bims-bac4me 2023-10-29 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2023–10–29
37 papers selected by
Chun-Chi Chang, University Hospital Zurich

An organotypic oral mucosal infection model to study host-pathogen interactions.
Commensal myeloid crosstalk in neonatal skin regulates long-term cutaneous type 17 inflammation.
Staphylococcus aureus Adaptation to the Skin in Health and Persistent/Recurrent Infections.
Transflammation in Tissue Regeneration and Response to Injury How cell-autonomous inflammatory signaling mediates cell plasticity.
Diabetes mellitus promotes the nasal colonization of high virulent Staphylococcus aureus through the regulation of SaeRS two-component systemnasal colonized S. aureus in type 2 diabetes.
SIgA structures bound to Streptococcus pyogenes M4 and human CD89 provide insights into host-pathogen interactions.
Platelet factor 4 improves survival in a murine model of antibiotic-susceptible and methicillin-resistant Staphylococcus aureus peritonitis.
Secretory IgA impacts the microbiota density in the human nose.
Exploring the complex relationship between the lung microbiome and ventilator-associated pneumonia.
The role of intestinal microbes on intestinal barrier function and host immunity from a metabolite perspective.
MUC1 attenuates neutrophilic airway inflammation in asthma by reducing NLRP3 inflammasome-mediated pyroptosis through the inhibition of the TLR4/MyD88/NF-κB pathway.
C-type lectin receptor 2d forms homodimers and heterodimers with TLR2 to negatively regulate IRF5-mediated antifungal immunity.
Nasal Nitric Oxide in Children: A Review of Current Outreach in Pediatric Respiratory Medicine.
Macrophages and fibrosis: how resident and infiltrating mononuclear phagocytes account for organ injury, regeneration or atrophy.
Epithelial Dual Oxidase 2 Shapes the Mucosal Microbiome and Contributes to Inflammatory Susceptibility.
The fungal-derived compound AM3 modulates pro-inflammatory cytokine production and skews the differentiation of human monocytes.
The application of multi-omics in the respiratory microbiome: Progresses, challenges and promises.
Trained immunity: a cutting edge approach for designing novel vaccines against parasitic diseases?
Probiotics and Their Bioproducts: A Promising Approach for Targeting Methicillin-Resistant Staphylococcus aureus and Vancomycin-Resistant Enterococcus.
Detoxification of reactive oxygen species by the hyaluronic acid capsule of group A Streptococcus.
Akkermansia muciniphila induces slow extramedullary hematopoiesis via cooperative IL-1R/TLR signals.
Interactions between Helicobacter pylori infection and host metabolic homeostasis: A comprehensive review.
BBQ methods: Streamlined workflows for Bacterial Burden Quantification in infected cells by confocal microscopy.
Plasticity in the cell division processes of obligate intracellular bacteria.
mSphere of Influence: Coordinating effective clearance of bacterial bloodstream infections.
Phage activity against Staphylococcus aureus is impaired in plasma and synovial fluid.
Metabolic sinkholes: Histones as methyl repositories.
Glycolytic reprogramming fuels myeloid cell-driven hypercoagulability.
Complementary Activities of Host Defence Peptides and Antibiotics in Combating Antimicrobial Resistant Bacteria.
STATs signaling pathways in dendritic cells: As potential therapeutic targets?
Identifying genetic determinants of Streptococcus pyogenes-host interactions in a murine intact skin infection model.
Factors Influencing Microbiota in Modulating Vaccine Immune Response: A Long Way to Go.
A Bacterial Quorum Sensing Regulated Protease Inhibits Host Immune Responses by Cleaving Death Domains of Innate Immune Adaptors.
Metabolites of non-aureus staphylococci affect the ability of Staphylococcus aureus to adhere to and internalize into bovine mammary epithelial cells.
Limited effects of azithromycin on the oropharyngeal microbiome in children with CF and early pseudomonas infection.
Mmp17-deficient mice exhibit heightened goblet cell effector expression in the colon and increased resistance to chronic Trichuris muris infection.
Immunosenescence and macrophages: From basics to therapeutics.

J Tissue Eng. 2023 Jan-Dec;14:14 20417314231197310

An organotypic oral mucosal infection model to study host-pathogen interactions.

Samantha J Gould, Andrew D Foey, Vehid M Salih.

  Early in vitro oral mucosal infection models (OMMs) failed to consider the suitability of the model environment to represent the host immune response. Denture stomatitis (DS) is mediated by Candida albicans, but the role of Staphylococcus aureus remains uncertain. A collagen hydrogel-based OMM containing HaCaT and HGF cell types was developed, characterised and employed to study of tissue invasion and pro-inflammatory cytokine production in response to pathogens. Models formed a robust epithelium. Despite their inflammatory baseline, 24-h infection with C. albicans, and/or S. aureus led to tissue invasion, and significantly upregulated IL-6 and IL-8 production by OMMs when compared to the unstimulated control. No significant difference in IL-6 or IL-8 production by OMMs was observed between single and dual infections. These attributes indicate that this newly developed OMM is suitable for the study of DS and could be implemented for the wider study of oral infection.

Keywords:  Candida albicans; Staphylococcus aureus; denture stomatitis; infection model; oral mucosa; organotypic; tissue-engineering

DOI:  https://doi.org/10.1177/20417314231197310
bioRxiv. 2023 Oct 02. pii: 2023.09.29.560039. [Epub ahead of print]

Commensal myeloid crosstalk in neonatal skin regulates long-term cutaneous type 17 inflammation.

Miqdad O Dhariwala, Andrea M DeRogatis, Joy N Okoro, Antonin Weckel, Victoria M Tran, Irek Habrylo, Oluwasunmisola T Ojewumi, Allison E Tammen, John M Leech, Geil R Merana, Ricardo O Carale, Rio Barrere-Cain, Kamir J Hiam-Galvez, Matthew H Spitzer, Tiffany C Scharschmidt.

Early life microbe-immune interactions at barrier surfaces have lasting impacts on the trajectory towards health versus disease. Monocytes, macrophages and dendritic cells are primary sentinels in barrier tissues, yet the salient contributions of commensal-myeloid crosstalk during tissue development remain poorly understood. Here, we identify that commensal microbes facilitate accumulation of a population of monocytes in neonatal skin. Transient postnatal depletion of these monocytes resulted in heightened IL-17A production by skin T cells, which was particularly sustained among CD4 + T cells into adulthood and sufficient to exacerbate inflammatory skin pathologies. Neonatal skin monocytes were enriched in expression of negative regulators of the IL-1 pathway. Functional in vivo experiments confirmed a key role for excessive IL-1R1 signaling in T cells as contributing to the dysregulated type 17 response in neonatal monocyte-depleted mice. Thus, a commensal-driven wave of monocytes into neonatal skin critically facilitates long-term immune homeostasis in this prominent barrier tissue.

DOI: https://doi.org/10.1101/2023.09.29.560039
Antibiotics (Basel). 2023 Oct 07. pii: 1520. [Epub ahead of print]12(10):

Staphylococcus aureus Adaptation to the Skin in Health and Persistent/Recurrent Infections.

Ana-Katharina E Gehrke, Constanza Giai, Marisa I Gómez.

  Staphylococcus aureus is a microorganism with an incredible capability to adapt to different niches within the human body. Approximately between 20 and 30% of the population is permanently but asymptomatically colonized with S. aureus in the nose, and another 30% may carry S. aureus intermittently. It has been established that nasal colonization is a risk factor for infection in other body sites, including mild to severe skin and soft tissue infections. The skin has distinct features that make it a hostile niche for many bacteria, therefore acting as a strong barrier against invading microorganisms. Healthy skin is desiccated; it has a low pH at the surface; the upper layer is constantly shed to remove attached bacteria; and several host antimicrobial peptides are produced. However, S. aureus is able to overcome these defenses and colonize this microenvironment. Moreover, this bacterium can very efficiently adapt to the stressors present in the skin under pathological conditions, as it occurs in patients with atopic dermatitis or suffering chronic wounds associated with diabetes. The focus of this manuscript is to revise the current knowledge concerning how S. aureus adapts to such diverse skin conditions causing persistent and recurrent infections.

