bims-bac4me 2024-08-11 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2024‒08‒11
twenty-six papers selected by
Chun-Chi Chang, University Hospital Zurich

Blocking HXA3-mediated neutrophil elastase release during S. pneumoniae lung infection limits pulmonary epithelial barrier disruption and bacteremia.
Revisiting the role of hypoxia-inducible factors and nuclear factor erythroid 2-related factor 2 in regulating macrophage inflammation and metabolism.
The epithelial cell types and their multi-phased defenses against fungi and other pathogens.
Alveolar macrophages and monocyte subpopulations during Plasmodium berghei NK65 experimental malaria-associated acute respiratory distress syndrome.
AMPK activation induces RALDH+ tolerogenic dendritic cells by rewiring glucose and lipid metabolism.
Coordinating energy metabolism and signaling pathways in epithelial self-renewal and differentiation.
The Central Roles of Keratinocytes in Coordinating Skin Immunity.
Evidence of innate training in bovine γδ T cells following subcutaneous BCG administration.
EGFR-MEK1/2 cascade negatively regulates bactericidal function of bone marrow macrophages in mice with Staphylococcus aureus osteomyelitis.
Types of cell death and their relations to host immunological pathways.
Stroke triggers an innate immune memory that drives cardiac dysfunction.
Transcriptomic analysis of primary nasal epithelial cells reveals altered interferon signalling in preterm birth survivors at one year of age.
How migrating cells define their back to move forward.
Author Correction: Commensal production of a broad-spectrum and short-lived antimicrobial peptide polyene eliminates nasal Staphylococcus aureus.
Reevaluating Human-Microbiota Symbiosis: Strain-Level Insights and Evolutionary Perspectives Across Animal Species.
Non-classical monocytes have the support of the whole vascular tree.
Spatial and phenotypic heterogeneity of resident and monocyte-derived macrophages during inflammatory exacerbations leading to pulmonary fibrosis.
Bifidobacterium and Lactobacillus Probiotics and Gut Dysbiosis in Preterm Infants: The PRIMAL Randomized Clinical Trial.
A novel approach to investigate severe asthma and COPD: the 3D Ex Vivo Respiratory Mucosa Model.
Preventive effects of probiotics on dental caries in vitro and in vivo.
Is Nasal Dysbiosis a Required Component for Neuroinflammation in Major Depressive Disorder?
Editorial: Phenotypic variation as an important aspect of staphylococcal pathogenesis.
From cytokines to chemokines: Understanding inflammatory signaling in bacterial meningitis.
Integrative Analyses Reveal the Correlation Between the Airway Microbiome and Host Metabolism in Severe Community-acquired Pneumonia.
Association of Staphylococcus aureus Bacterial Load and Colonization Sites With the Risk of Postoperative S. aureus Infection.
The Microbiome: A Foundation for Integrative Medicine.

mBio. 2024 Aug 09. e0185624

Blocking HXA3-mediated neutrophil elastase release during S. pneumoniae lung infection limits pulmonary epithelial barrier disruption and bacteremia.

Shuying Xu, Shumin Tan, Patricia Romanos, Jennifer L Reedy, Yihan Zhang, Michael K Mansour, Jatin M Vyas, Joan Mecsas, Hongmei Mou, John M Leong.

  Streptococcus pneumoniae (Sp), a leading cause of community-acquired pneumonia, can spread from the lung into the bloodstream to cause septicemia and meningitis, with a concomitant threefold increase in mortality. Limitations in vaccine efficacy and a rise in antimicrobial resistance have spurred searches for host-directed therapies that target pathogenic immune processes. Polymorphonuclear leukocytes (PMNs) are essential for infection control but can also promote tissue damage and pathogen spread. The major Sp virulence factor, pneumolysin, triggers acute inflammation by stimulating the 12-lipoxygenase (12-LOX) eicosanoid synthesis pathway in epithelial cells. This pathway is required for systemic spread in a mouse pneumonia model and produces a number of bioactive lipids, including hepoxilin A3 (HXA3), a hydroxy epoxide PMN chemoattractant that has been hypothesized to facilitate breach of mucosal barriers. To understand how 12-LOX-dependent inflammation promotes dissemination during Sp lung infection and dissemination, we utilized bronchial stem cell-derived air-liquid interface cultures that lack this enzyme to show that HXA3 methyl ester (HXA3-ME) is sufficient to promote basolateral-to-apical PMN transmigration, monolayer disruption, and concomitant Sp barrier breach. In contrast, PMN transmigration in response to the non-eicosanoid chemoattractant N-formyl-L-methionyl-L-leucyl-phenylalanine (fMLP) did not lead to epithelial disruption or bacterial translocation. Correspondingly, HXA3-ME but not fMLP increased the release of neutrophil elastase (NE) from Sp-infected PMNs. Pharmacologic blockade of NE secretion or activity diminished epithelial barrier disruption and bacteremia after pulmonary challenge of mice. Thus, HXA3 promotes barrier-disrupting PMN transmigration and NE release, pathological events that can be targeted to curtail systemic disease following pneumococcal pneumonia.IMPORTANCEStreptococcus pneumoniae (Sp), a leading cause of pneumonia, can spread from the lung into the bloodstream to cause systemic disease. Limitations in vaccine efficacy and a rise in antimicrobial resistance have spurred searches for host-directed therapies that limit pathologic host immune responses to Sp. Excessive polymorphonuclear leukocyte (PMN) infiltration into Sp-infected airways promotes systemic disease. Using stem cell-derived respiratory cultures that reflect bona fide lung epithelium, we identified eicosanoid hepoxilin A3 as a critical pulmonary PMN chemoattractant that is sufficient to drive PMN-mediated epithelial damage by inducing the release of neutrophil elastase. Inhibition of the release or activity of this protease in mice limited epithelial barrier disruption and bacterial dissemination, suggesting a new host-directed treatment for Sp lung infection.

