bims-bac4me 2023-05-21 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2023–05–21
23 papers selected by
Chun-Chi Chang, University Hospital Zurich

Innate Immune Memory in Macrophages.
Bacterial Lipoproteins Shift Cellular Metabolism to Glycolysis in Macrophages Causing Bone Erosion.
A new frontier for fat: dietary palmitic acid induces innate immune memory.
Butyrate regulates neutrophil homeostasis and impairs early antimicrobial activity in the lung.
IL-10 in combination with IL-12 and TNF-α attenuates CXCL8/CXCR1 axis in peritoneal macrophages of mice infected with Staphylococcus aureus through the TNFR1-IL-1R-NF-κB pathway.
Neutrophil diversity in inflammation and cancer.
Candida auris uses metabolic strategies to escape and kill macrophages while avoiding robust activation of the NLRP3 inflammasome response.
Airway dysbiosis accelerates lung function decline in chronic obstructive pulmonary disease.
IL-23/IL23R promote macrophage pyroptosis and Th1/Th17 cell differentiation in mycobacterial infection.
Influence of bacterial and alveolar cell co-culture on microbial VOC production using HS-GC/MS.
Biologic Mechanisms of Macrophage Phenotypes Responding to Infection and the Novel Therapies to Moderate Inflammation.
Ecology of the respiratory tract microbiome.
Molecular Imaging of Innate Immunity and Immunotherapy.
Immunomodulatory Activity on Human Macrophages by Cell-Free Supernatants to Explore the Probiotic and Postbiotic Potential of Lactiplantibacillus plantarum Strains of Plant Origin.
Epigenetic orchestration of host immune defences by Mycobacterium tuberculosis.
OMIP-92: Characterization of rat macrophage subsets, lymphocytes, and granulocytes in bronchoalveolar lavage fluid.
Inflammation as a Regulator of the Airway Surface Liquid pH in Cystic Fibrosis.
Basic Science Perspective on Engineering and Modeling the Large Airways.
Exopolysaccharide from Lacticaseibacillus rhamnosus induces IgA production in airways and alleviates allergic airway inflammation in mouse model.
A modified BCG with depletion of enzymes associated with peptidoglycan amidation induces enhanced protection against tuberculosis in mice.
Antibiotic treatment can exacerbate biofilm-associated infection by promoting quorum cheater development.
Metabolic Support in Acute Respiratory Distress Syndrome: A Narrative Review.
Hippo Kinase MST1-Mediated Cell Metabolism Reprograms the Homeostasis and Differentiation of Granulocyte Progenitor Cells.

Newborn (Clarksville). 2023 Jan-Mar;2(1):2(1): 60-79

Innate Immune Memory in Macrophages.

Akhil Maheshwari.

  Macrophages have been recognized as the primary mediators of innate immunity starting from embryonic/fetal development. Macrophage-mediated defenses may not be as antigen-specific as adaptive immunity, but increasing information suggests that these responses do strengthen with repeated immunological triggers. The concept of innate memory in macrophages has been described as "trained immunity" or "innate immune memory (IIM)." As currently understood, this cellular memory is rooted in epigenetic and metabolic reprogramming. The recognition of IIM may be particularly important in the fetus and the young neonate who are yet to develop protective levels of adaptive immunity, and could even be of preventive/therapeutic importance in many disorders. There may also be a possibility of therapeutic enhancement with targeted vaccination. This article presents a review of the properties, mechanisms, and possible clinical significance of macrophage-mediated IIM.

Keywords:  Chromatin; Development; Fetus; Fumarate; Lipoprotein(a); MMP-2; MMP-9; Neonate; Newborn; Succinic acid; α-ketoglutaric acid

DOI:  https://doi.org/10.5005/jp-journals-11002-0058
Microbiol Spectr. 2023 May 16. e0429322

Bacterial Lipoproteins Shift Cellular Metabolism to Glycolysis in Macrophages Causing Bone Erosion.

Minh-Thu Nguyen, Zhicheng Hu, Majd Mohammad, Hannah Schöttler, Silke Niemann, Michelle Schultz, Katarzyna Barczyk-Kahlert, Tao Jin, Heiko Hayen, Mathias Herrmann.

