bims-bac4me 2024-07-28 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2024–07–28
27 papers selected by
Chun-Chi Chang, Universitäts Spital Zürich

Metabolic Regulation in the Induction of Trained Immunity.
Roles of Critical Amino Acids Metabolism in The Interactions Between Intracellular Bacterial Infection and Macrophage Function.
Editorial: Mucosal adaptations to chronic airway injury: mechanisms and interrelationships of epithelial plasticity on innate immunity and airway remodeling.
Respiratory Epithelial Cell Surface Decoration Provides Defence to Bacterial Damage During Infection.
Host-induced cell wall remodeling impairs opsonophagocytosis of Staphylococcus aureus by neutrophils.
Antagonistic Effects of Corynebacterium pseudodiphtheriticum 090104 on Respiratory Pathogens.
Lung antimicrobial proteins and peptides: From host defense to therapeutic strategies.
Staphylococcus aureus wraps around Candida albicans and synergistically escapes from Neutrophil extracellular traps.
Immunometabolites in viral infections: Action mechanism and function.
A nasal airway-on-chip model to evaluate airflow pre-conditioning during epithelial cell maturation at the air-liquid interface.
Metabolism and immune memory in invertebrates: are they dissociated?
Distinct sequential death complexes regulate pyroptosis and IL-1β release in response to Yersinia blockade of immune signaling.
The role of galectins in the regulation of autophagy and inflammasome in host immunity.
Yin and Yang of innate immune cell death.
Ectopic Expression of C-Type Lectin Mincle Renders Mice Susceptible to Staphylococcal Pneumonia.
Probiotics in Dermatology: An Evidence-based Approach.
Innate immune memory after brain injury drives inflammatory cardiac dysfunction.
Shaping Microbiota During the First 1000 Days of Life.
Nasopharyngeal Dysbiosis Precedes the Development of Lower Respiratory Tract Infections in Young Infants, a Longitudinal Infant Cohort Study.
In Vitro Evaluation of Probiotic Properties and Anti-Pathogenic Effects of Lactobacillus and Bifidobacterium Strains as Potential Probiotics.
The role of airways microbiota on local and systemic diseases: a rationale for probiotics delivery to the respiratory tract.
Transcriptional programming mediated by the histone demethylase KDM5C regulates dendritic cell population heterogeneity and function.
From vacant to vivid: The nutritional landscape drives infant gut microbiota establishment.
Neisserial adhesin A (NadA) binds human Siglec-5 and Siglec-14 with high affinity and promotes bacterial adhesion/invasion.
Trained Immunity Generated by the Recombinant Zoster Vaccine.
Regulation of RIPK1 Phosphorylation: Implications for Inflammation, Cell Death, and Therapeutic Interventions.
Oxidative Metabolism as a Cause of Lipid Peroxidation in the Execution of Ferroptosis.

Semin Immunopathol. 2024 Jul 25. 46(3-4): 7

Metabolic Regulation in the Induction of Trained Immunity.

Anaisa V Ferreira, Jorge Domínguez-Andrés, Laura M Merlo Pich, Leo A B Joosten, Mihai G Netea.

  The innate immune system exhibits features of memory, termed trained immunity, which promote faster and more robust responsiveness to heterologous challenges. Innate immune memory is sustained through epigenetic modifications, affecting gene accessibility, and promoting a tailored gene transcription for an enhanced immune response. Alterations in the epigenetic landscape are intertwined with metabolic rewiring. Here, we review the metabolic pathways that underscore the induction and maintenance of trained immunity, including glycolysis, oxidative phosphorylation, the tricarboxylic acid cycle, and amino acid and lipid metabolism. The intricate interplay of these pathways is pivotal for establishing innate immune memory in distinct cellular compartments. We explore in particular the case of resident lung alveolar macrophages. We propose that leveraging the memory of the innate immune system may present therapeutic potential. Specifically, targeting the metabolic programs of innate immune cells is an emerging strategy for clinical interventions, either to boost immune responses in immunosuppressed conditions or to mitigate maladaptive activation in hyperinflammatory diseases.

Keywords:  Epigenetics; Metabolism; Therapy; Trained immunity

DOI:  https://doi.org/10.1007/s00281-024-01015-8
Curr Microbiol. 2024 Jul 20. 81(9): 280

Roles of Critical Amino Acids Metabolism in The Interactions Between Intracellular Bacterial Infection and Macrophage Function.

Zuowei Zhang, Yurou Wang, Lin Xia, Ying Zhang.

Macrophages, as crucial participants in the innate immune system, respond to pathogenic challenges through their dynamic metabolic adjustments, demonstrating the intimate interplay between cellular metabolism and immune function. Bacterial infection of macrophages causes changes in macrophage metabolism, affecting both macrophage function and bacterial virulence and intracellular survival. This review explores the reprogramming of amino acid metabolism in macrophages in response to bacterial infection, with a particular focus on the influence of critical amino acids such as serine, glutamine, and arginine on the immune functions of macrophages; highlights the roles of these metabolic pathways in macrophage functions such as phagocytosis, inflammatory response, immune regulation, and pathogen clearance; reveals how pathogens exploit and manipulate the amino acid metabolism within macrophages to support their own growth and replication, thereby showcasing the intricate interplay between macrophages and pathogens. It provides a foundation for understanding the interactions between macrophages amino acid metabolism and pathogens, offering potential strategies and therapeutic targets for the development of novel anti-infection therapies.

