAB_1132c as an asparagine transporter required for pathogenicity in M. abscessus. We show that this requirement is specifically associated with damage to the host: flies infected with MAB_1132c knockout bacteria, or with wild-type bacteria grown in asparagine-restricted conditions, are longer lived without showing a significant change in bacterial load. This is associated with a reduction in the host innate immune response, demonstrated by the decreased transcription of antimicrobial peptides as well as a significant reduction in the ability of the infection to disrupt systemic insulin signaling. Much of the increase in host survival during infection with asparagine-limited M. abscessus can be attributed to alterations in unpaired cytokine signaling. This demonstrates that asparagine transport in M. abscessus prior to infection is not required for replicative fitness in vivo but does significantly influence the interaction with the host immune responses.

Keywords:  Drosophila melanogaster; Mycobacterium abscessus; infection; innate immunity; metabolism

DOI:  https://doi.org/10.1073/pnas.2405719121
J Appl Toxicol. 2024 Nov 12.

The Impact of NO2 on Epithelial Barrier Integrity of a Primary Cell-Based Air-Liquid Interface Model of the Nasal Respiratory Epithelium.

Helena Moratin, Josephine Lang, Magdalena-Sophie Picker, Angela Rossi, Christian Wilhelm, Armin von Fournier, Manuel Stöth, Miguel Goncalves, Norbert Kleinsasser, Stephan Hackenberg, Agmal Scherzad, Till Jasper Meyer.

  Nitrogen dioxide (NO2) is a pervasive gaseous air pollutant with well-documented hazardous effects on health, necessitating precise toxicological characterization. While prior research has primarily focused on lower airway structures, the upper airways, serving as the first line of defense against airborne substances, remain understudied. This study aimed to investigate the functional effects of NO2 exposure alone or in combination with hypoxia as a secondary stimulus on nasal epithelium and elucidate its molecular mechanisms because hypoxia is considered a pathophysiological factor in the onset and persistence of chronic rhinosinusitis, a disease of the upper airways. Air-liquid interface cell cultures derived from primary nasal mucosa cells were utilized as an in vitro model, offering a high in vitro-in vivo correlation. Our findings demonstrate that NO2 exposure induces malfunction of the epithelial barrier, as evidenced by decreased transepithelial electrical resistance and increased fluorescein isothiocyanate (FITC)-dextran permeability. mRNA expression analysis revealed a significant increase in IL-6 and IL-8 expressions following NO2. Reduced mRNA expression of the tight junction component occludin was identified as a structural correlate of the damaged epithelial barrier. Notably, hypoxic conditions alone did not alter epithelial barrier integrity. These findings provide information on the harmful effects of NO2 exposure on the human nasal epithelium, including compromised barrier integrity and induction of inflammatory responses. Overall, this study contributes to our understanding of pathophysiological mechanisms underlying also upper airway respiratory diseases associated with air pollution exposure and emphasizes the importance of mitigating NO2 emissions to safeguard respiratory health.

Keywords:  NO2; hypoxia; nasal epithelial barrier; tight junctions; upper airway

DOI:  https://doi.org/10.1002/jat.4717
Science. 2024 Nov 15. 386(6723): eado8548

Chemical genetic approaches to dissect microbiota mechanisms in health and disease.

Xinglin Yang, Howard C Hang.

Advances in genomics, proteomics, and metabolomics have revealed associations between specific microbiota species in health and disease. However, the precise mechanism(s) of action for many microbiota species and molecules have not been fully elucidated, limiting the development of microbiota-based diagnostics and therapeutics. In this Review, we highlight innovative chemical and genetic approaches that are enabling the dissection of microbiota mechanisms and providing causation in health and disease. Although specific microbiota molecules and mechanisms have begun to emerge, new approaches are still needed to go beyond phenotypic associations and translate microbiota discoveries into actionable targets and therapeutic leads to prevent and treat diseases.

DOI: https://doi.org/10.1126/science.ado8548
Immunity. 2024 Nov 07. pii: S1074-7613(24)00482-5. [Epub ahead of print]

Sialylated IgG induces the transcription factor REST in alveolar macrophages to protect against lung inflammation and severe influenza disease.

Saborni Chakraborty, Bowie Yik-Ling Cheng, Desmond L Edwards, Joseph C Gonzalez, David Kung-Chun Chiu, Hong Zheng, Courtney Scallan, Xinrong Guo, Gene S Tan, Greg P Coffey, Pamela B Conley, Patrick S Hume, William J Janssen, Derek E Byers, Philip A Mudd, Jeffery Taubenberger, Matthew Memoli, Mark M Davis, Katrin F Chua, Michael S Diamond, Evangelos Andreakos, Purvesh Khatri, Taia T Wang.

  While most respiratory viral infections resolve with little harm to the host, severe symptoms arise when infection triggers an aberrant inflammatory response that damages lung tissue. Host regulators of virally induced lung inflammation have not been well defined. Here, we show that enrichment for sialylated, but not asialylated immunoglobulin G (IgG), predicted mild influenza disease in humans and was broadly protective against heterologous influenza viruses in a murine challenge model. Mechanistic studies show that sialylated IgG mediated this protection by inducing the transcription factor repressor element-1 silencing transcription factor (REST), which repressed nuclear factor κB (NF-κB)-driven responses, preventing severe lung inflammation and protecting lung function during influenza infection. Therapeutic administration of a recombinant, sialylated Fc molecule in clinical development similarly activated REST and protected against severe influenza disease, demonstrating that this pathway could be clinically harnessed. Overall, induction of REST through sialylated IgG signaling is a strategy to limit inflammatory disease sequelae in infections caused by antigenically distinct influenza strains.