  Belonging to a group of membrane proteins, bacterial lipoproteins (LPPs) are defined by a unique lipid structure at their N-terminus providing the anchor in the bacterial cell membrane. In Gram-positive bacteria, LPPs play a key role in host immune activation triggered through a Toll-like receptor 2 (TLR2)-mediated action resulting in macrophage stimulation and subsequent tissue damage demonstrated in in vivo experimental models. Yet the physiologic links between LPP activation, cytokine release, and any underlying switches in cellular metabolism remain unclear. In this study, we demonstrate that Staphylococcus aureus Lpl1 not only triggers cytokine production but also confers a shift toward fermentative metabolism in bone marrow-derived macrophages (BMDMs). Lpl1 consists of di- and tri-acylated LPP variants; hence, the synthetic P2C and P3C, mimicking di-and tri-acylated LPPs, were employed to reveal their effect on BMDMs. Compared to P3C, P2C was found to shift the metabolism of BMDMs and the human mature monocytic MonoMac 6 (MM6) cells more profoundly toward the fermentative pathway, as indicated by lactate accumulation, glucose consumption, pH reduction, and oxygen consumption. In vivo, P2C caused more severe joint inflammation, bone erosion, and lactate and malate accumulation than P3C. These observed P2C effects were completely abrogated in monocyte/macrophage-depleted mice. Taken together, these findings now solidly confirm the hypothesized link between LPP exposure, a macrophage metabolic shift toward fermentation, and ensuing bone destruction. IMPORTANCE Osteomyelitis caused by S. aureus is a severe infection of the bone, typically associated with severe bone function impairment, therapeutic failure, high morbidity, invalidity, and occasionally even death. The hallmark of staphylococcal osteomyelitis is the destruction of the cortical bone structures, yet the mechanisms contributing to this pathology are hitherto poorly understood. One bacterial membrane constituent found in all bacteria is bacterial lipoproteins (LPPs). Previously, we have shown that injection of purified S. aureus LPPs into wild-type mouse knee joints caused a TLR2-dependent chronic destructive arthritis but failed to elicit such effect in monocyte/macrophage-depleted mice. This observation stirred our interest in investigating the interaction of LPPs and macrophages and analyzing the underlying physiological mechanisms. This ascertainment of LPP-induced changes in the physiology of macrophages provides an important clue in the understanding of the mechanisms of bone disintegration, opening novel avenues to manage the course of S. aureus disease.

Keywords:  Pam2Cys; Pam3Cys; bacterial lipoprotein; bone erosion; bone marrow-derived macrophages; cellular metabolism; lactate

DOI:  https://doi.org/10.1128/spectrum.04293-22
Immunometabolism (Cobham). 2023 Apr;5(2): e00021

A new frontier for fat: dietary palmitic acid induces innate immune memory.

Amy L Seufert, Brooke A Napier.

  Dietary saturated fats have recently been appreciated for their ability to modify innate immune cell function, including monocytes, macrophages, and neutrophils. Many dietary saturated fatty acids (SFAs) embark on a unique pathway through the lymphatics following digestion, and this makes them intriguing candidates for inflammatory regulation during homeostasis and disease. Specifically, palmitic acid (PA) and diets enriched in PA have recently been implicated in driving innate immune memory in mice. PA has been shown to induce long-lasting hyper-inflammatory capacity against secondary microbial stimuli in vitro and in vivo, and PA-enriched diets alter the developmental trajectory of stem cell progenitors in the bone marrow. Perhaps the most relevant finding is the ability of exogenous PA to enhance clearance of fungal and bacterial burdens in mice; however, the same PA treatment enhances endotoxemia severity and mortality. Westernized countries are becoming increasingly dependent on SFA-enriched diets, and a deeper understanding of SFA regulation of innate immune memory is imperative in this pandemic era.

Keywords:  CD36; ceramide; chylomicron; epigenetics; hematopoietic stem cell; inflammation; innate immune memory; ketogenic diet; macrophages; metabolism; monocytes; oleic acid; palmitic acid; priming; saturated fatty acid; toll-like receptor; trained immunity; western diet

DOI:  https://doi.org/10.1097/IN9.0000000000000021
Mucosal Immunol. 2023 May 11. pii: S1933-0219(23)00036-3. [Epub ahead of print]

Butyrate regulates neutrophil homeostasis and impairs early antimicrobial activity in the lung.

