bims-bac4me 2023-09-10 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2023–09–10
25 papers selected by
Chun-Chi Chang, Universitäts Spital Zürich

Role of toll-like receptors and nod-like receptors in acute lung infection.
Transposon sequencing identifies genes impacting Staphylococcus aureus invasion in a human macrophage model.
Innate immune responses yield tissue-specific bottlenecks that scale with pathogen dose.
A Moonlighting Protein Secreted by a Nasal Microbiome Fortifies the Innate Host Defense Against Bacterial and Viral Infections.
NAD(H) homeostasis underlies host protection mediated by glycolytic myeloid cells in tuberculosis.
Shigella induces epigenetic reprogramming of zebrafish neutrophils.
Regulation of integrin α5β1-mediated Staphylococcus aureus cellular invasion by the septin cytoskeleton.
Do face masks increase the rate of the Staphylococcus aureus nasal carriers?
Mitochondrial Damage-Associated Molecular Patterns and Metabolism in the Regulation of Innate Immunity.
Infection-experienced HSPCs protect against infections by generating neutrophils with enhanced mitochondrial bactericidal activity.
Multifaceted role of CD14 in innate immunity and tissue homeostasis.
Disruption of the primocolonizing microbiota alters epithelial homeostasis and imprints stem cells in the colon of neonatal piglets.
BCG vaccination induces innate immune memory in gamma delta T cells in humans.
SIRPα: A key player in innate immunity.
Metabolic network construction reveals probiotic-specific alterations in the metabolic activity of a synthetic small intestinal community.
Airway metabolic profiling during Streptococcus pneumoniae infection identifies branched chain amino acids as signatures of upper airway colonisation.
S100A8 and S100A9 in Hematologic Malignancies: From Development to Therapy.
Hematopoietic stem and progenitor cells confer cross-protective trained immunity in mouse models.
The emerging roles of SUMOylation in pulmonary diseases.
The Protective Role of TLR4 in Intestinal Epithelial Cells through the Regulation of the Gut Microbiota in DSS-Induced Colitis in Mice.
Platelet Factor 4 (PF4) Improves Survival in a Murine Model of Antibiotic-Susceptible and Methicillin-Resistant Staphylococcus Aureus Peritonitis.
Orally delivered lactate-producing bacteria limit CNS autoimmunity.
Spatial lipidomics reveals biased phospholipid remodeling in acute Pseudomonas lung infection.
Pathogenesis of chronic rhinosinusitis with nasal polyp and a prominent T2 endotype.
Epithelial Yap/Taz are required for functional alveolar regeneration following acute lung injury.

Front Immunol. 2023 ;14 1249098

Role of toll-like receptors and nod-like receptors in acute lung infection.

John Le, Yathushigan Kulatheepan, Samithamby Jeyaseelan.

  The respiratory system exposed to microorganisms continuously, and the pathogenicity of these microbes not only contingent on their virulence factors, but also the host's immunity. A multifaceted innate immune mechanism exists in the respiratory tract to cope with microbial infections and to decrease tissue damage. The key cell types of the innate immune response are macrophages, neutrophils, dendritic cells, epithelial cells, and endothelial cells. Both the myeloid and structural cells of the respiratory system sense invading microorganisms through binding or activation of pathogen-associated molecular patterns (PAMPs) to pattern recognition receptors (PRRs), including Toll-like receptors (TLRs) and NOD-like receptors (NLRs). The recognition of microbes and subsequent activation of PRRs triggers a signaling cascade that leads to the activation of transcription factors, induction of cytokines/5chemokines, upregulation of cell adhesion molecules, recruitment of immune cells, and subsequent microbe clearance. Since numerous microbes resist antimicrobial agents and escape innate immune defenses, in the future, a comprehensive strategy consisting of newer vaccines and novel antimicrobials will be required to control microbial infections. This review summarizes key findings in the area of innate immune defense in response to acute microbial infections in the lung. Understanding the innate immune mechanisms is critical to design host-targeted immunotherapies to mitigate excessive inflammation while controlling microbial burden in tissues following lung infection.

Keywords:  NOD (nucleotide binding and oligomerization domain) and leucine rich repeat containing receptor (NLR); Neutrophil; TLR - toll-like receptor; cytokine; lung

DOI:  https://doi.org/10.3389/fimmu.2023.1249098
Infect Immun. 2023 Sep 07. e0022823

Transposon sequencing identifies genes impacting Staphylococcus aureus invasion in a human macrophage model.

Hsin-Yu Lo, Dustin R Long, Elizbeth A Holmes, Kelsi Penewit, Taylor Hodgson, Janessa D Lewis, Adam Waalkes, Stephen J Salipante.