Keywords:  CD209; IgG glycosylation; IgG sialylation; RE1-silencing transcription factor; REST; airway inflammation; alveolar macrophage; antibody signaling; influenza immunity

DOI:  https://doi.org/10.1016/j.immuni.2024.10.002
Front Immunol. 2024 ;15 1461455

Metabolic pathways fueling the suppressive activity of myeloid-derived suppressor cells.

Oliver Goldmann, Eva Medina.

  Myeloid-derived suppressor cells (MDSC) are considered an aberrant population of immature myeloid cells that have attracted considerable attention in recent years due to their potent immunosuppressive activity. These cells are typically absent or present in very low numbers in healthy individuals but become abundant under pathological conditions such as chronic infection, chronic inflammation and cancer. The immunosuppressive activity of MDSC helps to control excessive immune responses that might otherwise lead to tissue damage. This same immunosuppressive activity can be detrimental, particularly in cancer and chronic infection. In the cancer setting, tumors can secrete factors that promote the expansion and recruitment of MDSC, thereby creating a local environment that favors tumor progression by inhibiting the effective immune responses against cancer cells. This has made MDSC a target of interest in cancer therapy, with researchers exploring strategies to inhibit their function or reduce their numbers to improve the efficacy of cancer immunotherapies. In the context of chronic infections, MDSC can lead to persistent infections by suppressing protective immune responses thereby preventing the clearance of pathogens. Therefore, targeting MDSC may provide a novel approach to improve pathogen clearance during chronic infections. Ongoing research on MDSC aims to elucidate the exact processes behind their expansion, recruitment, activation and suppressive mechanisms. In this context, it is becoming increasingly clear that the metabolism of MDSC is closely linked to their immunosuppressive function. For example, MDSC exhibit high rates of glycolysis, which not only provides energy but also generates metabolites that facilitate their immunosuppressive activity. In addition, fatty acid metabolic pathways, such as fatty acid oxidation (FAO), have been implicated in the regulation of MDSC suppressive activity. Furthermore, amino acid metabolism, particularly arginine metabolism mediated by enzymes such as arginase-1, plays a critical role in MDSC-mediated immunosuppression. In this review, we discuss the metabolic signature of MDSC and highlight the therapeutic implications of targeting MDSC metabolism as a novel approach to modulate their immunosuppressive functions.

Keywords:  immunosuppression; infection; metabolic reprogramming; metabolism; myeloid-derived suppressor cells; tumor

DOI:  https://doi.org/10.3389/fimmu.2024.1461455
Cell Stem Cell. 2024 Nov 07. pii: S1934-5909(24)00370-9. [Epub ahead of print]31(11): 1555-1557

Trained immunity in the bone marrow: Hub of autoimmunity.

Mihai G Netea, Leo A B Joosten.

An inappropriate induction of trained immunity in the bone marrow progenitors of immune cells has been described to underlie chronic inflammatory processes. Mills and colleagues' recently published paper in Cell Stem Cell shows that maladaptive trained immunity drives inflammation in autoimmune processes,1 opening a new area of research in autoimmunity.

DOI: https://doi.org/10.1016/j.stem.2024.10.008
Phytother Res. 2024 Nov 07.

Tetrandrine Alleviates Pulmonary Fibrosis by Modulating Lung Microbiota-Derived Metabolism and Ameliorating Alveolar Epithelial Cell Senescence.

Jinzhong Zhuo, Lanhe Chu, Dongyu Liu, Jinming Zhang, Weimou Chen, Haohua Huang, Qi Yu, Xiaojin Meng, Fei Zou, Shaixi Cai, Hangming Dong.

  Tetrandrine (TET) is a minimally toxic drug extracted from the root of Stephania tetrandra. We previously demonstrated that TET could ameliorate pulmonary fibrosis (PF) by modulating autophagy. However, the mechanism behind TET's protective effects on PF remains unclear. In this study, we utilized 16S rRNA gene sequencing, nontargeted metabolomic analysis, and network pharmacology to identify changes in lung microbiota and metabolites that mediate alveolar epithelial cell senescence in bleomycin (BLM)-induced PF in mice. Additionally, we employed Western blot analysis, RT-PCR, and immunofluorescence staining to investigate the in vitro and in vivo effects of TET and its influential bacterial metabolites on PF. The TET intervention alleviated PF by regulating the compositions of lung microbial communities (Streptococcus, Micrococcus, Acinetobacter, Altererythrobacter, Atopostipes, Candidatus Cloacimonas, Clostridium sensu stricto 1, Sphingomonas, Listeria, Blautia, and Pseudomonas) and metabolites (3,4-dihydroxyphenylpropionic acid (3,4-DHPPA), 6-Aminonicotinamide, N-acetyl-5-methoxykynuramine, and resiniferatoxin). Through network pharmacological analysis, it was determined that 3,4-DHPPA played a crucial role in alleviating PF by further inhibiting the senescence of alveolar epithelial cells, a finding further validated in ex vivo experiments. TET mitigated BLM-induced PF in murine models through the modulation of lung microbiota composition and metabolism. Specifically, TET augmented the level of the microbiota-derived metabolite, 3,4-DHPPA, which in turn attenuated alveolar epithelial cell senescence.