DOI: https://doi.org/10.1007/s00284-024-03801-x
Front Immunol. 2024 ;15 1435120

Editorial: Mucosal adaptations to chronic airway injury: mechanisms and interrelationships of epithelial plasticity on innate immunity and airway remodeling.

Allan R Brasier, Yingxin Zhao, Kian Fan Chung.



Keywords:  airway remodeling; chronic airway injury; epithelial plasticity; epithelium; innate immunity; repair

DOI:  https://doi.org/10.3389/fimmu.2024.1435120
Am J Respir Cell Mol Biol. 2024 Jul 25.

Respiratory Epithelial Cell Surface Decoration Provides Defence to Bacterial Damage During Infection.

Harriet R Ellis, Luke P Allsopp.



Keywords:  Glycosaminoglycans; Heparan sulfate; Hyaluronan; Respiratory infection; Streptococcus pneumoniae

DOI:  https://doi.org/10.1165/rcmb.2024-0306ED
mBio. 2024 Jul 23. e0164324

Host-induced cell wall remodeling impairs opsonophagocytosis of Staphylococcus aureus by neutrophils.

Elizabeth V K Ledger, Andrew M Edwards.

  The bacterial pathogen Staphylococcus aureus responds to the host environment by increasing the thickness of its cell wall. However, the impact of cell wall thickening on susceptibility to host defenses is unclear. Using bacteria incubated in human serum, we show that host-induced increases in cell wall thickness led to a reduction in the exposure of bound antibody and complement and a corresponding reduction in phagocytosis and killing by neutrophils. The exposure of opsonins bound to protein antigens or lipoteichoic acid (LTA) was most significantly reduced, while opsonization by IgG against wall teichoic acid or peptidoglycan was largely unaffected. Partial digestion of accumulated cell wall using the enzyme lysostaphin restored opsonin exposure and promoted phagocytosis and killing. Concordantly, the antibiotic fosfomycin inhibited cell wall remodeling and maintained the full susceptibility of S. aureus to opsonophagocytic killing by neutrophils. These findings reveal that host-induced changes to the S. aureus cell wall reduce the ability of the immune system to detect and kill this pathogen through reduced exposure of protein- and LTA-bound opsonins.
IMPORTANCE: Understanding how bacteria adapt to the host environment is critical in determining fundamental mechanisms of immune evasion, pathogenesis, and the identification of targets for new therapeutic approaches. Previous work demonstrated that Staphylococcus aureus remodels its cell envelope in response to host factors and we hypothesized that this may affect recognition by antibodies and thus killing by immune cells. As expected, incubation of S. aureus in human serum resulted in rapid binding of antibodies. However, as bacteria adapted to the serum, the increase in cell wall thickness resulted in a significant reduction in exposure of bound antibodies. This reduced antibody exposure, in turn, led to reduced killing by human neutrophils. Importantly, while antibodies bound to some cell surface structures became obscured, this was not the case for those bound to wall teichoic acid, which may have important implications for vaccine design.

Keywords:  Staphylococcus aureus; antibody; immune evasion; neutrophil; opsonophagocytosis; peptidoglycan

DOI:  https://doi.org/10.1128/mbio.01643-24
Microorganisms. 2024 Jun 26. pii: 1295. [Epub ahead of print]12(7):

Antagonistic Effects of Corynebacterium pseudodiphtheriticum 090104 on Respiratory Pathogens.

Ramiro Ortiz Moyano, Stefania Dentice Maidana, Yoshiya Imamura, Mariano Elean, Fu Namai, Yoshihito Suda, Keita Nishiyama, Vyacheslav Melnikov, Haruki Kitazawa, Julio Villena.

  In previous studies, it was demonstrated that Corynebacterium pseudodiphtheriticum 090104, isolated from the human nasopharynx, modulates respiratory immunity, improving protection against infections. Here, the antagonistic effect of the 090104 strain on respiratory pathogens, including Streptococcus pneumoniae, Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii, was explored. In a series of in vitro studies, the capacity of C. pseudodiphtheriticum 090104, its bacterium-like particles, and its culture supernatants to coaggregate, inhibit the growth, and change the virulent phenotype of pathogenic bacteria was evaluated. The results showed that the 090104 strain was able to exert a bacteriostatic effect on K. pneumoniae and S. pneumoniae growth. In addition, C. pseudodiphtheriticum 090104 coaggregated, inhibited biofilm formation, and induced phenotypic changes in all the respiratory pathogens evaluated. In conclusion, this work demonstrated that, in addition to its beneficial effects exerted by host-microbe interactions, C. pseudodiphtheriticum 090104 can enhance protection against respiratory pathogens through its microbe-microbe interactions. The mechanisms involved in such interactions should be evaluated in future research.

Keywords:  Corynebacterium pseudodiphtheriticum; microbe–microbe interaction; respiratory pathogens

DOI:  https://doi.org/10.3390/microorganisms12071295
Physiol Rev. 2024 Jul 25.

Lung antimicrobial proteins and peptides: From host defense to therapeutic strategies.

Yuanpu Peter Di, Jenna Maria Kuhn, Maria Luisa Mangoni.