  Staphylococcus aureus is a facultative intracellular pathogen in many host cell types, facilitating its persistence in chronic infections. The genes contributing to intracellular pathogenesis have not yet been fully enumerated. Here, we cataloged genes influencing S. aureus invasion and survival within human THP-1 derived macrophages using two laboratory strains (ATCC2913 and JE2). We developed an in vitro transposition method to produce highly saturated transposon mutant libraries in S. aureus and performed transposon insertion sequencing (Tn-Seq) to identify candidate genes with significantly altered abundance following macrophage invasion. While some significant genes were strain-specific, 108 were identified as common across both S. aureus strains, with most (n = 106) being required for optimal macrophage infection. We used CRISPR interference (CRISPRi) to functionally validate phenotypic contributions for a subset of genes. Of the 20 genes passing validation, seven had previously identified roles in S. aureus virulence, and 13 were newly implicated. Validated genes frequently evidenced strain-specific effects, yielding opposing phenotypes when knocked down in the alternative strain. Genomic analysis of de novo mutations occurring in groups (n = 237) of clonally related S. aureus isolates from the airways of chronically infected individuals with cystic fibrosis (CF) revealed significantly greater in vivo purifying selection in conditionally essential candidate genes than those not associated with macrophage invasion. This study implicates a core set of genes necessary to support macrophage invasion by S. aureus, highlights strain-specific differences in phenotypic effects of effector genes, and provides evidence for selection of candidate genes identified by Tn-Seq analyses during chronic airway infection in CF patients in vivo.

Keywords:  Staphylococcus aureus; Tn-Seq; cell invasion; chronic infection; cystic fibrosis; facultatively intracellular pathogens; genomics; macrophages; persistence; transposons

DOI:  https://doi.org/10.1128/iai.00228-23
Proc Natl Acad Sci U S A. 2023 Sep 12. 120(37): e2309151120

Innate immune responses yield tissue-specific bottlenecks that scale with pathogen dose.

Karthik Hullahalli, Katherine G Dailey, Matthew K Waldor.

  To cause infection, pathogens must overcome bottlenecks imposed by the host immune system. These bottlenecks restrict the inoculum and largely determine whether pathogen exposure results in disease. Infection bottlenecks therefore quantify the effectiveness of immune barriers. Here, using a model of Escherichia coli systemic infection, we identify bottlenecks that tighten or widen with higher inoculum sizes, revealing that the efficacy of innate immune responses can increase or decrease with pathogen dose. We term this concept "dose scaling". During E. coli systemic infection, dose scaling is tissue specific, dependent on the lipopolysaccharide (LPS) receptor TLR4, and can be recapitulated by mimicking high doses with killed bacteria. Scaling therefore depends on sensing of pathogen molecules rather than interactions between the host and live bacteria. We propose that dose scaling quantitatively links innate immunity with infection bottlenecks and is a valuable framework for understanding how the inoculum size governs the outcome of pathogen exposure.

Keywords:  bottlenecks; dose–response; innate immunity; systemic infection

DOI:  https://doi.org/10.1073/pnas.2309151120
Immune Netw. 2023 Aug;23(4): e31

A Moonlighting Protein Secreted by a Nasal Microbiome Fortifies the Innate Host Defense Against Bacterial and Viral Infections.

Gwanghee Kim, Yoojin Lee, Jin Sun You, Wontae Hwang, Jeewon Hwang, Hwa Young Kim, Jieun Kim, Ara Jo, In Ho Park, Mohammed Ali, Jongsun Kim, Jeon-Soo Shin, Ho-Keun Kwon, Hyun Jik Kim, Sang Sun Yoon.

  Evidence suggests that the human respiratory tract, as with the gastrointestinal tract, has evolved to its current state in association with commensal microbes. However, little is known about how the airway microbiome affects the development of airway immune system. Here, we uncover a previously unidentified mode of interaction between host airway immunity and a unique strain (AIT01) of Staphylococcus epidermidis, a predominant species of the nasal microbiome. Intranasal administration of AIT01 increased the population of neutrophils and monocytes in mouse lungs. The recruitment of these immune cells resulted in the protection of the murine host against infection by Pseudomonas aeruginosa, a pathogenic bacterium. Interestingly, an AIT01-secreted protein identified as GAPDH, a well-known bacterial moonlighting protein, mediated this protective effect. Intranasal delivery of the purified GAPDH conferred significant resistance against other Gram-negative pathogens (Klebsiella pneumoniae and Acinetobacter baumannii) and influenza A virus. Our findings demonstrate the potential of a native nasal microbe and its secretory protein to enhance innate immune defense against airway infections. These results offer a promising preventive measure, particularly relevant in the context of global pandemics.

Keywords:  Glyceraldehyde-3-phosphate dehydrogenase (GAPDH); Human nasal microbiome; Innate immune defense; Staphylococcus epidermidis

DOI:  https://doi.org/10.4110/in.2023.23.e31
Nat Commun. 2023 Sep 06. 14(1): 5472

NAD(H) homeostasis underlies host protection mediated by glycolytic myeloid cells in tuberculosis.

Hayden T Pacl, Krishna C Chinta, Vineel P Reddy, Sajid Nadeem, Ritesh R Sevalkar, Kievershen Nargan, Kapongo Lumamba, Threnesan Naidoo, Joel N Glasgow, Anupam Agarwal, Adrie J C Steyn.

Mycobacterium tuberculosis (Mtb) disrupts glycolytic flux in infected myeloid cells through an unclear mechanism. Flux through the glycolytic pathway in myeloid cells is inextricably linked to the availability of NAD+, which is maintained by NAD+ salvage and lactate metabolism. Using lung tissue from tuberculosis (TB) patients and myeloid deficient LDHA (LdhaLysM-/-) mice, we demonstrate that glycolysis in myeloid cells is essential for protective immunity in TB. Glycolytic myeloid cells are essential for the early recruitment of multiple classes of immune cells and IFNγ-mediated protection. We identify NAD+ depletion as central to the glycolytic inhibition caused by Mtb. Lastly, we show that the NAD+ precursor nicotinamide exerts a host-dependent, antimycobacterial effect, and that nicotinamide prophylaxis and treatment reduce Mtb lung burden in mice. These findings provide insight into how Mtb alters host metabolism through perturbation of NAD(H) homeostasis and reprogramming of glycolysis, highlighting this pathway as a potential therapeutic target.