Keywords:  cell senescence; metabolome; microbiota; pulmonary fibrosis; tetrandrine

DOI:  https://doi.org/10.1002/ptr.8374
Med Microbiol Immunol. 2024 Nov 14. 213(1): 26

Inhibiting lipid droplet biogenesis enhances host protection against hypervirulent Klebsiella pneumoniae infections.

Hui-Jung Jung, Hyun Ah Kim, Miri Hyun, Ji Yeon Lee, Young Jae Kim, Seong-Il Suh, Eun-Kyeong Jo, Won-Ki Baek, Jin Kyung Kim.

  Hypervirulent Klebsiella pneumoniae (hvKp), an emerging Kp subtype, has become a serious global pathogen. However, the information regarding host interactions and innate immune responses during hvKp infection is limited. Here, we found that hvKp clinical strains increased triacylglycerol synthesis, resulting in lipid droplets (LDs) formation via the mammalian target of rapamycin signaling pathway in RAW264.7 cells. Treatment with rapamycin, an inhibitor of this pathway, affected LDs formation and antimicrobial responses against clinical hvKp infections. In accordance with the role of LDs in modulating inflammation, the pharmacological inhibition of lipogenesis reduced proinflammatory cytokine expression during hvKp infections. In addition, inhibition of LDs formation using pharmacological inhibitors and knockdown of lipogenesis regulators decreased the intracellular survival of hvKp in macrophages. Moreover, inhibiting LDs biogenesis reduced mortality, weight loss, and bacterial loads in hvKp-infected mice. Collectively, these data suggest that LDs biogenesis is crucial in linking host immune responses to clinical hvKp infections.

Keywords:   Klebsiella pneumoniae ; Hypervirulent; Lipid droplets; Macrophages; mTOR

DOI:  https://doi.org/10.1007/s00430-024-00807-x
J Cell Mol Med. 2024 Nov;28(21): e70178

Esculetin rebalances M1/M2 macrophage polarization to treat sepsis-induced acute lung injury through regulating metabolic reprogramming.

Feng Chen, Ning Wang, Jiabao Liao, Mengxue Jin, Fei Qu, Chengxin Wang, Min Lin, Huantian Cui, Weibo Wen, Fengjuan Chen.

  Sepsis-induced acute lung injury (SALI) is characterized by a high incidence and mortality rate, which has caused a serious medical burden. The pharmacological effects of esculetin (ELT), such as antibacterial and anti-inflammatory actions, have been widely confirmed. However, the therapeutic effects and mechanisms of ELT on SALI still need to be further clarified. In this study, we first evaluated the therapeutic potential of ELT on a caecal ligation and puncture (CLP) induced septic rat model, particularly in the treatment of acute lung injury. Afterwards, we explored the effect of ELT on macrophage polarization in vivo and in vitro. Then, we investigated the anti-inflammatory mechanism of ELT based on modulating the metabolic reprogramming of macrophage (the effect on glycolysis in M1, and the effect on fatty acid β-oxidation in M2). In addition, macrophage metabolic inhibitors (glycolysis inhibitor: 2-DG, and fatty acid β-oxidation inhibitor: etomoxir) were used to verify the regulatory effect of ELT on macrophage metabolic reprogramming. Our results proved that ELT intervention could effectively improve the survival rate of SALI rats and ameliorate pathological injury. Next, we found that ELT intervention inhibited M1 polarization and promoted M2 polarization of macrophages in vivo and in vitro, including the downregulation of M1-related markers (CD86, iNOS), the decrease of pro-inflammatory factors (nitric oxide, IL-1β, IL-6, and TNF-α), the upregulation of M2-related markers (CD206, ARG-1), the increase of immunomodulatory factors (IL-4 and IL-10). Subsequently, seahorse analysis showed that ELT intervention inhibited the glycolytic capacity in M1, and promoted the ability of fatty acid β-oxidation in M2. Besides, ELT intervention inhibited the level of glycolysis product (lactic acid), and the expression of glycolysis-related genes (Glut1, Hk2, Pfkfb1, Pkm and Ldha) and promoted the expression of fatty acid β-oxidation related genes (Cpt1a, Cpt2, Acox1). In addition, we found that the inhibitory effect of ELT on M1 polarization was comparable to that of 2-DG, while intervention with etomoxir abolished the promoting effect of ELT on M2 polarization. ELT inhibited the inflammatory response in SALI by correcting macrophage polarization (inhibiting M1 and promoting M2). The mechanism of ELT on macrophage polarization was associated with regulating metabolic reprogramming (inhibiting glycolysis in M1 and promoting fatty acid β-oxidation in M2).

Keywords:  esculetin; fatty acid β‐oxidation; glycolysis; macrophage polarization; metabolic reprogramming; sepsis‐induced acute lung injury

DOI:  https://doi.org/10.1111/jcmm.70178
Cell Rep. 2024 Nov 13. pii: S2211-1247(24)01320-2. [Epub ahead of print]43(11): 114969

Histone H1 kills MRSA.