  Representing severe morbidity and mortality globally, respiratory infections associated with chronic respiratory diseases, including complicated pneumonia, asthma, interstitial lung disease, and chronic obstructive pulmonary disease, are a major public health concern. Lung health and the prevention of pulmonary disease rely on the mechanisms of airway surface fluid secretion, mucociliary clearance, and adequate immune response to eradicate inhaled pathogens and particulate matter from the environment. The antimicrobial proteins and peptides contribute to maintaining an antimicrobial milieu in human lungs to eliminate pathogens and prevent them from causing pulmonary diseases. The predominant antimicrobial molecules of the lung environment include human α- and β-defensins and cathelicidins, among numerous other host defense molecules with antimicrobial and antibiofilm activity such as PLUNC (palate, lung, and nasal epithelium clone) family proteins, elafin, collectins, lactoferrin, lysozymes, mucins, secretory leukocyte proteinase inhibitor, surfactant proteins SP-A, and SP-D, and RNases. It has been demonstrated that changes in antimicrobial molecule expression levels are associated with regulating inflammation, potentiating exacerbations, pathological changes, and modifications in chronic lung disease severity. Antimicrobial molecules also display roles in both anticancer and tumorigenic effects. Lung antimicrobial proteins and peptides are promising alternative therapeutics for treating and preventing multidrug-resistant bacterial infections and anticancer therapies.

Keywords:  Lung Cancer; antibiotic resistance; antimicrobial peptide; immunomodulation; pneumonia

DOI:  https://doi.org/10.1152/physrev.00039.2023
Front Immunol. 2024 ;15 1422440

Staphylococcus aureus wraps around Candida albicans and synergistically escapes from Neutrophil extracellular traps.

Qi Jing, Rui Liu, Qingsong Jiang, Yingshuang Liu, Jinzhi He, Xuedong Zhou, Ollie Yiru Yu, Chun-Hung Chu, Lei Cheng, Biao Ren, Mingyun Li.

   Background: NETs, a unique neutrophil immune mechanism, are vital in defending against microbial invasions. Understanding the mechanisms of co-infection by Candida albicans and Staphylococcus aureus, which often leads to higher mortality and poorer prognosis, is crucial for studying infection progression.
Methods: In our study, we established a mouse model of subcutaneous infection to characterize the inflammation induced by co-infection. By purifying and extracting NETs to interact with microorganisms, we delve into the differences in their interactions with various microbial species. Additionally, we investigated the differences in NETs production by neutrophils in response to single or mixed microorganisms through the interaction between neutrophils and these microorganisms. Furthermore, we analyzed the gene expression differences during co-infection using transcriptomics.
Results: In vivo, C. albicans infections tend to aggregate, while S. aureus infections are more diffuse. In cases of co-infection, S. aureus adheres to and wraps C. albicans. NETs exhibit strong killing capability against C. albicans but weaker efficacy against S. aureus. When NETs interact with mixed microorganisms, they preferentially target and kill the outer layer of S. aureus. In the early stages, neutrophils primarily rely on phagocytosis to kill S. aureus, but as the bacteria accumulate, they stimulate neutrophils to produce NETs. Interestingly, in the presence of neutrophils, S. aureus promotes the proliferation and hyphal growth of C. albicans.
Conclusion: Our research has showed substantial differences in the progression of co-infections compared to single-microbial infections, thereby providing scientific evidence for NETs as potential therapeutic targets in the treatment of co-infections.

Keywords:  Candida albicans; Staphylococcus aureus; co-infection; immune response; neutrophil extracellular traps (NETs); subcutaneous infection

DOI:  https://doi.org/10.3389/fimmu.2024.1422440
J Med Virol. 2024 Jul;96(7): e29807

Immunometabolites in viral infections: Action mechanism and function.

Behnaz Bouzari, Uliana Y Chugaeva, Sajad Karampoor, Rasoul Mirzaei.

  The interplay between viral pathogens and host metabolism plays a pivotal role in determining the outcome of viral infections. Upon viral detection, the metabolic landscape of the host cell undergoes significant changes, shifting from oxidative respiration via the tricarboxylic acid (TCA) cycle to increased aerobic glycolysis. This metabolic shift is accompanied by elevated nutrient accessibility, which is vital for cell function, development, and proliferation. Furthermore, depositing metabolites derived from fatty acids, TCA intermediates, and amino acid catabolism accelerates the immunometabolic transition, facilitating pro-inflammatory and antimicrobial responses. Immunometabolites refer to small molecules involved in cellular metabolism regulating the immune response. These molecules include nutrients, such as glucose and amino acids, along with metabolic intermediates and signaling molecules adenosine, lactate, itaconate, succinate, kynurenine, and prostaglandins. Emerging evidence suggests that immunometabolites released by immune cells establish a complex interaction network within local niches, orchestrating and fine-tuning immune responses during viral diseases. However, our current understanding of the immense capacity of metabolites to convey essential cell signals from one cell to another or within cellular compartments remains incomplete. Unraveling these complexities would be crucial for harnessing the potential of immunometabolites in therapeutic interventions. In this review, we discuss specific immunometabolites and their mechanisms of action in viral infections, emphasizing recent findings and future directions in this rapidly evolving field.

Keywords:  antimicrobial defense; immune responses; immunometabolites; metabolism; viral infection

DOI:  https://doi.org/10.1002/jmv.29807
Biofabrication. 2024 Jul 22.

A nasal airway-on-chip model to evaluate airflow pre-conditioning during epithelial cell maturation at the air-liquid interface.

Amanda Coleman Walls, Manon van Vegchel, Abigail Lakey, Hemali Gauri, Joshua Dixon, Laís A Ferreira, Ishita Tandon, Kartik Balachandran.