Anh Thu Dang, Christina Begka, Céline Pattaroni, Laura R Caley, R Andres Floto, Daniel G Peckham, Benjamin J Marsland.

  Short-chain fatty acids (SCFAs) are metabolites that are produced following microbial fermentation of dietary fibre and impact cell metabolism and anti-inflammatory pathways both locally in the gut and systemically. In preclinical models, administration of SCFAs, such as butyrate, ameliorates a range of inflammatory disease models including allergic airway inflammation, atopic dermatitis and influenza infection. Here we report the effect of butyrate on a bacteria-induced acute neutrophil-driven immune response in the airways. Butyrate impacted discrete aspects of haematopoiesis in the bone marrow resulting in the accumulation of immature neutrophils. During Pseudomonas aeruginosa infection, butyrate treatment led to enhanced mobilization of neutrophils to the lungs as a result of increased CXCR2 expression by lung macrophages. Despite this increase in granulocyte numbers and their enhanced phagocytic capacity, neutrophils failed to control early bacterial growth. Butyrate reduced expression of nicotinamide adenine dinucleotide phosphate (NADPH), oxidase complex components required for reactive oxygen species (ROS) production, and reduced secondary granule enzymes, culminating in impaired bactericidal activity. These data reveal that SCFAs tune neutrophil maturation and effector function in the bone marrow under homeostatic conditions, potentially to mitigate against excessive granulocyte-driven immunopathology, but their consequently restricted bactericidal capacity impairs early control of Pseudomonas infection.

Keywords:  butyrate; hematopoiesis; lung; metabolite; neutrophil

DOI:  https://doi.org/10.1016/j.mucimm.2023.05.005
Int Immunopharmacol. 2023 May 17. pii: S1567-5769(23)00620-3. [Epub ahead of print]120 110297

IL-10 in combination with IL-12 and TNF-α attenuates CXCL8/CXCR1 axis in peritoneal macrophages of mice infected with Staphylococcus aureus through the TNFR1-IL-1R-NF-κB pathway.

Puja Dutta, Biswadev Bishayi.

  Overexpression of Staphylococcus aureus mediated CXCL8/CXCR1 axis is a major cause of sepsis and severe inflammatory diseases. This chemokine acts conjointly with various pro-inflammatory and anti-inflammatory cytokines that govern the severity of inflammation. The effects of different combinations of exogenous cytokines on CXCR1 expression in macrophages remain undetermined. Exogenous cytokine and anti-inflammatory cytokine therapy had been used to modulate CXCL8 and CXCR1 expression in peritoneal macrophages. Male Swiss albino mice were inoculated with live S. aureus (106 cells/ mouse) for the development of infection. Exogenous cytokines (TNF-α, IL-12, IFN-γ and IL-10) were administered intraperitoneally (single or combination) 24 h post S. aureus infection. The mice were sacrificed and peritoneal macrophages were isolated three days post infection. CXCL8, IL-12, IL-10 secretion, ROS generation and the bacterial phagocytic process had been evaluated. Western blot was used to study the expressions of TNFR1, IL-1R, CXCR1 and NF-κB. TNF-α, IL-12 and IFN-γ treatments aggravated CXCL8 and CXCR1 expression in the macrophages of infected mice. TNF-α + IFN-γ treatment was a major inducer of nitric oxide release and mediated maximum bacterial killing. IL-12 + TNF-α treatment was most potent in increasing ROS, CXCL8/CXCR1 expression through increased levels of TNFR1, IL-1R and NF-κB activation. IL-10 reversed the effects of exogenous cytokines but also impaired the bacterial clearance phenomenon in peritoneal lavage. Treatment with IL-12 + TNF-α + IL-10 was most effective in ameliorating oxidative stress, reduced CXCL8 release and expression levels of TNFR1, IL-1R, and NF-κB. Concludingly, IL-12 + TNF-α + IL-10 treatment mitigated CXCL8/CXCR1 expression and inflammatory signalling via downregulation of TNFR1-IL-1R-NF-κB pathway in peritoneal macrophages and inflammatory sequelae during S. aureus infection.