DOI: https://doi.org/10.1038/s41467-023-40545-x
Sci Adv. 2023 Sep 08. 9(36): eadf9706

Shigella induces epigenetic reprogramming of zebrafish neutrophils.

Margarida C Gomes, Dominik Brokatzky, Magdalena K Bielecka, Fiona C Wardle, Serge Mostowy.

Trained immunity is a long-term memory of innate immune cells, generating an improved response upon reinfection. Shigella is an important human pathogen and inflammatory paradigm for which there is no effective vaccine. Using zebrafish larvae, we demonstrate that after Shigella training, neutrophils are more efficient at bacterial clearance. We observe that Shigella-induced protection is nonspecific and has differences with training by BCG and β-glucan. Analysis of histone ChIP-seq on trained neutrophils revealed that Shigella training deposits the active H3K4me3 mark on promoter regions of 1612 genes, dramatically changing the epigenetic landscape of neutrophils toward enhanced microbial recognition and mitochondrial ROS production. Last, we demonstrate that mitochondrial ROS plays a key role in enhanced antimicrobial activity of trained neutrophils. It is envisioned that signals and mechanisms we discover here can be used in other vertebrates, including humans, to suggest new therapeutic strategies involving neutrophils to control bacterial infection.

DOI: https://doi.org/10.1126/sciadv.adf9706
Eur J Cell Biol. 2023 Sep 03. pii: S0171-9335(23)00074-2. [Epub ahead of print]102(4): 151359

Regulation of integrin α5β1-mediated Staphylococcus aureus cellular invasion by the septin cytoskeleton.

Stevens Robertin, Dominik Brokatzky, Damián Lobato-Márquez, Serge Mostowy.

  Staphylococcus aureus, a Gram-positive bacterial pathogen, is an urgent health threat causing a wide range of clinical infections. Originally viewed as a strict extracellular pathogen, accumulating evidence has revealed S. aureus to be a facultative intracellular pathogen subverting host cell signalling to support invasion. The majority of clinical isolates produce fibronectin-binding proteins A and B (FnBPA and FnBPB) to interact with host integrin α5β1, a key component of focal adhesions. S. aureus binding of integrin α5β1 promotes its clustering on the host cell surface, triggering activation of focal adhesion kinase (FAK) and cytoskeleton rearrangements to promote bacterial invasion into non-phagocytic cells. Here, we discover that septins, a component of the cytoskeleton that assembles on membranes, are recruited as collar-like structures with actin to S. aureus invasion sites engaging integrin α5β1. To investigate septin recruitment to the plasma membrane in a bacteria-free system, we used FnBPA-coated latex beads and showed that septins are recruited upon activation of integrin α5β1. SEPT2 depletion reduced S. aureus invasion, but increased surface expression of integrin α5 and adhesion of S. aureus to host cells. Consistent with this, SEPT2 depletion increased cellular protein levels of integrin α5 and β1 subunits, as well as FAK. Collectively, these results provide insights into regulation of integrin α5β1 and invasion of S. aureus by the septin cytoskeleton.

Keywords:  Cytoskeleton; Integrin; Septins; Staphylococcus aureus

DOI:  https://doi.org/10.1016/j.ejcb.2023.151359
Rev Esp Quimioter. 2023 Sep 07. pii: urquia07sep2023. [Epub ahead of print]

Do face masks increase the rate of the Staphylococcus aureus nasal carriers?

S Urquía-Cutillas, M L Gómez-Lus, D Sevillano, N González, L Alou.



Keywords:  Staphylococcus aureus; face mask; microbiology; nasal carrier; nasal microbiota; pre-clinical students

DOI:  https://doi.org/10.37201/req/082.2023
J Innate Immun. 2023 Sep 04.

Mitochondrial Damage-Associated Molecular Patterns and Metabolism in the Regulation of Innate Immunity.

Yanmin Lyu, Tianyu Wang, Shuhong Huang, Zhaoqiang Zhang.

The innate immune system, as the host's first line of defense against intruders, plays a critical role in recognizing, identifying, and reacting to a wide range of microbial intruders. There is increasing evidence that mitochondrial stress is a major initiator of innate immune responses. When mitochondria's integrity is disrupted or dysfunction occurs, the mitochondria's contents are released into the cytosol. These contents, like reactive oxygen species, mitochondrial DNA, and double-stranded RNA, among others, act as damage-related molecular patterns (DAMPs) that can bind to multiple innate immune sensors, particularly pattern recognition receptors, thereby leading to inflammation. To avoid the production of DAMPs, in addition to safeguarding organelle's integrity and functionality, mitochondria may activate mitophagy or apoptosis. Moreover, mitochondrial components and specific metabolic regulations modify properties of innate immune cells. These include macrophages, dendritic cells, innate lymphoid cells and so on, in steady state or in stimulation, that are involved in processes ranging from the tricarboxylic acid cycle to oxidative phosphorylation and fatty acid metabolism. Here we provide a brief summary of mitochondrial DAMPs' initiated and potentiated inflammatory response in the innate immune system. We also provide insights into how the state of activation, differentiation, and functional polarization of innate immune cells can be influenced by alteration to the metabolic pathways in mitochondria.