Keywords:  12-lipoxygenase; Streptococcus pneumoniae; airway mucosal barrier; neutrophil elastase; neutrophil transmigration

DOI:  https://doi.org/10.1128/mbio.01856-24
Front Cell Infect Microbiol. 2024 ;14 1403915

Revisiting the role of hypoxia-inducible factors and nuclear factor erythroid 2-related factor 2 in regulating macrophage inflammation and metabolism.

Kenneth K Y Ting.

  The recent birth of the immunometabolism field has comprehensively demonstrated how the rewiring of intracellular metabolism is critical for supporting the effector functions of many immune cell types, such as myeloid cells. Among all, the transcriptional regulation mediated by Hypoxia-Inducible Factors (HIFs) and Nuclear factor erythroid 2-related factor 2 (NRF2) have been consistently shown to play critical roles in regulating the glycolytic metabolism, redox homeostasis and inflammatory responses of macrophages (Mφs). Although both of these transcription factors were first discovered back in the 1990s, new advances in understanding their function and regulations have been continuously made in the context of immunometabolism. Therefore, this review attempts to summarize the traditionally and newly identified functions of these transcription factors, including their roles in orchestrating the key events that take place during glycolytic reprogramming in activated myeloid cells, as well as their roles in mediating Mφ inflammatory responses in various bacterial infection models.

Keywords:  HIF-1a hypoxia-inducible factor-1a; LPS; NADPH; NRF2; immunometabolism; inflammation; macrophage; redox

DOI:  https://doi.org/10.3389/fcimb.2024.1403915
Clin Chim Acta. 2024 Aug 06. pii: S0009-8981(24)02142-9. [Epub ahead of print] 119889

The epithelial cell types and their multi-phased defenses against fungi and other pathogens.

Kevin Roe.

  Mucus and its movements are essential to epithelial tissue immune defenses against pathogens, including fungal pathogens, which can infect respiratory, gastrointestinal or the genito-urinary tracts. Several epithelial cell types contribute to their immune defense. This review focuses on the respiratory tract because of its paramount importance, but the observations will apply to epithelial cell defenses of other mucosal tissue, including the gastrointestinal and genito-urinary tracts. Mucus and its movements can enhance or degrade the immune defenses of the respiratory tract, particularly the lungs. The enhancements include inhaled pathogen entrapments, including fungal pathogens, pollutants and particulates, for their removal. The detriments include smaller lung airway obstructions by mucus, impairing the physical removal of pathogens and impairing vital transfers of oxygen and carbon dioxide between the alveolar circulatory system and the pulmonary air. Inflammation, edema and/or alveolar cellular damage can also reduce vital transfers of oxygen and carbon dioxide between the lung alveolar circulatory system and the pulmonary air. Furthermore, respiratory tract defenses are affected by several fatty acid mediators which activate cellular receptors to manipulate neutrophils, macrophages, dendritic cells, various innate lymphoid cells including the natural killer cells, T cells, γδ T cells, mucosal-associated invariant T cells, NKT cells and mast cells. These mediators include the inflammatory and frequently immunosuppressive prostaglandins and leukotrienes, and the special pro-resolving mediators, which normally resolve inflammation and immunosuppression. The total effects on the various epithelial cell and immune cell types, after exposures to pathogens, pollutants or particulates, will determine respiratory tract health or disease.

Keywords:  Epithelial Cells; Mucociliary Clearance; Mucus; Respiratory Defenses; Respiratory Pathogens; Special Pro-Resolving Mediators

DOI:  https://doi.org/10.1016/j.cca.2024.119889
Heliyon. 2024 Jul 30. 10(14): e33739

Alveolar macrophages and monocyte subpopulations during Plasmodium berghei NK65 experimental malaria-associated acute respiratory distress syndrome.

Flaviane Vieira-Santos, Ramayana Morais de Medeiros Brito, Camila de Almeida Lopes, Thais Leal-Silva, Jorge Lucas Nascimento Souza, Chiara Cássia Oliveira Amorim, Ana Cristina Loiola Ruas, Luiza de Lima Silva Padrão, Lucas Kraemer, Fabrício Marcus Silva Oliveira, Marcelo Vidigal Caliari, Remo Castro Russo, Ricardo Toshio Fujiwara, Luisa Mourão Dias Magalhães, Lilian Lacerda Bueno.

  Alveolar macrophages (AM) and monocytes (MO) are myeloid cells that play a substantial role in the development and establishment of the innate and adaptive immune response. These cells are crucial for host defense against various pathogens, but their role in malaria is poorly understood. Here, we characterize the dynamics of AMs and recruited leukocytes subpopulations in the airways during experimental Plasmodium berghei NK65-NY (PbNK65). We show that PbNK65 infection induces an increased pulmonary vascular permeability that provides Ly6Clow MOs, neutrophils (NEU), CD4+ and CD8+ lymphocytes in the airways. This inflammatory environment resulted in an increase in the population and alteration of the activation state of the AMs. Taken together, the data presented provide new insights into airway inflammation associated with pulmonary malaria.

Keywords:  Acute respiratory distress syndrome; Alveolar macrophages; Inflammation; Monocytes; Plasmodium berghei NK65-NY

DOI:  https://doi.org/10.1016/j.heliyon.2024.e33739
J Cell Biol. 2024 Oct 07. pii: e202401024. [Epub ahead of print]223(10):

AMPK activation induces RALDH+ tolerogenic dendritic cells by rewiring glucose and lipid metabolism.

Eline C Brombacher, Thiago A Patente, Alwin J van der Ham, Tijmen J A Moll, Frank Otto, Fenne W M Verheijen, Esther A Zaal, Arnoud H de Ru, Rayman T N Tjokrodirijo, Celia R Berkers, Peter A van Veelen, Bruno Guigas, Bart Everts.