Keywords:  CXCL8; CXCR1; IL-10; IL-12; Murine peritoneal macrophage; Staphylococcus aureus; TNF-α

DOI:  https://doi.org/10.1016/j.intimp.2023.110297
Front Immunol. 2023 ;14 1180810

Neutrophil diversity in inflammation and cancer.

Silvia Carnevale, Irene Di Ceglie, Giovanna Grieco, Anna Rigatelli, Eduardo Bonavita, Sebastien Jaillon.

  Neutrophils are the most abundant circulating leukocytes in humans and the first immune cells recruited at the site of inflammation. Classically perceived as short-lived effector cells with limited plasticity and diversity, neutrophils are now recognized as highly heterogenous immune cells, which can adapt to various environmental cues. In addition to playing a central role in the host defence, neutrophils are involved in pathological contexts such as inflammatory diseases and cancer. The prevalence of neutrophils in these conditions is usually associated with detrimental inflammatory responses and poor clinical outcomes. However, a beneficial role for neutrophils is emerging in several pathological contexts, including in cancer. Here we will review the current knowledge of neutrophil biology and heterogeneity in steady state and during inflammation, with a focus on the opposing roles of neutrophils in different pathological contexts.

Keywords:  cancer; inflammation; innate immunity; neutrophil; tumor immunology

DOI:  https://doi.org/10.3389/fimmu.2023.1180810
Cell Rep. 2023 May 18. pii: S2211-1247(23)00533-8. [Epub ahead of print]42(5): 112522

Candida auris uses metabolic strategies to escape and kill macrophages while avoiding robust activation of the NLRP3 inflammasome response.

Harshini Weerasinghe, Claudia Simm, Tirta Mario Djajawi, Irma Tedja, Tricia L Lo, Daniel S Simpson, David Shasha, Naama Mizrahi, Françios A B Olivier, Mary Speir, Kate E Lawlor, Ronen Ben-Ami, Ana Traven.

  Metabolic adaptations regulate the response of macrophages to infection. The contributions of metabolism to macrophage interactions with the emerging fungal pathogen Candida auris are poorly understood. Here, we show that C. auris-infected macrophages undergo immunometabolic reprogramming and increase glycolysis but fail to activate a strong interleukin (IL)-1β cytokine response or curb C. auris growth. Further analysis shows that C. auris relies on its own metabolic capacity to escape from macrophages and proliferate in vivo. Furthermore, C. auris kills macrophages by triggering host metabolic stress through glucose starvation. However, despite causing macrophage cell death, C. auris does not trigger robust activation of the NLRP3 inflammasome. Consequently, inflammasome-dependent responses remain low throughout infection. Collectively, our findings show that C. auris uses metabolic regulation to eliminate macrophages while remaining immunologically silent to ensure its own survival. Thus, our data suggest that host and pathogen metabolism could represent therapeutic targets for C. auris infections.

Keywords:  CP: Immunology; Candida auris; NLRP3 inflammasome; immunometabolism; innate immunity; macrophage

DOI:  https://doi.org/10.1016/j.celrep.2023.112522
Cell Host Microbe. 2023 May 16. pii: S1931-3128(23)00167-1. [Epub ahead of print]

Airway dysbiosis accelerates lung function decline in chronic obstructive pulmonary disease.

Weijie Liang, Yuqiong Yang, Shenhai Gong, Mingyuan Wei, Yingfei Ma, Ruipei Feng, Jingyuan Gao, Xiaomin Liu, Fuyi Tu, Wei Ma, Xinzhu Yi, Zhenyu Liang, Fengyan Wang, Lingwei Wang, Dandan Chen, Wensheng Shu, Bruce E Miller, Ruth Tal-Singer, Gavin C Donaldson, Jadwiga A Wedzicha, Dave Singh, Tom M A Wilkinson, Christopher E Brightling, Rongchang Chen, Nanshan Zhong, Zhang Wang.

