bims-bac4me 2024-03-03 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2024–03–03
thirty-one papers selected by
Chun-Chi Chang, Universitäts Spital Zürich

The role of Staphylococcus aureus quorum sensing in cutaneous and systemic infections.
Potent induction of trained immunity by Saccharomyces cerevisiae β-glucans.
I. IDC Key-note Lecture: Trained immunity: a memory for innate host defense.
Staphylococcus aureus: The Bug Behind the Itch in Atopic Dermatitis.
Metabolic rewiring of macrophages by epidermal-derived lactate promotes sterile inflammation in the murine skin.
Epithelial regulation of microbiota-immune cell dynamics.
Early life vaccination reprograms the metabolism and function of myeloid cells in neonates.
An exploration of mechanisms underlying Desemzia incerta colonization resistance to methicillin-resistant Staphylococcus aureus on the skin.
Intoxication of antibiotic persisters by host RNS inactivates their efflux machinery during infection.
β-glucans from Agaricus bisporus mushroom products drive Trained Immunity.
Granulocytic myeloid-derived suppressor cell activity during biofilm infection is regulated by a glycolysis-HIF1a axis.
Conservation and similarity of bacterial and eukaryotic innate immunity.
From monocyte-derived macrophages to resident macrophages-how metabolism leads their way in cancer.
Early-life Nasal Microbiota Dynamics Relate to Longitudinal Respiratory Phenotypes in Urban Children.
Surface RNAs move neutrophils.
Intestinal stroma guides monocyte differentiation to macrophages through GM-CSF.
No time to die: Epigenetic regulation of natural killer cell survival.
Experimentally evolved Staphylococcus aureus shows increased survival in the presence of Pseudomonas aeruginosa by acquiring mutations in the amino acid transporter, GltT.
Laminin-derived peptide, IKVAV, modulates macrophage phenotype through integrin mediation.
Reduced interleukin-18 secretion by human monocytic cells in response to infections with hyper-virulent Streptococcus pyogenes.
Unveiling the hidden language of bacteria: anti-quorum sensing strategies for gram-negative bacteria infection control.
Advanced probiotics: bioengineering and their therapeutic application.
Estimates of differential toxin expression governing heterogeneous intracellular lifespans of Streptococcus pneumoniae.
High-Throughput Host-Microbe Single-Cell RNA Sequencing Reveals Ferroptosis-Associated Heterogeneity during Acinetobacter baumannii Infection.
Histone butyrylation in the mouse intestine is mediated by the microbiota and associated with regulation of gene expression.
The molecular basis of cell memory in mammals: The epigenetic cycle.
Elemental iron protects gut microbiota against oxygen-induced dysbiosis.
Advanced lung organoids for respiratory system and pulmonary disease modeling.
Visualizing the invisible: novel approaches to visualizing bacterial proteins and host-pathogen interactions.
Nutrients: Signal 4 in T cell immunity.
Metabolic cell death in cancer: Ferroptosis, cuproptosis, disulfidptosis, and beyond.

Inflamm Regen. 2024 Mar 01. 44(1): 9

The role of Staphylococcus aureus quorum sensing in cutaneous and systemic infections.

Yuriko Yamazaki, Tomoka Ito, Masakazu Tamai, Seitaro Nakagawa, Yuumi Nakamura.

   BACKGROUND: Staphylococcus aureus is a leading cause of human bacterial infections worldwide. It is the most common causative agent of skin and soft tissue infections, and can also cause various other infections, including pneumonia, osteomyelitis, as well as life-threatening infections, such as sepsis and infective endocarditis. The pathogen can also asymptomatically colonize human skin, nasal cavity, and the intestine. S. aureus colonizes approximately 20-30% of human nostrils, being an opportunistic pathogen for subsequent infection. Its strong ability to silently spread via human contact makes it difficult to eradicate S. aureus. A major concern with S. aureus is its capacity to develop antibiotic resistance and adapt to diverse environmental conditions. The variability in the accessory gene regulator (Agr) region of the genome contributes to a spectrum of phenotypes within the bacterial population, enhancing the likelihood of survival in different environments. Agr functions as a central quorum sensing (QS) system in S. aureus, allowing bacteria to adjust gene expression in response to population density. Depending on Agr expression, S. aureus secretes various toxins, contributing to virulence in infectious diseases. Paradoxically, expressing Agr may be disadvantageous in certain situations, such as in hospitals, causing S. aureus to generate Agr mutants responsible for infections in healthcare settings.
MAIN BODY: This review aims to demonstrate the molecular mechanisms governing the diverse phenotypes of S. aureus, ranging from a harmless colonizer to an organism capable of infecting various human organs. Emphasis will be placed on QS and its role in orchestrating S. aureus behavior across different contexts.
SHORT CONCLUSION: The pathophysiology of S. aureus infection is substantially influenced by phenotypic changes resulting from factors beyond Agr. Future studies are expected to give the comprehensive understanding of S. aureus overall profile in various settings.

Keywords:   Staphylococcus aureus ; Accessory gene regulator; Atopic dermatitis; Infectious diseases; Quorum sensing; Skin infection; Systemic infection

DOI:  https://doi.org/10.1186/s41232-024-00323-8
Front Immunol. 2024 ;15 1323333

Potent induction of trained immunity by Saccharomyces cerevisiae β-glucans.

Patricia Vuscan, Brenda Kischkel, Aikaterini Hatzioannou, Efrosyni Markaki, Andrei Sarlea, Maria Tintoré, Jordi Cuñé, Panayotis Verginis, Carlos de Lecea, Triantafyllos Chavakis, Leo A B Joosten, Mihai G Netea.

  Candida albicans cell wall component β-glucan has been extensively studied for its ability to induce epigenetic and functional reprogramming of innate immune cells, a process termed trained immunity. We show that a high-complexity blend of two individual β-glucans from Saccharomyces cerevisiae possesses strong bioactivity, resulting in an enhanced trained innate immune response by human primary monocytes. The training required the Dectin-1/CR3, TLR4, and MMR receptors, as well as the Raf-1, Syk, and PI3K downstream signaling molecules. By activating multiple receptors and downstream signaling pathways, the components of this β-glucan preparation are able to act synergistically, causing a robust secondary response upon an unrelated challenge. In in-vivo murine models of melanoma and bladder cell carcinoma, pre-treatment of mice with the β-glucan preparation led to a significant reduction in tumor growth. These insights may aid in the development of future therapies based on β-glucan structures that induce an effective trained immunity response.