  The function of a well-differentiated nasal epithelium is largely affected by airflow-induced wall shear stress, yet few in vitro models recapitulate this dynamic condition. Models which do expose cells to airflow exclusively initiate flow after the differentiation process has occurred. In vivo, basal cells are constantly replenishing the epithelium under airflow conditions, indicating that airflow may affect the development and function of the differentiated epithelium. To address this gap in the field, we developed a physiologically relevant microphysiological model of the human nasal epithelium and investigated the effects of exposing cells to airflow during epithelial maturation at the air-liquid interface. The nasal airway-on-chip platform was engineered to mimic bi-directional physiological airflow during normal breathing. Primary human nasal epithelial cells were seeded on chips and subjected to either: 1) no flow, 2) single flow (0.5 dyne/cm2flow on Day 21 of ALI only), or 3) pre-conditioning flow (0.05 dyne/cm2on Days 14-20 and 0.5 dyne/cm2flow on Day 21) treatments. Cells exposed to pre-conditioning showed decreased morphological changes and mucus secretions, as well as a decreased inflammation, compared to unconditioned cells. Our results indicate that flow exposure only post-differentiation may impose acute stress on cells, while pre-conditioning may potentiate a properly functioning epithelium in vitro. &#xD.

Keywords:  Airflow; Airway-on-chip; Mucus; Preconditioning; Wall shear stress

DOI:  https://doi.org/10.1088/1758-5090/ad663d
Front Immunol. 2024 ;15 1379471

Metabolism and immune memory in invertebrates: are they dissociated?

Texca T Méndez-López, Julio César Carrero, Humberto Lanz-Mendoza, Alejandra Ochoa-Zarzosa, Krishnendu Mukherjee, Jorge Contreras-Garduño.

  Since the discovery of specific immune memory in invertebrates, researchers have investigated its immune response to diverse microbial and environmental stimuli. Nevertheless, the extent of the immune system's interaction with metabolism, remains relatively enigmatic. In this mini review, we propose a comprehensive investigation into the intricate interplay between metabolism and specific immune memory. Our hypothesis is that cellular endocycles and epigenetic modifications play pivotal roles in shaping this relationship. Furthermore, we underscore the importance of the crosstalk between metabolism and specific immune memory for understanding the evolutionary costs. By evaluating these costs, we can gain deeper insights into the adaptive strategies employed by invertebrates in response to pathogenic challenges. Lastly, we outline future research directions aimed at unraveling the crosstalk between metabolism and specific immune memory. These avenues of inquiry promise to illuminate fundamental principles governing host-pathogen interactions and evolutionary trade-offs, thus advancing our understanding of invertebrate immunology.

Keywords:  ecoimmunology; host-parasite relationship; immune priming; immunometabolism; innate immune response; specific memory; trade-offs

DOI:  https://doi.org/10.3389/fimmu.2024.1379471
Sci Adv. 2024 Jul 26. 10(30): eadl3629

Distinct sequential death complexes regulate pyroptosis and IL-1β release in response to Yersinia blockade of immune signaling.

Ronit Schwartz Wertman, Winslow Yost, Beatrice I Herrmann, Christopher M Bourne, Daniel Sorobetea, Christina K Go, Benedikt S Saller, Olaf Groß, Phillip Scott, Anthony Rongvaux, Cornelius Y Taabazuing, Igor E Brodsky.

Pathogen infection of host cells triggers an inflammatory cell death termed pyroptosis via activation of inflammatory caspases. However, blockade of immune signaling kinases by the Yersinia virulence factor YopJ triggers cell death involving both apoptotic caspase-8 and pyroptotic caspase-1. While caspase-1 is normally activated within inflammasomes, Yersinia-induced caspase-1 activation is independent of known inflammasome components. We report that caspase-8 is an essential initiator, while caspase-1 is an essential amplifier of its own activation through two feed-forward loops involving caspase-1 auto-processing and caspase-1-dependent activation of gasdermin D and NLPR3. Notably, while Yersinia-induced caspase-1 activation and cell death are inflammasome-independent, IL-1β release requires NLPR3 inflammasome activation. Mechanistically, caspase-8 is rapidly activated within multiple foci throughout the cell, followed by assembly of a canonical inflammasome speck, indicating that caspase-8 and canonical inflammasome complex assemblies are kinetically and spatially distinct. Our findings reveal that functionally interconnected but distinct death complexes mediate pyroptosis and IL-1β release in response to pathogen blockade of immune signaling.

DOI: https://doi.org/10.1126/sciadv.adl3629
Semin Immunopathol. 2024 Jul 23. 46(3-4): 6

The role of galectins in the regulation of autophagy and inflammasome in host immunity.

Tzu-Han Lo, I-Chun Weng, Hung-Lin Chen, Fu-Tong Liu.

  Galectins, a family of glycan-binding proteins have been shown to bind a wide range of glycans. In the cytoplasm, these glycans can be endogenous (or "self"), originating from damaged endocytic vesicles, or exogenous (or "non-self"), found on the surface of invading microbial pathogens. Galectins can detect these unusual cytosolic exposures to glycans and serve as critical regulators in orchestrating immune responses in innate and adaptive immunity. This review provides an overview of how galectins modulate host cellular responses, such as autophagy, xenophagy, and inflammasome-dependent cell death program, to infection.

Keywords:  Autophagy; Galectins; Glycans; Infection; Inflammasome

DOI:  https://doi.org/10.1007/s00281-024-01018-5
Cell Res. 2024 Jul 26.

Yin and Yang of innate immune cell death.

Yaqiu Wang, Thirumala-Devi Kanneganti.

DOI: https://doi.org/10.1038/s41422-024-01007-1
J Infect Dis. 2024 Jul 25. 230(1): 198-208

Ectopic Expression of C-Type Lectin Mincle Renders Mice Susceptible to Staphylococcal Pneumonia.