  Progressive lung function decline is a hallmark of chronic obstructive pulmonary disease (COPD). Airway dysbiosis occurs in COPD, but whether it contributes to disease progression remains unknown. Here, we show, through a longitudinal analysis of two cohorts involving four UK centers, that baseline airway dysbiosis in COPD patients, characterized by the enrichment of opportunistic pathogenic taxa, associates with a rapid forced expiratory volume in 1 s (FEV1) decline over 2 years. Dysbiosis associates with exacerbation-related FEV1 fall and sudden FEV1 fall at stability, contributing to long-term FEV1 decline. A third cohort in China further validates the microbiota-FEV1-decline association. Human multi-omics and murine studies show that airway Staphylococcus aureus colonization promotes lung function decline through homocysteine, which elicits a neutrophil apoptosis-to-NETosis shift via the AKT1-S100A8/A9 axis. S. aureus depletion via bacteriophages restores lung function in emphysema mice, providing a fresh approach to slow COPD progression by targeting the airway microbiome.

Keywords:  COPD; airway microbiome; bacteriophage; homocysteine; lung function decline; multi-omics

DOI:  https://doi.org/10.1016/j.chom.2023.04.018
J Invest Dermatol. 2023 May 13. pii: S0022-202X(23)02062-6. [Epub ahead of print]

IL-23/IL23R promote macrophage pyroptosis and Th1/Th17 cell differentiation in mycobacterial infection.

Chuan Wang, Tingting Liu, Zhenzhen Wang, Wenchao Li, Qing Zhao, Zihao Mi, Xiaotong Xue, Peidian Shi, Yonghu Sun, Yuan Zhang, Na Wang, Fangfang Bao, Wenjie Chen, Hong Liu, Furen Zhang.

  Pathogen-induced epigenetic modifications can reshape anti-infection immune processes and control the magnitude of host responses. DNA methylation profiling has identified crucial aberrant methylation changes associated with diseases, thus providing biological insights into the roles of epigenetic factors in mycobacterial infection. Here, we performed a genome-wide methylation analysis of skin biopsies from patients with leprosy and healthy controls. The Th17 differentiation pathway was found to be significantly associated with leprosy through functional enrichment analysis. As a key gene in this pathway, IL23R was found to be critical to mycobacterial immunity in leprosy, according to integrated analysis with DNA methylation, RNA sequencing and genome-wide association studies. Functional analysis revealed IL-23/IL23R enhanced bacterial clearance by activating caspase-1/GSDMD-mediated pyroptosis in a manner dependent on NLRP3 through STAT3 signaling in macrophages. Moreover, IL23/IL23R promoted Th1 and Th17 cell differentiation and proinflammatory cytokine secretion, thereby increasing host bactericidal activity. IL23R knockout attenuated the aforementioned effects and increased susceptibility to mycobacterial infection. These findings illustrate biological functions of IL-23/IL23R in modulating intracellular bacterial clearance in macrophages and further support their regulatory effects in Th cell differentiation. Our study highlights IL-23/IL23R might serve as potential targets for the prevention and treatment of leprosy and other mycobacterial infections.

Keywords:  Differentiation; IL-23/IL23R; Mycobacterial infection; Pyroptosis

DOI:  https://doi.org/10.1016/j.jid.2023.04.019
Front Mol Biosci. 2023 ;10 1160106

Influence of bacterial and alveolar cell co-culture on microbial VOC production using HS-GC/MS.

Dominic Fenn, Waqar M Ahmed, Thijs A Lilien, Renate Kos, Anita M Tuip de Boer, Stephen J Fowler, Marcus J Schultz, Anke H Maitland-van der Zee, Paul Brinkman, Lieuwe D J Bos.

