bims-bac4me 2023-07-30 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2023–07–30
twenty-two papers selected by
Chun-Chi Chang, Universitäts Spital Zürich

Metabolism, metabolites, and macrophages in cancer.
Blood myeloid cells differentiate to lung resident cells and respond to pathogen stimuli in a 3D human tissue-engineered lung model.
Combining 16S Sequencing and qPCR Quantification Reveals Staphylococcus aureus Driven Bacterial Overgrowth in the Skin of Severe Atopic Dermatitis Patients.
Unique microbial landscape in the human oropharynx during different types of acute respiratory tract infections.
Streptococcus pneumoniae drives specific and lasting Natural Killer cell memory.
Staphylococcus aureus in Polymicrobial Skinand Soft Tissue Infections: Impact of Inter-Species Interactionsin Disease Outcome.
Pulmonary Pathogen-Induced Epigenetic Modifications.
Inflammatory macrophages exploited by oral streptococcus increase IL-1B release via NLRP6 inflammasome.
Integrated genomic and functional analyses of human skin-associated Staphylococcus reveals extensive inter- and intra-species diversity.
Microbiota and IL-33/31 Axis Linkage: Implications and Therapeutic Perspectives in Atopic Dermatitis and Psoriasis.
Myeloid-derived suppressor cells impair CD4+ T cell responses during chronic Staphylococcus aureus infection via lactate metabolism.
IL-33-induced neutrophilic inflammation and NETosis underlie rhinovirus-triggered exacerbations of asthma.
The Potential of Probiotics as Ingestible Adjuvants and Immune Modulators for Antiviral Immunity and Management of SARS-CoV-2 Infection and COVID-19.
Hypoxia inducible factor-1α is an important regulator of macrophage biology.
NR4A1 destabilizes TNF mRNA in microglia and modulates stroke outcomes.
Airway Epithelium Senescence as a Driving Mechanism in COPD Pathogenesis.
CD9 co-operation with syndecan-1 is required for a major staphylococcal adhesion pathway.
Lactobacillus gasseri and Gardnerella vaginalis produce extracellular vesicles that contribute to the function of the vaginal microbiome and modulate host-Trichomonas vaginalis interactions.
Innovative three-dimensional models for understanding mechanisms underlying lung diseases: powerful tools for translational research.
Mechanism of action of gut microbiota and probiotic Lactobacillus rhamnosus GG on skeletal remodeling in mice.
Antibiotic perturbations to the gut microbiome.
Bacterial metabolism and susceptibility to cell wall-active antibiotics.

J Hematol Oncol. 2023 07 25. 16(1): 80

Metabolism, metabolites, and macrophages in cancer.

Mengyuan Li, Yuhan Yang, Liting Xiong, Ping Jiang, Junjie Wang, Chunxiao Li.

  Tumour-associated macrophages (TAMs) are crucial components of the tumour microenvironment and play a significant role in tumour development and drug resistance by creating an immunosuppressive microenvironment. Macrophages are essential components of both the innate and adaptive immune systems and contribute to pathogen resistance and the regulation of organism homeostasis. Macrophage function and polarization are closely linked to altered metabolism. Generally, M1 macrophages rely primarily on aerobic glycolysis, whereas M2 macrophages depend on oxidative metabolism. Metabolic studies have revealed that the metabolic signature of TAMs and metabolites in the tumour microenvironment regulate the function and polarization of TAMs. However, the precise effects of metabolic reprogramming on tumours and TAMs remain incompletely understood. In this review, we discuss the impact of metabolic pathways on macrophage function and polarization as well as potential strategies for reprogramming macrophage metabolism in cancer treatment.

Keywords:  Cancer; Metabolism; Metabolism reprogramming; Tumour microenvironment; Tumour-associated macrophages

DOI:  https://doi.org/10.1186/s13045-023-01478-6
Front Bioeng Biotechnol. 2023 ;11 1212230

Blood myeloid cells differentiate to lung resident cells and respond to pathogen stimuli in a 3D human tissue-engineered lung model.

Mandi M Roe, Taylor Do, Sean Turner, Allison M Jevitt, Magdalena Chlebicz, Karley White, Antonius G P Oomens, Susannah Rankin, Susan Kovats, Heather Gappa-Fahlenkamp.