Keywords:  bladder cell carcinoma; immunotherapy; innate immunity; melanoma; probiotics

DOI:  https://doi.org/10.3389/fimmu.2024.1323333
J Stem Cells Regen Med. 2023 ;19(2): 37-39

I. IDC Key-note Lecture: Trained immunity: a memory for innate host defense.

Prof Dr Mihai G Netea.

DOI: https://doi.org/10.46582/jsrm.1902009
J Invest Dermatol. 2024 Feb 29. pii: S0022-202X(24)00002-2. [Epub ahead of print]

Staphylococcus aureus: The Bug Behind the Itch in Atopic Dermatitis.

Richard L Gallo, Alexander R Horswill.

  Pruritus or itch is a defining symptom of atopic dermatitis (AD). The origins of itch are complex, and it is considered both a defense mechanism and a cause of disease that leads to inflammation and psychological stress. Considerable progress has been made in understanding the processes that trigger itch, particularly the pruritoceptive origins that are generated in the skin. This perspective review discusses the implications of a recent observation that the V8 protease expressed by Staphylococcus aureus can directly trigger sensory neurons in the skin through activation of protease-activated receptor 1. This may be a key to understanding why itch is so common in AD because S. aureus commonly overgrows in this disease owing to deficient antimicrobial defense from both the epidermis and the cutaneous microbiome. Increased understanding of the role of microbes in AD provides increased opportunities for safely improving the treatment of this disorder.

Keywords:  Eczema; Holobiome; Microbiome; Neuron; Protease

DOI:  https://doi.org/10.1016/j.jid.2024.01.001
EMBO J. 2024 Feb 28.

Metabolic rewiring of macrophages by epidermal-derived lactate promotes sterile inflammation in the murine skin.

Uttkarsh Ayyangar, Aneesh Karkhanis, Heather Tay, Aliya Farissa Binte Afandi, Oindrila Bhattacharjee, Lalitha Ks, Sze Han Lee, James Chan, Srikala Raghavan.

  Dysregulated macrophage responses and changes in tissue metabolism are hallmarks of chronic inflammation in the skin. However, the metabolic cues that direct and support macrophage functions in the skin are poorly understood. Here, we show that during sterile skin inflammation, the epidermis and macrophages uniquely depend on glycolysis and the TCA cycle, respectively. This compartmentalisation is initiated by ROS-induced HIF-1α stabilization leading to enhanced glycolysis in the epidermis. The end-product of glycolysis, lactate, is then exported by epithelial cells and utilized by the dermal macrophages to induce their M2-like fates through NF-κB pathway activation. In addition, we show that psoriatic skin disorder is also driven by such lactate metabolite-mediated crosstalk between the epidermis and macrophages. Notably, small-molecule inhibitors of lactate transport in this setting attenuate sterile inflammation and psoriasis disease burden, and suppress M2-like fate acquisition in dermal macrophages. Our study identifies an essential role for the metabolite lactate in regulating macrophage responses to inflammation, which may be effectively targeted to treat inflammatory skin disorders such as psoriasis.

Keywords:  Epithelial-immune Crosstalk; Lactate Metabolism; Metabolic Compartmentation; Psoriasis; Sterile Inflammation

DOI:  https://doi.org/10.1038/s44318-024-00039-y
Mucosal Immunol. 2024 Feb 28. pii: S1933-0219(24)00017-5. [Epub ahead of print]

Epithelial regulation of microbiota-immune cell dynamics.

Bailey J Didriksen, Emily M Eshleman, Theresa Alenghat.

The mammalian gastrointestinal tract hosts a diverse community of trillions of microorganisms, collectively termed the microbiota, which play a fundamental role in regulating tissue physiology and immunity. Recent studies have sought to dissect the cellular and molecular mechanisms mediating communication between the microbiota and host immune system. Epithelial cells line the intestine and form an initial barrier separating the microbiota from underlying immune cells, and disruption of epithelial function has been associated with various conditions ranging from infection to inflammatory bowel diseases and cancer. From several studies, it is now clear that epithelial cells integrate signals from commensal microbes. Importantly, these non-hematopoietic cells also direct regulatory mechanisms that instruct recruitment and function of microbiota-sensitive immune cells. In this Review, we discuss the central role that has emerged for epithelial cells in orchestrating intestinal immunity and highlight epithelial pathways through which the microbiota can calibrate tissue-intrinsic immune responses.

DOI: https://doi.org/10.1016/j.mucimm.2024.02.008
Immunology. 2024 Feb 29.

Early life vaccination reprograms the metabolism and function of myeloid cells in neonates.

Yingying Chen, Hui Li, Jie Zhou.

  Vaccination after birth provides protection against pathogen infection and immune related disorders in healthy children. The detailed effects of vaccination on neonatal immunity, however, remain largely unknown. Here, we reported that vaccination using Bacillus Calmette-Guérin (BCG) diminished the immunosuppressive function of myeloid-derived suppressor cells in neonatal mice, an immature myeloid population. A combination of single-cell transcriptome, metabolite profiling, and functional analysis demonstrated that upregulation of mTOR/HIF1a signalling and the enhanced glycolysis explained the effects of BCG on neonatal myeloid cells. Pharmalogical inhibition of glycolysis or mTOR signalling efficiently rescued the effects of BCG on neonatal myeloid cells. These observations suggest that BCG facilitates the maturation of myeloid cells in early life, which may contribute to its beneficial effects against immune disorders later in life.

Keywords:  bacillus Calmette-Guérin; glycolysis; mTOR signalling; myeloid-derived suppressor cells

DOI:  https://doi.org/10.1111/imm.13772
mSphere. 2024 Feb 28. e0063623

An exploration of mechanisms underlying Desemzia incerta colonization resistance to methicillin-resistant Staphylococcus aureus on the skin.

Monica Wei, Simon A B Knight, Hossein Fazelinia, Lynn Spruce, Jennifer Roof, Emily Chu, Daniel Y Kim, Preeti Bhanap, Jasmine Walsh, Laurice Flowers, Jun Zhu, Elizabeth A Grice.