  Volatile organic compounds (VOCs) found in exhaled breath continue to garner interest as an alternative diagnostic tool in pulmonary infections yet, their clinical integration remains a challenge with difficulties in translating identified biomarkers. Alterations in bacterial metabolism secondary to host nutritional availability may explain this but is often inadequately modelled in vitro. The influence of more clinically relevant nutrients on VOC production for two common respiratory pathogens was investigated. VOCs from Staphylococcus aureus (S.aureus) and Pseudomonas aeruginosa (P.aeruginosa) cultured with and without human alveolar A549 epithelial cells were analyzed using headspace extraction coupled with gas chromatography-mass spectrometry. Untargeted and targeted analyses were performed, volatile molecules identified from published data, and the differences in VOC production evaluated. Principal component analysis (PCA) could differentiate alveolar cells from either S. aureus or P. aeruginosa when cultured in isolation based on PC1 (p = 0.0017 and 0.0498, respectively). However, this separation was lost for S. aureus (p = 0.31) but not for P. aeruginosa (p = 0.028) when they were cultured with alveolar cells. S. aureus cultured with alveolar cells led to higher concentrations of two candidate biomarkers, 3-methyl-1-butanol (p = 0.001) and 3-methylbutanal (p = 0.002) when compared to S. aureus, alone. P. aeruginosa metabolism resulted in less generation of pathogen-associated VOCs when co-cultured with alveolar cells compared to culturing in isolation. VOC biomarkers previously considered indicative of bacterial presence are influenced by the local nutritional environment and this should be considered when evaluating their biochemical origin.

Keywords:  HS-GC/MS; VOC; bacterial VOCs; co-culture model; culture media composition

DOI:  https://doi.org/10.3389/fmolb.2023.1160106
Int J Mol Sci. 2023 May 06. pii: 8358. [Epub ahead of print]24(9):

Biologic Mechanisms of Macrophage Phenotypes Responding to Infection and the Novel Therapies to Moderate Inflammation.

Renhao Ni, Lingjing Jiang, Chaohai Zhang, Mujie Liu, Yang Luo, Zeming Hu, Xianbo Mou, Yabin Zhu.

  Pro-inflammatory and anti-inflammatory types are the main phenotypes of the macrophage, which are commonly notified as M1 and M2, respectively. The alteration of macrophage phenotypes and the progression of inflammation are intimately associated; both phenotypes usually coexist throughout the whole inflammation stage, involving the transduction of intracellular signals and the secretion of extracellular cytokines. This paper aims to address the interaction of macrophages and surrounding cells and tissues with inflammation-related diseases and clarify the crosstalk of signal pathways relevant to the phenotypic metamorphosis of macrophages. On these bases, some novel therapeutic methods are proposed for regulating inflammation through monitoring the transition of macrophage phenotypes so as to prevent the negative effects of antibiotic drugs utilized in the long term in the clinic. This information will be quite beneficial for the diagnosis and treatment of inflammation-related diseases like pneumonia and other disorders involving macrophages.

Keywords:  biologic mechanism; cellular signal; inflammation; macrophage phenotype

DOI:  https://doi.org/10.3390/ijms24098358
Trends Microbiol. 2023 May 10. pii: S0966-842X(23)00120-8. [Epub ahead of print]

Ecology of the respiratory tract microbiome.

Ana Elena Pérez-Cobas, Jerónimo Rodríguez-Beltrán, Fernando Baquero, Teresa M Coque.

  A thriving multi-kingdom microbial ecosystem inhabits the respiratory tract: the respiratory tract microbiome (RTM). In recent years, the contribution of the RTM to human health has become a crucial research aspect. However, research into the key ecological processes, such as robustness, resilience, and microbial interaction networks, has only recently started. This review leans on an ecological framework to interpret the human RTM and determine how the ecosystem functions and assembles. Specifically, the review illustrates the ecological RTM models and discusses microbiome establishment, community structure, diversity stability, and critical microbial interactions. Lastly, the review outlines the RTM responses to ecological disturbances, as well as the promising approaches for restoring ecological balance.

Keywords:  disturbance; ecology; respiratory tract microbiome (RTM); restoration; succession

DOI:  https://doi.org/10.1016/j.tim.2023.04.006
Adv Drug Deliv Rev. 2023 May 12. pii: S0169-409X(23)00180-1. [Epub ahead of print] 114865

Molecular Imaging of Innate Immunity and Immunotherapy.

Wenxi Xia, Neetu Singh, Shreya Goel, Sixiang Shi.