Dendritic cell (DC) activation and function are underpinned by profound changes in cellular metabolism. Several studies indicate that the ability of DCs to promote tolerance is dependent on catabolic metabolism. Yet the contribution of AMP-activated kinase (AMPK), a central energy sensor promoting catabolism, to DC tolerogenicity remains unknown. Here, we show that AMPK activation renders human monocyte-derived DCs tolerogenic as evidenced by an enhanced ability to drive differentiation of regulatory T cells, a process dependent on increased RALDH activity. This is accompanied by several metabolic changes, including increased breakdown of glycerophospholipids, enhanced mitochondrial fission-dependent fatty acid oxidation, and upregulated glucose catabolism. This metabolic rewiring is functionally important as we found interference with these metabolic processes to reduce to various degrees AMPK-induced RALDH activity as well as the tolerogenic capacity of moDCs. Altogether, our findings reveal a key role for AMPK signaling in shaping DC tolerogenicity and suggest AMPK as a target to direct DC-driven tolerogenic responses in therapeutic settings.

DOI: https://doi.org/10.1083/jcb.202401024
Biol Direct. 2024 Aug 07. 19(1): 63

Coordinating energy metabolism and signaling pathways in epithelial self-renewal and differentiation.

Maria Pia Polito, Alessio Romaldini, Serena Rinaldo, Elena Enzo.

  Epidermal stem cells (EPSCs) are essential for maintaining skin homeostasis and ensuring a proper wound healing. During in vitro cultivations, EPSCs give rise to transient amplifying progenitors and differentiated cells, finally forming a stratified epithelium that can be grafted onto patients. Epithelial grafts have been used in clinics to cure burned patients or patients affected by genetic diseases. The long-term success of these advanced therapies relies on the presence of a correct amount of EPSCs that guarantees long-term epithelial regeneration. For this reason, a deeper understanding of self-renewal and differentiation is fundamental to fostering their clinical applications.The coordination between energetic metabolism (e.g., glycolysis, tricarboxylic acid cycle, oxidative phosphorylation, and amino acid synthesis pathways), molecular signalling pathways (e.g., p63, YAP, FOXM1, AMPK/mTOR), and epigenetic modifications controls fundamental biological processes as proliferation, self-renewal, and differentiation. This review explores how these signalling and metabolic pathways are interconnected in the epithelial cells, highlighting the distinct metabolic demands and regulatory mechanisms involved in skin physiology.

Keywords:  Epidermal stem cells; Metabolism; Signaling pathways

DOI:  https://doi.org/10.1186/s13062-024-00510-0
J Invest Dermatol. 2024 Aug 07. pii: S0022-202X(24)01882-7. [Epub ahead of print]

The Central Roles of Keratinocytes in Coordinating Skin Immunity.

Jared Simmons, Richard L Gallo.

  The function of keratinocytes (KCs) to form a barrier and produce cytokines is well-known, but recent progress has revealed many different roles for KCs in regulation of skin immunity. In this review, we provide an update on the current understanding of how KCs communicate with microbes, immunocytes, neurons, and other cells to form an effective immune barrier. We catalog the large list of genes and metabolites of KCs that participate in host defense and discuss the mechanisms of immune crosstalk, addressing how KCs simultaneously form a physical barrier, communicate with fibroblasts, and control immune signals. Overall, the signals sent and received by KCs are an exciting group of therapeutic targets to explore in the treatment of dermatologic disorders.

Keywords:  Cytokines; Epidermis; ILs; Inflammation; Microbiome

DOI:  https://doi.org/10.1016/j.jid.2024.06.1280
Front Immunol. 2024 ;15 1423843

Evidence of innate training in bovine γδ T cells following subcutaneous BCG administration.

Beulah Esther Rani Samuel, Fabian E Diaz, Teresia W Maina, Ryan J Corbett, Christopher K Tuggle, Jodi L McGill.

  The Bacillus Calmette Guerin (BCG) vaccine has been shown to induce non-specific protection against diseases other than tuberculosis in vaccinated individuals, attributed to the induction of trained immunity. We have previously demonstrated that BCG administration induces innate immune training in mixed peripheral blood mononuclear cells and monocytes in calves. Gamma Delta (γδ) T cells are non-conventional T cells that exhibit innate and adaptive immune system features. They are in higher proportion in the peripheral blood of cattle than humans or rodents and play an essential role in bovine immune response to pathogens. In the current study, we determined if BCG administration induced innate immune training in bovine γδ T cells. A group of 16 pre-weaned Holstein calves (2-4 d age) were enrolled in the study and randomly assigned to vaccine and control groups (n=8/group). The vaccine group received two doses of 106 colony forming units (CFU) BCG Danish strain subcutaneously, separated by 2 weeks. The control group remained unvaccinated. Gamma delta T cells were purified from peripheral blood using magnetic cell sorting three weeks after receiving the 1st BCG dose. We observed functional changes in the γδ T cells from BCG-treated calves shown by increased IL-6 and TNF-α cytokine production in response to in vitro stimulation with Escherichia coli LPS and PAM3CSK4. ATAC-Seq analysis of 78,278 regions of open chromatin (peaks) revealed that γδ T cells from BCG-treated calves had an altered epigenetic status compared to cells from the control calves. Differentially accessible peaks (DAP) found near the promoters of innate immunity-related genes like Siglec14, Irf4, Ifna2, Lrrfip1, and Tnfrsf10d were 1 to 4-fold more accessible in cells from BCG-treated calves. MOTIF enrichment analysis of the sequences within DAPs, which explores transcription factor binding motifs (TFBM) upstream of regulatory elements, revealed TFBM for Eomes and IRF-5 were among the most enriched transcription factors. GO enrichment analysis of genes proximal to the DAPs showed enrichment of pathways such as regulation of IL-2 production, T-cell receptor signaling pathway, and other immune regulatory pathways. In conclusion, our study shows that subcutaneous BCG administration in pre-weaned calves can induce innate immune memory in the form of trained immunity in γδ T cells. This memory is associated with increased chromatin accessibility of innate immune response-related genes, thereby inducing a functional trained immune response evidenced by increased IL-6 and TNF-α cytokine production.