  Introduction: Respiratory infections remain a leading global health concern. Models that recapitulate the cellular complexity of the lower airway of humans will provide important information about how the immune response reflects the interactions between diverse cell types during infection. We developed a 3D human tissue-engineered lung model (3D-HTLM) composed of primary human pulmonary epithelial and endothelial cells with added blood myeloid cells that allows assessment of the innate immune response to respiratory infection. Methods: The 3D-HTLM consists of small airway epithelial cells grown at air-liquid interface layered on fibroblasts within a collagen matrix atop a permeable membrane with pulmonary microvascular endothelial cells layered underneath. After the epithelial and endothelial layers had reached confluency, an enriched blood monocyte population, containing mostly CD14+ monocytes (Mo) with minor subsets of CD1c+ classical dendritic cells (cDC2s), monocyte-derived dendritic cells (Mo-DCs), and CD16+ non-classical monocytes, was added to the endothelial side of the model. Results: Immunofluorescence imaging showed the myeloid cells migrate through and reside within each layer of the model. The myeloid cell subsets adapted to the lung environment in the 3D-HTLM, with increased proportions of the recovered cells expressing lung tissue resident markers CD206, CD169, and CD163 compared with blood myeloid cells, including a population with features of alveolar macrophages. Myeloid subsets recovered from the 3D-HTLM displayed increased expression of HLA-DR and the co-stimulatory markers CD86, CD40, and PDL1. Upon stimulation of the 3D-HTLM with the toll-like receptor 4 (TLR4) agonist bacterial lipopolysaccharide (LPS), the CD31+ endothelial cells increased expression of ICAM-1 and the production of IL-10 and TNFα was dependent on the presence of myeloid cells. Challenge with respiratory syncytial virus (RSV) led to increased expression of macrophage activation and antiviral pathway genes by cells in the 3D-HTLM. Discussion: The 3D-HTLM provides a lower airway environment that promotes differentiation of blood myeloid cells into lung tissue resident cells and enables the study of respiratory infection in a physiological cellular context.

Keywords:  differentiation; innate immune; lung model; macrophage; monocyte; respiratory syncytial virus

DOI:  https://doi.org/10.3389/fbioe.2023.1212230
Biomolecules. 2023 Jun 23. pii: 1030. [Epub ahead of print]13(7):

Combining 16S Sequencing and qPCR Quantification Reveals Staphylococcus aureus Driven Bacterial Overgrowth in the Skin of Severe Atopic Dermatitis Patients.

Amedeo De Tomassi, Anna Reiter, Matthias Reiger, Luise Rauer, Robin Rohayem, Ck-Care Study Group, Claudia Traidl-Hoffmann, Avidan U Neumann, Claudia Hülpüsch.

  Atopic dermatitis (AD) is an inflammatory skin disease with a microbiome dysbiosis towards a high relative abundance of Staphylococcus aureus. However, information is missing on the actual bacterial load on AD skin, which may affect the cell number driven release of pathogenic factors. Here, we combined the relative abundance results obtained by next-generation sequencing (NGS, 16S V1-V3) with bacterial quantification by targeted qPCR (total bacterial load = 16S, S. aureus = nuc gene). Skin swabs were sampled cross-sectionally (n = 135 AD patients; n = 20 healthy) and longitudinally (n = 6 AD patients; n = 6 healthy). NGS and qPCR yielded highly inter-correlated S. aureus relative abundances and S. aureus cell numbers. Additionally, intra-individual differences between body sides, skin status, and consecutive timepoints were also observed. Interestingly, a significantly higher total bacterial load, in addition to higher S. aureus relative abundance and cell numbers, was observed in AD patients in both lesional and non-lesional skin, as compared to healthy controls. Moreover, in the lesional skin of AD patients, higher S. aureus cell numbers significantly correlated with the higher total bacterial load. Furthermore, significantly more severe AD patients presented with higher S. aureus cell number and total bacterial load compared to patients with mild or moderate AD. Our results indicate that severe AD patients exhibit S. aureus driven increased bacterial skin colonization. Overall, bacterial quantification gives important insights in addition to microbiome composition by sequencing.

Keywords:  Staphylococcus aureus; absolute quantification; atopic dermatitis; next-generation sequencing; qPCR; skin microbiome

DOI:  https://doi.org/10.3390/biom13071030
Microbiome. 2023 07 24. 11(1): 157

Unique microbial landscape in the human oropharynx during different types of acute respiratory tract infections.

Hui Li, Xiaorong Wu, Hong Zeng, Bozhen Chang, Ying Cui, Jingxiang Zhang, Ruixia Wang, Tao Ding.

   BACKGROUND: Secondary bacterial infections and pneumonia are major mortality causes of respiratory viruses, and the disruption of the upper respiratory tract (URT) microbiota is a crucial component of this process. However, whether this URT dysbiosis associates with the viral species (in other words, is viral type-specific) is unclear.
RESULTS: Here, we recruited 735 outpatients with upper respiratory symptoms, identified the infectious virus types in 349 participants using multiplex RT-PCR, and profiled their upper respiratory microbiome using the 16S ribosomal RNA gene and metagenomic gene sequencing. Microbial and viral data were subsequently used as inputs for multivariate analysis aimed at revealing viral type-specific disruption of the upper respiratory microbiota. We found that the oropharyngeal microbiota shaped by influenza A virus (FluA), influenza B virus (FluB), respiratory syncytial virus (RSV), and human rhinovirus (HRV) infections exhibited three distinct patterns of dysbiosis, and Veillonella was identified as a prominent biomarker for any type of respiratory viral infections. Influenza virus infections are significantly correlated with increased oropharynx microbiota diversity and enrichment of functional metabolic pathways such as L-arginine biosynthesis and tetracycline resistance gene tetW. We used the GRiD algorithm and found the predicted growth rate of common respiratory pathogens was increased upon influenza virus infection, while commensal bacteria, such as Streptococcus infantis and Streptococcus mitis, may act as a colonization resistance to the overgrowth of these pathogens.
CONCLUSIONS: We found that respiratory viral infections are linked with viral type-specific disruption of the upper respiratory microbiota, particularly, influenza infections uniquely associated with increased microbial diversity and growth rates of specific pathogens in URT. These findings are essential for clarifying the differences and dynamics of respiratory microbiota in healthy participants and acute respiratory viral infections, which contribute to elucidating the pathogenesis of viral-host-bacterial interactions to provide insights into future studies on effective prevention and treatment of respiratory tract infections. Video Abstract.