DOI: https://doi.org/10.1159/000533602
Sci Adv. 2023 Sep 08. 9(36): eadf9904

Infection-experienced HSPCs protect against infections by generating neutrophils with enhanced mitochondrial bactericidal activity.

Hannah Darroch, Pramuk Keerthisinghe, Yih Jian Sung, Leah Rolland, Anneke Prankerd-Gough, Philip S Crosier, Jonathan W Astin, Christopher J Hall.

Hematopoietic stem and progenitor cells (HSPCs) respond to infection by proliferating and generating in-demand neutrophils through a process called emergency granulopoiesis (EG). Recently, infection-induced changes in HSPCs have also been shown to underpin the longevity of trained immunity, where they generate innate immune cells with enhanced responses to subsequent microbial threats. Using larval zebrafish to live image neutrophils and HSPCs, we show that infection-experienced HSPCs generate neutrophils with enhanced bactericidal functions. Transcriptomic analysis of EG neutrophils uncovered a previously unknown function for mitochondrial reactive oxygen species in elevating neutrophil bactericidal activity. We also reveal that driving expression of zebrafish C/EBPβ within infection-naïve HSPCs is sufficient to generate neutrophils with similarly enhanced bactericidal capacity. Our work suggests that this demand-adapted source of neutrophils contributes to trained immunity by providing enhanced protection toward subsequent infections. Manipulating demand-driven granulopoiesis may provide a therapeutic strategy to boost neutrophil function and treat infectious disease.

DOI: https://doi.org/10.1126/sciadv.adf9904
Cytokine Growth Factor Rev. 2023 Aug 23. pii: S1359-6101(23)00055-2. [Epub ahead of print]

Multifaceted role of CD14 in innate immunity and tissue homeostasis.

Kunhee Na, Byung-Chul Oh, YunJae Jung.

  CD14 is a co-receptor of Toll-like receptor (TLR)- 4, with a critical role in innate immune responses. CD14 recognizes bacterial lipopolysaccharides, pathogen-, and damage-associated molecular patterns, thereby facilitating inflammatory immune responses. In addition to its well-established association with TLR4, CD14 is also implicated in TLR4-independent signaling, which leads to the apoptotic death of differentiated dendritic cells and activation of the noncanonical inflammasome pathway. CD14 also has a role beyond that of the immune responses. It contributes to tissue homeostasis by promoting the clearance of various apoptotic cells via recognizing externalized phosphatidylinositol phosphates. CD14 also has context-dependent roles, particularly in barrier tissues that include the skin and gastrointestinal tract. For example, CD14+ dendritic cells in the skin can induce immunostimulatory or immunosuppressive responses. In the gastrointestinal system, CD14 is involved in producing inflammatory cytokines in inflammatory bowel disease and maintaining of intestinal integrity. This review focuses on the multifaceted roles of CD14 in innate immunity and its potential regulatory functions in barrier tissues characterized by rapid cell renewal. By providing insights into the diverse functions of CD14, this review offers potential therapeutic implications for this versatile molecule in immune modulation and tissue homeostasis.

Keywords:  Apoptosis; Barrier tissues; CD14; Homeostasis; Lipopolysaccharide; TLR4

DOI:  https://doi.org/10.1016/j.cytogfr.2023.08.008
FASEB J. 2023 10;37(10): e23149

Disruption of the primocolonizing microbiota alters epithelial homeostasis and imprints stem cells in the colon of neonatal piglets.

Martin Beaumont, Corinne Lencina, Katia Fève, Céline Barilly, Laurence Le-Normand, Sylvie Combes, Guillaume Devailly, Gaëlle Boudry.

  The gut microbiota plays a key role in the postnatal development of the intestinal epithelium. However, the bacterial members of the primocolonizing microbiota driving these effects are not fully identified and the mechanisms underlying their long-term influence on epithelial homeostasis remain poorly described. Here, we used a model of newborn piglets treated during the first week of life with the antibiotic colistin in order to deplete specific gram-negative bacteria that are transiently dominant in the neonatal gut microbiota. Colistin depleted Proteobacteria and Fusobacteriota from the neonatal colon microbiota, reduced the bacterial predicted capacity to synthetize lipopolysaccharide (LPS), and increased the concentration of succinate in the colon. The colistin-induced disruption of the primocolonizing microbiota was associated with altered gene expression in the colon epithelium including a reduction of toll-like receptor 4 (TLR4) and lysozyme (LYZ). Our data obtained in porcine colonic organoid cell monolayers suggested that these effects were not driven by the variation of succinate or LPS levels nor by a direct effect of colistin on epithelial cells. The disruption of the primocolonizing microbiota imprinted colon epithelial stem cells since the expression of TLR4 and LYZ remained lower in organoids derived from colistin-treated piglet colonic crypts after several passages when compared to control piglets. Finally, the stable imprinting of LYZ in colon organoids was independent of the H3K4me3 level in its transcription start site. Altogether, our results show that disruption of the primocolonizing gut microbiota alters epithelial innate immunity in the colon and imprints stem cells, which could have long-term consequences for gut health.