Femke D Hollwedel, Regina Maus, Jennifer Stolper, Satoru Iwai, Hayato Kasai, Silva Holtfreter, Andreas Pich, Lavinia Neubert, Tobias Welte, Sho Yamasaki, Ulrich A Maus.

  Staphylococcus aureus is a prevalent pathogen in pneumonia and harbors glycolipids, which may serve as molecular patterns in Mincle (macrophage-inducible C-type lectin)-dependent pathogen recognition. We examined the role of Mincle in lung defense against S aureus in wild-type (WT), Mincle knockout (KO), and Mincle transgenic (tg) mice. Two glycolipids, glucosyl-diacylglycerol (Glc-DAG) and diglucosyl-diacylglycerol (Glc2-DAG), were purified, of which only Glc-DAG triggered Mincle reporter cell activation and professional phagocyte responses. Proteomic profiling revealed that Glc2-DAG blocked Glc-DAG-induced cytokine responses, thereby acting as inhibitor of Glc-DAG/Mincle signaling. WT mice responded to S aureus with a similar lung pathology as Mincle KO mice, most likely due to Glc2-DAG-dependent inhibition of Glc-DAG/Mincle signaling. In contrast, ectopic Mincle expression caused severe lung pathology in S aureus-infected mice, characterized by bacterial outgrowth and fatal pneumonia. Collectively, Glc2-DAG inhibits Glc-DAG/Mincle-dependent responses in WT mice, whereas sustained Mincle expression overrides Glc2-DAG-mediated inhibitory effects, conferring increased host susceptibility to S aureus.

Keywords:   S aureus ; Glc-DAG; Mincle; lung; pattern recognition

DOI:  https://doi.org/10.1093/infdis/jiad608
Indian Dermatol Online J. 2024 Jul-Aug;15(4):15(4): 571-583

Probiotics in Dermatology: An Evidence-based Approach.

Vaishnavi Gowda, Rashmi Sarkar, Damini Verma, Anupam Das.

  Probiotics are viable microorganisms that confer health benefits when administered to the host in adequate amounts. Over the past decade, there has been a growing demand for the use of oral and topical probiotics in several inflammatory conditions such as atopic dermatitis, psoriasis, acne vulgaris, etc., although their role in a few areas still remains controversial. The objective of this article is to shed light on understanding the origin and implications of microbiota in the pathophysiology of these dermatological conditions and the effect of probiotic usage. We have conducted a comprehensive search of the literature across multiple databases (PubMed, EMBASE, MEDLINE, and Google Scholar) on the role of probiotics in dermatological disorders. Commensal microbes of the skin and gastrointestinal tract play an important role in both health and disease. Increased use of probiotics has asserted a good safety profile, especially in this era of antibiotic resistance. With the advent of new products in the market, the indications, mechanism of action, efficacy, and safety profile of these agents need to be validated. Further studies are required. Oral and topical probiotics may be tried as a treatment or prevention modality in cutaneous inflammatory disorders, thus facilitating decreased requirement for topical or systemic steroids and antimicrobial agents. Tempering microbiota with probiotics is a safe and well-tolerated approach in this era of antimicrobial resistance.

Keywords:  Acne vulgaris; atopic dermatitis; gut microbiome; probiotics

DOI:  https://doi.org/10.4103/idoj.idoj_614_23
Cell. 2024 Jul 12. pii: S0092-8674(24)00702-5. [Epub ahead of print]

Innate immune memory after brain injury drives inflammatory cardiac dysfunction.

Alba Simats, Sijia Zhang, Denise Messerer, Faye Chong, Sude Beşkardeş, Aparna Sharma Chivukula, Jiayu Cao, Simon Besson-Girard, Felipe A Montellano, Caroline Morbach, Olga Carofiglio, Alessio Ricci, Stefan Roth, Gemma Llovera, Rashween Singh, Yiming Chen, Severin Filser, Nikolaus Plesnila, Christian Braun, Hannah Spitzer, Ozgun Gokce, Martin Dichgans, Peter U Heuschmann, Kinta Hatakeyama, Eduardo Beltrán, Sebastian Clauss, Boyan Bonev, Christian Schulz, Arthur Liesz.

  The medical burden of stroke extends beyond the brain injury itself and is largely determined by chronic comorbidities that develop secondarily. We hypothesized that these comorbidities might share a common immunological cause, yet chronic effects post-stroke on systemic immunity are underexplored. Here, we identify myeloid innate immune memory as a cause of remote organ dysfunction after stroke. Single-cell sequencing revealed persistent pro-inflammatory changes in monocytes/macrophages in multiple organs up to 3 months after brain injury, notably in the heart, leading to cardiac fibrosis and dysfunction in both mice and stroke patients. IL-1β was identified as a key driver of epigenetic changes in innate immune memory. These changes could be transplanted to naive mice, inducing cardiac dysfunction. By neutralizing post-stroke IL-1β or blocking pro-inflammatory monocyte trafficking with a CCR2/5 inhibitor, we prevented post-stroke cardiac dysfunction. Such immune-targeted therapies could potentially prevent various IL-1β-mediated comorbidities, offering a framework for secondary prevention immunotherapy.

Keywords:  brain ischemia; cardiac fibrosis; cenicriviroc; innate immune memory; interleukin-1; myeloid cells; stroke; systemic inflammation; trained immunity

DOI:  https://doi.org/10.1016/j.cell.2024.06.028
Adv Exp Med Biol. 2024 ;1449 1-28

Shaping Microbiota During the First 1000 Days of Life.