Keywords:  Influenza A virus; Microbiome; Pathogen; Upper respiratory tract

DOI:  https://doi.org/10.1186/s40168-023-01597-9
PLoS Pathog. 2023 Jul 24. 19(7): e1011159

Streptococcus pneumoniae drives specific and lasting Natural Killer cell memory.

Tiphaine M N Camarasa, Júlia Torné, Christine Chevalier, Orhan Rasid, Melanie A Hamon.

NK cells are important mediators of innate immunity and play an essential role for host protection against infection, although their responses to bacteria are poorly understood. Recently NK cells were shown to display memory properties, as characterized by an epigenetic signature leading to a stronger secondary response. Although NK cell memory could be a promising mechanism to fight against infection, it has not been described upon bacterial infection. Using a mouse model, we reveal that NK cells develop specific and long-term memory following sub-lethal infection with the extracellular pathogen Streptococcus pneumoniae. Memory NK cells display intrinsic sensing and response to bacteria in vitro, in a manner that is enhanced post-bacterial infection. In addition, their transfer into naïve mice confers protection from lethal infection for at least 12 weeks. Interestingly, NK cells display enhanced cytotoxic molecule production upon secondary stimulation and their protective role is dependent on Perforin and independent of IFNγ. Thus, our study identifies a new role for NK cells during bacterial infection, opening the possibility to harness innate immune memory for therapeutic purposes.

DOI: https://doi.org/10.1371/journal.ppat.1011159
Antibiotics (Basel). 2023 Jul 08. pii: 1164. [Epub ahead of print]12(7):

Staphylococcus aureus in Polymicrobial Skinand Soft Tissue Infections: Impact of Inter-Species Interactionsin Disease Outcome.

Florencia Mariani, Estela Maria Galvan.

  Polymicrobial biofilms provide a complex environment where co-infecting microorganisms can behave antagonistically, additively, or synergistically to alter the disease outcome compared to monomicrobial infections. Staphylococcus aureus skin and soft tissue infections (Sa-SSTIs) are frequently reported in healthcare and community settings, and they can also involve other bacterial and fungal microorganisms. This polymicrobial aetiology is usually found in chronic wounds, such as diabetic foot ulcers, pressure ulcers, and burn wounds, where the establishment of multi-species biofilms in chronic wounds has been extensively described. This review article explores the recent updates on the microorganisms commonly found together with S. aureus in SSTIs, such as Pseudomonas aeruginosa, Escherichia coli, Enterococcus spp., Acinetobacter baumannii, and Candida albicans, among others. The molecular mechanisms behind these polymicrobial interactions in the context of infected wounds and their impact on pathogenesis and antimicrobial susceptibility are also revised.

Keywords:  Staphylococcus aureus; interspecies interactions; polymicrobial infection; skin and soft tissue infection

DOI:  https://doi.org/10.3390/antibiotics12071164
Epigenomes. 2023 Jul 06. pii: 13. [Epub ahead of print]7(3):

Pulmonary Pathogen-Induced Epigenetic Modifications.

Dylan Wrede, Mika Bordak, Yeabtsega Abraham, Masfique Mehedi.

  Epigenetics generally involves genetic control by factors other than our own DNA sequence. Recent research has focused on delineating the mechanisms of two major epigenetic phenomena: DNA methylation and histone modification. As epigenetics involves many cellular processes, it is no surprise that it can also influence disease-associated gene expression. A direct link between respiratory infections, host cell epigenetic regulations, and chronic lung diseases is still unknown. Recent studies have revealed bacterium- or virus-induced epigenetic changes in the host cells. In this review, we focused on respiratory pathogens (viruses, bacteria, and fungi) induced epigenetic modulations (DNA methylation and histone modification) that may contribute to lung disease pathophysiology by promoting host defense or allowing pathogen persistence.

Keywords:  DNA methylation; RSV; bacteria; epigenetics; fungi; histone modification; transcriptional factors; virus

DOI:  https://doi.org/10.3390/epigenomes7030013
J Leukoc Biol. 2023 Jul 27. pii: qiad089. [Epub ahead of print]

Inflammatory macrophages exploited by oral streptococcus increase IL-1B release via NLRP6 inflammasome.

Sarah Metcalfe, Michelle Panasiewicz, Jason G Kay.