Keywords:  colistin; epigenetics; gut microbiota; lipopolysaccharide; lysozyme; metabolites; monolayers; organoids; succinate; toll-like receptor 4

DOI:  https://doi.org/10.1096/fj.202301182R
J Leukoc Biol. 2023 Sep 06. pii: qiad103. [Epub ahead of print]

BCG vaccination induces innate immune memory in gamma delta T cells in humans.

Tsz K Suen, Simone J C F M Moorlag, Wenchao Li, Charlotte L J de Bree, Valerie A C M Koeken, Vera P Mourits, Helga Dijkstra, Heidi Lemmers, Jaydeep Bhat, Cheng-Jian Xu, Leo A B Joosten, Joachim L Schultze, Yang Li, Katarzyna Placek, Mihai G Netea.

  Bacillus Calmette-Guérin (BCG) vaccine is well-known for inducing trained immunity in myeloid and natural killer cells, which can explain its cross-protective effect against heterologous infections. Although displaying functional characteristics of both adaptive and innate immunity, γδ T cell memory has been only addressed in a pathogen-specific context. In this study we aimed to determine whether human γδ T cells can mount trained immunity and therefore contribute to the cross-protective effect of the BCG vaccine. We investigated in vivo induction of innate memory in γδ T cells by BCG vaccination in healthy human volunteers by combining single-cell RNA-sequencing technology with immune functional assays. The total number of γδ T cells and membrane markers of activation were not influenced by BCG vaccination. In contrast, BCG changed γδ T cells transcriptional programs and increased their responsiveness to heterologous bacterial and fungal stimuli, including LPS and Candida albicans, as simultaneously characterized by higher TNF and IFN-γ production, weeks after vaccination. Human γδ T cells in adults display the potential to develop a trained immunity phenotype after BCG vaccination.

Keywords:  BCG vaccine; immune memory; trained immunity; γδ T cells

DOI:  https://doi.org/10.1093/jleuko/qiad103
Eur J Immunol. 2023 Sep 06. e2350375

SIRPα: A key player in innate immunity.

Yongyi Feng, Chunliu Huang, Yingzhao Wang, Jun Chen.

  Signal regulatory protein alpha (SIRPα) is a crucial inhibitory regulator expressed on the surface of myeloid cells, including macrophages, dendritic cells (DCs), monocytes, neutrophils and microglia. SIRPα plays an indispensable role in innate immune and adoptive immune responses in cancer immunology, tissue homeostasis and other physiological or phycological conditions. This review provides an overview of the research history, ligands, signal transduction pathways and functional mechanisms associated with SIRPα. Additionally, we summarize the therapeutic implications of targeting SIRPα as a promising novel strategy in immuno-oncology. This article is protected by copyright. All rights reserved.

Keywords:  CD47; SIRPα; cancer immunology; diseases; innate immunity

DOI:  https://doi.org/10.1002/eji.202350375
mSystems. 2023 Sep 05. e0033223

Metabolic network construction reveals probiotic-specific alterations in the metabolic activity of a synthetic small intestinal community.

Jack Jansma, Anastasia Chrysovalantou Chatziioannou, Kitty Castricum, Saskia van Hemert, Sahar El Aidy.

  The gut microbiota plays a crucial role in maintaining overall health and probiotics have emerged as a promising microbiota-targeted therapy for improving human health. However, the molecular mechanisms of probiotics action in general and the targeting of small intestinal microbiota by probiotics are not well understood. To address this, we constructed a synthetic community of three species, which resembles the upper small intestinal microbiota. Our results indicate that probiotic supplementation can directly affect the metabolism of the community, resulting in colonization resistance in a probiotic-specific manner. Supplementation with Streptococcus thermophilus led to increased lactate production and a decrease in pH, while Lactobacillus casei supplementation increased the resistance to perturbations and nutrient utilization without affecting lactate production or pH. Additionally, when combined with kynurenine, Lactobacillus casei enhanced the kynurenine pathway metabolism resulting in elevated kynurenic acid levels and possibly indirect colonization resistance. Overall, our study reveals how selecting probiotics with distinct functional capacities can unlock the full potential of microbiota-targeted therapies.IMPORTANCEThe development of probiotic therapies targeted at the small intestinal microbiota represents a significant advancement in the field of probiotic interventions. This region poses unique opportunities due to its low number of gut microbiota, along with the presence of heightened immune and metabolic host responses. However, progress in this area has been hindered by a lack of detailed understanding regarding the molecular mechanisms through which probiotics exert their effects in the small intestine. Our study, utilizing a synthetic community of three small intestinal bacterial strains and the addition of two different probiotic species, and kynurenine as a representative dietary or endogenously produced compound, highlights the importance of selecting probiotic species with diverse genetic capabilities that complement the functional capacity of the resident microbiota, or alternatively, constructing a multispecies formula. This approach holds great promise for the development of effective probiotic therapies and underscores the need to consider the functional capacity of probiotic species when designing interventions.

Keywords:  dynamic metabolic networks; kynurenic acid; microbiota; probiotics; small intestine

DOI:  https://doi.org/10.1128/msystems.00332-23
PLoS Pathog. 2023 Sep 05. 19(9): e1011630

Airway metabolic profiling during Streptococcus pneumoniae infection identifies branched chain amino acids as signatures of upper airway colonisation.

Angharad E Green, Sian Pottenger, Manal S Monshi, Thomas E Barton, Marie Phelan, Daniel R Neill.