Keywords:  Staphylococcus aureus; adaptation; persistence

DOI:  https://doi.org/10.3390/antibiotics12101520
Adv Drug Deliv Rev. 2023 Oct 24. pii: S0169-409X(23)00433-7. [Epub ahead of print] 115118

Transflammation in Tissue Regeneration and Response to Injury How cell-autonomous inflammatory signaling mediates cell plasticity.

John P Cooke, Li Lai.

  Inflammation is a first responder against injury and infection and is also critical for the regeneration and repair of tissue after injury. The role of professional immune cells in tissue healing is well characterized. Professional immune cells respond to pathogens with humoral and cytotoxic responses; remove cellular debris through efferocytosis; secrete angiogenic cytokines and growth factors to repair the microvasculature and parenchyma. However, non-immune cells are also capable of responding to damage or pathogens. Non-immune somatic cells express pattern recognition receptors (PRRs) to detect pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). The PRRs activation leads to the release of inflammatory cytokines required for tissue defense and repair. Notably, the activation of PRRs also triggers epigenetic changes that promote DNA accessibility and cellular plasticity. Thus, non-immune cells directly respond to the local inflammatory cues and can undergo phenotypic modifications or even cell lineage transitions to facilitate tissue regeneration. This review will focus on the novel role of cell-autonomous inflammatory signaling in mediating cell plasticity, a process which is termed transflammation. We will discuss the regulation of this process by changes in the functions and expression levels of epigenetic modifiers, as well as metabolic and ROS/RNS-mediated epigenetic modulation of DNA accessibility during cell fate transition. We will highlight the recent technological developments in detecting cell plasticity and potential therapeutic applications of transflammation in tissue regeneration.

Keywords:  DNA accessibility; RNS; ROS; Transflammation; epigenetics; innate immunity; metabolism; regeneration; single-cell omics

DOI:  https://doi.org/10.1016/j.addr.2023.115118
Emerg Microbes Infect. 2023 Oct 26. 2276335

Diabetes mellitus promotes the nasal colonization of high virulent Staphylococcus aureus through the regulation of SaeRS two-component systemnasal colonized S. aureus in type 2 diabetes.

Qichen Wang, Nadira Nurxat, Lei Zhang, Yao Liu, Yanan Wang, Lei Zhang, Na Zhao, Yingxin Dai, Ying Jian, Lei He, Hua Wang, Taeok Bae, Min Li, Qian Liu.

  AbstractDiabetic foot infections are a common complication of diabetes. Staphylococcus aureus is frequently isolated from diabetic foot infections and commonly colonizes human nares. According to the study, the nasal microbiome analysis revealed that diabetic patients had a significantly altered nasal microbial composition and diversity. Typically, the fasting blood glucose (FBG) level had an impact on the abundance and sequence type (ST) of S. aureus in diabetic patients. We observed that highly virulent S. aureus ST7 strains were more frequently colonized in diabetic patients, especially those with poorly controlled FBG, while ST59 was dominant in healthy individuals. S. aureus ST7 strains were more resistant to human antimicrobial peptides and formed stronger biofilms than ST59 strains. Critically, S. aureus ST7 strains displayed higher virulence compared to ST59 strains in vivo. The dominance of S. aureus ST7 strains in hyperglycemic environment is due to the higher activity of the SaeRS two-component system (TCS). S. aureus ST7 strains outcompeted ST59 both in vitro, and in nasal colonization model in diabetic mice, which was abolished by the deletion of the SaeRS TCS. Our data indicated that highly virulent S. aureus strains preferentially colonize diabetic patients with poorly controlled FBG through SaeRS TCS. Detection of S. aureus colonization and elimination of colonizing S. aureus are critical in the care of diabetic patients with high FBG.

Keywords:  Diabetes; SaeRS two-component system; Staphylococcus aureus; colonization; microbiome

DOI:  https://doi.org/10.1080/22221751.2023.2276335
Nat Commun. 2023 Oct 23. 14(1): 6726

SIgA structures bound to Streptococcus pyogenes M4 and human CD89 provide insights into host-pathogen interactions.

Qianqiao Liu, Beth M Stadtmueller.

Immunoglobulin (Ig) A functions as monomeric IgA in the serum and Secretory (S) IgA in mucosal secretions. Host IgA Fc receptors (FcαRs), including human FcαR1/CD89, mediate IgA effector functions; however, human pathogen Streptococcus pyogenes has evolved surface-protein virulence factors, including M4, that also engage the CD89-binding site on IgA. Despite human mucosa serving as a reservoir for pathogens, SIgA interactions with CD89 and M4 remain poorly understood. Here we report cryo-EM structures of M4-SIgA and CD89-SIgA complexes, which unexpectedly reveal different SIgA-binding stoichiometry for M4 and CD89. Structural data, supporting experiments, and modeling indicate that copies of SIgA bound to S. pyogenes M4 will adopt similar orientations on the bacterium surface and leave one host FcαR binding site open. Results suggest unappreciated functional consequences associated with SIgA binding to host and bacterial FcαRs relevant to understanding host-microbe co-evolution, IgA effector functions and improving the outcomes of group A Streptococcus infection.

DOI: https://doi.org/10.1038/s41467-023-42469-y
Front Cell Infect Microbiol. 2023 ;13 1217103

Platelet factor 4 improves survival in a murine model of antibiotic-susceptible and methicillin-resistant Staphylococcus aureus peritonitis.

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

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

Keywords:  CD11b/CD18; CR3; CXCL4; PF4; antibiotic resistance; antimicrobial activity; integrin Mac-1; phagocytosis

DOI:  https://doi.org/10.3389/fcimb.2023.1217103
Microbiome. 2023 Oct 21. 11(1): 233

Secretory IgA impacts the microbiota density in the human nose.

Rob van Dalen, Ahmed M A Elsherbini, Mareike Harms, Svenja Alber, Regine Stemmler, Andreas Peschel.

   BACKGROUND: Respiratory mucosal host defense relies on the production of secretory IgA (sIgA) antibodies, but we currently lack a fundamental understanding of how sIgA is induced by contact with microbes and how such immune responses may vary between humans. Defense of the nasal mucosal barrier through sIgA is critical to protect from infection and to maintain homeostasis of the microbiome, which influences respiratory disorders and hosts opportunistic pathogens.
METHODS: We applied IgA-seq analysis to nasal microbiota samples from male and female healthy volunteers, to identify which bacterial genera and species are targeted by sIgA on the level of the individual host. Furthermore, we used nasal sIgA from the same individuals in sIgA deposition experiments to validate the IgA-seq outcomes.
CONCLUSIONS: We observed that the amount of sIgA secreted into the nasal mucosa by the host varied substantially and was negatively correlated with the bacterial density, suggesting that nasal sIgA limits the overall bacterial capacity to colonize. The interaction between mucosal sIgA antibodies and the nasal microbiota was highly individual with no obvious differences between potentially invasive and non-invasive bacterial species. Importantly, we could show that for the clinically relevant opportunistic pathogen and frequent nasal resident Staphylococcus aureus, sIgA reactivity was in part the result of epitope-independent interaction of sIgA with the antibody-binding protein SpA through binding of sIgA Fab regions. This study thereby offers a first comprehensive insight into the targeting of the nasal microbiota by sIgA antibodies. It thereby helps to better understand the shaping and homeostasis of the nasal microbiome by the host and may guide the development of effective mucosal vaccines against bacterial pathogens. Video Abstract.

Keywords:  IgA-seq; Mucosal immunology; Nasal antibodies; Nasal microbiota; Secretory IgA

DOI:  https://doi.org/10.1186/s40168-023-01675-y
Expert Rev Respir Med. 2023 Oct 23. 1-13

Exploring the complex relationship between the lung microbiome and ventilator-associated pneumonia.