  Chronic inflammatory periodontal disease develops in part from the infiltration of a large number of classically activated inflammatory macrophages that release inflammatory cytokines important for disease progression, including inflammasome-dependent IL-1β. Streptococcus gordonii is a normally commensal oral microorganism; while not causative, recent evidence indicates that commensal oral microbes are required for the full development of periodontal disease. We have recently reported that inflammatory macrophages counterintuitively allow for the increased survival of phagocytosed S. gordonii over non-activated or alternatively activated macrophages. This survival is dependent on increased ROS production within the phagosome of the inflammatory macrophages and resistance by the bacterium and can result in S. gordonii damaging the phagolysosomes. Here we show that activated macrophages infected with live S. gordonii release more IL-1β than macrophages infected with other oral microbes, both classical pathogens and commensals. We also find that S. gordonii dependent inflammatory macrophage inflammasome activation requires the cytoplasmic NLRP6. Overall, our results suggest S. gordonii is capable of evading immune destruction, increasing inflammatory mediators, and increasing inflammatory macrophage response; and that this ability is increased under conditions of inflammation. This work reveals additional mechanisms by which normally commensal oral streptococci-macrophage interactions can change, resulting in increased release of mature IL-1β, potentially contributing to an environment that perpetuates inflammation.

Keywords:  Inflammasome; Streptococcus gordonii; commensal; macrophages

DOI:  https://doi.org/10.1093/jleuko/qiad089
bioRxiv. 2023 Jun 23. pii: 2023.06.22.546190. [Epub ahead of print]

Integrated genomic and functional analyses of human skin-associated Staphylococcus reveals extensive inter- and intra-species diversity.

NISC Comparative Sequencing Program

Human skin is stably colonized by a distinct microbiota that functions together with epidermal cells to maintain a protective physical barrier. Staphylococcus , a prominent genus of the skin microbiota, participates in colonization resistance, tissue repair, and host immune regulation in strain specific manners. To unlock the potential of engineering skin microbial communities, we aim to fully characterize the functional diversity of this genus within the context of the skin environment. We conducted metagenome and pan-genome analyses of isolates obtained from distinct body sites of healthy volunteers, providing a detailed biogeographic depiction of staphylococcal species that colonize our skin. S. epidermidis , S. capitis, and S. hominis were the most abundant species present in all volunteers and were detected at all body sites. Pan-genome analysis of these three species revealed that the genus-core was dominated by central metabolism genes. Species-specific core genes were enriched in host colonization functions. The majority (∼68%) of genes were detected only in a fraction of isolate genomes, underscoring the immense strain-specific gene diversity. Conspecific genomes grouped into phylogenetic clades, exhibiting body site preference. Each clade was enriched for distinct gene-sets that are potentially involved in site tropism. Finally, we conducted gene expression studies of select isolates showing variable growth phenotypes in skin-like medium. In vitro expression revealed extensive intra- and inter-species gene expression variation, substantially expanding the functional diversification within each species. Our study provides an important resource for future ecological and translational studies to examine the role of shared and strain-specific staphylococcal genes within the skin environment.
SIGNIFICANCE: The bacterial genus Staphylococcus is a prominent member of the human skin microbiome, performing important and diverse functions such as tuning immunity, driving tissue repair, and preventing pathogen colonization. Each of these functions is carried out by a subset of staphylococcal strains, displaying differences in gene content and regulation. Delineating the genomic and functional diversity of Staphylococcus will enable researchers to unlock the potential of engineering skin communities to promote health. Here, we present a comprehensive multi-omics analysis to characterize the inter- and intra-species diversity present in human skin-associated staphylococci. Our study is the first to conduct a detailed pan-genome comparison between prominent skin staphylococcal species giving a valuable insight into gene sharing and provides an important resource.

DOI: https://doi.org/10.1101/2023.06.22.546190
Biomolecules. 2023 Jul 10. pii: 1100. [Epub ahead of print]13(7):

Microbiota and IL-33/31 Axis Linkage: Implications and Therapeutic Perspectives in Atopic Dermatitis and Psoriasis.

Laura Bonzano, Francesco Borgia, Rossella Casella, Andrea Miniello, Eustachio Nettis, Sebastiano Gangemi.

  Microbiome dysbiosis and cytokine alternations are key features of atopic dermatitis (AD) and psoriasis (PsO), two of the most prevalent and burdensome pruritic skin conditions worldwide. Interleukin (IL)-33 and IL-31 have been recognized to be major players who act synergistically in the pathogenesis and maintenance of different chronic inflammatory conditions and pruritic skin disorders, including AD and PsO, and their potential role as therapeutic targets is being thoroughly investigated. The bidirectional interplay between dysbiosis and immunological changes has been extensively studied, but there is still debate regarding which of these two factors is the actual causative culprit behind the aetiopathological process that ultimately leads to AD and PsO. We conducted a literature review on the Pubmed database assessing articles of immunology, dermatology, microbiology and allergology with the aim to strengthen the hypothesis that dysbiosis is at the origin of the IL-33/IL-31 dysregulation that contributes to the pathogenesis of AD and PsO. Finally, we discussed the therapeutic options currently in development for the treatment of these skin conditions targeting IL-31, IL-33 and/or the microbiome.

Keywords:  IL-31; IL-33; atopic dermatitis; cytokines; inflammation; microbiota; pathogenesis; psoriasis; skin; treatment

DOI:  https://doi.org/10.3390/biom13071100
Cell Mol Life Sci. 2023 Jul 22. 80(8): 221

Myeloid-derived suppressor cells impair CD4+ T cell responses during chronic Staphylococcus aureus infection via lactate metabolism.

Oliver Goldmann, Eva Medina.