Gerben Marsman, Xuhui Zheng, Dora Čerina, Keenan A Lacey, Menghan Liu, Daniel Humme, Christian Goosmann, Volker Brinkmann, C J Harbort, Victor J Torres, Arturo Zychlinsky.

  The antimicrobial activity of histones was discovered in the 1940s, but their mechanism of action is not fully known. Here we show that methicillin-resistant Staphylococcus aureus (MRSA) is susceptible to histone H1 (H1), even in the presence of divalent cations and serum. Through selective evolution and a genome-wide screen of a transposon library, as well as physiological and pharmacological experiments, we elucidated how H1 kills MRSA. We show that H1 first binds to wall teichoic acids with high affinity. Once bound, H1 requires a potentiated membrane and a metabolically active bacterium to permeabilize the membrane and enter the cell. Upon entry, H1 accumulates intracellularly, in close association with the bacterial DNA. Of note, anti-H1 antibodies inhibit neutrophil extracellular trap killing of MRSA. Moreover, H1 colocalizes with bacterial DNA in abscess samples of MRSA-infected patients, suggesting a role for H1 in combating MRSA in vivo.

Keywords:  CP: Microbiology; MRSA; Staphylococcus aureus; antimicrobial peptides; antimicrobial resistance; histones; neutrophil extracellular traps; wall teichoic acids

DOI:  https://doi.org/10.1016/j.celrep.2024.114969
Cell Host Microbe. 2024 Nov 13. pii: S1931-3128(24)00394-9. [Epub ahead of print]32(11): 1927-1943.e9

Microbiota-induced alteration of kynurenine metabolism in macrophages drives formation of creeping fat in Crohn's disease.

Jinjie Wu, Wanyi Zeng, Hongyu Xie, Mujia Cao, Jingyi Yang, Yanchun Xie, Zhanhao Luo, Zongjin Zhang, Haoyang Xu, Weidong Huang, Tingyue Zhou, Jinyu Tan, Xiaomin Wu, Zihuan Yang, Shu Zhu, Ren Mao, Zhen He, Ping Lan.

  Hyperplasia of mesenteric tissues in Crohn's disease, called creeping fat (CrF), is associated with surgical recurrence. Although microbiota translocation and colonization have been found in CrF, convincing mouse phenotypes and the underlying mechanisms of CrF formation remain unclear. Utilizing single-nucleus RNA (snRNA) sequencing of CrF and different mouse models, we demonstrate that the commensal Achromobacter pulmonis induces mesenteric adipogenesis through macrophage alteration. Targeted metabolome analysis reveals that L-kynurenine is the most enriched metabolite in CrF. Upregulation of indoleamine 2,3-dioxygenase 1 (IDO1) enhances kynurenine metabolism and drives mesenteric adipogenesis. Leveraging single-cell RNA (scRNA) sequencing of mouse mesenteric tissues and macrophage-specific IDO1 knockout mice, we verify the role of macrophage-sourced L-kynurenine in mesenteric adipogenesis. Mechanistically, L-kynurenine-induced adipogenesis is mediated by the aryl hydrocarbon receptors in adipocytes. Administration of an IDO1 inhibitor or bacteria engineered to degrade L-kynurenine alleviates mesenteric adipogenesis in mice. Collectively, our study demonstrates that microbiota-induced modulation of macrophage metabolism potentiates CrF formation.

Keywords:  Crohn’s disease; creeping fat; kynurenine; macrophages; microbiota

DOI:  https://doi.org/10.1016/j.chom.2024.10.008
J Adv Res. 2024 Nov 09. pii: S2090-1232(24)00529-0. [Epub ahead of print]

Lactate-mediated lactylation in human health and diseases: Progress and remaining challenges.

Xue-Ting Hu, Xiao-Feng Wu, Jin-Yi Xu, Xiang Xu.

   BACKGROUND: Lactate was once considered as metabolic waste for a long time. In 2019, Professor Zhao Yingming's team from the University of Chicago found that lactate could also be used as a substrate to induce histone lactylation and regulate gene expression. Since then, researchers have discovered that lactate-mediated lactylation play important regulatory roles in various physiological and pathological processes.
AIM OF REVIEW: In this review, we aim to discuss the roles and mechanisms of lactylation in human health and diseases, as well as the effects of lactylation on proteins and metabolic modulators targeting lactylation.
KEY SCIENTIFIC CONCEPTS OF REVIEW: In this work, we emphasize the crucial regulatory roles of lactylation in the development of numerous physiological and pathological processes. Of relevance, we discuss the current issues and challenges pertaining to lactylation. This review provides directions and a theoretical basis for future research and clinical translation of lactylation.

Keywords:  Epigenetic; Lactate; Lactylation; Metabolism; Posttranslational modification

DOI:  https://doi.org/10.1016/j.jare.2024.11.010
Int J Mol Sci. 2024 Oct 30. pii: 11669. [Epub ahead of print]25(21):

Single-Cell RNA Sequencing Reveals Monocyte-Derived Interstitial Macrophages with a Pro-Fibrotic Phenotype in Bleomycin-Induced Pulmonary Fibrosis.