Ingrid G Bustos, Ignacio Martín-Loeches, Alejandro Acosta-González, Sanjay H Chotirmall, Robert P Dickson, Luis Felipe Reyes.

   INTRODUCTION: Understanding the presence and function of a diverse lung microbiome in acute lung infections, particularly ventilator-associated pneumonia (VAP), is still limited, evidencing significant gaps in our knowledge.
AREAS COVERED: In this comprehensive narrative review, we aim to elucidate the contribution of the respiratory microbiome in the development of VAP by examining the current knowledge on the interactions among microorganisms. By exploring these intricate connections, we endeavor to enhance our understanding of the disease's pathophysiology and pave the way for novel ideas and interventions in studying the respiratory tract microbiome.
EXPERT OPINION: The conventional perception of lungs as sterile is deprecated since it is currently recognized the existence of a diverse microbial community within them. However, despite extensive research on the role of the respiratory microbiome in healthy lungs, respiratory chronic diseases and acute lung infections such as pneumonia are not fully understood. It is crucial to investigate further the relationship between the pathophysiology of VAP and the pulmonary microbiome, elucidating the mechanisms underlying the interactions between the microbiome, host immune response and mechanical ventilation for the development of VAP.

Keywords:  Lung microbiome; dysbiosis; immune response; lung microbiota; mechanical ventilation; ventilator-associated pneumonia

DOI:  https://doi.org/10.1080/17476348.2023.2273424
Front Immunol. 2023 ;14 1277102

The role of intestinal microbes on intestinal barrier function and host immunity from a metabolite perspective.

Yifeng Fu, Jin Lyu, Shuangshuang Wang.

  The gut is colonized by many commensal microorganisms, and the diversity and metabolic patterns of microorganisms profoundly influence the intestinal health. These microbial imbalances can lead to disorders such as inflammatory bowel disease (IBD). Microorganisms produce byproducts that act as signaling molecules, triggering the immune system in the gut mucosa and controlling inflammation. For example, metabolites like short-chain fatty acids (SCFA) and secondary bile acids can release inflammatory-mediated signals by binding to specific receptors. These metabolites indirectly affect host health and intestinal immunity by interacting with the intestinal epithelial and mucosal immune cells. Moreover, Tryptophan-derived metabolites also play a role in governing the immune response by binding to aromatic hydrocarbon receptors (AHR) located on the intestinal mucosa, enhancing the intestinal epithelial barrier. Dietary-derived indoles, which are synthetic precursors of AHR ligands, work together with SCFA and secondary bile acids to reduce stress on the intestinal epithelium and regulate inflammation. This review highlights the interaction between gut microbial metabolites and the intestinal immune system, as well as the crosstalk of dietary fiber intake in improving the host microbial metabolism and its beneficial effects on the organism.

Keywords:  AHR; dietary fibre; intestinal microorganisms; short-chain fatty acids; tryptophan

DOI:  https://doi.org/10.3389/fimmu.2023.1277102
Respir Res. 2023 Oct 25. 24(1): 255

MUC1 attenuates neutrophilic airway inflammation in asthma by reducing NLRP3 inflammasome-mediated pyroptosis through the inhibition of the TLR4/MyD88/NF-κB pathway.

Lu Liu, Ling Zhou, Lingling Wang, Zhenyu Mao, Pengdou Zheng, Fengqin Zhang, Huojun Zhang, Huiguo Liu.

   BACKGROUND: Neutrophilic airway inflammation is a challenge in asthma management and is associated with poor patient prognosis. Mucin 1 (MUC1), which contains a cytoplasmic tail (MUC1-CT), has been found to mediate glucocorticoid sensitivity in asthma; however, its role in modulating neutrophilic airway inflammation in asthma remains unknown.
METHODS: Human-induced sputum cells were collected from healthy participants (n = 12), patients with mild-to-moderate asthma (n = 34), and those with severe asthma (n = 18). In vitro human lung bronchial 1 epithelial cell line (BEAS-2B) was transfected with small interfering RNA against MUC1 (MUC1-siRNA) and then stimulated by lipopolysaccharide (LPS), where some cells were pretreated with a TLR4 inhibitor (TAK-242). In vivo mouse model of asthmatic neutrophil airway inflammation was induced by ovalbumin (OVA)/LPS. Some groups were intraperitoneally injected with MUC1-CT inhibitor (GO-203) and/or TAK-242 .
RESULTS: The mRNA expression of MUC1 was downregulated in the induced sputum of patients with asthma and correlated with asthmatic neutrophilic airway inflammation. The mRNA expressions of TLR4, MyD88, nucleotide-binding oligomerization domain-like pyrin domain-containing protein 3 (NLRP3), caspase-1, interleukin (IL)-18, and IL-1β in induced sputum cells of patients with asthma were upregulated and related to the mRNA expression of MUC1. LPS activated the TLR4 pathway and NLRP3-mediated pyroptosis in BEAS-2B cells in vitro, which were significantly aggravated after MUC1-siRNA transfection. Furthermore, MUCl-CT interacted with TLR4, and the interaction between TLR4 and MyD88 was significantly increased after MUCl-siRNA transfection. Moreover, TAK-242 ameliorated TLR4/MyD88/nuclear factor kappa B (NF-κB) pathway activation, NLRP3 inflammasome-mediated pyroptosis, and neutrophilic inflammation exacerbated by MUC1 downregulation. GO-203 exacerbated TLR4/MyD88/NF-κB pathway activation in vivo, and NLRP3 inflammasome-mediated pyroptosis reduced in a mouse model of asthmatic neutrophil airway inflammation induced by OVA/LPS; these pathological changes were partially alleviated after TAK-242 application.
CONCLUSION: This study revealed that MUC1 downregulation plays an important role in asthmatic neutrophilic airway inflammation. MUC1-CT reduces NLRP3 inflammasome-mediated pyroptosis by inhibiting the activation of the TLR4/MyD88/NF-κB pathway, thereby attenuating neutrophil airway inflammation in patients with asthma.

Keywords:  Asthma; Inflammation; MUC1; Pyroptosis

DOI:  https://doi.org/10.1186/s12931-023-02550-y
Nat Commun. 2023 Oct 23. 14(1): 6718

C-type lectin receptor 2d forms homodimers and heterodimers with TLR2 to negatively regulate IRF5-mediated antifungal immunity.

Fan Li, Hui Wang, Yan-Qi Li, Yebo Gu, Xin-Ming Jia.

Dimerization of C-type lectin receptors (CLRs) or Toll-like receptors (TLRs) can alter their ligand binding ability, thereby modulating immune responses. However, the possibilities and roles of dimerization between CLRs and TLRs remain unclear. Here we show that C-type lectin receptor-2d (CLEC2D) forms homodimers, as well as heterodimers with TLR2. Quantitative ligand binding assays reveal that both CLEC2D homodimers and CLEC2D/TLR2 heterodimers have a higher binding ability to fungi-derived β-glucans than TLR2 homodimers. Moreover, homo- or hetero-dimeric CLEC2D mediates β-glucan-induced ubiquitination and degradation of MyD88 to inhibit the activation of transcription factor IRF5 and subsequent IL-12 production. Clec2d-deficient female mice are resistant to infection with Candida albicans, a human fungal pathogen, owing to the increase of IL-12 production and subsequent generation of IFN-γ-producing NK cells. Together, these data indicate that CLEC2D forms homodimers or heterodimers with TLR2, which negatively regulate antifungal immunity through suppression of IRF5-mediated IL-12 production. These homo- and hetero-dimers of CLEC2D and TLR2 provide an example of receptor dimerization to regulate host innate immunity against microbial infections.

DOI: https://doi.org/10.1038/s41467-023-42216-3
Children (Basel). 2023 Oct 09. pii: 1671. [Epub ahead of print]10(10):

Nasal Nitric Oxide in Children: A Review of Current Outreach in Pediatric Respiratory Medicine.