Keywords:  BCG vaccine; bovine γδ T cells; chromatin accessibility; epigenetic reprogramming; trained immunity

DOI:  https://doi.org/10.3389/fimmu.2024.1423843
PLoS Pathog. 2024 Aug 05. 20(8): e1012437

EGFR-MEK1/2 cascade negatively regulates bactericidal function of bone marrow macrophages in mice with Staphylococcus aureus osteomyelitis.

Mingchao Jin, Xiaohu Wu, Jin Hu, Yijie Chen, Bingsheng Yang, Chubin Cheng, Mankai Yang, Xianrong Zhang.

The ability of Staphylococcus aureus (S. aureus) to survive within macrophages is a critical strategy for immune evasion, contributing to the pathogenesis and progression of osteomyelitis. However, the underlying mechanisms remain poorly characterized. This study discovered that inhibiting the MEK1/2 pathway reduced bacterial load and mitigated bone destruction in a mouse model of S. aureus osteomyelitis. Histological staining revealed increased phosphorylated MEK1/2 levels in bone marrow macrophages surrounding abscess in the mouse model of S. aureus osteomyelitis. Activation of MEK1/2 pathway and its roles in impairing macrophage bactericidal function were confirmed in primary mouse bone marrow-derived macrophages (BMDMs). Transcriptome analysis and in vitro experiments demonstrated that S. aureus activates the MEK1/2 pathway through EGFR signaling. Moreover, we found that excessive activation of EGFR-MEK1/2 cascade downregulates mitochondrial reactive oxygen species (mtROS) levels by suppressing Chek2 expression, thereby impairing macrophage bactericidal function. Furthermore, pharmacological inhibition of EGFR signaling prevented upregulation of phosphorylated MEK1/2 and restored Chek2 expression in macrophages, significantly enhancing S. aureus clearance and improving bone microstructure in vivo. These findings highlight the critical role of the EGFR-MEK1/2 cascade in host immune defense against S. aureus, suggesting that S. aureus may reduce mtROS levels by overactivating the EGFR-MEK1/2 cascade, thereby suppressing macrophage bactericidal function. Therefore, combining EGFR-MEK1/2 pathway blockade with antibiotics could represent an effective therapeutic approach for the treatment of S. aureus osteomyelitis.

DOI: https://doi.org/10.1371/journal.ppat.1012437
Aging (Albany NY). 2024 Aug 08. 16

Types of cell death and their relations to host immunological pathways.

Kuo-Cheng Lu, Kuo-Wang Tsai, Yu-Kuen Wang, Wan-Chung Hu.

  Various immune pathways have been identified in the host, including TH1, TH2, TH3, TH9, TH17, TH22, TH1-like, and THαβ immune reactions. While TH2 and TH9 responses primarily target multicellular parasites, host immune pathways directed against viruses, intracellular microorganisms (such as bacteria, protozoa, and fungi), and extracellular microorganisms can employ programmed cell death mechanisms to initiate immune responses or execute effective strategies for pathogen elimination. The types of programmed cell death involved include apoptosis, autophagy, pyroptosis, ferroptosis, necroptosis, and NETosis. Specifically, apoptosis is associated with host anti-virus eradicable THαβ immunity, autophagy with host anti-virus tolerable TH3 immunity, pyroptosis with host anti-intracellular microorganism eradicable TH1 immunity, ferroptosis with host anti-intracellular microorganism tolerable TH1-like immunity, necroptosis with host anti-extracellular microorganism eradicable TH22 immunity, and NETosis with host anti-extracellular microorganism tolerable TH17 immunity.

Keywords:  NETosis; apoptosis; autophagy; ferroptosis; necroptosis; pyroptosis

DOI:  https://doi.org/10.18632/aging.206035
Nat Rev Cardiol. 2024 Aug 07.

Stroke triggers an innate immune memory that drives cardiac dysfunction.

Irene Fernández-Ruiz.

DOI: https://doi.org/10.1038/s41569-024-01069-z
Front Cell Dev Biol. 2024 ;12 1399005

Transcriptomic analysis of primary nasal epithelial cells reveals altered interferon signalling in preterm birth survivors at one year of age.

Denby J Evans, Jessica K Hillas, Thomas Iosifidis, Shannon J Simpson, Anthony Kicic, Patricia Agudelo-Romero.

  Introduction: Many survivors of preterm birth (<37 weeks gestation) have lifelong respiratory deficits, the drivers of which remain unknown. Influencers of pathophysiological outcomes are often detectable at the gene level and pinpointing these differences can help guide targeted research and interventions. This study provides the first transcriptomic analysis of primary nasal airway epithelial cells in survivors of preterm birth at approximately 1 year of age. Methods: Nasal airway epithelial brushings were collected, and primary cell cultures established from term (>37 weeks gestation) and very preterm participants (≤32 weeks gestation). Ex vivo RNA was collected from brushings with sufficient cell numbers and in vitro RNA was extracted from cultured cells, with bulk RNA sequencing performed on both the sample types. Differential gene expression was assessed using the limma-trend pipeline and pathway enrichment identified using Reactome and GO analysis. To corroborate gene expression data, cytokine concentrations were measured in cell culture supernatant. Results: Transcriptomic analysis to compare term and preterm cells revealed 2,321 genes differentially expressed in ex vivo samples and 865 genes differentially expressed in cultured basal cell samples. Over one third of differentially expressed genes were related to host immunity, with interferon signalling pathways dominating the pathway enrichment analysis and IRF1 identified as a hub gene. Corroboration of disrupted interferon release showed that concentrations of IFN-α2 were below measurable limits in term samples but elevated in preterm samples [19.4 (76.7) pg/ml/µg protein, p = 0.03]. IFN-γ production was significantly higher in preterm samples [3.3 (1.5) vs. 9.4 (17.7) pg/ml/µg protein; p = 0.01] as was IFN-β [7.8 (2.5) vs. 13.6 (19.5) pg/ml/µg protein, p = 0.01]. Conclusion: Host immunity may be compromised in the preterm nasal airway epithelium in early life. Altered immune responses may lead to cycles of repeated infections, causing persistent inflammation and tissue damage which can have significant impacts on long-term respiratory function.