Streptococcus pneumoniae is a leading cause of community-acquired pneumonia and bacteraemia and is capable of remarkable phenotypic plasticity, responding rapidly to environmental change. Pneumococcus is a nasopharyngeal commensal, but is responsible for severe, acute infections following dissemination within-host. Pneumococcus is adept at utilising host resources, but the airways are compartmentalised and those resources are not evenly distributed. Challenges and opportunities in metabolite acquisition within different airway niches may contribute to the commensal-pathogen switch when pneumococcus moves from nasopharynx into lungs. We used NMR to characterise the metabolic landscape of the mouse airways, in health and during infection. Using paired nasopharynx and lung samples from naïve animals, we identified fundamental differences in metabolite bioavailability between airway niches. Pneumococcal pneumonia was associated with rapid and dramatic shifts in the lung metabolic environment, whilst nasopharyngeal carriage led to only modest change in upper airway metabolite profiles. NMR spectra derived from the nasopharynx of mice infected with closely-related pneumococcal strains that differ in their colonisation potential could be distinguished from one another using multivariate dimensionality reduction methods. The resulting models highlighted that increased branched-chain amino acid (BCAA) bioavailability in nasopharynx is a feature of infection with the high colonisation potential strain. Subsequent analysis revealed increased expression of BCAA transport genes and increased intracellular concentrations of BCAA in that same strain. Movement from upper to lower airway environments is associated with shifting challenges in metabolic resource allocation for pneumococci. Efficient biosynthesis, liberation or acquisition of BCAA is a feature of adaptation to nasopharyngeal colonisation.

DOI: https://doi.org/10.1371/journal.ppat.1011630
Int J Mol Sci. 2023 Aug 29. pii: 13382. [Epub ahead of print]24(17):

S100A8 and S100A9 in Hematologic Malignancies: From Development to Therapy.

Farnaz Razmkhah, Sena Kim, Sora Lim, Abdul-Jalil Dania, Jaebok Choi.

  S100A8 and S100A9 are multifunctional proteins that can initiate various signaling pathways and modulate cell function both inside and outside immune cells, depending on their receptors, mediators, and molecular environment. They have been reported as dysregulated genes and proteins in a wide range of cancers, including hematologic malignancies, from diagnosis to response to therapy. The role of S100A8 and S100A9 in hematologic malignancies is highlighted due to their ability to work together or as antagonists to modify cell phenotype, including viability, differentiation, chemosensitivity, trafficking, and transcription strategies, which can lead to an oncogenic phase or reduced symptoms. In this review article, we discuss the critical roles of S100A8, S100A9, and calprotectin (heterodimer or heterotetramer forms of S100A8 and S100A9) in forming and promoting the malignant bone marrow microenvironment. We also focus on their potential roles as biomarkers and therapeutic targets in various stages of hematologic malignancies from diagnosis to treatment.

Keywords:  S100A8; S100A9; calprotectin; hematologic malignancies; signal transduction

DOI:  https://doi.org/10.3390/ijms241713382
iScience. 2023 Sep 15. 26(9): 107596

Hematopoietic stem and progenitor cells confer cross-protective trained immunity in mouse models.

Bailee N Kain, Brandon T Tran, Pamela N Luna, Ruoqiong Cao, Duy T Le, Marcus A Florez, Laure Maneix, Jack D Toups, Daniel E Morales-Mantilla, Scott Koh, Hyojeong Han, Roman Jaksik, Yun Huang, Andre Catic, Chad A Shaw, Katherine Y King.

  Recent studies suggest that infection reprograms hematopoietic stem and progenitor cells (HSPCs) to enhance innate immune responses upon secondary infectious challenge, a process called "trained immunity." However, the specificity and cell types responsible for this response remain poorly defined. We established a model of trained immunity in mice in response to Mycobacterium avium infection. scRNA-seq analysis revealed that HSPCs activate interferon gamma-response genes heterogeneously upon primary challenge, while rare cell populations expand. Macrophages derived from trained HSPCs demonstrated enhanced bacterial killing and metabolism, and a single dose of recombinant interferon gamma exposure was sufficient to induce similar training. Mice transplanted with influenza-trained HSPCs displayed enhanced immunity against M. avium challenge and vice versa, demonstrating cross protection against antigenically distinct pathogens. Together, these results indicate that heterogeneous responses to infection by HSPCs can lead to long-term production of bone marrow derived macrophages with enhanced function and confer cross-protection against alternative pathogens.

Keywords:  Cell biology; Immunology; Microbiology; Stem cells research; Transcriptomics

DOI:  https://doi.org/10.1016/j.isci.2023.107596
Mol Med. 2023 09 05. 29(1): 119

The emerging roles of SUMOylation in pulmonary diseases.

Xuyang Zheng, Lingqiao Wang, Zhen Zhang, Huifang Tang.

  Small ubiquitin-like modifier mediated modification (SUMOylation) is a critical post-translational modification that has a broad spectrum of biological functions, including genome replication and repair, transcriptional regulation, protein stability, and cell cycle progression. Perturbation or deregulation of a SUMOylation and deSUMOylation status has emerged as a new pathophysiological feature of lung diseases. In this review, we highlighted the link between SUMO pathway and lung diseases, especially the sumoylated substrate such as C/EBPα in bronchopulmonary dysplasia (BDP), PPARγ in pneumonia, TFII-I in asthma, HDAC2 in chronic obstructive pulmonary disease (COPD), KLF15 in hypoxic pulmonary hypertension (HPH), SMAD3 in idiopathic pulmonary fibrosis (IPF), and YTHDF2 in cancer. By exploring the impact of SUMOylation in pulmonary diseases, we intend to shed light on its potential to inspire the development of innovative diagnostic and therapeutic strategies, holding promise for improving patient outcomes and overall respiratory health.