Iva Mrkić Kobal, Mirjana Turkalj, Davor Plavec.

  Nasal nitric oxide (nNO) is a gas synthesized by the inducible and constitutive NO synthase (NOS) enzyme in the airway cells of the nasal mucosa. Like lung nitric oxide, it is thought to be associated with airway inflammation in various respiratory diseases in children. The aim of our review was to investigate the current state of use of nNO measurement in children. A comprehensive search was conducted using the Web of Science and PubMed databases specifically targeting publications in the English language, with the following keywords: nasal NO, children, allergic rhinitis, chronic rhinosinusitis, acute rhinosinusitis, primary ciliary dyskinesia (PCD), and cystic fibrosis (CF). We describe the use of nNO in pediatric allergic rhinitis, chronic rhinosinusitis, acute rhinosinusitis, PCD, and CF based on the latest literature. nNO is a noninvasive, clinically applicable test for use in pediatric allergic rhinitis, chronic rhinosinusitis, acute rhinosinusitis, PCD, and CF. It can be used as a complementary method in the diagnosis of these respiratory diseases and as a monitoring method for the treatment of allergic rhinitis and acute and chronic rhinosinusitis.

Keywords:  allergic rhinitis; children; chronic rhinosinusitis; cystic fibrosis; nasal nitric oxide; primary ciliary dyskinesia

DOI:  https://doi.org/10.3390/children10101671
Front Immunol. 2023 ;14 1194988

Macrophages and fibrosis: how resident and infiltrating mononuclear phagocytes account for organ injury, regeneration or atrophy.

Hao Long, Julia Lichtnekert, Joachim Andrassy, Barbara U Schraml, Paola Romagnani, Hans-Joachim Anders.

  Mononuclear phagocytes (MP), i.e., monocytes, macrophages, and dendritic cells (DCs), are essential for immune homeostasis via their capacities to clear pathogens, pathogen components, and non-infectious particles. However, tissue injury-related changes in local microenvironments activate resident and infiltrating MP towards pro-inflammatory phenotypes that contribute to inflammation by secreting additional inflammatory mediators. Efficient control of injurious factors leads to a switch of MP phenotype, which changes the microenvironment towards the resolution of inflammation. In the same way, MP endorses adaptive structural responses leading to either compensatory hypertrophy of surviving cells, tissue regeneration from local tissue progenitor cells, or tissue fibrosis and atrophy. Under certain circumstances, MP contribute to the reversal of tissue fibrosis by clearance of the extracellular matrix. Here we give an update on the tissue microenvironment-related factors that, upon tissue injury, instruct resident and infiltrating MP how to support host defense and recover tissue function and integrity. We propose that MP are not intrinsically active drivers of organ injury and dysfunction but dynamic amplifiers (and biomarkers) of specific tissue microenvironments that vary across spatial and temporal contexts. Therefore, MP receptors are frequently redundant and suboptimal targets for specific therapeutic interventions compared to molecular targets upstream in adaptive humoral or cellular stress response pathways that influence tissue milieus at a contextual level.

Keywords:  dendritic cells; fibrosis; inflammation; macrophages; necrosis; polyploidy

DOI:  https://doi.org/10.3389/fimmu.2023.1194988
Antioxidants (Basel). 2023 Oct 21. pii: 1889. [Epub ahead of print]12(10):

Epithelial Dual Oxidase 2 Shapes the Mucosal Microbiome and Contributes to Inflammatory Susceptibility.

Juan Camilo Castrillón-Betancur, Víctor Alonso López-Agudelo, Nina Sommer, Sven Cleeves, Joana Pimenta Bernardes, Saskia Weber-Stiehl, Philip Rosenstiel, Felix Sommer.

  Reactive oxygen species (ROS) are highly reactive molecules formed from diatomic oxygen. They act as cellular signals, exert antibiotic activity towards invading microorganisms, but can also damage host cells. Dual oxidase 2 (DUOX2) is the main ROS-producing enzyme in the intestine, regulated by cues of the commensal microbiota and functions in pathogen defense. DUOX2 plays multiple roles in different organs and cell types, complicating the functional analysis using systemic deletion models. Here, we interrogate the precise role of epithelial DUOX2 for intestinal homeostasis and host-microbiome interactions. Conditional Duox2∆IEC mice lacking DUOX2, specifically in intestinal epithelial cells, were generated, and their intestinal mucosal immune phenotype and microbiome were analyzed. Inflammatory susceptibility was evaluated by challenging Duox2∆IEC mice in the dextran sodium sulfate (DSS) colitis model. DUOX2-microbiome interactions in humans were investigated by paired analyses of mucosal DUOX2 expression and fecal microbiome data in patients with intestinal inflammation. Under unchallenged conditions, we did not observe any obvious phenotype of Duox2∆IEC mice, although intestinal epithelial ROS production was drastically decreased, and the mucosal microbiome composition was altered. When challenged with DSS, Duox2∆IEC mice were protected from colitis, possibly by inhibiting ROS-mediated damage and fostering epithelial regenerative responses. Finally, in patients with intestinal inflammation, DUOX2 expression was increased in inflamed tissue, and high DUOX2 levels were linked to a dysbiotic microbiome. Our findings demonstrate that bidirectional DUOX2-microbiome interactions contribute to mucosal homeostasis, and their dysregulation may drive disease development, thus highlighting this axis as a therapeutic target to treat intestinal inflammation.

Keywords:  DUOX2; ROS; inflammation; microbiome

DOI:  https://doi.org/10.3390/antiox12101889
Front Immunol. 2023 ;14 1165683

The fungal-derived compound AM3 modulates pro-inflammatory cytokine production and skews the differentiation of human monocytes.

Büsra Geckin, Gizem Kilic, Priya A Debisarun, Konstantin Föhse, Azahara Rodríguez-Luna, Pablo Fernández-González, Ana López Sánchez, Jorge Domínguez-Andrés.

  The proper functioning of the immune system depends on an appropriate balance between pro-inflammation and anti-inflammation. When the balance is disrupted and the system is excessively biased towards inflammation, immune responses cannot return within the normal range, which favors the onset of diseases of autoimmune or inflammatory nature. In this scenario, it is fundamental to find new compounds that can help restore this balance and contribute to the normal functioning of the immune system in humans. Here, we show the properties of a fungal compound with a strong safety profile in humans, AM3, as an immunomodulatory molecule to decrease excessive cytokine production in human cells. Our results present that AM3 treatment of human peripheral blood mononuclear cells and monocytes decreased their pro-inflammatory cytokine secretion following the challenge with bacterial lipopolysaccharide. Additionally, AM3 skewed the differentiation profile of human monocytes to macrophages towards a non-inflammatory phenotype without inducing tolerance, meaning these cells kept their capacity to respond to different stimuli. These effects were similar in young and elderly individuals. Thus, the fungal compound, AM3 may help reduce excessive immune activation in inflammatory conditions and keep the immune responses within a normal homeostatic range, regardless of the age of the individual.

Keywords:  AM3; cytokines; disease; homeostasis; immune response; inflammation; macrophages; monocytes

DOI:  https://doi.org/10.3389/fimmu.2023.1165683
Comput Struct Biotechnol J. 2023 ;21 4933-4943

The application of multi-omics in the respiratory microbiome: Progresses, challenges and promises.

Jingyuan Gao, Xinzhu Yi, Zhang Wang.

  The study of the respiratory microbiome has entered a multi-omic era. Through integrating different omic data types such as metagenome, metatranscriptome, metaproteome, metabolome, culturome and radiome surveyed from respiratory specimens, holistic insights can be gained on the lung microbiome and its interaction with host immunity and inflammation in respiratory diseases. The power of multi-omics have moved the field forward from associative assessment of microbiome alterations to causative understanding of the lung microbiome in the pathogenesis of chronic, acute and other types of respiratory diseases. However, the application of multi-omics in respiratory microbiome remains with unique challenges from sample processing, data integration, and downstream validation. In this review, we first introduce the respiratory sample types and omic data types applicable to studying the respiratory microbiome. We next describe approaches for multi-omic integration, focusing on dimensionality reduction, multi-omic association and prediction. We then summarize progresses in the application of multi-omics to studying the microbiome in respiratory diseases. We finally discuss current challenges and share our thoughts on future promises in the field.