  Colonization of human skin and nares by methicillin-resistant Staphylococcus aureus (MRSA) leads to the community spread of MRSA. This spread is exacerbated by the transfer of MRSA between humans and livestock, particularly swine. Here, we capitalized on the shared features between human and porcine skin, including shared MRSA colonization, to study novel bacterial mediators of MRSA colonization resistance. We focused on the poorly studied bacterial species Desemzia incerta, which we found to exert antimicrobial activity through a secreted product and exhibited colonization resistance against MRSA in an in vivo murine skin model. Using parallel genomic and biochemical investigation, we discovered that D. incerta secretes an antimicrobial protein. Sequential protein purification and proteomics analysis identified 24 candidate inhibitory proteins, including a promising peptidoglycan hydrolase candidate. Aided by transcriptional analysis of D. incerta and MRSA cocultures, we found that exposure to D. incerta leads to decreased MRSA biofilm production. These results emphasize the value of exploring microbial communities across a spectrum of hosts, which can lead to novel therapeutic agents as well as an increased understanding of microbial competition.IMPORTANCEMethicillin-resistant Staphylococcus aureus (MRSA) causes a significant healthcare burden and can be spread to the human population via livestock transmission. Members of the skin microbiome can prevent MRSA colonization via a poorly understood phenomenon known as colonization resistance. Here, we studied the colonization resistance of S. aureus by bacterial inhibitors previously identified from a porcine skin model. We identify a pig skin commensal, Desemzia incerta, that reduced MRSA colonization in a murine model. We employ a combination of genomic, proteomic, and transcriptomic analyses to explore the mechanisms of inhibition between D. incerta and S. aureus. We identify 24 candidate antimicrobial proteins secreted by D. incerta that could be responsible for its antimicrobial activity. We also find that exposure to D. incerta leads to decreased S. aureus biofilm formation. These findings show that the livestock transmission of MRSA can be exploited to uncover novel mechanisms of MRSA colonization resistance.

Keywords:  S. aureus; colonization resistance; microbiome; skin

DOI:  https://doi.org/10.1128/msphere.00636-23
PLoS Pathog. 2024 Feb;20(2): e1012033

Intoxication of antibiotic persisters by host RNS inactivates their efflux machinery during infection.

Séverin Ronneau, Charlotte Michaux, Rachel T Giorgio, Sophie Helaine.

The host environment is of critical importance for antibiotic efficacy. By impacting bacterial machineries, stresses encountered by pathogens during infection promote the formation of phenotypic variants that are transiently insensitive to the action of antibiotics. It is assumed that these recalcitrant bacteria-termed persisters-contribute to antibiotic treatment failure and relapsing infections. Recently, we demonstrated that host reactive nitrogen species (RNS) transiently protect persisters against the action of β-lactam antibiotics by delaying their regrowth within host cells. Here, we discovered that RNS intoxication of persisters also collaterally sensitizing them to fluoroquinolones during infection, explaining the higher efficiency of fluoroquinolones against intramacrophage Salmonella. By reducing bacterial respiration and the proton-motive force, RNS inactivate the AcrAB efflux machinery of persisters, facilitating the accumulation of fluoroquinolones intracellularly. Our work shows that target inactivity is not the sole reason for Salmonella persisters to withstand antibiotics during infection, with active efflux being a major contributor to survival. Thus, understanding how the host environment impacts persister physiology is critical to optimize antibiotics efficacy during infection.

DOI: https://doi.org/10.1371/journal.ppat.1012033
Front Nutr. 2024 ;11 1346706

β-glucans from Agaricus bisporus mushroom products drive Trained Immunity.

Sarah Case, Tara O'Brien, Anna E Ledwith, Shilong Chen, Cian J H Horneck Johnston, Emer E Hackett, Michele O'Sullivan, Hugo Charles-Messance, Elaine Dempsey, Supriya Yadav, Jude Wilson, Sinead C Corr, Shipra Nagar, Frederick J Sheedy.

   Introduction: Macrofungi, such as edible mushrooms, have been used as a valuable medical resource for millennia as a result of their antibacterial and immuno-modulatory components. Mushrooms contain dietary fibers known as β-glucans, a class of polysaccharides previously linked to the induction of Trained Immunity. However, little is known about the ability of mushroom-derived β-glucans to induce Trained Immunity.
Methods & results: Using various powdered forms of the white button mushroom (Agaricus bisporus), we found that mouse macrophages pre-treated with whole mushroom powder (WMP) displayed enhanced responses to restimulation with TLR ligands, being particularly sensitive to Toll-like receptor (TLR)-2 stimulation using synthetic lipopeptides. This trained response was modest compared to training observed with yeast-derived β-glucans and correlated with the amount of available β-glucans in the WMP. Enriching for β-glucans content using either a simulated in-vitro digestion or chemical fractionation retained and boosted the trained response with WMP, respectively. Importantly, both WMP and digested-WMP preparations retained β-glucans as identified by nuclear magnetic resonance analysis and both displayed the capacity to train human monocytes and enhanced responses to restimulation. To determine if dietary incorporation of mushroom products can lead to Trained Immunity in myeloid cells in vivo, mice were given a regimen of WMP by oral gavage prior to sacrifice. Flow cytometric analysis of bone-marrow progenitors indicated alterations in hematopoietic stem and progenitor cells population dynamics, with shift toward myeloid-committed multi-potent progenitor cells. Mature bone marrow-derived macrophages derived from these mice displayed enhanced responses to restimulation, again particularly sensitive to TLR2.
Discussion: Taken together, these data demonstrate that β-glucans from common macrofungi can train innate immune cells and could point to novel ways of delivering bio-available β-glucans for education of the innate immune system.

Keywords:  Trained Immunity; digestion; immunometabolism; mushroom; β-glucan

DOI:  https://doi.org/10.3389/fnut.2024.1346706
J Clin Invest. 2024 Feb 29. pii: e174051. [Epub ahead of print]

Granulocytic myeloid-derived suppressor cell activity during biofilm infection is regulated by a glycolysis-HIF1a axis.

Christopher M Horn, Prabhakar Arumugam, Zachary Van Roy, Cortney E Heim, Rachel W Fallet, Blake P Bertrand, Dhananjay Shinde, Vinai C Thomas, Svetlana G Romanova, Tatiana K Bronich, Curtis W Hartman, Kevin L Garvin, Tammy Kielian.