  Staphylococcus aureus is an important cause of chronic infections resulting from the failure of the host to eliminate the pathogen. Effective S. aureus clearance requires CD4+ T cell-mediated immunity. We previously showed that myeloid-derived suppressor cells (MDSC) expand during staphylococcal infections and support infection chronicity by inhibiting CD4+ T cell responses. The aim of this study was to elucidate the mechanisms underlying the suppressive effect exerted by MDSC on CD4+ T cells during chronic S. aureus infection. It is well known that activated CD4+ T cells undergo metabolic reprogramming from oxidative metabolism to aerobic glycolysis to meet their increased bioenergetic requirements. In this process, pyruvate is largely transformed into lactate by lactate dehydrogenase with the concomitant regeneration of NAD+, which is necessary for continued glycolysis. The by-product lactate needs to be excreted to maintain the glycolytic flux. Using SCENITH (single-cell energetic metabolism by profiling translation inhibition), we demonstrated here that MDSC inhibit CD4+ T cell responses by interfering with their metabolic activity. MDSC are highly glycolytic and excrete large amount of lactate in the local environment that alters the transmembrane concentration gradient and prevent removal of lactate by activated CD4+ T. Accumulation of endogenous lactate impedes the regeneration of NAD+, inhibit NAD-dependent glycolytic enzymes and stop glycolysis. Together, the results of this study have uncovered a role for metabolism on MDSC suppression of CD4+ T cell responses. Thus, reestablishment of their metabolic activity may represent a mean to improve the functionality of CD4+ T cells during chronic S. aureus infection.

Keywords:  CD4+ T cells; Lactate; Myeloid-derived suppressor cells (MDSC); NAD+/NADH redox; SCENITH; Staphylococcus aureus

DOI:  https://doi.org/10.1007/s00018-023-04875-9
Mucosal Immunol. 2023 Jul 26. pii: S1933-0219(23)00054-5. [Epub ahead of print]

IL-33-induced neutrophilic inflammation and NETosis underlie rhinovirus-triggered exacerbations of asthma.

Bodie Curren, Tufael Ahmed, Daniel R Howard, Md Ashik Ullah, Ismail Sebina, Ridwan B Rashid, Md Al Amin Sikder, Patricia Namubiru, Alec Bissell, Sylvia Ngo, David J Jackson, Marie Toussaint, Michael R Edwards, Sebastian L Johnston, Henry J McSorley, Simon Phipps.

  Rhinovirus-induced neutrophil extracellular traps (NETs) contribute to acute asthma exacerbations, however the molecular factors that trigger NETosis in this context remain ill-defined. Here, we sought to implicate a role for IL-33, an epithelial cell-derived alarmin rapidly released in response to infection. In mice with chronic experimental asthma (CEA), but not naïve controls, rhinovirus inoculation induced an early (1 day post infection; dpi) inflammatory response dominated by neutrophils, neutrophil-associated cytokines (IL-1α, IL-1β, CXCL1) and NETosis, followed by a later, type-2 inflammatory phase (3-7 dpi), characterized by eosinophils, elevated IL-4 levels, and goblet cell hyperplasia. Notably, both phases were ablated by HpARI (Heligmosomoides polygyrus Alarmin Release Inhibitor), which blocks IL-33 release and signalling. Instillation of exogenous IL-33 recapitulated the rhinovirus-induced early phase, including the increased presence of NETs in the airway mucosa, in a PAD4-dependent manner. Ex vivo IL-33-stimulated neutrophils from mice with CEA, but not naïve mice, underwent NETosis, and produced greater amounts of IL-1α/β IL-4, and IL-5. In nasal samples from rhinovirus-infected people with asthma, but not healthy controls, IL-33 levels correlated with neutrophil elastase and dsDNA. Our findings suggest that IL-33 blockade ameliorates the severity of an asthma exacerbation by attenuating neutrophil recruitment and the downstream generation of NETs.

Keywords:  Asthma; HpARI; IL-33; NETosis; PAD4; ST2; dsDNA; eosinophil; neutrophil; rhinovirus

DOI:  https://doi.org/10.1016/j.mucimm.2023.07.002
Pathogens. 2023 Jul 11. pii: 928. [Epub ahead of print]12(7):

The Potential of Probiotics as Ingestible Adjuvants and Immune Modulators for Antiviral Immunity and Management of SARS-CoV-2 Infection and COVID-19.

Sophie Tomkinson, Cloe Triscott, Emily Schenk, Andrew Foey.

  Probiotic bacteria are able to modulate general antiviral responsiveness, including barrier functionality and innate and adaptive immune responses. The COVID-19 pandemic, resulting from SARS-CoV-2 infection, has created a need to control and treat this viral infection and its ensuing immunopathology with a variety of approaches; one such approach may involve the administration of probiotic bacteria. As with most viral infections, its pathological responses are not fully driven by the virus, but are significantly contributed to by the host's immune response to viral infection. The potential adoption of probiotics in the treatment of COVID-19 will have to appreciate the fine line between inducing antiviral immunity without over-provoking immune inflammatory responses resulting in host-derived immunopathological tissue damage. Additionally, the effect exerted on the immune system by SARS-CoV-2 evasion strategies will also have to be considered when developing a robust response to this virus. This review will introduce the immunopathology of COVID-19 and the immunomodulatory effects of probiotic strains, and through their effects on a range of respiratory pathogens (IAV, SARS-CoV, RSV), as well as SARS-CoV-2, will culminate in a focus on how these bacteria can potentially manipulate both infectivity and immune responsiveness via barrier functionality and both innate and adaptive immunity. In conclusion, the harnessing of induction and augmentation of antiviral immunity via probiotics may not only act as an ingestible adjuvant, boosting immune responsiveness to SARS-CoV-2 infection at the level of barrier integrity and innate and adaptive immunity, but also act prophylactically to prevent infection and enhance protection afforded by current vaccine regimens.