Keywords:  Microbiome-host interaction; Multi-Omics; Respiratory diseases; Respiratory microbiome

DOI:  https://doi.org/10.1016/j.csbj.2023.10.016
Front Immunol. 2023 ;14 1252554

Trained immunity: a cutting edge approach for designing novel vaccines against parasitic diseases?

Jinhang Zhu, Jiaxi Liu, Chao Yan, Dahui Wang, Wei Pan.

  The preventive situation of parasitosis, a global public health burden especially for developing countries, is not looking that good. Similar to other infections, vaccines would be the best choice for preventing and controlling parasitic infection. However, ideal antigenic molecules for vaccine development have not been identified so far, resulting from the complicated life history and enormous genomes of the parasites. Furthermore, the suppression or down-regulation of anti-infectious immunity mediated by the parasites or their derived molecules can compromise the effect of parasitic vaccines. Comparing the early immune profiles of several parasites in the permissive and non-permissive hosts, a robust innate immune response is proposed to be a critical event to eliminate the parasites. Therefore, enhancing innate immunity may be essential for designing novel and effective parasitic vaccines. The newly emerging trained immunity (also termed innate immune memory) has been increasingly recognized to provide a novel perspective for vaccine development targeting innate immunity. This article reviews the current status of parasitic vaccines and anti-infectious immunity, as well as the conception, characteristics, and mechanisms of trained immunity and its research progress in Parasitology, highlighting the possible consideration of trained immunity in designing novel vaccines against parasitic diseases.

Keywords:  innate immune memory; metabolic and epigenetic programming; parasitic diseases; trained immunity; vaccine

DOI:  https://doi.org/10.3389/fimmu.2023.1252554
Microorganisms. 2023 Sep 25. pii: 2393. [Epub ahead of print]11(10):

Probiotics and Their Bioproducts: A Promising Approach for Targeting Methicillin-Resistant Staphylococcus aureus and Vancomycin-Resistant Enterococcus.

Manav Jain, Gideon Stitt, Luke Son, Elena Y Enioutina.

  Antibiotic resistance is a serious global health problem that poses a threat to the successful treatment of various bacterial infections, especially those caused by methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE). Conventional treatment of MRSA and VRE infections is challenging and often requires alternative or combination therapies that may have limited efficacy, higher costs, and/or more adverse effects. Therefore, there is an urgent need to find new strategies to combat antibiotic-resistant bacteria. Probiotics and antimicrobial peptides (AMPs) are two promising approaches that have shown potential benefits in various diseases. Probiotics are live microorganisms that confer health benefits to the host when administered in adequate amounts. AMPs, usually produced with probiotic bacteria, are short amino acid sequences that have broad-spectrum activity against bacteria, fungi, viruses, and parasites. Both probiotics and AMPs can modulate the host immune system, inhibit the growth and adhesion of pathogens, disrupt biofilms, and enhance intestinal barrier function. In this paper, we review the current knowledge on the role of probiotics and AMPs in targeting multi-drug-resistant bacteria, with a focus on MRSA and VRE. In addition, we discuss future directions for the clinical use of probiotics.

Keywords:  alternative treatment; antimicrobial peptides; bacteriocins; conventional treatment; methicillin-resistant Staphylococcus aureus (MRSA); multi-drug resistant bacteria; probiotics; vancomycin-resistant Enterococcus (VRE)

DOI:  https://doi.org/10.3390/microorganisms11102393
Infect Immun. 2023 Oct 24. e0025823

Detoxification of reactive oxygen species by the hyaluronic acid capsule of group A Streptococcus.

Shyra Wilde, Ananya Dash, Anders Johnson, Kialani Mackey, Cheryl Y M Okumura, Christopher N LaRock.

  The pro-inflammatory cytokine IL-6 regulates antimicrobial responses that are broadly crucial in the defense against infection. Our prior work shows that IL-6 promotes the killing of the M4 serotype group A Streptococcus (GAS) but does not impact the globally disseminated M1T1 serotype associated with invasive infections. Using in vitro and in vivo infection models, we show that IL-6 induces phagocyte reactive oxygen species (ROS) that are responsible for the differential susceptibility of M4 and M1T1 GAS to IL-6-mediated defenses. Clinical isolates naturally deficient in capsule, or M1T1 strains deficient in capsule production, are sensitive to this ROS killing. The GAS capsule is made of hyaluronic acid, an antioxidant that detoxifies ROS and can protect acapsular M4 GAS when added exogenously. During in vitro interactions with macrophages and neutrophils, acapsular GAS can also be rescued with the antioxidant N-acetylcysteine, suggesting this is a major virulence contribution of the capsule. In an intradermal infection model with gp91phox-/- (chronic granulomatous disease [CGD]) mice, phagocyte ROS production had a modest effect on bacterial proliferation and the cytokine response but significantly limited the size of the bacterial lesion in the skin. These data suggest that the capsule broadly provides enhanced resistance to phagocyte ROS but is not essential for invasive infection. Since capsule-deficient strains are observed across several GAS serotypes and are competent for transmission and both mild and invasive infections, additional host or microbe factors may contribute to ROS detoxification during GAS infections.

Keywords:  Streptococcus pyogenes; capsule; group A Streptococcus; interleukins; oxygen radicals

DOI:  https://doi.org/10.1128/iai.00258-23
EMBO Rep. 2023 Oct 23. e57485

Akkermansia muciniphila induces slow extramedullary hematopoiesis via cooperative IL-1R/TLR signals.

Yuxin Wang, Tatsuya Morishima, Maiko Sezaki, Ryo Sato, Gaku Nakato, Shinji Fukuda, Kouji Kobiyama, Ken J Ishii, Yuhua Li, Hitoshi Takizawa.

  Bacterial infections can activate and mobilize hematopoietic stem and progenitor cells (HSPCs) from the bone marrow (BM) to the spleen, a process termed extramedullary hematopoiesis (EMH). Recent studies suggest that commensal bacteria regulate not only the host immune system but also hematopoietic homeostasis. However, the impact of gut microbes on hematopoietic pathology remains unclear. Here, we find that systemic single injections of Akkermansia muciniphila (A. m.), a mucin-degrading bacterium, rapidly activate BM myelopoiesis and slow but long-lasting hepato-splenomegaly, characterized by the expansion and differentiation of functional HSPCs, which we term delayed EMH. Mechanistically, delayed EMH triggered by A. m. is mediated entirely by the MYD88/TRIF innate immune signaling pathway, which persistently stimulates splenic myeloid cells to secrete interleukin (IL)-1α, and in turn, activates IL-1 receptor (IL-1R)-expressing splenic HSPCs. Genetic deletion of Toll-like receptor-2 and -4 (TLR2/4) or IL-1α partially diminishes A. m.-induced delayed EMH, while inhibition of both pathways alleviates splenomegaly and EMH. Our results demonstrate that cooperative IL-1R- and TLR-mediated signals regulate commensal bacteria-driven EMH, which might be relevant for certain autoimmune disorders.

Keywords:  Akkermansia muciniphila; IL-1; TLR; extramedullary hematopoiesis; hematopoietic stem and progenitor cell

DOI:  https://doi.org/10.15252/embr.202357485
Helicobacter. 2023 Oct 23. e13030

Interactions between Helicobacter pylori infection and host metabolic homeostasis: A comprehensive review.

Junzhao Ye, Ting Feng, Lei Su, Jin Li, Yingying Gong, Xiaoyi Ma.