Keywords:  Hypoxic pulmonary hypertension; Idiopathic pulmonary fibrosis; Pneumonia; SUMOylation; cancer

DOI:  https://doi.org/10.1186/s10020-023-00719-1
Front Biosci (Landmark Ed). 2023 08 23. 28(8): 175

The Protective Role of TLR4 in Intestinal Epithelial Cells through the Regulation of the Gut Microbiota in DSS-Induced Colitis in Mice.

Yun-Jie Shi, Cheng Huang, Pi-Qing Gong, Cong Liu, Zhi-Qian Hu, Hao Wang.

   BACKGROUND: The cause of ulcerative colitis (UC) is not yet fully understood. Previous research has pointed towards a potential role for mutations in nucleotide-binding oligomerization domain-containing protein 2 (NOD2) in promoting the onset and progression of inflammatory bowel disease (IBD) by altering the microbiota of the gut. However, the relationship between toll-like receptor 4 (TLR4) and gut microbiota in IBD is not well understood. To shed light on this, the interaction between TLR4 and gut microbiota was studied using a mouse model of IBD.
METHODS: To examine the function of TLR4 signaling in intestinal injury repair, researchers developed Dextran Sulfate Sodium Salt (DSS)-induced colitis and injury models in both wild-type (WT) mice and TLR4 knockout (TLR4-KO) mice. To assess changes in the gut microbiota, 16S rRNA sequencing was conducted on fecal samples from both the TLR4-KO and WT enteritis mouse models.
RESULTS: The data obtained depicted a protective function of TLR4 against DSS-induced colitis. The gut microbiota composition was found to vary considerably between the WT and TLR4-KO mice groups as indicated by β-diversity analysis and operational taxonomic units (OTUs) cluster. Statistical analysis of microbial multivariate variables depicted an elevated abundance of Escherichia coli/Shigella, Gammaproteobacteria, Tenerlcutes, Deferribacteres, Enterobacteria, Rikenellaceae, and Proteobacteria in the gut microbiota of TLR4-KO mice, whereas there was a considerable reduction in Bacteroidetes at five different levels of the phylogenetic hierarchy including phylum, class, order, family, and genus in comparison with the WT control.
CONCLUSIONS: TLR4 may protect intestinal epithelial cells from damage in response to DSS-induced injury by controlling the microbiota in the gut.

Keywords:  16S rRNA sequencing; DSS-induced colitis; gut microbiota; toll-like receptor 4

DOI:  https://doi.org/10.31083/j.fbl2808175
bioRxiv. 2023 Aug 26. pii: 2023.08.25.554865. [Epub ahead of print]

Platelet Factor 4 (PF4) Improves Survival in a Murine Model of Antibiotic-Susceptible and Methicillin-Resistant Staphylococcus Aureus Peritonitis.

Nataly P Podolnikova, Valeryi K Lishko, Robert Roberson, Zhqian Koh, Dmitry Derkach, David Richardson, Michael Sheller, Tatiana P Ugarova.

The complement receptor CR3, also known as integrin Mac-1 (CD11b/CD18), is one of the major phagocytic receptors on the surface of neutrophils and macrophages. We previously demonstrated that in its protein ligands, Mac-1 binds sequences enriched in basic and hydrophobic residues and strongly disfavors negatively charged sequences. The avoidance by Mac-1 of negatively charged surfaces suggests that the bacterial wall and bacterial capsule possessing net negative electrostatic charge may repel Mac-1 and that the cationic Mac-1 ligands can overcome this evasion by acting as opsonins. Indeed, we previously showed that opsonization of Gram-negative Escherichia coli with several cationic peptides, including PF4 (Platelet Factor 4), strongly augmented phagocytosis by macrophages. Here, we investigated the effect of recombinant PF4 (rPF4) on phagocytosis of Gram-positive Staphylococcus aureus in vitro and examined its impact in a mouse model of S. aureus peritonitis. Characterization of the interaction of rPF4 with nonencapsulated and encapsulated S. aureus showed that rPF4 localizes on the bacterial surface, thus making it available for Mac-1. Furthermore, rPF4 did not have direct bactericidal and bacteriostatic activity and was not toxic to host cells. rPF4 enhanced phagocytosis of S. aureus bioparticles by various primary and cultured Mac-1-expressing leukocytes by several folds. It also increased phagocytosis of live nonencapsulated and encapsulated bacteria. Notably, the augmentation of phagocytosis by rPF4 did not compromise the intracellular killing of S. aureus by macrophages. Using a murine S. aureus peritonitis model, we showed that treatment of infected mice with rPF4 caused a significant increase in the clearance of antibiotic-susceptible S. aureus and its methicillin-resistant (MRSA) variant and markedly improved survival. These findings indicate that rPF4 binding to the bacterial surface circumvents its antiphagocytic properties, improving host defense against antibiotic-susceptible and antibiotic-resistant bacteria.

DOI: https://doi.org/10.1101/2023.08.25.554865
Nat Rev Immunol. 2023 Sep 04.