Keywords:  RNA seq analysis; airway epithelial; bronchopulmonary dysplasia; interferon; preterm

DOI:  https://doi.org/10.3389/fcell.2024.1399005
Nature. 2024 Aug 07.

How migrating cells define their back to move forward.



Keywords:  Cell biology; Molecular biology

DOI:  https://doi.org/10.1038/d41586-024-02572-6
Nat Microbiol. 2024 Aug 08.

Author Correction: Commensal production of a broad-spectrum and short-lived antimicrobial peptide polyene eliminates nasal Staphylococcus aureus.

Benjamin O Torres Salazar, Taulant Dema, Nadine A Schilling, Daniela Janek, Jan Bornikoel, Anne Berscheid, Ahmed M A Elsherbini, Sophia Krauss, Simon J Jaag, Michael Lämmerhofer, Min Li, Norah Alqahtani, Malcolm J Horsburgh, Tilmann Weber, José Manuel Beltrán-Beleña, Heike Brötz-Oesterhelt, Stephanie Grond, Bernhard Krismer, Andreas Peschel.

DOI: https://doi.org/10.1038/s41564-024-01798-4
Biosystems. 2024 Aug 03. pii: S0303-2647(24)00168-0. [Epub ahead of print] 105283

Reevaluating Human-Microbiota Symbiosis: Strain-Level Insights and Evolutionary Perspectives Across Animal Species.

Gabriel Trueba, Paul Cardenas, German Romo, Bernardo Gutierrez.

  The prevailing consensus in scientific literature underscores the mutualistic bond between the microbiota and the human host, suggesting a finely tuned coevolutionary partnership that enhances the fitness of both parties. This symbiotic relationship has been extensively studied, with certain bacterial attributes being construed as hallmarks of natural selection favoring the benefit of the human host. Some scholars go as far as equating the intricate interplay between humans and their intestinal microbiota to that of endosymbiotic relationships, even conceptualizing microbiota as an integral human organ. However, amidst the prevailing narrative of bacterial species being categorized as beneficial or detrimental to human health, a critical oversight often emerges - the inherent functional diversity within bacterial strains. Such reductionist perspectives risk oversimplifying the complex dynamics at play within the microbiome. Recent genomic analysis at the strain level is highly limited, which is surprising given that strain information provides critical data about selective pressures in the intestine. These pressures appear to focus more on the well-being of bacteria rather than human health. Connected to this is the extent to which animals depend on metabolic activity from intestinal bacteria, which varies widely across species. While omnivores like humans exhibit lower dependency, certain herbivores rely entirely on bacterial activity and have developed specialized compartments to house these bacteria.

Keywords:  Microbiota; mobile genetic elements; mutualism; natural selection

DOI:  https://doi.org/10.1016/j.biosystems.2024.105283
Nat Rev Immunol. 2024 Aug 08.

Non-classical monocytes have the support of the whole vascular tree.

Kirsty Minton.

DOI: https://doi.org/10.1038/s41577-024-01078-6
Front Immunol. 2024 ;15 1425466

Spatial and phenotypic heterogeneity of resident and monocyte-derived macrophages during inflammatory exacerbations leading to pulmonary fibrosis.

Philip J Moos, Jenna R Cheminant, Sophie Cowman, Jessica Noll, Qiuming Wang, Teresa Musci, Alessandro Venosa.

  Introduction: Genetic mutations in critical nodes of pulmonary epithelial function are linked to the pathogenesis of pulmonary fibrosis (PF) and other interstitial lung diseases. The slow progression of these pathologies is often intermitted and accelerated by acute exacerbations, complex non-resolving cycles of inflammation and parenchymal damage, resulting in lung function decline and death. Excess monocyte mobilization during the initial phase of an acute exacerbation, and their long-term persistence in the lung, is linked to poor disease outcome.Methods: The present work leverages a clinical idiopathic PF dataset and a murine model of acute inflammatory exacerbations triggered by mutation in the alveolar type-2 cell-restricted Surfactant Protein-C [SP-C] gene to spatially and phenotypically define monocyte/macrophage changes in the fibrosing lung.
Results: SP-C mutation triggered heterogeneous CD68+ macrophage activation, with highly active peri-injured cells relative to those sampled from fully remodeled and healthy regions. Ingenuity pathway analysis of sorted CD11b-SigF+CD11c+ alveolar macrophages defined asynchronous activation of extracellular matrix re-organization, cellular mobilization, and Apolipoprotein E (Apoe) signaling in the fibrosing lung. Cell-cell communication analysis of single cell sequencing datasets predicted pro-fibrogenic signaling (fibronectin/Fn1, osteopontin/Spp1, and Tgfb1) emanating from Trem2/TREM2 + interstitial macrophages. These cells also produced a distinct lipid signature from alveolar macrophages and monocytes, characterized by Apoe expression. Mono- and di-allelic genetic deletion of ApoE in SP-C mutant mice had limited impact on inflammation and mortality up to 42 day after injury.
Discussion: Together, these results provide a detailed spatio-temporal picture of resident, interstitial, and monocyte-derived macrophages during SP-C induced inflammatory exacerbations and end-stage clinical PF, and propose ApoE as a biomarker to identify activated macrophages involved in tissue remodeling.