Shunli Wang, Jie Li, Caixia Wu, Zhengyao Lei, Tong Wang, Xinxin Huang, Suxia Zhang, Yuting Liu, Xiaohan Bi, Fanshuo Zheng, Xuyou Zhu, Ziling Huang, Xianghua Yi.

  Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease with limited effective therapies. Interstitial macrophages (IMs), especially those derived from monocytes, play an unknown role in IPF pathogenesis. By using single-cell RNA sequencing (scRNA-seq), bleomycin (BLM)-induced pulmonary fibrosis mouse lungs were analyzed to characterize the cellular landscape and heterogeneity of macrophages in this model. scRNA-seq was used to identify distinct interstitial macrophage subpopulations in fibrotic lungs, with monocyte-derived macrophages exhibiting a pro-fibrotic gene expression profile enriched in wound healing, extracellular matrix (ECM) remodeling, and pro-fibrotic cytokine production functions. A pseudotime analysis revealed that IMs originated from monocytes and differentiated along a specific trajectory. A cell-cell communication analysis demonstrated strong interactions between monocyte-derived interstitial macrophages (Mo-IMs) and fibroblasts through the transforming growth factor beta (TGFβ), secreted phosphoprotein 1 (SPP1), and platelet-derived growth factor (PDGF) signaling pathways. Flow cytometry validated the presence and expansion of Mo-IMs subpopulations in BLM-treated mice. This study reveals the cellular heterogeneity and developmental trajectory of lung macrophages in early BLM-induced pulmonary fibrosis, highlighting the crucial role of Mo-IMs with a pro-fibrotic phenotype in IPF pathogenesis via interactions with fibroblasts. Targeting these specific macrophage subpopulations and associated signaling pathways may provide novel therapeutic strategies for IPF.

Keywords:  bleomycin; cell–cell communication; idiopathic pulmonary fibrosis; interstitial macrophages; monocyte-derived macrophages; single-cell RNA sequencing

DOI:  https://doi.org/10.3390/ijms252111669
Adv Immunol. 2024 ;pii: S0065-2776(24)00062-2. [Epub ahead of print]164 73-100

System-level integrative omics analysis to identify the virus-host immunometabolic footprint during infection.

Anoop Ambikan, Sara Svensson Akusjärvi, Maike Sperk, Ujjwal Neogi.

  The emergence and re-emergence of infectious diseases present significant global health threats. Understanding their pathogenesis is crucial for developing diagnostics, therapeutics, and preventive strategies. System-level integrative omics analysis offers a comprehensive approach to deciphering virus-host immunometabolic interactions during infections. Multi-omics approaches, integrating genomics, transcriptomics, proteomics, and metabolomics, provide holistic insights into disease mechanisms, host-pathogen interactions, and immune responses. The interplay between the immune system and metabolic processes, termed immunometabolism, has gained attention, particularly in infectious diseases. Immunometabolic studies reveal how metabolic processes regulate immune cell function, shaping immune responses and influencing infection outcomes. Metabolic reprogramming is crucial for immune cell activation, differentiation, and function. Using systems biological algorithms to understand the immunometabolic alterations can provide a holistic view of immune and metabolic pathway interactions, identifying regulatory nodes and predicting responses to perturbations. Understanding these pathways enhances the knowledge of immune regulation and offers avenues for therapeutic interventions. This review highlights the contributions of multi-omics systems biology studies in understanding infectious disease pathogenesis, focusing on RNA viruses. The integrative approach enables personalized medicine strategies, considering individual metabolic and immune variations. Leveraging these interdisciplinary approaches promises advancements in combating RNA virus infections and improving health outcomes, highlighting the transformative impact of multi-omics technologies in infectious disease research.

Keywords:  Integrative omics; genome scale metabolic models; systems biology; virus

DOI:  https://doi.org/10.1016/bs.ai.2024.08.002
Curr Pharm Biotechnol. 2024 Nov 14.

Therapeutic Modulation of the Microbiome in Oncology: Current Trends and Future Directions.

Istuti Saraswat, Anjana Goel.

  Cancer is a predominant cause of mortality worldwide, necessitating the development of innovative therapeutic techniques. The human microbiome, particularly the gut microbiota, has become a significant element in cancer research owing to its essential role in sustaining health and influencing disease progression. This review examines the microbiome's makeup and essential functions, including immunological modulation and metabolic regulation, which may be evaluated using sophisticated methodologies such as metagenomics and 16S rRNA sequencing. The microbiome influences cancer development by promoting inflammation, modulating the immune system, and producing carcinogenic compounds. Dysbiosis, or microbial imbalance, can undermine the epithelial barrier and facilitate cancer. The microbiome influences chemotherapy and radiation results by modifying drug metabolism, either enhancing or reducing therapeutic efficacy and contributing to side effects and toxicity. Comprehending these intricate relationships emphasises the microbiome's significance in oncology and accentuates the possibility for microbiome-targeted therapeutics. Contemporary therapeutic approaches encompass the utilisation of probiotics and dietary components to regulate the microbiome, enhance treatment efficacy, and minimise unwanted effects. Advancements in research indicate that personalised microbiome-based interventions, have the potential to transform cancer therapy, by providing more effective and customised treatment alternatives. This study aims to provide a comprehensive analysis of the microbiome's influence on the onset and treatment of cancer, while emphasising current trends and future possibilities for therapeutic intervention.