  Staphylococcus aureus is a leading cause of biofilm-associated prosthetic joint infection (PJI). A primary contributor to infection chronicity is an expansion of granulocytic myeloid-derived suppressor cells (G-MDSCs) that are critical for orchestrating the anti-inflammatory biofilm milieu. Single-cell sequencing and bioinformatic metabolic algorithms were used to explore the link between G-MDSC metabolism and S. aureus PJI outcome. Glycolysis and the hypoxia response through hypoxia-inducible factor-1 alpha (HIF-1a) were significantly enriched in G-MDSCs. Interfering with both pathways in vivo, using a 2-deoxyglucose nanopreparation and granulocyte-targeted HIF-1a conditional knockout mice, respectively, attenuated G-MDSC-mediated immunosuppression and reduced bacterial burden in a mouse model of S. aureus PJI. In addition, scRNA-seq analysis of granulocytes from PJI patients also showed an enrichment in glycolysis and hypoxia response genes. These findings support the importance of a glycolysis/HIF-1a axis in promoting G-MDSC anti-inflammatory activity and biofilm persistence during PJI.

Keywords:  Bacterial infections; Immunology; Infectious disease; Innate immunity; Orthopedics

DOI:  https://doi.org/10.1172/JCI174051
Nat Rev Microbiol. 2024 Feb 28.

Conservation and similarity of bacterial and eukaryotic innate immunity.

Hannah E Ledvina, Aaron T Whiteley.

Pathogens are ubiquitous and a constant threat to their hosts, which has led to the evolution of sophisticated immune systems in bacteria, archaea and eukaryotes. Bacterial immune systems encode an astoundingly large array of antiviral (antiphage) systems, and recent investigations have identified unexpected similarities between the immune systems of bacteria and animals. In this Review, we discuss advances in our understanding of the bacterial innate immune system and highlight the components, strategies and pathogen restriction mechanisms conserved between bacteria and eukaryotes. We summarize evidence for the hypothesis that components of the human immune system originated in bacteria, where they first evolved to defend against phages. Further, we discuss shared mechanisms that pathogens use to overcome host immune pathways and unexpected similarities between bacterial immune systems and interbacterial antagonism. Understanding the shared evolutionary path of immune components across domains of life and the successful strategies that organisms have arrived at to restrict their pathogens will enable future development of therapeutics that activate the human immune system for the precise treatment of disease.

DOI: https://doi.org/10.1038/s41579-024-01017-1
Mol Oncol. 2024 Feb 27.

From monocyte-derived macrophages to resident macrophages-how metabolism leads their way in cancer.

Ummi Ammarah, Andreia Pereira-Nunes, Marcello Delfini, Massimiliano Mazzone.

  Macrophages are innate immune cells that play key roles during both homeostasis and disease. Depending on the microenvironmental cues sensed in different tissues, macrophages are known to acquire specific phenotypes and exhibit unique features that, ultimately, orchestrate tissue homeostasis, defense, and repair. Within the tumor microenvironment, macrophages are referred to as tumor-associated macrophages (TAMs) and constitute a heterogeneous population. Like their tissue resident counterpart, TAMs are plastic and can switch function and phenotype according to the niche-derived stimuli sensed. While changes in TAM phenotype are known to be accompanied by adaptive alterations in their cell metabolism, it is reported that metabolic reprogramming of macrophages can dictate their activation state and function. In line with these observations, recent research efforts have been focused on defining the metabolic traits of TAM subsets in different tumor malignancies and understanding their role in cancer progression and metastasis formation. This knowledge will pave the way to novel therapeutic strategies tailored to cancer subtype-specific metabolic landscapes. This review outlines the metabolic characteristics of distinct TAM subsets and their implications in tumorigenesis across multiple cancer types.

Keywords:  cancer metabolism; immunometabolism; monocyte-derived macrophages; tissue-resident macrophages; tumor microenvironment; tumor-associated macrophages

DOI:  https://doi.org/10.1002/1878-0261.13618
J Allergy Clin Immunol. 2024 Feb 27. pii: S0091-6749(24)00195-7. [Epub ahead of print]

Early-life Nasal Microbiota Dynamics Relate to Longitudinal Respiratory Phenotypes in Urban Children.

National Institute of Allergy and Infectious Diseases-sponsored Childhood Asthma in Urban Settings Consortium

   BACKGROUND: Five distinct respiratory phenotypes based on latent classes of longitudinal patterns of wheezing, allergic sensitization and pulmonary function measured from 0-7 years have been described in urban children.
OBJECTIVE: To determine whether distinct respiratory phenotypes associate with early-life upper respiratory microbiota development and environmental microbial exposures.
METHODS: Microbiota profiling was performed using 16S rRNA-based sequencing of nasal samples collected at 12 (n=120) or 36 (n=142) months of age and paired house dust samples collected at 3 months (12-month, N=73; 36-month, N=90) from all four centers in the Urban Environment and Childhood Asthma (URECA) cohort.
RESULTS: In these high-risk urban children, nasal microbiota increased in diversity between 12 and 36 months of age (ß= 2.04, P=0.006). Age-related changes in microbiota evenness differed significantly by respiratory phenotypes (Interaction P=0.0007) increasing most in the transient-wheeze group. At 12 months of age, respiratory illness (R2=0.055, p=0.0001) and dominant bacterial genus (R2=0.59, p=0.0001) explained variance in nasal microbiota composition and enrichment of Moraxella and Haemophilus members was associated with both transient- and high-wheeze phenotypes. By 36 months, nasal microbiota significantly associated with respiratory phenotypes (R2=0.019, P=0.0376) and Moraxella dominated microbiota associated specifically with atopy-associated respiratory phenotypes.
CONCLUSION: Nasal microbiota development over the course of early childhood and composition at three years of age associates with longitudinal respiratory phenotypes. These data provide evidence for an early-life window of airway microbiota development that is influenced by environmental microbial exposures in infancy and associated with wheeze- and atopy-associated respiratory phenotypes through 7 years of age.

Keywords:  Asthma; airway microbiota; atopy; early childhood; respiratory phenotypes

DOI:  https://doi.org/10.1016/j.jaci.2023.12.032
Nat Immunol. 2024 Mar;25(3): 382

Surface RNAs move neutrophils.

Paula Jáuregui.

DOI: https://doi.org/10.1038/s41590-024-01785-1
Nat Commun. 2024 Feb 26. 15(1): 1752

Intestinal stroma guides monocyte differentiation to macrophages through GM-CSF.