Anna Samarra, Eduard Flores, Manuel Bernabeu, Raul Cabrera-Rubio, Christine Bäuerl, Marta Selma-Royo, Maria Carmen Collado.

  Given that the host-microbe interaction is shaped by the immune system response, it is important to understand the key immune system-microbiota relationship during the period from conception to the first years of life. The present work summarizes the available evidence concerning human reproductive microbiota, and also, the microbial colonization during early life, focusing on the potential impact on infant development and health outcomes. Furthermore, we conclude that some dietary strategies including specific probiotics and other-biotics could become potentially valuable tools to modulate the maternal-neonatal microbiota during this early critical window of opportunity for targeted health outcomes throughout the entire lifespan.

Keywords:  Antibiotics; Diet; Gestation; Health; Microbiota; Prebiotics; Probiotics; Vagina

DOI:  https://doi.org/10.1007/978-3-031-58572-2_1
Gates Open Res. 2022 ;6 48

Nasopharyngeal Dysbiosis Precedes the Development of Lower Respiratory Tract Infections in Young Infants, a Longitudinal Infant Cohort Study.

Rotem Lapidot, Tyler Faits, Arshad Ismail, Mushal Allam, Zamantungwak Khumalo, William MacLeod, Geoffrey Kwenda, Zachariah Mupila, Ruth Nakazwe, Daniel Segrè, William Evan Johnson, Donald M Thea, Lawrence Mwananyanda, Christopher J Gill.

   Background: Infants suffering from lower respiratory tract infections (LRTIs) have distinct nasopharyngeal (NP) microbiome profiles that correlate with severity of disease. Whether these profiles precede the infection or are a consequence of it, is unknown. In order to answer this question, longitudinal studies are needed.
Methods: We conducted a retrospective analysis of NP samples collected in a longitudinal birth cohort study of Zambian mother-infant pairs. Samples were collected every two weeks from 1-week through 14-weeks of age. Ten of the infants in the cohort who developed LRTI were matched 1:3 with healthy comparators. We completed 16S rRNA gene sequencing on the samples each of these infants contributed and compared the NP microbiome of the healthy infants to infants who developed LRTI.
Results: The infant NP microbiome maturation was characterized by transitioning from Staphylococcus dominant to respiratory-genera dominant profiles during the first three months of life, similar to what is described in the literature. Interestingly, infants who developed LRTI had distinct NP microbiome characteristics before infection, in most cases as early as the first week of life. Their NP microbiome was characterized by the presence of Novosphingobium, Delftia, high relative abundance of Anaerobacillus, Bacillus, and low relative abundance of Dolosigranulum, compared to the healthy controls. Mothers of infants with LRTI also had low relative abundance of Dolosigranulum in their baseline samples compared to mothers of infants that did not develop an LRTI.
Conclusions: Our results suggest that specific characteristics of the NP microbiome precede LRTI in young infants and may be present in their mothers as well. Early dysbiosis may play a role in the causal pathway leading to LRTI or could be a marker of underlying immunological, environmental, or genetic characteristics that predispose to LRTI.

Keywords:  Dysbiosis; Longitudinal Cohort study; Lower Respiratory Tract Infection; Nasopharyngeal Microbiome

DOI:  https://doi.org/10.12688/gatesopenres.13561.2
Foods. 2024 Jul 22. pii: 2301. [Epub ahead of print]13(14):

In Vitro Evaluation of Probiotic Properties and Anti-Pathogenic Effects of Lactobacillus and Bifidobacterium Strains as Potential Probiotics.

Jaekoo Lee, Jaehyun Jo, Jungho Wan, Hanseul Seo, Seung-Won Han, Yoon-Jung Shin, Dong-Hyun Kim.

  Probiotics restore gut microbial balance, thereby providing health-promoting effects to the host. They have long been suggested for managing intestinal disorders caused by pathogens and for improving gut health. This study evaluated the probiotic properties and anti-pathogenic effects of specific probiotic strains against the intestinal pathogens Staphylococcus aureus and Escherichia coli. The tested strains-Lactiplantibacillus plantarum LC27, Limosilactobacillus reuteri NK33, Lacticaseibacillus rhamnosus NK210, Bifidobacterium longum NK46, and Bifidobacterium bifidum NK175-were able to survive harsh conditions simulating gastric and intestinal fluids. These strains exhibited good auto-aggregation abilities (41.8-92.3%) and ideal hydrophobicity (30.9-85.6% and 38.3-96.1% for xylene and chloroform, respectively), along with the ability to co-aggregate with S. aureus (40.6-68.2%) and E. coli (38.6-75.2%), indicating significant adhesion levels to Caco-2 cells. Furthermore, these strains' cell-free supernatants (CFSs) demonstrated antimicrobial and antibiofilm activity against S. aureus and E. coli. Additionally, these strains inhibited gas production by E. coli through fermentative activity. These findings suggest that the strains tested in this study have potential as novel probiotics to enhance gut health.

Keywords:  anti-pathogenic effects; gut health; probiotic properties; probiotics

DOI:  https://doi.org/10.3390/foods13142301
Expert Opin Drug Deliv. 2024 Jul 23. 1-15

The role of airways microbiota on local and systemic diseases: a rationale for probiotics delivery to the respiratory tract.

Stefania Glieca, Eride Quarta, Benedetta Bottari, Vivek C Lal, Fabio Sonvico, Francesca Buttini.