  The microbiota actively and extensively participates in the regulation of human metabolism, playing a crucial role in the development of metabolic diseases. Helicobacter pylori (H. pylori), when colonizing gastric epithelial cells, not only induces local tissue inflammation or malignant transformation but also leads to systemic and partial changes in host metabolism. These shifts can be mediated through direct contact, toxic components, or indirect immune responses. Consequently, they influence various molecular metabolic events that impact nutritional status and iron absorption in the host. Unraveling the intricate and diverse molecular interaction links between H. pylori and human metabolism modulation is essential for understanding pathogenesis mechanisms and developing targeted treatments for related diseases. However, significant challenges persist in comprehensively understanding the complex association networks among H. pylori itself, the infected host's status, the host microbiome, and the immune response. Previous metabolomics research has indicated that H. pylori infection and eradication may selectively shape the metabolite and microbial profiles of gastric lesions. Yet, it remains largely unknown how these diverse metabolic pathways, including isovaleric acid, cholesterol, fatty acids, and phospholipids, specifically modulate gastric carcinogenesis or affect the host's serum metabolism, consequently leading to the development of metabolic-associated diseases. The direct contribution of H. pylori to metabolisms still lacks conclusive evidence. In this review, we summarize recent advances in clinical evidence highlighting associations between chronic H. pylori infection and metabolic diseases, as well as its potential molecular regulatory patterns.

Keywords:   Helicobacter pylori ; insulin resistance; metabolism; metabolites; microbiota; nonalcoholic fatty liver disease

DOI:  https://doi.org/10.1111/hel.13030
bioRxiv. 2023 Oct 02. pii: 2023.10.01.560379. [Epub ahead of print]

BBQ methods: Streamlined workflows for Bacterial Burden Quantification in infected cells by confocal microscopy.

Jacques Augenstreich, Michael Shuster, Yongqiang Fan, Zhihui Lyu, Jiqiang Ling, Volker Briken.

Accurate quantification of bacterial burden within macrophages, termed Bacterial Burden Quantification (BBQ), is crucial for understanding host-pathogen interactions. Various methods have been employed, each with strengths and weaknesses. This article addresses limitations in existing techniques and introduces two novel automated methods for BBQ within macrophages based on confocal microscopy data analysis. The first method refines total fluorescence quantification by incorporating filtering steps to exclude uninfected cells, while the second method calculates total bacterial volume per cell to mitigate potential biases in fluorescence-based readouts. These workflows utilize PyImageJ and Cellpose software, providing reliable, unbiased, and rapid quantification of bacterial load. The proposed workflows were validated using Salmonella enterica serovar Typhimurium and Mycobacterium tuberculosis models, demonstrating their effectiveness in accurately assessing bacterial burden. These automated workflows offer valuable tools for studying bacterial interactions within host cells and provide insights for various research applications.

DOI: https://doi.org/10.1101/2023.10.01.560379
Front Cell Infect Microbiol. 2023 ;13 1205488

Plasticity in the cell division processes of obligate intracellular bacteria.

McKenna Harpring, John V Cox.

  Most bacteria divide through a highly conserved process called binary fission, in which there is symmetric growth of daughter cells and the synthesis of peptidoglycan at the mid-cell to enable cytokinesis. During this process, the parental cell replicates its chromosomal DNA and segregates replicated chromosomes into the daughter cells. The mechanisms that regulate binary fission have been extensively studied in several model organisms, including Eschericia coli, Bacillus subtilis, and Caulobacter crescentus. These analyses have revealed that a multi-protein complex called the divisome forms at the mid-cell to enable peptidoglycan synthesis and septation during division. In addition, rod-shaped bacteria form a multi-protein complex called the elongasome that drives sidewall peptidoglycan synthesis necessary for the maintenance of rod shape and the lengthening of the cell prior to division. In adapting to their intracellular niche, the obligate intracellular bacteria discussed here have eliminated one to several of the divisome gene products essential for binary fission in E. coli. In addition, genes that encode components of the elongasome, which were mostly lost as rod-shaped bacteria evolved into coccoid organisms, have been retained during the reductive evolutionary process that some coccoid obligate intracellular bacteria have undergone. Although the precise molecular mechanisms that regulate the division of obligate intracellular bacteria remain undefined, the studies summarized here indicate that obligate intracellular bacteria exhibit remarkable plasticity in their cell division processes.

Keywords:  cell division; divisome; elongasome; obligate intracellular bacteria; peptidoglycan

DOI:  https://doi.org/10.3389/fcimb.2023.1205488
mSphere. 2023 Oct 24. e0052123

mSphere of Influence: Coordinating effective clearance of bacterial bloodstream infections.

Caitlyn L Holmes.

  Caitlyn Holmes works in the field of bacterial pathogenesis and host-pathogen interactions. In this mSphere of Influence article, she reflects on how the papers "Innate Lymphocyte/Ly6Chi Monocyte Crosstalk Promotes Klebsiella pneumoniae Clearance" by Xiong et al. (H. Xiong, J. W. Keith, D. W. Samilo, R. A. Carter, et al., Cell 165:679-89, 2016, https://doi.org/10.1016/j.cell.2016.03.017) and "Dual-Track Clearance of Circulating Bacteria Balances Rapid Restoration of Blood Sterility with Induction of Adaptive Immunity" by Broadley et al. (S. P. Broadley, A. Plaumann, R. Coletti, C. Lehmann, et al., Cell Host Microbe 20:36-48, 2016, https://doi.org/10.1016/j.chom.2016.05.023) impacted her research by highlighting the tangled web of immune responses that influence bacterial bloodstream infections.

Keywords:  Gram-negative bacteria; Klebsiella; bacteremia; bloodstream infections

DOI:  https://doi.org/10.1128/msphere.00521-23
Sci Rep. 2023 10 24. 13(1): 18204

Phage activity against Staphylococcus aureus is impaired in plasma and synovial fluid.

Michele Mutti, David Sáez Moreno, Marcela Restrepo-Córdoba, Zehra Visram, Grégory Resch, Lorenzo Corsini.

S. aureus is a pathogen that frequently causes severe morbidity and phage therapy is being discussed as an alternative to antibiotics for the treatment of S. aureus infections. In this in vitro and animal study, we demonstrated that the activity of anti-staphylococcal phages is severely impaired in 0.5% plasma or synovial fluid. Despite phage replication in these matrices, lysis of the bacteria was slower than phage propagation, and no reduction of the bacterial population was observed. The inhibition of the phages associated with a reduction in phage adsorption, quantified to 99% at 10% plasma. S. aureus is known to bind multiple coagulation factors, resulting in the formation of aggregates and blood clots that might protect the bacterium from the phages. Here, we show that purified fibrinogen at a sub-physiological concentration of 0.4 mg/ml is sufficient to impair phage activity. In contrast, dissolution of the clots by tissue plasminogen activator (tPA) partially restored phage activity. Consistent with these in vitro findings, phage treatment did not reduce bacterial burdens in a neutropenic mouse S. aureus thigh infection model. In summary, phage treatment of S. aureus infections inside the body may be fundamentally challenging, and more investigation is needed prior to proceeding to in-human trials.

DOI: https://doi.org/10.1038/s41598-023-45405-8
PLoS Biol. 2023 Oct;21(10): e3002371

Metabolic sinkholes: Histones as methyl repositories.

Ansar Karimian, Maria Vogelauer, Siavash K Kurdistani.

Perez and Sarkies uncover histones as methyl group repositories in normal and cancer human cells, shedding light on an intriguing function of histone methylation in optimizing the cellular methylation potential independently of gene regulation.

DOI: https://doi.org/10.1371/journal.pbio.3002371
J Thromb Haemost. 2023 Oct 19. pii: S1538-7836(23)00774-2. [Epub ahead of print]

Glycolytic reprogramming fuels myeloid cell-driven hypercoagulability.

Aisling M Rehill, Gemma Leon, Sean McCluskey, Ingmar Schoen, Yasmina Hernandez-Santana, Stephanie Annett, Paula Klavina, Tracy Robson, Annie M Curtis, Thomas Renné, Seamus Hussey, James S O'Donnell, Patrick T Walsh, Roger J S Preston.