Keywords:  alveolar macrophages; alveolar type-2 cell; apolipoprotein-E; fibronectin1; monocyte-derived macrophages; osteopontin1; pulmonary fibrosis; surfactant protein-C I73T mutant

DOI:  https://doi.org/10.3389/fimmu.2024.1425466
JAMA Pediatr. 2024 Aug 05.

Bifidobacterium and Lactobacillus Probiotics and Gut Dysbiosis in Preterm Infants: The PRIMAL Randomized Clinical Trial.

Thea Van Rossum, Annette Haiß, Rebecca L Knoll, Janina Marißen, Daniel Podlesny, Julia Pagel, Marina Bleskina, Maren Vens, Ingmar Fortmann, Bastian Siller, Isabell Ricklefs, Jonas Klopp, Katja Hilbert, Claudius Meyer, Roman Thielemann, Sybelle Goedicke-Fritz, Martin Kuntz, Christian Wieg, Norbert Teig, Thorsten Körner, Angela Kribs, Hannes Hudalla, Markus Knuf, Anja Stein, Christian Gille, Soyhan Bagci, Frank Dohle, Hans Proquitté, Dirk M Olbertz, Esther Schmidt, Lutz Koch, Sabine Pirr, Jan Rupp, Juliane Spiegler, Matthias V Kopp, Wolfgang Göpel, Egbert Herting, Sofia K Forslund, Dorothee Viemann, Michael Zemlin, Peer Bork, Stephan Gehring, Inke R König, Philipp Henneke, Christoph Härtel.

Importance: The effects of probiotic interventions on colonization with resistant bacteria and early microbiome development in preterm infants remain to be clarified.Objective: To examine the efficacy of Bifidobacterium longum subsp infantis, Bifidobacterium animalis subsp lactis (BB-12), and Lactobacillus acidophilus (La-5) probiotics to prevent colonization with multidrug-resistant organisms or highly epidemic bacteria (MDRO+) and to shape the microbiome of preterm infants toward the eubiotic state of healthy full-term infants.
Design, Setting, and Participants: The multicenter, double-blinded, placebo-controlled, group sequential, phase 3 Priming Immunity at the Beginning of Life (PRIMAL) randomized clinical trial, conducted from April 2018 to June 2020, included infants with gestational age of 28 to 32 weeks at 18 German neonatal units. Data analyses were conducted from March 2020 to August 2023.
Intervention: A total of 28 days of multistrain probiotics diluted in human milk/formula starting within the first 72 hours of life.
Main Outcomes and Measures: Colonization with MDRO+ at day 30 of life (primary end point), late-onset sepsis and severe gastrointestinal complication (safety end points), and gut dysbiosis, ie, deviations from the microbiome of healthy, term infants (eubiosis score) based on 16-subunit ribosomal RNA and metagenomic sequencing.
Results: Among the 643 infants randomized until the stop of recruitment based on interim results, 618 (median [IQR] gestational age, 31.0 [29.7-32.1] weeks; 333 male [53.9%]; mean [SD] birth weight, 1502 [369] g) had follow-up at day 30. The interim analysis with all available data from 219 infants revealed MDRO+ colonization in 43 of 115 infants (37.4%) in the probiotics group and in 39 of 104 infants (37.5%) in the control group (adjusted risk ratio, 0.99; 95% CI, 0.54-1.81; P = .97). Safety outcomes were similar in both groups, ie, late-onset sepsis (probiotics group: 8 of 316 infants [2.5%]; control group: 12 of 322 infants [3.7%]) and severe gastrointestinal complications (probiotics group: 6 of 316 infants [1.9%]; control group: 7 of 322 infants [2.2%]). The probiotics group had higher eubiosis scores than the control group at the genus level (254 vs 258 infants; median scores, 0.47 vs 0.41; odds ratio [OR], 1.07; 95% CI, 1.02-1.13) and species level (96 vs 83 infants; median scores, 0.87 vs 0.59; OR, 1.28; 95% CI, 1.19-1.38). Environmental uptake of the B infantis probiotic strain in the control group was common (41 of 84 [49%]), which was highly variable across sites and particularly occurred in infants with a sibling who was treated with probiotics.
Conclusions and Relevance: Multistrain probiotics did not reduce the incidence of MDRO+ colonization at day 30 of life in preterm infants but modulated their microbiome toward eubiosis.
Trial Registration: German Clinical Trials Register: DRKS00013197.

DOI: https://doi.org/10.1001/jamapediatrics.2024.2626
J Asthma. 2024 Aug 03. 1-12

A novel approach to investigate severe asthma and COPD: the 3D Ex Vivo Respiratory Mucosa Model.

Alberto Fucarino, Alessandro Pitruzzella, Stefano Burgio, Giorgia Intili, Olga Maria Manna, Michele Domenico Modica, Salvatore Poma, Alida Benfante, Alessandra Tomasello, Nicola Scichilone, Fabio Bucchieri.

  Biologic drugs have been shown to enhance the treatment of severe asthma and COPD. Monoclonal antibodies against specific targets have dramatically changed the management of these conditions. Although the inflammatory pathways of asthma and COPD have already been clearly outlined, alternative mechanisms of action remain mostly unexplored. They could provide additional insights into these diseases and their clinical management. In vivo or in vitro models have thus been developed to test alternative hypotheses. This study describes sophisticated ex vivo models that mimic the response of human respiratory mucosa to disease triggers, aiming to narrow the gap between laboratory studies and clinical practice. These models successfully replicate crucial aspects of these diseases, such as inflammatory cell presence, cytokine production, and changes in tissue structure, offering a dynamic platform for investigating disease processes and evaluating potential treatments, such as monoclonal antibodies. The proposed models have the potential to enhance personalized medicine approaches and patient-specific treatments, helping to advance the understanding and management of respiratory diseases. This article illustrates the replication of asthma and COPD conditions in a laboratory setting and the potential applications of this methodology.