   INTRODUCTION: Recent discoveries in the field of lung microbiota have enabled the investigation of new therapeutic interventions involving the use of inhaled probiotics.
AREAS COVERED: This review provides an overview of what is known about the correlation between airway dysbiosis and the development of local and systemic diseases, and how this knowledge can be exploited for therapeutic interventions. In particular, the review focused on attempts to formulate probiotics that can be deposited directly on the airways.
EXPERT OPINION: Despite considerable progress since the emergence of respiratory microbiota restoration as a new research field, numerous clinical implications and benefits remain to be determined. In the case of local diseases, once the pathophysiology is understood, manipulating the lung microbiota through probiotic administration is an approach that can be exploited. In contrast, the effect of pulmonary dysbiosis on systemic diseases remains to be clarified; however, this approach could represent a turning point in their treatment.

Keywords:  Airway microbiota; inhalation; lung cancer; lung infections; neurodegenerative disease; probiotic

DOI:  https://doi.org/10.1080/17425247.2024.2380334
Cell Rep. 2024 Jul 23. pii: S2211-1247(24)00835-0. [Epub ahead of print]43(8): 114506

Transcriptional programming mediated by the histone demethylase KDM5C regulates dendritic cell population heterogeneity and function.

Hannah Guak, Matthew Weiland, Alexandra Vander Ark, Lukai Zhai, Kin Lau, Mario Corrado, Paula Davidson, Ebenezer Asiedu, Batsirai Mabvakure, Shelby Compton, Lisa DeCamp, Catherine A Scullion, Russell G Jones, Sara M Nowinski, Connie M Krawczyk.

  Functional and phenotypic heterogeneity of dendritic cells (DCs) play crucial roles in facilitating the development of diverse immune responses essential for host protection. Here, we report that KDM5C, a histone lysine demethylase, regulates conventional or classical DC (cDC) and plasmacytoid DC (pDC) population heterogeneity and function. Mice deficient in KDM5C in DCs have increased proportions of cDC2Bs and cDC1s, which is partly dependent on type I interferon (IFN) and pDCs. Loss of KDM5C results in an increase in Ly6C- pDCs, which, compared to Ly6C+ pDCs, have limited ability to produce type I IFN and more efficiently stimulate antigen-specific CD8 T cells. KDM5C-deficient DCs have increased expression of inflammatory genes, altered expression of lineage-specific genes, and decreased function. In response to Listeria infection, KDM5C-deficient mice mount reduced CD8 T cell responses due to decreased antigen presentation by cDC1s. Thus, KDM5C is a key regulator of DC heterogeneity and critical driver of the functional properties of DCs.

Keywords:  CP: Immunology; CP: Molecular biology; DC development; IRF; IRF8; KDM5C; antigen presentation; dendritic cells; epigenetics; histone demethylase; interferon; metabolism

DOI:  https://doi.org/10.1016/j.celrep.2024.114506
Mol Microbiol. 2024 Jul 23.

From vacant to vivid: The nutritional landscape drives infant gut microbiota establishment.

Reut Melki, Yael Litvak.

  From the moment of birth, the newborn gastrointestinal tract is infiltrated by various bacteria originating from both maternal and environmental sources. These colonizing bacteria form a complex microbiota community that undergoes continuous changes until adulthood and plays an important role in infant health. The maturation of the infant gut microbiota is driven by many factors and follows a distinct patterned trajectory, with specific bacterial taxa establish in the intestine in accordance with developmental milestones as the infant grows. In this review, we highlight how elements such as diet and host physiology select for specific microbial functions and shape the composition of the bacterial community in the large intestine.

Keywords:  gastroentrology; neonatology; pediatrics; succession

DOI:  https://doi.org/10.1111/mmi.15296
mBio. 2024 Jul 23. e0110724

Neisserial adhesin A (NadA) binds human Siglec-5 and Siglec-14 with high affinity and promotes bacterial adhesion/invasion.

Barbara Benucci, Zaira Spinello, Valeria Calvaresi, Viola Viviani, Andrea Perrotta, Agnese Faleri, Sabrina Utrio Lanfaloni, Werner Pansegrau, Liana d'Alterio, Erika Bartolini, Irene Pinzuti, Katia Sampieri, Anna Giordano, Rino Rappuoli, Mariagrazia Pizza, Vega Masignani, Nathalie Norais, Domenico Maione, Marcello Merola.