   BACKGROUND: Myeloid cell metabolic reprogramming is a hallmark of inflammatory disease, however, its role in inflammation-induced hypercoagulability is poorly understood.
OBJECTIVE: /Methods: Using novel myeloid cell-based global haemostasis assays and murine models of immunometabolic disease, we evaluated the role of inflammation-associated metabolic reprogramming in regulating blood coagulation.
RESULTS: Glycolysis was essential for enhanced activated myeloid cell tissue factor expression and decryption, driving increased cell-dependent thrombin generation in response to inflammatory challenge. Similarly, inhibition of glycolysis enhanced activated macrophage fibrinolytic activity via reduced plasminogen activator inhibitor 1 (PAI-1)-activity. Macrophage polarisation or activation markedly increased endothelial protein C receptor (EPCR) expression on monocytes and macrophages, leading to increased myeloid cell-dependent protein C activation. Importantly, inflammation-dependent EPCR expression on tissue-resident macrophages was also observed in vivo. Adipose tissue macrophages from obese mice fed a high-fat diet exhibited significantly enhanced EPCR expression and APC generation compared to macrophages isolated from the adipose tissue of healthy mice. Similarly, the induction of colitis in mice prompted infiltration of EPCR+ innate myeloid cells within inflamed colonic tissue that were absent from the intestinal tissue of healthy mice.
CONCLUSION: Collectively, this study identifies immunometabolic regulation of myeloid cell hypercoagulability, opening new therapeutic possibilities for targeted mitigation of thrombo-inflammatory disease.

Keywords:  coagulation; fibrinolysis; inflammation; macrophages; protein C

DOI:  https://doi.org/10.1016/j.jtha.2023.10.006
Antibiotics (Basel). 2023 Oct 06. pii: 1518. [Epub ahead of print]12(10):

Complementary Activities of Host Defence Peptides and Antibiotics in Combating Antimicrobial Resistant Bacteria.

Patrick R Lennard, Pieter S Hiemstra, Peter H Nibbering.

  Due to their ability to eliminate antimicrobial resistant (AMR) bacteria and to modulate the immune response, host defence peptides (HDPs) hold great promise for the clinical treatment of bacterial infections. Whereas monotherapy with HDPs is not likely to become an effective first-line treatment, combinations of such peptides with antibiotics can potentially provide a path to future therapies for AMR infections. Therefore, we critically reviewed the recent literature regarding the antibacterial activity of combinations of HDPs and antibiotics against AMR bacteria and the approaches taken in these studies. Of the 86 studies compiled, 56 featured a formal assessment of synergy between agents. Of the combinations assessed, synergistic and additive interactions between HDPs and antibiotics amounted to 84.9% of the records, while indifferent and antagonistic interactions accounted for 15.1%. Penicillin, aminoglycoside, fluoro/quinolone, and glycopeptide antibiotic classes were the most frequently documented as interacting with HDPs, and Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, and Enterococcus faecium were the most reported bacterial species. Few studies formally evaluated the effects of combinations of HDPs and antibiotics on bacteria, and even fewer assessed such combinations against bacteria within biofilms, in animal models, or in advanced tissue infection models. Despite the biases of the current literature, the studies suggest that effective combinations of HDPs and antibiotics hold promise for the future treatment of infections caused by AMR bacteria.

Keywords:  antibiotics; antimicrobial peptide; antimicrobial resistance; host defence peptide; synergism

DOI:  https://doi.org/10.3390/antibiotics12101518
Int Rev Immunol. 2023 Oct 27. 1-22

STATs signaling pathways in dendritic cells: As potential therapeutic targets?

Sepideh Sohrabi, Javad Masoumi, Bahar Naseri, Farid Ghorbaninezhad, Shiva Alipour, Tohid Kazemi, Javad Ahmadian Heris, Leili Aghebati Maleki, Pedram Basirjafar, Raziyeh Zandvakili, Mohammad Amin Doustvandi, Behzad Baradaran.

  Dendritic cells (DCs) are professional antigen-presenting cells (APCs), including heterogenous populations with phenotypic and functional diversity that coordinate bridging innate and adaptive immunity. Signal transducer and activator of transcriptions (STAT) factors as key proteins in cytokine signaling were shown to play distinct roles in the maturation and antigen presentation of DCs and play a pivotal role in modulating immune responses mediated by DCs such as differentiation of T cells to T helper (Th) 1, Th2 or regulatory T (Treg) cells. This review sheds light on the importance of STAT transcription factors' signaling pathways in different subtypes of DCs and highlights their targeting potential usages for improving DC-based immunotherapies for patients who suffer from cancer or diverse autoimmune conditions according to the type of the STAT transcription factor and its specific activating or inhibitory agent.

Keywords:  Autoimmune disease; JAK/STAT signaling; T cell; cancer; dendritic cell

DOI:  https://doi.org/10.1080/08830185.2023.2274576
Cell Rep. 2023 Oct 26. pii: S2211-1247(23)01344-X. [Epub ahead of print]42(11): 113332

Identifying genetic determinants of Streptococcus pyogenes-host interactions in a murine intact skin infection model.

Reid V Wilkening, Christophe Langouët-Astrié, Morgan M Severn, Michael J Federle, Alexander R Horswill.

  Streptococcus pyogenes is an obligate human pathobiont associated with many disease states. Here, we present a model of S. pyogenes infection using intact murine epithelium. We were able to perform RNA sequencing to evaluate genetic changes undertaken by both the bacterium and host at 5 and 24 h post-infection. Analysis of these genomic data demonstrate that S. pyogenes undergoes genetic adaptation to successfully infect the murine epithelium, including changes to metabolism and activation of the Rgg2/Rgg3 quorum-sensing (QS) system. Subsequent experiments demonstrate that an intact Rgg2/Rgg3 QS cascade is necessary to establish a stable superficial skin infection. QS cascade activation results in increased murine morbidity and bacterial burden on the skin. This phenotype is associated with gross changes to the murine skin and with evidence of inflammation. These experiments offer a method to investigate S. pyogenes-epithelial interactions and demonstrate that a well-studied QS pathway is critical to a persistent infection.

Keywords:  CP: Microbiology; NZ131; RNA-seq; Rgg2/Rgg3; Streptococcus pyogenes; animal models; host response; quorum sensing; skin infection; transcriptome

DOI:  https://doi.org/10.1016/j.celrep.2023.113332
Vaccines (Basel). 2023 Oct 18. pii: 1609. [Epub ahead of print]11(10):

Factors Influencing Microbiota in Modulating Vaccine Immune Response: A Long Way to Go.

Francesca Romana Ponziani, Gaetano Coppola, Pierluigi Rio, Mario Caldarelli, Raffaele Borriello, Giovanni Gambassi, Antonio Gasbarrini, Rossella Cianci.

  Vaccine immunogenicity still represents an unmet need in specific populations, such as people from developing countries and "edge populations". Both intrinsic and extrinsic factors, such as the environment, age, and dietary habits, influence cellular and humoral immune responses. The human microbiota represents a potential key to understanding how these factors impact the immune response to vaccination, with its modulation being a potential step to address vaccine immunogenicity. The aim of this narrative review is to explore the intricate interactions between the microbiota and the immune system in response to vaccines, highlighting the state of the art in gut microbiota modulation as a novel therapeutic approach to enhancing vaccine immunogenicity and laying the foundation for future, more solid data for its translation to the clinical practice.

Keywords:  immune system; microbiota; vaccine immunogenicity

DOI:  https://doi.org/10.3390/vaccines11101609
Adv Sci (Weinh). 2023 Oct 23. e2304891

A Bacterial Quorum Sensing Regulated Protease Inhibits Host Immune Responses by Cleaving Death Domains of Innate Immune Adaptors.

Xiangke Duan, Zhao Zhi Boo, Song Lin Chua, Kelvin Han Chung Chong, Ziqi Long, Renliang Yang, Yachun Zhou, Baptiste Janela, Sanjay Haresh Chotirmall, Florent Ginhoux, Qinghua Hu, Bin Wu, Liang Yang.