Egle Kvedaraite, Magda Lourda, Natalia Mouratidou, Tim Düking, Avinash Padhi, Kirsten Moll, Paulo Czarnewski, Indranil Sinha, Ioanna Xagoraris, Efthymia Kokkinou, Anastasios Damdimopoulos, Whitney Weigel, Olga Hartwig, Telma E Santos, Tea Soini, Aline Van Acker, Nelly Rahkonen, Malin Flodström Tullberg, Emma Ringqvist, Marcus Buggert, Carl Jorns, Ulrik Lindforss, Caroline Nordenvall, Christopher T Stamper, David Unnersjö-Jess, Mira Akber, Ruta Nadisauskaite, Jessica Jansson, Niels Vandamme, Chiara Sorini, Marijke Elise Grundeken, Helena Rolandsdotter, George Rassidakis, Eduardo J Villablanca, Maja Ideström, Stefan Eulitz, Henrik Arnell, Jenny Mjösberg, Jan-Inge Henter, Mattias Svensson.

Stromal cells support epithelial cell and immune cell homeostasis and play an important role in inflammatory bowel disease (IBD) pathogenesis. Here, we quantify the stromal response to inflammation in pediatric IBD and reveal subset-specific inflammatory responses across colon segments and intestinal layers. Using data from a murine dynamic gut injury model and human ex vivo transcriptomic, protein and spatial analyses, we report that PDGFRA+CD142-/low fibroblasts and monocytes/macrophages co-localize in the intestine. In primary human fibroblast-monocyte co-cultures, intestinal PDGFRA+CD142-/low fibroblasts foster monocyte transition to CCR2+CD206+ macrophages through granulocyte-macrophage colony-stimulating factor (GM-CSF). Monocyte-derived CCR2+CD206+ cells from co-cultures have a phenotype similar to intestinal CCR2+CD206+ macrophages from newly diagnosed pediatric IBD patients, with high levels of PD-L1 and low levels of GM-CSF receptor. The study describes subset-specific changes in stromal responses to inflammation and suggests that the intestinal stroma guides intestinal macrophage differentiation.

DOI: https://doi.org/10.1038/s41467-024-46076-3
Immunol Rev. 2024 Mar 01.

No time to die: Epigenetic regulation of natural killer cell survival.

Leen Hermans, Timothy E O'Sullivan.

  NK cells are short-lived innate lymphocytes that can mediate antigen-independent responses to infection and cancer. However, studies from the past two decades have shown that NK cells can acquire transcriptional and epigenetic modifications during inflammation that result in increased survival and lifespan. These findings blur the lines between the innate and adaptive arms of the immune system, and suggest that the homeostatic mechanisms that govern the persistence of innate immune cells are malleable. Indeed, recent studies have shown that NK cells undergo continuous and strictly regulated adaptations controlling their survival during development, tissue residency, and following inflammation. In this review, we summarize our current understanding of the critical factors regulating NK cell survival throughout their lifespan, with a specific emphasis on the epigenetic modifications that regulate the survival of NK cells in various contexts. A precise understanding of the molecular mechanisms that govern NK cell survival will be important to enhance therapies for cancer and infectious diseases.

Keywords:  NK cells; epigenetics; inflammation; memory; survival

DOI:  https://doi.org/10.1111/imr.13314
Microbiology (Reading). 2024 Mar;170(3):

Experimentally evolved Staphylococcus aureus shows increased survival in the presence of Pseudomonas aeruginosa by acquiring mutations in the amino acid transporter, GltT.

Ashley M Alexander, Justin M Luu, Vishnu Raghuram, Giulia Bottacin, Simon van Vliet, Timothy D Read, Joanna B Goldberg.

  When cultured together under standard laboratory conditions Pseudomonas aeruginosa has been shown to be an effective inhibitor of Staphylococcus aureus. However, P. aeruginosa and S. aureus are commonly observed in coinfections of individuals with cystic fibrosis (CF) and in chronic wounds. Previous work from our group revealed that S. aureus isolates from CF infections are able to persist in the presence of P. aeruginosa strain PAO1 with a range of tolerances with some isolates being eliminated entirely and others maintaining large populations. In this study, we designed a serial transfer, evolution experiment to identify mutations that allow S. aureus to survive in the presence of P. aeruginosa. Using S. aureus USA300 JE2 as our ancestral strain, populations of S. aureus were repeatedly cocultured with fresh P. aeruginosa PAO1. After eight coculture periods, S. aureus populations that survived better in the presence of PAO1 were observed. We found two independent mutations in the highly conserved S. aureus aspartate transporter, gltT, that were unique to evolved P. aeruginosa-tolerant isolates. Subsequent phenotypic testing demonstrated that gltT mutants have reduced uptake of glutamate and outcompeted wild-type S. aureus when glutamate was absent from chemically defined media. These findings together demonstrate that the presence of P. aeruginosa exerts selective pressure on S. aureus to alter its uptake and metabolism of key amino acids when the two are cultured together.

Keywords:  Pseudomonas aeruginosa; Staphylococcus aureus; amino acid metabolism; cystic fibrosis; experimental evolution; interspecies competition

DOI:  https://doi.org/10.1099/mic.0.001445
Matrix Biol Plus. 2024 Jun;22 100143

Laminin-derived peptide, IKVAV, modulates macrophage phenotype through integrin mediation.

Aakanksha Jha, Erika Moore.

  Macrophages are highly plastic immune cells known to exist on a spectrum of phenotypes including pro-inflammatory (M1) or pro-healing (M2). Macrophages interact with extracellular matrix (ECM) ligands, such as fragments of collagen and laminin. Interaction of macrophages with ECM ligands is mediated through integrin receptors. However, the role of ECM ligands in directing macrophage function through integrins is not yet fully understood. Particularly, α2β1 has been implicated in modulating macrophage function, but complexity in mechanisms employed for integrin-ligation especially with laminin-derived peptides makes it challenging to understand macrophage-ECM interactions. We hypothesize that targeting α2β1 through laminin-derived peptide, IKVAV, will modulate macrophage phenotype. In this work we: i) investigated macrophage response to IKVAV in 2D and in a 3D platform, and ii) identified α2β1's role as it pertains to macrophage modulation via IKVAV. Soluble IKVAV treatment significantly reduced M1 markers and increased M2 markers via immunocytochemistry and gene expression. While the 3D ECM-mimicking PEG-IKVAV hydrogels did not have significant effects in modulating macrophage phenotype, we found that macrophage modulation via IKVAV is dependent on the concentration of peptide used and duration of exposure. To investigate integrin-ligand interactions for macrophages, α2β1 signaling was modulated by antagonists and agonists. We observed that blocking α2β1 reduces M1 activation. To understand integrin-ligand interactions and leveraging the therapeutic ability of macrophages in designing immunomodulatory solutions, it is critical to elucidate IKVAV's role in mediating macrophage phenotype.