Keywords:  16S rRNA sequencing; Chemotherapy; metagenomics; microbiota; probiotics

DOI:  https://doi.org/10.2174/0113892010353600241109132441
Nat Commun. 2024 Nov 12. 15(1): 9554

Label-free biosensor assay decodes the dynamics of Toll-like receptor signaling.

Janine Holze, Felicitas Lauber, Sofía Soler, Evi Kostenis, Günther Weindl.

The discovery of Toll-like receptors (TLRs) represented a significant breakthrough that paved the way for the study of host-pathogen interactions in innate immunity. However, there are still major gaps in understanding TLR function, especially regarding the early dynamics of downstream TLR pathways. Here, we present a label-free optical biosensor-based assay as a method for detecting TLR activation in a native and label-free environment and defining the dynamics of TLR pathway activation. This technology is sufficiently sensitive to detect TLR signaling and readily discriminates between different TLR signaling pathways. We define pharmacological modulators of cell surface and endosomal TLRs and downstream signaling molecules and uncover TLR signaling signatures, including potential biased receptor signaling. These findings highlight that optical biosensor assays complement traditional assays that use a single endpoint and have the potential to facilitate the future design of selective drugs targeting TLRs and their downstream effector cascades.

DOI: https://doi.org/10.1038/s41467-024-53770-9
Gut Microbes. 2024 Jan-Dec;16(1):16(1): 2419567

PPARα exacerbates Salmonella Typhimurium infection by modulating the immunometabolism and macrophage polarization.

Jessica R Taddeo, Naomi Wilson, Anita Kowal, Joris Beld, Klein-Szanto Andres, Çagla Tükel, Vincent C Tam.

   Salmonella enterica serovar Typhimurium (STm) is a causative pathogen for robust inflammatory gastrointestinal disease and can lead to systemic infection. Eicosanoids, bioactive lipid mediators, play a crucial role in modulating both the induction and resolution of inflammatory responses during an infection. A subset of eicosanoids activates PPARs, nuclear receptor/transcription factors that regulate fatty acid metabolism, lipid body formation, and macrophage function. In this study, we determined that mice lacking PPARα exhibited reduced inflammatory hallmarks of STm infection, including lower inflammatory gene expression, cecal inflammation, and bacterial dissemination, along with a significant increase in cecal eicosanoid metabolism compared to wildtype C57BL/6 mice. In macrophages, STm favored M2b-polarized macrophages for intracellular infection, leading to reduced arachidonic acid and ceramide production.   Inhibition of fatty acid oxidation via Etomoxir in STm-infected macrophages reduced bacterial burdens and promoted cell death. In Etomoxir-treated wildtype mice, STm infection increased ceramide production, decreased inflammatory gene expression in the cecum, and increased the number of STm-containing M1 macrophages in mesenteric lymph nodes. These findings revealed a novel role for the lipid-immune signaling axis in Salmonella infections, providing significant insights into the lipid-mediated regulation of inflammation during bacterial infections in the gut.

Keywords:  Salmonella Typhimurium; eicosanoids; fatty acids; lipidomic analysis; macrophages

DOI:  https://doi.org/10.1080/19490976.2024.2419567
Int Forum Allergy Rhinol. 2024 Nov 13.

Hops bitter β-acids have antibacterial effects against sinonasal Staphylococcus aureus but also induce sinonasal cilia and mitochondrial dysfunction.

Yobouet Ines Kouakou, Joel C Thompson, Li Hui Tan, Zoey A Miller, Ray Z Ma, Nithin D Adappa, James N Palmer, Noam A Cohen, Robert J Lee.

   BACKGROUND: Routine prescription of antibiotics to treat chronic rhinosinusitis (CRS) exacerbations may contribute to the propagation of antibiotic resistance. Hops bitter β-acids lupulone and colupulone possess potent antibacterial activities and, as T2R1, T2R14, and/or T2R40 agonists, may improve the impaired mucociliary clearance described in CRS patients. We investigated these molecules as alternative treatments to antibiotics in CRS management based on their antibacterial and T2Rs agonists properties.
METHODS: Human nasal primary cells (HNECs) and RPMI2650 cells cultures were used as study models. T2Rs expression in cell culture models and human nasal tissue was assessed using immunofluorescence, quantitative PCR, and Western blot. We performed calcium imaging and cilia beat frequency experiments to investigate T2Rs activation in study models in response to lupulone and colupulone stimulations. Finally, we studied hops β-acids cytotoxicity on cells using CellEvent, crystal violet, lactate dehydrogenase assays, immunofluorescence, and transepithelial electrical resistance assays.
RESULTS: We confirmed lupulone and colupulone potent antibacterial effect on CRS-relevant methicillin-resistant Staphylococcus aureus but found minimal impact on P. aeruginosa. We also report T2R1, T2R14 and T2R40 expression in HNECs and RPMI2650 cell cultures. Lupulone and colupulone induced an increase in cytosolic calcium that appeared dependent on T2Rs signaling. This response was accompanied by mitochondrial membrane depolarization, cellular energy stress, decreased cell proliferation, ciliostasis, and HNECs remodeling after a single exposure to lupulone at micromolar concentrations.
CONCLUSION: Our data suggest that hops β-acids may not be beneficial as treatments in CRS patients and instead contribute to the disease by impairing cell health and further deteriorating the MCC.