  Neisserial adhesin A (NadA) is a meningococcal surface protein included as recombinant antigen in 4CMenB, a protein-based vaccine able to induce protective immune responses against Neisseria meningitidis serogroup B (MenB). Although NadA is involved in the adhesion/invasion of epithelial cells and human myeloid cells, its function in meningococcal physiology is still poorly understood. To clarify the role played by NadA in the host-pathogen interaction, we sought to identify its cellular receptors. We screened a protein microarray encompassing 2,846 human and 297 mouse surface/secreted recombinant proteins using recombinant NadA as probe. Efficient NadA binding was revealed on the paired sialic acid-binding immunoglobulin-type lectins receptors 5 and 14 (Siglec-5 and Siglec-14), but not on Siglec-9 therein used as control. The interaction was confirmed by biochemical tools with the determination of the KD value in the order of nanomolar and the identification of the NadA binding site by hydrogen-deuterium exchange coupled to mass spectrometry. The N-terminal domain of the Siglec-5 that recognizes the sialic acid was identified as the NadA binding domain. Intriguingly, exogenously added recombinant soluble Siglecs, including Siglec-9, were found to decorate N. meningitidis surface in a NadA-dependent manner. However, Siglec-5 and Siglec-14 transiently expressed in CHO-K1 cells endorsed NadA binding and increased N. meningitidis adhesion/invasion while Siglec-9 did not. Taken together, Siglec-5 and Siglec-14 satisfy all features of NadA receptors suggesting a possible role of NadA in the acute meningococcal infection.IMPORTANCEBacteria have developed several strategies for cell colonization and immune evasion. Knowledge of the host and pathogen factors involved in these mechanisms is crucial to build efficacious countermoves. Neisserial adhesin A (NadA) is a meningococcal surface protein included in the anti-meningococcus B vaccine 4CMenB, which mediates adhesion to and invasion of epithelial cells. Although NadA has been shown to bind to other cell types, like myeloid and endothelial cells, it still remains orphan of a defined host receptor. We have identified two strong NadA interactors, Siglec-5 and Siglec-14, which are mainly expressed on myeloid cells. This showcases that NadA is an additional and key player among the Neisseria meningitidis factors targeting immune cells. We thus provide novel insights on the strategies exploited by N. meningitidis during the infection process, which can progress to a severe illness and death.

Keywords:  NadA receptor; Neisseria meningitidis; Neisserial adhesin A (NadA); Siglec-14; Siglec-5; Siglec-9

DOI:  https://doi.org/10.1128/mbio.01107-24
Res Sq. 2024 Jul 10. pii: rs.3.rs-4607744. [Epub ahead of print]

Trained Immunity Generated by the Recombinant Zoster Vaccine.

Adriana Weinberg, Michael Johnson, Megan Crotteau, Debashis Ghosh, Thao Vu, Myron J Levin.

Trained immunity may play a role in vaccine-induced protection against infections. We showed that the highly efficacious recombinant VZV-gE zoster vaccine (RZV) generated trained immunity in monocytes, natural killer (NK) cells, and dendritic cells (DCs) and that the less efficacious live zoster vaccine did not. RZV stimulated ex vivo gE-specific monocyte, DC and NK cell responses that did not correlate with CD4 + T-cell responses. These responses were also elicited in purified monocyte and NK cell cocultures stimulated with VZV-gE and persisted above prevaccination levels for ≥ 4 years post-RZV administration. RZV administration also increased ex vivo heterologous monocyte and NK cell responses to herpes simplex and cytomegalovirus antigens. ATAC-seq analysis and ex vivo TGFβ1 supplementation and inhibition experiments demonstrated that decreased tgfβ1 transcription resulting from RZV-induced chromatin modifications may explain the development of monocyte trained immunity. The role of RZV-trained immunity in protection against herpes zoster and other infections should be further studied.

DOI: https://doi.org/10.21203/rs.3.rs-4607744/v1
Biomedicines. 2024 Jul 09. pii: 1525. [Epub ahead of print]12(7):

Regulation of RIPK1 Phosphorylation: Implications for Inflammation, Cell Death, and Therapeutic Interventions.

Jingchun Du, Zhigao Wang.

  Receptor-interacting protein kinase 1 (RIPK1) plays a crucial role in controlling inflammation and cell death. Its function is tightly controlled through post-translational modifications, enabling its dynamic switch between promoting cell survival and triggering cell death. Phosphorylation of RIPK1 at various sites serves as a critical mechanism for regulating its activity, exerting either activating or inhibitory effects. Perturbations in RIPK1 phosphorylation status have profound implications for the development of severe inflammatory diseases in humans. This review explores the intricate regulation of RIPK1 phosphorylation and dephosphorylation and highlights the potential of targeting RIPK1 phosphorylation as a promising therapeutic strategy for mitigating human diseases.

Keywords:  RIPK1; apoptosis; cell death; dephosphorylation; inflammation; kinase; necroptosis; phosphatase; phosphorylation; therapeutics

DOI:  https://doi.org/10.3390/biomedicines12071525
Int J Mol Sci. 2024 Jul 09. pii: 7544. [Epub ahead of print]25(14):

Oxidative Metabolism as a Cause of Lipid Peroxidation in the Execution of Ferroptosis.

Junichi Fujii, Hirotaka Imai.

  Ferroptosis is a type of nonapoptotic cell death that is characteristically caused by phospholipid peroxidation promoted by radical reactions involving iron. Researchers have identified many of the protein factors that are encoded by genes that promote ferroptosis. Glutathione peroxidase 4 (GPX4) is a key enzyme that protects phospholipids from peroxidation and suppresses ferroptosis in a glutathione-dependent manner. Thus, the dysregulation of genes involved in cysteine and/or glutathione metabolism is closely associated with ferroptosis. From the perspective of cell dynamics, actively proliferating cells are more prone to ferroptosis than quiescent cells, which suggests that radical species generated during oxygen-involved metabolism are responsible for lipid peroxidation. Herein, we discuss the initial events involved in ferroptosis that dominantly occur in the process of energy metabolism, in association with cysteine deficiency. Accordingly, dysregulation of the tricarboxylic acid cycle coupled with the respiratory chain in mitochondria are the main subjects here, and this suggests that mitochondria are the likely source of both radical electrons and free iron. Since not only carbohydrates, but also amino acids, especially glutamate, are major substrates for central metabolism, dealing with nitrogen derived from amino groups also contributes to lipid peroxidation and is a subject of this discussion.

Keywords:  glycolysis; metabolic remodeling; tricarboxylic acid cycle; urea cycle

DOI:  https://doi.org/10.3390/ijms25147544