Keywords:  COVID-19; SARS-CoV-2; antiviral immunity; immune evasion; probiotics

DOI:  https://doi.org/10.3390/pathogens12070928
Heliyon. 2023 Jun;9(6): e17167

Hypoxia inducible factor-1α is an important regulator of macrophage biology.

Bingquan Qiu, Piaoliu Yuan, Xiaojuan Du, Hongfang Jin, Junbao Du, Yaqian Huang.

  Hypoxia-inducible factor-1 (HIF-1), a heterodimeric transcription factor composed of the α and β subunits, regulates cellular adaptive responses to hypoxia. Macrophages, which are derived from monocytes, function as antigen-presenting cells that activate various immune responses. HIF-1α regulates the immune response, viability, migration, phenotypic plasticity, and metabolism of macrophages. Specifically, macrophage-derived HIF-1α can prevent excessive pro-inflammatory responses by attenuating the transcriptional activity of nuclear factor-kappa B in vivo and in vitro. HIF-1α modulates macrophage migration by inducing the release of various chemokines and providing necessary energy. HIF-1α promotes macrophage M1 polarization by targeting glucose metabolism. Additionally, HIF-1α induces the upregulation of glycolysis-related enzymes and intermediates of the tricarboxylic acid cycle and pentose phosphate pathway. HIF-1α promotes macrophage apoptosis, necroptosis and reduces autophagy. The current review highlights the mechanisms associated with the regulation of HIF-1α stabilization in macrophages as well as the role of HIF-1α in modulating the physiological functions of macrophages.

Keywords:  Biology; Diseases; HIF-1α; Macrophage; Stability

DOI:  https://doi.org/10.1016/j.heliyon.2023.e17167
PLoS Biol. 2023 07;21(7): e3002226

NR4A1 destabilizes TNF mRNA in microglia and modulates stroke outcomes.

Yao Yao.

Microglia play a dual role in stroke depending on their pro-inflammatory and anti-inflammatory polarization. A study in PLOS Biology identifies a new mechanism, through which the transcription factor NR4A1 negatively regulates TNF expression in microglia.

DOI: https://doi.org/10.1371/journal.pbio.3002226
Biomedicines. 2023 Jul 23. pii: 2072. [Epub ahead of print]11(7):

Airway Epithelium Senescence as a Driving Mechanism in COPD Pathogenesis.

Georgia Bateman, Hong Guo-Parke, Aoife M Rodgers, Dermot Linden, Melanie Bailey, Sinéad Weldon, Joseph C Kidney, Clifford C Taggart.

  Cellular senescence is a state of permanent cell cycle arrest triggered by various intrinsic and extrinsic stressors. Cellular senescence results in impaired tissue repair and remodeling, loss of physiological integrity, organ dysfunction, and changes in the secretome. The systemic accumulation of senescence cells has been observed in many age-related diseases. Likewise, cellular senescence has been implicated as a risk factor and driving mechanism in chronic obstructive pulmonary disease (COPD) pathogenesis. Airway epithelium exhibits hallmark features of senescence in COPD including activation of the p53/p21WAF1/CIP1 and p16INK4A/RB pathways, leading to cell cycle arrest. Airway epithelial senescent cells secrete an array of inflammatory mediators, the so-called senescence-associated secretory phenotype (SASP), leading to a persistent low-grade chronic inflammation in COPD. SASP further promotes senescence in an autocrine and paracrine manner, potentially contributing to the onset and progression of COPD. In addition, cellular senescence in COPD airway epithelium is associated with telomere dysfunction, DNA damage, and oxidative stress. This review discusses the potential mechanisms of airway epithelial cell senescence in COPD, the impact of cellular senescence on the development and severity of the disease, and highlights potential targets for modulating cellular senescence in airway epithelium as a potential therapeutic approach in COPD.

Keywords:  COPD; SASP; airway epithelial cells; cellular senescence; pathogenesis

DOI:  https://doi.org/10.3390/biomedicines11072072
mBio. 2023 Jul 24. e0148223

CD9 co-operation with syndecan-1 is required for a major staphylococcal adhesion pathway.

Luke R Green, Rahaf Issa, Fawzyah Albaldi, Lucy Urwin, Ruth Thompson, Henna Khalid, Claire E Turner, Barbara Ciani, Lynda J Partridge, Peter N Monk.