Keywords:  Air-Liquid Interface (ALI) Cultures; Asthma; Chronic Obstructive Pulmonary Disease (COPD); drug efficacy evaluation; ex vivo respiratory mucosa model; inflammatory lung diseases; tissue remodeling

DOI:  https://doi.org/10.1080/02770903.2024.2388781
BMC Oral Health. 2024 Aug 08. 24(1): 915

Preventive effects of probiotics on dental caries in vitro and in vivo.

Jingyan Zhang, Qian Wang, Zhi Duan.

  BACKGROUND: Dental caries is a common disease in the oral cavity, and the microorganisms in the cavity are colonized in the form of dental plaque biofilm. Streptococcus mutans is the main pathogen causing dental caries. Using probiotics to inhibit the growth and colonization of pathogenic bacteria, regulate mucosal immunity and improve oral microecological balance is an effective way to prevent or treat dental caries. The aim of this study was to evaluate the caries-prevention of probiotics in vitro and in rat caries models.METHODS: The probiotics used in this study are a combination of 4 strains of bacteria. After the fermentation of 4 strains (L. plantarum, L. salivarius, L. rhamnosus, and L. paracasei) was completed, they were mixed in equal volume proportions and used as samples to be tested. The mixture was then assessed the ability to inhibit the growth of S. mutans in vitro and in vivo. SPSS Statistics 22.0 (SPSS, Inc., Chicago, IL, USA) was used for analysis.
RESULTS: In vitro the probiotics mixture could inhibit the growth of S. mutans and was able to remove biofilms formed by S. mutans. In a 42-day in vivo experiment, the probiotics group significantly reduced the level of S. mutans on the tooth surface of rats, reducing more than half the bacterial quantities compared with the caries model group (P < 0.05). The amount of S. mutans in the antagonist group was low and highly significant compared with the caries model group. Moreover, the mixture of 4 strains significantly reduced the caries scores (modified Keyes scoring method) in both the probiotic and antagonist groups (p < 0.05).
CONCLUSIONS: The study showed that the combination of the four strains can reduce the cavity scores, and the four strains can be used as products in oral care products. At the same time, the study also suggests that probiotic therapy can be an effective way to prevent dental caries.

Keywords:   S. mutans ; Caries models; Dental caries; Probiotics

DOI:  https://doi.org/10.1186/s12903-024-04703-x
Mol Neurobiol. 2024 Aug 09.

Is Nasal Dysbiosis a Required Component for Neuroinflammation in Major Depressive Disorder?

Jorge Manuel Vásquez-Pérez, Edith González-Guevara, Diana Gutiérrez-Buenabad, Pablo Eliasib Martínez-Gopar, Juan Carlos Martinez-Lazcano, Graciela Cárdenas.

  Human microbiota is known to influence immune and cerebral responses by direct and/or indirect mechanisms, including hypothalamic-pituitary-adrenal axis signaling, activation of neural afferent circuits to the brain, and by altering the peripheral immune responses (cellular and humoral immune function, circulatory inflammatory cells, and the production of several inflammatory mediators, such as cytokines, chemokines, and reactive oxygen species). The inflammatory responses in the nasal mucosa (rhinitis) or paranasal sinuses (chronic rhinosinusitis) are dual conditions related with a greater risk for developing depression. In the nasal cavity, anatomic components of the olfactive function are in direct contact with the CNS through the olfactory receptors, neurons, and axons that end in the olfactory bulb and the entorhinal cortex. Local microbiome alterations (dysbiosis) are linked to transepithelial translocation of microorganisms and their metabolites, which disrupts the epithelial barrier and favors vascular permeability, increasing the levels of several inflammatory molecules (both cytokines and non-cytokine mediators: extracellular vesicles (exosomes) and neuropeptides), triggering local inflammation (rhinitis) and the spread of these components into the central nervous system (neuroinflammation). In this review, we discuss the role of microbiota-related immunity in conditions affecting the nasal mucosa (chronic rhinosinusitis and allergic rhinitis) and their relevance in major depressive disorders, focusing on the few mechanisms known to be involved and providing some hypothetical proposals on the pathophysiology of depression.

Keywords:  Major depressive disorder; Nasal dysbiosis; Neurodegeneration; Neuroinflammation

DOI:  https://doi.org/10.1007/s12035-024-04375-2
Front Cell Infect Microbiol. 2024 ;14 1456380

Editorial: Phenotypic variation as an important aspect of staphylococcal pathogenesis.

Agnieszka Bogut, Agnieszka Magryś.



Keywords:  Manuka honey; SCV (small colony variant); cardiac implantable electronic device; phenotypic variability; siderophores; small colony variants; staphylococcus

DOI:  https://doi.org/10.3389/fcimb.2024.1456380
Mol Immunol. 2024 Aug 07. pii: S0161-5890(24)00124-X. [Epub ahead of print]173 117-126

From cytokines to chemokines: Understanding inflammatory signaling in bacterial meningitis.

Ahsan Ibrahim, Nida Saleem, Faiza Naseer, Sagheer Ahmed, Nayla Munawar, Rukhsana Nawaz.