Keywords:  Biomaterials; ECM-derived peptide; Extracellular matrix; Integrins; Macrophages

DOI:  https://doi.org/10.1016/j.mbplus.2024.100143
J Biomed Sci. 2024 Feb 27. 31(1): 26

Reduced interleukin-18 secretion by human monocytic cells in response to infections with hyper-virulent Streptococcus pyogenes.

Lea A Tölken, Antje D Paulikat, Lana H Jachmann, Alexander Reder, Manuela Gesell Salazar, Laura M Palma Medina, Stephan Michalik, Uwe Völker, Mattias Svensson, Anna Norrby-Teglund, Katharina J Hoff, Michael Lammers, Nikolai Siemens.

   BACKGROUND: Streptococcus pyogenes (group A streptococcus, GAS) causes a variety of diseases ranging from mild superficial infections of the throat and skin to severe invasive infections, such as necrotizing soft tissue infections (NSTIs). Tissue passage of GAS often results in mutations within the genes encoding for control of virulence (Cov)R/S two component system leading to a hyper-virulent phenotype. Dendritic cells (DCs) are innate immune sentinels specialized in antigen uptake and subsequent T cell priming. This study aimed to analyze cytokine release by DCs and other cells of monocytic origin in response to wild-type and natural covR/S mutant infections.
METHODS: Human primary monocyte-derived (mo)DCs were used. DC maturation and release of pro-inflammatory cytokines in response to infections with wild-type and covR/S mutants were assessed via flow cytometry. Global proteome changes were assessed via mass spectrometry. As a proof-of-principle, cytokine release by human primary monocytes and macrophages was determined.
RESULTS: In vitro infections of moDCs and other monocytic cells with natural GAS covR/S mutants resulted in reduced secretion of IL-8 and IL-18 as compared to wild-type infections. In contrast, moDC maturation remained unaffected. Inhibition of caspase-8 restored secretion of both molecules. Knock-out of streptolysin O in GAS strain with unaffected CovR/S even further elevated the IL-18 secretion by moDCs. Of 67 fully sequenced NSTI GAS isolates, 28 harbored mutations resulting in dysfunctional CovR/S. However, analyses of plasma IL-8 and IL-18 levels did not correlate with presence or absence of such mutations.
CONCLUSIONS: Our data demonstrate that strains, which harbor covR/S mutations, interfere with IL-18 and IL-8 responses in monocytic cells by utilizing the caspase-8 axis. Future experiments aim to identify the underlying mechanism and consequences for NSTI patients.

Keywords:  CovR/S; Dendritic cells; Interleukin-18; Necrotizing soft tissue infection; Streptococcus pyogenes

DOI:  https://doi.org/10.1186/s12929-024-01014-9
Arch Microbiol. 2024 Feb 27. 206(3): 124

Unveiling the hidden language of bacteria: anti-quorum sensing strategies for gram-negative bacteria infection control.

Mahmoud A Elfaky.

  Quorum sensing (QS) is a communication mechanism employed by many bacteria to regulate gene expression in a population density-dependent manner. It plays a crucial role in coordinating various bacterial behaviors, including biofilm formation, virulence factor production, and antibiotic resistance. However, the dysregulation of QS can lead to detrimental effects, making it an attractive target for developing novel therapeutic strategies. Anti-QS approaches aim to interfere with QS signaling pathways, inhibiting the communication between bacteria, and disrupting their coordinated activities. Various strategies have been explored to achieve this goal. Advances in understanding QS mechanisms and the discovery of new targets have paved the way for the development of innovative anti-QS approaches. Combining multiple anti-QS strategies or utilizing them in combination with traditional antibiotics holds great promise for combating bacterial infections and addressing the challenges posed by antibiotic resistance. Anti-QS approaches offer a diverse range of strategies including natural compounds, antibody-mediated quorum quenching (QQ), computer-aided drug design for QQ, repurposing of Drugs approved by FDA as anti-QS agents and modulating quorum-sensing molecules which were discussed in detail in this review. This review, comprehensively and for the first time, sheds light on the significance of diverse anti-QS strategies in solving antimicrobial resistance problem in Gram-negative microbial infection.

Keywords:  Antibiotic resistance; Biofilm; Drug repurposing; Gram-negative bacteria; Quorum quenching; Quorum sensing

DOI:  https://doi.org/10.1007/s00203-024-03900-0
Mol Biol Rep. 2024 Feb 25. 51(1): 361

Advanced probiotics: bioengineering and their therapeutic application.

Tamanna Parvin, Sudha Rani Sadras.

  The role of gut bacteria in human health has long been acknowledged and dysbiosis of the gut microbiota has been correlated with a variety of disorders. Synthetic biology has rapidly grown over the past few years offering a variety of biological applications such as harnessing the relationship between bacteria and human health. Lactic acid bacteria (LAB) are thought to be appropriate chassis organisms for genetic modification with potential biomedical applications. A thorough understanding of the molecular mechanisms behind their beneficial qualities is essential to assist the multifunctional medicinal sectors. Effective genome editing will aid in the creation of next-generation designer probiotics with enhanced resilience and specialized capabilities, furthering our knowledge of the molecular mechanisms behind the physiological impacts of probiotics and their interactions with the host and microbiota. The goal of this review is to provide a brief overview of the methods used to create modified probiotics with the scientific rationale behind gene editing technology, the mechanism of action of engineered probiotics along with their application to treat conditions like inflammatory bowel disease, cancer, bacterial infections, and various metabolic diseases. In addition, application concerns and future directions are also presented.

Keywords:  CRISPR-CAS9; Genetic engineering; Gut microbiota; Probiotics; Synthetic biology

DOI:  https://doi.org/10.1007/s11033-024-09309-8
J Cell Sci. 2024 Feb 15. pii: jcs260891. [Epub ahead of print]137(4):

Estimates of differential toxin expression governing heterogeneous intracellular lifespans of Streptococcus pneumoniae.