Keywords:  antibiotic‐resistance; chronic rhinosinusitis; phytochemical; protein kinase C

DOI:  https://doi.org/10.1002/alr.23487
Trends Biochem Sci. 2024 Nov 07. pii: S0968-0004(24)00230-5. [Epub ahead of print]

A two-way relationship between histone acetylation and metabolism.

Evelina Charidemou, Antonis Kirmizis.

  A link between epigenetics and metabolism was initially recognized because the cellular metabolic state is communicated to the genome through the concentration of intermediary metabolites that are cofactors of chromatin-modifying enzymes. Recently, an additional interaction was postulated due to the capacity of the epigenome to store substantial amounts of metabolites that could become available again to cellular metabolite pools. Here, we focus on histone acetylation and review recent evidence illustrating this reciprocal relationship: in one direction, signaling-induced acetyl-coenzyme A (acetyl-CoA) changes influence histone acetylation levels to regulate genomic functions, and in the opposite direction histone acetylation acts as an acetate reservoir to directly affect downstream acetyl-CoA-mediated metabolism. This review highlights the current understanding, experimental challenges, and future perspectives of this bidirectional interplay.

Keywords:  acetate reservoir; aging; epigenetics; genome function; hyperacetylated histones; metabolic disease

DOI:  https://doi.org/10.1016/j.tibs.2024.10.005
Int J Infect Dis. 2024 Nov 09. pii: S1201-9712(24)00377-1. [Epub ahead of print] 107301

The battle against antimicrobial resistance is more important now than ever: time to educate, advocate and act.

Laura M A Oliveira, Natália S Costa, Tomislav Mestrovic, Elita Jauneikaite, Tatiana C A Pinto.



Keywords:  World AMR Awareness Week; antimicrobial resistance; bacterial pathogens; drug-resistant infection; drug-resistant pathogen; multidrug resistant infections

DOI:  https://doi.org/10.1016/j.ijid.2024.107301
Integr Med (Encinitas). 2024 Nov;23(5): 10-14

Lifestyle Medicine and the Microbiome: Holistic Prevention and Treatment.

Shawn Manske.
Cytokine Growth Factor Rev. 2024 Nov 08. pii: S1359-6101(24)00090-X. [Epub ahead of print]

I don't know about you, but I'm feeling IL-22.

Logan S Dean, Alissa N Threatt, Kaylee Jones, Emmanuel O Oyewole, Morgan Pauly, Maëlis Wahl, Melea Barahona, Rose W Reiter, Tara M Nordgren.

  Defense of the human body against damaging and pathogenic insults is a heavily regulated affair. A primary mechanism of defense at sites of insult are soluble mediators whose defensive maneuvers increase barrier integrity and promote pro-reparative and resolution processes. IL-22 is a cytokine in the IL-10 cytokine family that has garnered increased attention in recent years due to its intimate link in promoting resolution of inflammatory insults, while simultaneously being over expressed in certain fibrotic and chronic inflammatory-skewed diseases. The spatial action of IL-22 centers around the barrier sites of the body, including the skin, lungs, and gut mucosa. As such, a detailed understanding of the role of this cytokine, the producers and responders, and the diseases resulting from over- or under-expression have prominent impacts on a variety of disease outcomes. Herein we present a comprehensive review of IL-22; from historical perspectives and initial discovery, as well as more recent data that dramatically expands on the cellular sources and impact of this cytokine. We aim to showcase the duality of IL-22 and highlight addressable gaps in the field of IL-22 crosstalk and impacts at the ever-important mucosal and tissue barrier sites.

Keywords:  Epithelial integrity; IL-22; ILC’s; Inflammation; Macrophages; Pro-resolution

DOI:  https://doi.org/10.1016/j.cytogfr.2024.11.001
mBio. 2024 Nov 11. e0304624

A model of proximate protection against pathogenic infection through shared immunity.

Douglas F Nixon, Margarita Kyza-Karavioti, Sreeradha Mallick, Lillia Daley, Nathaniel Hupert, Nathaniel D Bachtel, Ioannis Eleftherianos.

  Drosophila melanogaster exhibits innate immune priming, a mechanism leading to protection upon repeated challenge with a given pathogen. However, whether immunological priming can be propagated from a challenged host to naive bystanders is unknown. Here, we show that priming half a vial of D. melanogaster adult flies with non-pathogenic Escherichia coli bacteria leads to protection of the whole vial from a lethal dose of the insect pathogen, Photorhabdus luminescens. The protective effect observed in these bystander flies was similar in magnitude to that of the E. coli primed hosts themselves but did not require transfer of E. coli to occur. This work broadens the scope of how immunological priming can occur and suggests that infected hosts can produce signals that influence immunity in their neighbors, leading to a shared immune collective.IMPORTANCEHere, we have introduced the new concept of shared immunity and priming by proximity. These findings are of particular significance because they indicate that the presence of compromised hosts can increase the response to the pathogenic challenge of healthy individuals that cohabitate within close distance. This shared immunity may involve proximate boosting of the host's immune defenses via the sensing of specific chemical, behavioral, or microbial signals. Determining the breadth, mechanistic basis, and translatability of these findings has the potential to transform biomedical research and public health.