  Epithelial colonization is a critical first step in bacterial pathogenesis. Staphylococcus aureus can utilize several host factors to associate with cells, including α5β1 integrin and heparan sulfate proteoglycans, such as the syndecans. Here, we demonstrate that a partner protein of both integrins and syndecans, the host membrane adapter protein tetraspanin CD9, is essential for syndecan-mediated staphylococcal adhesion. Fibronectin is also essential in this process, while integrins are only critical for post-adhesion entry into human epithelial cells. Treatment of epithelial cells with CD9-derived peptide or heparin caused significant reductions in staphylococcal adherence, dependent on both CD9 and syndecan-1. Exogenous fibronectin caused a CD9-dependent increase in staphylococcal adhesion, whereas blockade of β1 integrins did not affect adhesion but did reduce the subsequent internalization of adhered bacteria. CD9 disruption or deletion increased β1 integrin-mediated internalization, suggesting that CD9 coordinates sequential staphylococcal adhesion and internalization. CD9 controls staphylococcal adhesion through syndecan-1, using a mechanism that likely requires CD9-mediated syndecan organization to correctly display fibronectin at the host cell surface. We propose that CD9-derived peptides or heparin analogs could be developed as anti-adhesion treatments to inhibit the initial stages of staphylococcal pathogenesis. IMPORTANCE Staphylococcus aureus infection is a significant cause of disease and morbidity. Staphylococci utilize multiple adhesion pathways to associate with epithelial cells, including interactions with proteoglycans or β1 integrins through a fibronectin bridge. Interference with another host protein, tetraspanin CD9, halves staphylococcal adherence to epithelial cells, although CD9 does not interact directly with bacteria. Here, we define the role of CD9 in staphylococcal adherence and uptake, observing that CD9 coordinates syndecan-1, fibronectin, and β1 integrins to allow efficient staphylococcal infection. Two treatments that disrupt this action are effective and may provide an alternative to antibiotics. We provide insights into the mechanisms that underlie staphylococcal infection of host cells, linking two known adhesion pathways together through CD9 for the first time.

Keywords:  CD9; HSPG; Staphylococcus aureus; bacterial adhesion; epithelial; fibronectin; syndecan; tetraspanin

DOI:  https://doi.org/10.1128/mbio.01482-23
Mol Microbiol. 2023 Jul 24.

Lactobacillus gasseri and Gardnerella vaginalis produce extracellular vesicles that contribute to the function of the vaginal microbiome and modulate host-Trichomonas vaginalis interactions.

Anastasiia Artuyants, Jiwon Hong, Priscila Dauros-Singorenko, Anthony Phillips, Augusto Simoes-Barbosa.

  Trichomonas vaginalis is an extracellular protozoan parasite of the human urogenital tract, responsible for a prevalent sexually transmitted infection. Trichomoniasis is accompanied by a dysbiotic microbiome that is characterised by the depletion of host-protective commensals such as Lactobacillus gasseri, and the flourishing of a bacterial consortium that is comparable to the one seen for bacterial vaginosis, including the founder species Gardnerella vaginalis. These two vaginal bacteria are known to have opposite effects on T. vaginalis pathogenicity. Studies on extracellular vesicles (EVs) have been focused on the direction of a microbial producer (commensal or pathogen) to a host recipient, and largely in the context of the gut microbiome. Here, taking advantage of the simplicity of the human cervicovaginal microbiome, we determined the molecular cargo of EVs produced by L. gasseri and G. vaginalis and examined how these vesicles modulate the interaction of T. vaginalis and host cells. We show that these EVs carry a specific cargo of proteins, which functions can be attributed to the opposite roles that these bacteria play in the vaginal biome. Furthermore, these bacterial EVs are delivered to host and protozoan cells, modulating host-pathogen interactions in a way that mimics the opposite effects that these bacteria have on T. vaginalis pathogenicity. This is the first study to describe side-by-side the protein composition of EVs produced by two bacteria belonging to the opposite spectrum of a microbiome and to demonstrate that these vesicles modulate the pathogenicity of a protozoan parasite. Such as in trichomoniasis, infections and dysbiosis co-occur frequently resulting in significant co-morbidities. Therefore, studies like this provide the knowledge for the development of antimicrobial therapies that aim to clear the infection while restoring a healthy microbiome.

Keywords:   Trichomonas vaginalis ; extracellular vesicles; host-pathogen interaction; vaginal microbiome

DOI:  https://doi.org/10.1111/mmi.15130
Eur Respir Rev. 2023 Sep 30. pii: 230042. [Epub ahead of print]32(169):

Innovative three-dimensional models for understanding mechanisms underlying lung diseases: powerful tools for translational research.

Mehmet Nizamoglu, Mugdha M Joglekar, Catarina R Almeida, Anna-Karin Larsson Callerfelt, Isabelle Dupin, Olivier T Guenat, Pauline Henrot, Lisette van Os, Jorge Otero, Linda Elowsson, Ramon Farre, Janette K Burgess.