Shweta Santra, Indrani Nayak, Ankush Paladhi, Dibyendu Das, Anirban Banerjee.

  Following invasion of the host cell, pore-forming toxins secreted by pathogens compromise vacuole integrity and expose the microbe to diverse intracellular defence mechanisms. However, the quantitative correlation between toxin expression levels and consequent pore dynamics, fostering the intracellular life of pathogens, remains largely unexplored. In this study, using Streptococcus pneumoniae and its secreted pore-forming toxin pneumolysin (Ply) as a model system, we explored various facets of host-pathogen interactions in the host cytosol. Using time-lapse fluorescence imaging, we monitored pore formation dynamics and lifespans of different pneumococcal subpopulations inside host cells. Based on experimental histograms of various event timescales such as pore formation time, vacuolar death or cytosolic escape time and total degradation time, we developed a mathematical model based on first-passage processes that could correlate the event timescales to intravacuolar toxin accumulation. This allowed us to estimate Ply production rate, burst size and threshold Ply quantities that trigger these outcomes. Collectively, we present a general method that illustrates a correlation between toxin expression levels and pore dynamics, dictating intracellular lifespans of pathogens.

Keywords:   Streptococcus pneumoniae ; Autophagy; First-passage process; Galectin; Pneumolysin; Pore formation

DOI:  https://doi.org/10.1242/jcs.260891
Angew Chem Int Ed Engl. 2024 Feb 28. e202400538

High-Throughput Host-Microbe Single-Cell RNA Sequencing Reveals Ferroptosis-Associated Heterogeneity during Acinetobacter baumannii Infection.

Hongen Meng, Tianyu Zhang, Wang Zhang, Yuyi Zhu, Yingying Yu, Jiaye Chen, Hangfei Chen, Fudi Wang, Yunsong Yu, Xiaoting Hua, Yongcheng Wang.

  Interactions between host and bacterial cells are integral to human physiology. The complexity of host-microbe interactions extends to different cell types, spatial aspects, and phenotypic heterogeneity, requiring high-resolution approaches to capture their full complexity. The latest breakthroughs in single-cell RNA sequencing (scRNA-seq) have opened up a new era of studies in host-pathogen interactions. Here, we first report a high-throughput cross-species dual scRNA-seq technology by using random primers to simultaneously capture both eukaryotic and bacterial RNAs (scRandom-seq). Using reference cells, scRandom-seq can detect individual eukaryotic and bacterial cells with high throughput and high specifity. Acinetobacter baumannii (A.b) is a highly opportunistic and nosocomial pathogen that is highly attainable antibiotic resistance posing a significant threat to human health, calling for new discoveries and treatment. In the A.b infection model, scRandom-seq witnessed polarization of THP-1 derived-macrophages and the intracellular A.b induced ferroptosis-stress in host cells. The inhibition of ferroptosis by Ferrostatin-1 (Fer-1) resulted in the improvement of cell vitality and resistance to A.b infection, indicating the potential activity to resist related infections. scRandom-seq provides a high-throughput cross-species dual single-cell RNA profiling tool that will facilitate future discoveries in unraveling the complex interactions of host-microbe interactions in infection systems and tumor micro-environments.

Keywords:  Acinetobacter baumannii infection; Droplet microfluidics; Host-pathogen interactions; Single cell RNA-seq; ferroptosis

DOI:  https://doi.org/10.1002/anie.202400538
Nat Metab. 2024 Feb 27.

Histone butyrylation in the mouse intestine is mediated by the microbiota and associated with regulation of gene expression.

Leah A Gates, Bernardo Sgarbi Reis, Peder J Lund, Matthew R Paul, Marylene Leboeuf, Annaelle M Djomo, Zara Nadeem, Mariana Lopes, Francisca N Vitorino, Gokhan Unlu, Thomas S Carroll, Kivanç Birsoy, Benjamin A Garcia, Daniel Mucida, C David Allis.

Post-translational modifications (PTMs) on histones are a key source of regulation on chromatin through impacting cellular processes, including gene expression1. These PTMs often arise from metabolites and are thus impacted by metabolism and environmental cues2-7. One class of metabolically regulated PTMs are histone acylations, which include histone acetylation, butyrylation, crotonylation and propionylation3,8. As these PTMs can be derived from short-chain fatty acids, which are generated by the commensal microbiota in the intestinal lumen9-11, we aimed to define how microbes impact the host intestinal chromatin landscape, mainly in female mice. Here we show that in addition to acetylation, intestinal epithelial cells from the caecum and distal mouse intestine also harbour high levels of butyrylation and propionylation on lysines 9 and 27 of histone H3. We demonstrate that these acylations are regulated by the microbiota and that histone butyrylation is additionally regulated by the metabolite tributyrin. Tributyrin-regulated gene programmes are correlated with histone butyrylation, which is associated with active gene-regulatory elements and levels of gene expression. Together, our study uncovers a regulatory layer of how the microbiota and metabolites influence the intestinal epithelium through chromatin, demonstrating a physiological setting in which histone acylations are dynamically regulated and associated with gene regulation.

DOI: https://doi.org/10.1038/s42255-024-00992-2
Sci Adv. 2024 Mar;10(9): eadl3188

The molecular basis of cell memory in mammals: The epigenetic cycle.

Mencía Espinosa-Martínez, María Alcázar-Fabra, David Landeira.

Cell memory refers to the capacity of cells to maintain their gene expression program once the initiating environmental signal has ceased. This exceptional feature is key during the formation of mammalian organisms, and it is believed to be in part mediated by epigenetic factors that can endorse cells with the landmarks required to maintain transcriptional programs upon cell duplication. Here, we review current literature analyzing the molecular basis of epigenetic memory in mammals, with a focus on the mechanisms by which transcriptionally repressive chromatin modifications such as methylation of DNA and histone H3 are propagated through mitotic cell divisions. The emerging picture suggests that cellular memory is supported by an epigenetic cycle in which reversible activities carried out by epigenetic regulators in coordination with cell cycle transition create a multiphasic system that can accommodate both maintenance of cell identity and cell differentiation in proliferating stem cell populations.

DOI: https://doi.org/10.1126/sciadv.adl3188
PLoS One. 2024 ;19(2): e0298592

Elemental iron protects gut microbiota against oxygen-induced dysbiosis.