  Innate immune adaptor proteins are critical components of the innate immune system that propagate pro-inflammatory responses from their upstream receptors, and lead to pathogen clearance from the host. Bacterial pathogens have developed strategies to survive inside host cells without triggering the innate immune surveillance in ways that are still not fully understood. Here, it is reported that Pseudomonas aeruginosa induces its quorum sensing mechanism after macrophage engulfment. Further investigation of its secretome identified a quorum sensing regulated product, LasB, is responsible for innate immune suppression depending on the MyD88-mediated signaling. Moreover, it is showed that this specific type of pathogen-mediated innate immune suppression is due to the enzymatic digestion of the death domains of the innate immune adaptors, mainly MyD88, and attributed to LasB's large substrate binding groove. Lastly, it is demonstrated that the secretion of LasB from P. aeruginosa directly contributed to MyD88 degradation within macrophages. Hence, it is discovered an example of bacterial quorum sensing-regulated cellular innate immune suppression by direct cleavage of immune adaptors.

Keywords:  Pseudomonas aeruginosa; host-microbe interaction; innate immune adaptor MyD88; protease; quorum sensing

DOI:  https://doi.org/10.1002/advs.202304891
Vet Res. 2023 Oct 26. 54(1): 100

Metabolites of non-aureus staphylococci affect the ability of Staphylococcus aureus to adhere to and internalize into bovine mammary epithelial cells.

Bruno Toledo-Silva, Ana Cláudia Dumont Oliveira, Fernando N Souza, Freddy Haesebrouck, Sarne De Vliegher.

  This study investigated whether cell-free supernatants (SN) from four bovine non-aureus staphylococcal (NAS) isolates prevent Staphylococcus aureus adhesion to and internalization into bovine mammary epithelial cells (MAC-T cells) and if so, to determine whether such effects were potentially associated with the S. aureus accessory gene regulator (agr) system. Overall, we demonstrated that all SN obtained from the NAS isolates promoted adhesion of a S. aureus agr+ strain to, yet reduced the internalization into MAC-T cells, while similar effects were not observed for its agr- mutant strain. Our findings provide novel anti-virulence strategies for treating and controlling bovine S. aureus mastitis.

Keywords:  Non-aureus staphylococci; S. aureus; dairy cow; mammary epithelial cell; mastitis

DOI:  https://doi.org/10.1186/s13567-023-01232-3
BMC Microbiol. 2023 Oct 27. 23(1): 312

Limited effects of azithromycin on the oropharyngeal microbiome in children with CF and early pseudomonas infection.

Brandie D Wagner, Edith T Zemanick, Scott D Sagel, Charles E Robertson, Mark J Stevens, Nicole Mayer-Hamblett, George Retsch-Bogart, Bonnie W Ramsey, J Kirk Harris.

   BACKGROUND: Tobramycin inhalation solution (TIS) and chronic azithromycin (AZ) have known clinical benefits for children with CF, likely due to antimicrobial and anti-inflammatory activity. The effects of chronic AZ in combination with TIS on the airway microbiome have not been extensively investigated. Oropharyngeal swab samples were collected in the OPTIMIZE multicenter, randomized, placebo-controlled trial examining the addition of AZ to TIS in 198 children with CF and early P. aeruginosa infection. Bacterial small subunit rRNA gene community profiles were determined. The effects of TIS and AZ were assessed on oropharyngeal microbial diversity and composition to uncover whether effects on the bacterial community may be a mechanism of action related to the observed changes in clinical outcomes.
RESULTS: Substantial changes in bacterial communities (total bacterial load, diversity and relative abundance of specific taxa) were observed by week 3 of TIS treatment for both the AZ and placebo groups. On average, these shifts were due to changes in non-traditional CF taxa that were not sustained at the later study visits (weeks 13 and 26). Bacterial community measures did not differ between the AZ and placebo groups.
CONCLUSIONS: This study provides further evidence that the mechanism for AZ's effect on clinical outcomes is not due solely to action on airway microbial composition.

Keywords:  Beta diversity; Macrolides; Microbiome; Oropharyngeal swab; Pulmonary exacerbation; Tobramycin

DOI:  https://doi.org/10.1186/s12866-023-03073-8
Front Immunol. 2023 ;14 1243528

Mmp17-deficient mice exhibit heightened goblet cell effector expression in the colon and increased resistance to chronic Trichuris muris infection.

Pia M Vornewald, Ruth Forman, Rouan Yao, Naveen Parmar, Håvard T Lindholm, Lilith S K Lee, Mara Martín-Alonso, Kathryn J Else, Menno J Oudhoff.

  Intestinal epithelial homeostasis is maintained by intrinsic and extrinsic signals. The extrinsic signals include those provided by mesenchymal cell populations that surround intestinal crypts and is further facilitated by the extracellular matrix (ECM), which is modulated by proteases such as matrix metalloproteinases (MMPs). Extrinsic signals ensure an appropriate balance between intestinal epithelial proliferation and differentiation. This study explores the role of MMP17, which is preferentially expressed by smooth muscle cells in the intestine, in intestinal homeostasis and during immunity to infection. Mice lacking MMP17 expressed high levels of goblet-cell associated genes and proteins, such as CLCA1 and RELM-β, which are normally associated with immune responses to infection. Nevertheless, Mmp17 KO mice did not have altered resistance during a bacterial Citrobacter rodentium infection. However, when challenged with a low dose of the helminth Trichuris muris, Mmp17 KO mice had increased resistance, without a clear role for an altered immune response during infection. Mechanistically, we did not find changes in traditional modulators of goblet cell effectors such as the NOTCH pathway or specific cytokines. We found MMP17 expression in smooth muscle cells as well as lamina propria cells such as macrophages. Together, our data suggest that MMP17 extrinsically alters goblet cell maturation which is sufficient to alter clearance in a helminth infection model.

Keywords:  Citrobacter rodentium; MMP17; Trichuris muris; goblet cell; helminth; intestinal immunity; matrix metalloproteinases (MMPs); niche factor

DOI:  https://doi.org/10.3389/fimmu.2023.1243528
Int J Biochem Cell Biol. 2023 Oct 20. pii: S1357-2725(23)00118-8. [Epub ahead of print]165 106479

Immunosenescence and macrophages: From basics to therapeutics.

Hongkang Zhu, Fanglin Shen, Tingting Liao, He Qian, Yu Liu.

  Ageing decreases the function of the immune system and increases susceptibility to some chronic, infectious, and autoimmune diseases. Senescence cells, which produce senescence-associated secretory phenotypes (SASPs), can activate the innate and adaptive immune responses. Macrophages are among the most abundant innate immune cell types in senescent microenvironments. Senescence-associated macrophages, recruited by SASPs, play a vital role in establishing the essential microenvironments for maintaining tissue homeostasis. However, it's important to note that these senescence-associated macrophages can also influence senescent processes, either by enhancing or impeding the functions of tissue-resident senescent cells. In this discussion, we describe the potential targets of immunosenescence and shed light on the probable mechanisms by which macrophages influence cellular senescence. Furthermore, we analyze their dual function in both clearing senescent cells and modulating age-related diseases. This multifaceted influence operates through processes including heightened inflammation, phagocytosis, efferocytosis, and autophagy. Given the potential off-target effects and immune evasion mechanisms associated with traditional anti-ageing strategies (senolytics and senomorphics), 'resetting' immune system tolerance or targeting senescence-related macrophage functions (i.e., phagocytotic capacity and immunosurveillance) will inform treatment of age-related diseases. Therefore, we review recent advances in the use of macrophage therapeutics to treat ageing and age-associated disorders, and outline the key gaps in this field.

Keywords:  Ageing; Macrophages; SASP; Senescent microenvironment; Therapeutics

DOI:  https://doi.org/10.1016/j.biocel.2023.106479