Keywords:  Drosophila; bacterial infection; immunity; shared immunity; shared protection

DOI:  https://doi.org/10.1128/mbio.03046-24
J Leukoc Biol. 2024 Nov 14. pii: qiae246. [Epub ahead of print]

Cannabinoid Receptor type 2 agonist GP1a attenuates macrophage activation induced by M. bovis-BCG by inhibiting NF-ĸB signaling.

Jessica Do Prado Valeriano, Magaiver Andrade-Silva, Filipe Pereira-Dutra, Leonardo Noboru Seito, Patricia Torres Bozza, Elaine Cruz Rosas, Maria Fernanda de Souza Costa, Maria das Graças Henriques.

  Tuberculosis (TB) is one of the leading causes of death worldwide and a major public health problem. Immune evasion mechanisms and antibiotic resistance highlight the need to better understand this disease and explore alternative treatment approaches. Mycobacterial infection modulates the macrophage response and metabolism to persist and proliferate inside the cell. Cannabinoid receptor type 2 (CB2) is expressed mainly in leukocytes and modulates the course of inflammatory diseases. Therefore, our study aimed to evaluate the effects of the CB2-selective agonist GP1a on irradiated M. bovis-BCG (iBCG)-induced J774A.1 macrophage activation. We observed increased expression of CB2 in macrophages after iBCG stimulation. The pretreatment with CB2-agonists, GP1a, JWH-133, and GW-833972A (10 µM), reduced iBCG-induced TNF-α and IL-6 release by these cells. Moreover, the CB2-antagonist AM630 (200nM) treatment confirmed the activity of GP1a on CB2 by scale down its effect on cytokine production. GP1a pretreatment (10 µM) also inhibited the iBCG-induced production of inflammatory mediators as prostaglandin (PG)E2 and nitric oxide (NO) by macrophages. Additionally, GP1a pretreatment also reduced the transcription of proinflammatory genes (inos, il1b, cox2) and genes related to lipid metabolism (dgat1, acat1, plin2, atgl, cd36). Indeed, lipid droplet accumulation was reduced by GP1a treatment which was partially blockade by AM630 pretreatment. Finally, GP1a pretreatment reduced the activation of the NF-κB signaling pathway. In conclusion, the activation of CB2 by GP1a modulated the macrophage response to iBCG by reducing inflammatory mediator levels and metabolic reprogramming.

Keywords:  BCG; cannabinoid receptor 2; macrophage; tuberculosis

DOI:  https://doi.org/10.1093/jleuko/qiae246
Commun Biol. 2024 Nov 09. 7(1): 1475

Ferroptosis as a new tool for tumor suppression through lipid peroxidation.

Xin Yang, Yanqing Liu, Zhe Wang, Ying Jin, Wei Gu.

As a newly defined type of programmed cell death, ferroptosis is considered a potent weapon against tumors due to its distinct mechanism from other types of programmed cell death. Ferroptosis is triggered by the uncontrolled accumulation of hydroperoxyl polyunsaturated fatty acid-containing phospholipids, also called lipid peroxidation. The lipid peroxidation, generated through enzymatic and non-enzymatic mechanisms, drives changes in cell morphology and the destruction of membrane integrity. Here, we dissect the mechanisms of ferroptosis induced enzymatically or non-enzymatically, summarize the major metabolism pathways in modulating lipid peroxidation, and provide insights into the relationship between ferroptosis and tumor suppression. In this review, we discuss the recent advances of ferroptosis in tumor microenvironments and the prospect of potential therapeutic application.

DOI: https://doi.org/10.1038/s42003-024-07180-8
Int J Mol Sci. 2024 Nov 02. pii: 11801. [Epub ahead of print]25(21):

Epigenetic Mechanisms Induced by Mycobacterium tuberculosis to Promote Its Survival in the Host.

Shwetha Susan Thomas, Kuniyil Abhinand, Arjun M Menon, Bipin G Nair, Geetha B Kumar, K B Arun, Lekshmi K Edison, Aravind Madhavan.

  Tuberculosis caused by the obligate intracellular pathogen, Mycobacterium tuberculosis, is one among the prime causes of death worldwide. An urgent remedy against tuberculosis is of paramount importance in the current scenario. However, the complex nature of this appalling disease contributes to the limitations of existing medications. The quest for better treatment approaches is driving the research in the field of host epigenomics forward in context with tuberculosis. The interplay between various host epigenetic factors and the pathogen is under investigation. A comprehensive understanding of how Mycobacterium tuberculosis orchestrates such epigenetic factors and favors its survival within the host is in increasing demand. The modifications beneficial to the pathogen are reversible and possess the potential to be better targets for various therapeutic approaches. The mechanisms, including histone modifications, DNA methylation, and miRNA modification, are being explored for their impact on pathogenesis. In this article, we are deciphering the role of mycobacterial epigenetic regulators on various strategies like cytokine expression, macrophage polarization, autophagy, and apoptosis, along with a glimpse of the potential of host-directed therapies.

Keywords:  apoptosis; autophagy; epigenetics; macrophage polarization; miRNA modification; tuberculosis

DOI:  https://doi.org/10.3390/ijms252111801