Orally delivered lactate-producing bacteria limit CNS autoimmunity.

Kirsty Minton.

DOI: https://doi.org/10.1038/s41577-023-00938-x
iScience. 2023 Sep 15. 26(9): 107700

Spatial lipidomics reveals biased phospholipid remodeling in acute Pseudomonas lung infection.

Alison J Scott, Shane R Ellis, Casey E Hofstaedter, Ron M A Heeren, Robert K Ernst.

  Pseudomonas aeruginosa (Pa) is a pathogen causing chronic pulmonary infections in patients with cystic fibrosis (CF). Manipulation of lipids is an important feature of Pa infection and on a tissue-level scale is poorly understood. Using a mouse model of acute Pa pulmonary infection, we explored the whole-lung phospholipid response using mass spectrometry imaging (MSI) and spatial lipidomics. Using a histology-driven analysis, we isolated airways and parenchyma from both mock- and Pa-infected lungs and used systems biology tools to identify enriched metabolic pathways from the differential phospholipid identities. Infection was associated with a set of 26 ions, with 11 unique to parenchyma and 6 unique to airways. Acyl remodeling was differentially enriched in infected parenchyma as the predominant biological function. These functions correlated with markers of polymorphonuclear (PMN) cell influx, a defining feature of the lung response to Pa infection, implicating enzymes active in phospholipid remodeling.

Keywords:  Biological sciences; Lipidomics; Microbiology

DOI:  https://doi.org/10.1016/j.isci.2023.107700
Heliyon. 2023 Sep;9(9): e19249

Pathogenesis of chronic rhinosinusitis with nasal polyp and a prominent T2 endotype.

Said Ahmad Shah, Masayoshi Kobayashi.

  Chronic rhinosinusitis is a heterogenous and multifactorial disease, characterized by persistent inflammation of the nose and paranasal sinuses, which causes nasal obstruction, nasal discharge, facial pain, and smell disturbance. Chronic rhinosinusitis is divided into two phenotypes: chronic rhinosinusitis with nasal polyp and chronic rhinosinusitis without nasal polyp. Nasal polyps can be associated with many inflammatory cells including eosinophil cells, neutrophil cells, plasma cells, and lymphocytes. T2 endotype is characterized by the type-2 immune response and nasal polyps are associated with eosinophilic dominant infiltration. In contrast, in the T1 and T3 endotypes, chronic rhinosinusitis can be associated with neutrophilic dominant infiltration. In addition, there are mixed types of inflammation with different proportions of eosinophils-neutrophils in chronic rhinosinusitis. In the T2 endotype, there is an increase in the production of Th2 cytokines, including interleukin-4, interleukin-5, and interleukin-13, high levels of immunoglobulin-E in polyp tissue, and eosinophilia. Stimulation of Th2 cells, type-2 innate lymphoid cells, epithelial cell damage, Staphylococcus aureus enterotoxins, and autoimmune antibodies have important roles in the enhancement of Th2 cytokines and pathogenesis of chronic rhinosinusitis with nasal polyp. Monoclonal antibodies target type-2 inflammation, decrease nasal polyp size, and improve the clinical symptoms of CRSwNP patients. The present review will focus on factors involved in the pathogenesis of chronic rhinosinusitis and its treatment.

Keywords:  Chronic rhinosinusitis; Eosinophilia; Monoclonal antibody; Nasal polyp; T cell response

DOI:  https://doi.org/10.1016/j.heliyon.2023.e19249
JCI Insight. 2023 Sep 07. pii: e173374. [Epub ahead of print]

Epithelial Yap/Taz are required for functional alveolar regeneration following acute lung injury.

Gianluca T DiGiovanni, Wei Han, Taylor P Sherrill, Chase J Taylor, David S Nichols, Natalie M Geis, Ujjal K Singha, Carla L Calvi, A Scott McCall, Molly M Dixon, Yang Liu, Ji-Hoon Jang, Sergey S Gutor, Vasiliy V Polosukhin, Timothy S Blackwell, Jonathan A Kropski, Jason J Gokey.

  A hallmark of idiopathic pulmonary fibrosis (IPF) and other interstitial lung diseases is dysregulated repair of the alveolar epithelium. The Hippo pathway effector transcription factors YAP and TAZ are implicated as essential for type 1 and type 2 alveolar epithelial cell (AT1 and AT2) differentiation in the developing lung, yet aberrant activation of YAP/TAZ is a prominent feature of the dysregulated alveolar epithelium in IPF. In these studies, we sought to define the functional role of YAP/TAZ activity during alveolar regeneration. We demonstrated that Yap and Taz are normally activated in AT2 cells shortly after injury, and deletion of Yap/Taz in AT2 cells led to pathologic alveolar remodeling, failure of AT2 to AT1 cell differentiation, increased collagen deposition, exaggerated neutrophilic inflammation, and increased mortality following injury induced by a single dose of bleomycin. Loss of Yap/Taz activity prior to a LPS injury prevented AT1 cell regeneration, led to intra-alveolar collagen deposition, and resulted in persistent innate inflammation. Together these findings established that AT2 cell Yap/Taz activity is essential for functional alveolar epithelial repair and prevention of fibrotic remodeling.

Keywords:  Fibrosis; Mouse stem cells; Pulmonology

DOI:  https://doi.org/10.1172/jci.insight.173374