Chronic lung diseases result from alteration and/or destruction of lung tissue, inevitably causing decreased breathing capacity and quality of life for patients. While animal models have paved the way for our understanding of pathobiology and the development of therapeutic strategies for disease management, their translational capacity is limited. There is, therefore, a well-recognised need for innovative in vitro models to reflect chronic lung diseases, which will facilitate mechanism investigation and the advancement of new treatment strategies. In the last decades, lungs have been modelled in healthy and diseased conditions using precision-cut lung slices, organoids, extracellular matrix-derived hydrogels and lung-on-chip systems. These three-dimensional models together provide a wide spectrum of applicability and mimicry of the lung microenvironment. While each system has its own limitations, their advantages over traditional two-dimensional culture systems, or even over animal models, increases the value of in vitro models. Generating new and advanced models with increased translational capacity will not only benefit our understanding of the pathobiology of lung diseases but should also shorten the timelines required for discovery and generation of new therapeutics. This article summarises and provides an outline of the European Respiratory Society research seminar "Innovative 3D models for understanding mechanisms underlying lung diseases: powerful tools for translational research", held in Lisbon, Portugal, in April 2022. Current in vitro models developed for recapitulating healthy and diseased lungs are outlined and discussed with respect to the challenges associated with them, efforts to develop best practices for model generation, characterisation and utilisation of models and state-of-the-art translational potential.

DOI: https://doi.org/10.1183/16000617.0042-2023
Endocrinol Diabetes Metab. 2023 Jul 28. e440

Mechanism of action of gut microbiota and probiotic Lactobacillus rhamnosus GG on skeletal remodeling in mice.

Abdul Malik Tyagi.

   INTRODUCTION: Gut microbiota (GM) is the collection of small organisms such as bacteria, fungi, bacteriophages and protozoans living in the intestine in symbiotics relation within their host. GM regulates host metabolism by various mechanisms.
METHODS: This review aims to consolidate current information for physicians on the effect of GM on bone health. For this, an online search of the literature was conducted using the keywords gut microbiota, bone mass, osteoporosis, Lactobacillus and sex steroid.
RESULTS AND CONCLUSIONS: There is a considerable degree of variation in bone mineral density (BMD) within populations, and it is estimated that a significant component of BMD variability is due to genetics. However, the remaining causes of bone mass variance within populations remain largely unknown. A well-recognized cause of phenotypic variation in bone mass is the composition of the microbiome. Studies have shown that germ-free (GF) mice have higher bone mass compared to conventionally raised (CR) mice. Furthermore, GM dysbiosis, also called dysbacteriosis, is defined as any alteration in the composition of the microbial community that has been colonized in the host intestine and associated with the development of bone diseases. For instance, postmenopausal osteoporosis (PMO) and diabetes. GM can be modulated by several factors such as genetics, age, drugs, food habits and probiotics. Probiotics are defined as viable bacteria that confer health benefits by modulating GM when administered in adequate quantity. Lactobacillus rhamnosus GG (LGG) is a great example of such a probiotic. LGG has been shown to regulate bone mass in healthy mice as well as ovariectomized (OVX) mice via two different mechanisms. This review will focus on the literature regarding the mechanism by which GM and probiotic LGG regulate bone mass in healthy mice as well as in OVX mice, a model of PMO.

Keywords:   Lactobacillus ; bone mass; gut microbiota; osteoporosis; sex steroid

DOI:  https://doi.org/10.1002/edm2.440
Nat Rev Microbiol. 2023 Jul 25.

Antibiotic perturbations to the gut microbiome.

Skye R S Fishbein, Bejan Mahmud, Gautam Dantas.

Antibiotic-mediated perturbation of the gut microbiome is associated with numerous infectious and autoimmune diseases of the gastrointestinal tract. Yet, as the gut microbiome is a complex ecological network of microorganisms, the effects of antibiotics can be highly variable. With the advent of multi-omic approaches for systems-level profiling of microbial communities, we are beginning to identify microbiome-intrinsic and microbiome-extrinsic factors that affect microbiome dynamics during antibiotic exposure and subsequent recovery. In this Review, we discuss factors that influence restructuring of the gut microbiome on antibiotic exposure. We present an overview of the currently complex picture of treatment-induced changes to the microbial community and highlight essential considerations for future investigations of antibiotic-specific outcomes. Finally, we provide a synopsis of available strategies to minimize antibiotic-induced damage or to restore the pretreatment architectures of the gut microbial community.

DOI: https://doi.org/10.1038/s41579-023-00933-y
Adv Microb Physiol. 2023 ;pii: S0065-2911(23)00015-2. [Epub ahead of print]83 181-219

Bacterial metabolism and susceptibility to cell wall-active antibiotics.

Megan Renee Keller, Tobias Dörr.

  Bacterial infections are increasingly resistant to antimicrobial therapy. Intense research focus has thus been placed on identifying the mechanisms that bacteria use to resist killing or growth inhibition by antibiotics and the ways in which bacteria share these traits with one another. This work has led to the advancement of new drugs, combination therapy regimens, and a deeper appreciation for the adaptability seen in microorganisms. However, while the primary mechanisms of action of most antibiotics are well understood, the more subtle contributions of bacterial metabolic state to repairing or preventing damage caused by antimicrobials (thereby promoting survival) are still understudied. Here, we review a modern viewpoint on a classical system: examining bacterial metabolism's connection to antibiotic susceptibility. We dive into the relationship between metabolism and antibiotic efficacy through the lens of growth rate, energy state, resource allocation, and the infection environment, focusing on cell wall-active antibiotics.

Keywords:  Antibiotic resistance; Antibiotic tolerance; Beta-lactams

DOI:  https://doi.org/10.1016/bs.ampbs.2023.04.002