Ievgeniia Ostrov, Yongjia Gong, Joshua B Zuk, Purni C K Wickramasinghe, Irina Tmenova, Diana E Roopchand, Liping Zhao, Ilya Raskin.

Gut dysbiosis induced by oxygen and reactive oxygen species may be related to the development of inflammation, resulting in metabolic syndrome and associated-conditions in the gut. Here we show that elemental iron can serve as an antioxidant and reverse the oxygen-induced dysbiosis. Fecal samples from three healthy donors were fermented with elemental iron and/or oxygen. 16S rRNA analysis revealed that elemental iron reversed the oxygen-induced disruption of Shannon index diversity of the gut microbiota.The bacteria lacking enzymatic antioxidant systems also increased after iron treatment. Inter-individual differences, which corresponded to iron oxidation patterns, were observed for the tested donors. Gut bacteria responding to oxygen and iron treatments were identified as guilds, among which, Escherichia-Shigella was promoted by oxygen and depressed by elemental iron, while changes in bacteria such as Bifidobacterium, Blautia, Eubacterium, Ruminococcaceae, Flavonifractor, Oscillibacter, and Lachnospiraceae were reversed by elemental iron after oxygen treatment. Short-chain fatty acid production was inhibited by oxygen and this effect was partially reversed by elemental iron. These results suggested that elemental iron can regulate the oxygen/ROS state and protect the gut microbiota from oxidative stress.

DOI: https://doi.org/10.1371/journal.pone.0298592
J Tissue Eng. 2024 Jan-Dec;15:15 20417314241232502

Advanced lung organoids for respiratory system and pulmonary disease modeling.

Hyebin Joo, Sungjin Min, Seung-Woo Cho.

  Amidst the recent coronavirus disease 2019 (COVID-19) pandemic, respiratory system research has made remarkable progress, particularly focusing on infectious diseases. Lung organoid, a miniaturized structure recapitulating lung tissue, has gained global attention because of its advantages over other conventional models such as two-dimensional (2D) cell models and animal models. Nevertheless, lung organoids still face limitations concerning heterogeneity, complexity, and maturity compared to the native lung tissue. To address these limitations, researchers have employed co-culture methods with various cell types including endothelial cells, mesenchymal cells, and immune cells, and incorporated bioengineering platforms such as air-liquid interfaces, microfluidic chips, and functional hydrogels. These advancements have facilitated applications of lung organoids to studies of pulmonary diseases, providing insights into disease mechanisms and potential treatments. This review introduces recent progress in the production methods of lung organoids, strategies for improving maturity, functionality, and complexity of organoids, and their application in disease modeling, including respiratory infection and pulmonary fibrosis.

Keywords:  Lung organoid; bioengineeing platform; cellular niches; pulmonary fibrosis; respiratory infection

DOI:  https://doi.org/10.1177/20417314241232502
Front Bioeng Biotechnol. 2024 ;12 1334503

Visualizing the invisible: novel approaches to visualizing bacterial proteins and host-pathogen interactions.

Moirangthem Kiran Singh, Linda J Kenney.

  Host-pathogen interactions play a critical role in infectious diseases, and understanding the underlying mechanisms is vital for developing effective therapeutic strategies. The visualization and characterization of bacterial proteins within host cells is key to unraveling the dynamics of these interactions. Various protein labeling strategies have emerged as powerful tools for studying host-pathogen interactions, enabling the tracking, localization, and functional analysis of bacterial proteins in real-time. However, the labeling and localization of Salmonella secreted type III secretion system (T3SS) effectors in host cells poses technical challenges. Conventional methods disrupt effector stoichiometry and often result in non-specific staining. Bulky fluorescent protein fusions interfere with effector secretion, while other tagging systems such as 4Cys-FLaSH/Split-GFP suffer from low labeling specificity and a poor signal-to-noise ratio. Recent advances in state-of-the-art techniques have augmented the existing toolkit for monitoring the translocation and dynamics of bacterial effectors. This comprehensive review delves into the bacterial protein labeling strategies and their application in imaging host-pathogen interactions. Lastly, we explore the obstacles faced and potential pathways forward in the realm of protein labeling strategies for visualizing interactions between hosts and pathogens.

Keywords:  bacterial proteins; genetic code expansion; host-pathogen interactions; imaging techniques; protein labeling; super-resolution microscopy

DOI:  https://doi.org/10.3389/fbioe.2024.1334503
J Exp Med. 2024 Mar 04. pii: e20221839. [Epub ahead of print]221(3):

Nutrients: Signal 4 in T cell immunity.

Jana L Raynor, Hongbo Chi.

T cells are integral in mediating adaptive immunity to infection, autoimmunity, and cancer. Upon immune challenge, T cells exit from a quiescent state, followed by clonal expansion and effector differentiation. These processes are shaped by three established immune signals, namely antigen stimulation (Signal 1), costimulation (Signal 2), and cytokines (Signal 3). Emerging findings reveal that nutrients, including glucose, amino acids, and lipids, are crucial regulators of T cell responses and interplay with Signals 1-3, highlighting nutrients as Signal 4 to license T cell immunity. Here, we first summarize the functional importance of Signal 4 and the underlying mechanisms of nutrient transport, sensing, and signaling in orchestrating T cell activation and quiescence exit. We also discuss the roles of nutrients in programming T cell differentiation and functional fitness and how nutrients can be targeted to improve disease therapy. Understanding how T cells respond to Signal 4 nutrients in microenvironments will provide insights into context-dependent functions of adaptive immunity and therapeutic interventions.

DOI: https://doi.org/10.1084/jem.20221839
Protein Cell. 2024 Mar 01. pii: pwae003. [Epub ahead of print]

Metabolic cell death in cancer: Ferroptosis, cuproptosis, disulfidptosis, and beyond.

Chao Mao, Min Wang, Li Zhuang, Boyi Gan.

  Cell death resistance represents a hallmark of cancer. Recent studies have identified metabolic cell death as unique forms of regulated cell death resulting from an imbalance in the cellular metabolism. This review discusses the mechanisms of metabolic cell death-ferroptosis, cuproptosis, disulfidptosis, lysozincrosis, and alkaliptosis-and explores their potential in cancer therapy. Our review underscores the complexity of the metabolic cell death pathways and offers insights into innovative therapeutic avenues for cancer treatment.

Keywords:  cancer treatment; cell death; cuproptosis; disulfidptosis; ferroptosis

DOI:  https://doi.org/10.1093/procel/pwae003