  Bacterial meningitis is a serious central nervous system (CNS) infection, claiming millions of human lives annually around the globe. The deadly infection involves severe inflammation of the protective sheath of the brain, i.e., meninges, and sometimes also consists of the brain tissue, called meningoencephalitis. Several inflammatory pathways involved in the pathogenesis of meningitis caused by Streptococcus pneumoniae, Neisseria meningitidis, Escherichia coli, Haemophilus influenzae, Mycobacterium tuberculosis, Streptococcus suis, etc. are mentioned in the scientific literature. Many in-vitro and in-vivo analyses have shown that after the disruption of the blood-brain barrier (BBB), these pathogens trigger several inflammatory pathways including Toll-Like Receptor (TLR) signaling in response to Pathogen-Associated Molecular Patterns (PAMPs), Nucleotide oligomerization domain (NOD)-like receptor-mediated signaling, pneumolysin related signaling, NF-κB signaling and many other pathways that lead to pro-inflammatory cascade and subsequent cytokine release including interleukine (IL)-1β, tumor necrosis factor(TNF)-α, IL-6, IL-8, chemokine (C-X-C motif) ligand 1 (CXCL1) along with other mediators, leading to neuroinflammation. The activation of another protein complex, nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome, also takes place resulting in the maturation and release of IL-1β and IL-18, hence potentiating neuroinflammation. This review aims to outline the inflammatory signaling pathways associated with the pathogenesis of bacterial meningitis leading to extensive pathological changes in neurons, astrocytes, oligodendrocytes, and other central nervous system cells.

Keywords:  Bacterial meningitis; Blood-brain barrier; Infection of central nervous system; Meninges; Neuroinflammation; PAMPs

DOI:  https://doi.org/10.1016/j.molimm.2024.07.004
Am J Respir Cell Mol Biol. 2024 Aug 05.

Integrative Analyses Reveal the Correlation Between the Airway Microbiome and Host Metabolism in Severe Community-acquired Pneumonia.

Siqin Chen, Ping Chen, Minhong Su, Jia Jiang, Xiang Liu, Panxiao Shen, Xi Li, Fu Rong, Shaofeng Zhang, Jiayi Liu, Yaling Zeng, Wei Lei, Junhang Li, Kongqiu Wang, Gongqi Chen, Xiaobin Zheng, Xin Chen, Qiang Xiao.

  Community-acquired pneumonia (CAP) is a significant global health concern, responsible for high mortality and morbidity. Recent research has revealed a potential link between disordered microbiome and metabolism in pneumonia, although the precise relationship between these factors and severe CAP remains unclear. To address this knowledge gap, we conducted a comprehensive analysis utilizing 16S sequencing and LC-MS/MS metabolomics data to characterize the microbial profile in sputum and metabolic profile in serum in patients with severe community-acquired pneumonia (sCAP). Our analysis identified 13 genera through LEfSe analysis and 15 metabolites meeting specific criteria (P < 0.05, VIP ≥ 2, and |Log2(FC)| ≥ 2). The findings of this study demonstrate the presence of altered coordination between the microbiome of the lower respiratory tract and host metabolism in patients with sCAP. The observed concentration trends of specific metabolites across different disease stages further support the potential involvement of the serum metabolism in the development of sCAP. These correlations between the airway microbiome and host metabolism in sCAP patients have important implications for optimizing early diagnosis and developing individualized therapeutic strategies.

Keywords:  16S sequencing analysis; LC-MS/MS metabolomics; correlation analysis

DOI:  https://doi.org/10.1165/rcmb.2024-0030OC
Open Forum Infect Dis. 2024 Aug;11(8): ofae414

Association of Staphylococcus aureus Bacterial Load and Colonization Sites With the Risk of Postoperative S. aureus Infection.

ASPIRE-SSI Study Group

  Background: The independent effects of extranasal-only carriage, carriage at multiple bodily sites, or the bacterial load of colonizing Staphylococcus aureus (SA) on the risk of developing SA surgical site infections and postoperative bloodstream infections (SA SSI/BSIs) are unclear. We aimed to quantify these effects in this large prospective cohort study.Methods: Surgical patients aged 18 years or older were screened for SA carriage in the nose, throat, or perineum within 30 days before surgery. SA carriers and noncarriers were enrolled in a prospective cohort study in a 2:1 ratio. Weighted multivariable Cox proportional hazard models were used to assess the independent associations between different measures of SA carriage and occurrence of SA SSI/BSI within 90 days after surgery.
Results: We enrolled 5004 patients in the study cohort; 3369 (67.3%) were SA carriers. 100 SA SSI/BSI events occurred during follow-up, and 86 (86%) of these events occurred in SA carriers. The number of colonized bodily sites (adjusted hazard ratio [aHR], 3.5-8.5) and an increasing SA bacterial load in the nose (aHR, 1.8-3.4) were associated with increased SA SSI/BSI risk. However, extranasal-only carriage was not independently associated with SA SSI/BSI (aHR, 1.5; 95% CI, 0.9-2.5).
Conclusions: Nasal SA carriage was associated with an increased risk of SA SSI/BSI and accounted for the majority of SA infections. Higher bacterial load, as well as SA colonization at multiple bodily sites, further increased this risk.

Keywords:  Staphylococcus aureus; bloodstream infection; colonization; health care–associated infection; hospital-acquired infection; nasal carriage; surgical site infection

DOI:  https://doi.org/10.1093/ofid/ofae414
Integr Med (Encinitas). 2024 Jul;23(3): 28-31

The Microbiome: A Foundation for Integrative Medicine.

Shawn Manske.

Context: No organ system better integrates interconnectivity across specialties and disciplines than the microbiome. Scientific focus is shifting from microbes as harbingers of disease toward microbes as symbiotic, balanced, commensal ecologies.Objective: The study intended to discuss and examine the human microbiome, including its development in early life; its impact on various physiological processes that occur throughout the body; and its relationship to dysbiosis; and to investigate microbial mechanisms with clinical applicability across medical specialties.
Setting: The study took place at Biocidin Botanicals in Watsonville CA, USA.
Results: Accumulating research upholds the human microbiome as both a predictive biomarker for disease risk and a viable treatment option for modulating the course of illness. Prebiotic and probiotic interventions continue to demonstrate clinical utility, particularly for gastrointestinal, dermatological, inflammatory, metabolic, and mental-health disorders.
Conclusions: Just as germ theory revolutionized infection control in the twentieth century, microbiome systems science stands to transform the conceptualization of health as the balanced coexistence of human and microbial cells in the twenty-first century.