  The innate immune system plays a key role as the first line of defense in various human diseases including cancer, cardiovascular and inflammatory diseases. In contrast to tissue biopsies and blood biopsies, in vivo imaging of the innate immune system can provide whole body measurements of immune cell location and function and changes in response to disease progression and therapy. Rationally developed molecular imaging strategies can be used in evaluating the status and spatio-temporal distributions of the innate immune cells in near real-time, mapping the biodistribution of novel innate immunotherapies, monitoring their efficacy and potential toxicities, and eventually for stratifying patients that are likely to benefit from these immunotherapies. In this review, we will highlight the current state-of-the-art in noninvasive imaging techniques for preclinical imaging of the innate immune system particularly focusing on cell trafficking, biodistribution, as well as pharmacokinetics and dynamics of promising immunotherapies in cancer and other diseases; discuss the unmet needs and current challenges in integrating imaging modalities and immunology and suggest potential solutions to overcome these barriers.

Keywords:  dendritic cells; innate immunity; innate immunotherapy; macrophages; molecular imaging

DOI:  https://doi.org/10.1016/j.addr.2023.114865
Probiotics Antimicrob Proteins. 2023 May 18.

Immunomodulatory Activity on Human Macrophages by Cell-Free Supernatants to Explore the Probiotic and Postbiotic Potential of Lactiplantibacillus plantarum Strains of Plant Origin.

Maria Teresa Rocchetti, Pasquale Russo, Nicola De Simone, Vittorio Capozzi, Giuseppe Spano, Daniela Fiocco.

  Upon dietary administration, probiotic microorganisms can reach as live cells the human gut, where they interact with the microbiota and host cells, thereby exerting a beneficial impact on host functions, mainly through immune-modulatory activities. Recently, attention has been drawn by postbiotics, i.e. non-viable probiotic microbes, including their metabolic products, which possess biological activities that benefit the host. Lactiplantibacillus plantarum is a bacterial species that comprises recognised probiotic strains. In this study, we investigated in vitro the probiotic (and postbiotic) potential of seven L. plantarum strains, including five newly isolated from plant-related niches. The strains were shown to possess some basic probiotic attributes, including tolerance to the gastrointestinal environment, adhesion to the intestinal epithelium and safety. Besides, their cell-free culture supernatants modulated cytokine patterns in human macrophages in vitro, promoting TNF-α gene transcription and secretion, while attenuating the transcriptional activation and secretion of both TNF-α and IL-8 in response to a pro-inflammatory signal, and enhancing the production of IL-10. Some strains induced a high IL-10/IL-12 ratio that may correlate to an anti-inflammatory capacity in vivo. Overall, the investigated strains are good probiotic candidates, whose postbiotic fraction exhibits immunomodulatory properties that need further in vivo studies. The main novelty of this work consists in the polyphasic characterisation of candidate beneficial L. plantarum strains obtained from relatively atypical plant-associated niches, by an approach that explores both probiotic and postbiotic potentials, in particular studying the effect of microbial culture-conditioned media on cytokine pattern, analysed at both transcriptional and secretion level in human macrophages.

Keywords:  Adhesion; Anti-inflammatory; Caco-2; Cytokines; Immune response; Lactobacilli; Plant-associated

DOI:  https://doi.org/10.1007/s12602-023-10084-4
Microbiol Res. 2023 May 03. pii: S0944-5013(23)00102-7. [Epub ahead of print]273 127400

Epigenetic orchestration of host immune defences by Mycobacterium tuberculosis.

Srabasti Sengupta, Kali Prasad Pattanaik, Snehasish Mishra, Avinash Sonawane.

  Being among the top 10 causes of adult deaths, tuberculosis (TB) disease is considered a major global public health concern to address. The human tuberculosis pathogen, Mycobacterium tuberculosis (Mtb), is an extremely competent and well-versed pathogen that promotes pathogenesis by evading the host immune systems through numerous tactics. Investigations revealed that Mtb could evade the host defense mechanisms by reconfiguring the host gene transcription and causing epigenetic changes. Although results indicate the link between epigenetics and disease manifestation in other bacterial infections, little is known regarding the kinetics of the epigenetic alterations in mycobacterial infection. This literature review discusses the studies in Mtb-induced epigenetic alterations inside the host and its contribution in the host immune evasion strategies. It also discusses how the Mtb-induced alterations could be used as 'epibiomarkers' to diagnose TB. Additionally, this review also discusses therapeutic interventions to be enhanced through remodification by 'epidrugs'.

Keywords:  Antigen presentation; Apoptosis; Autophagy; Cell motility; Cytokines; DNA methylation; Epibiomarkers; Epigenetic drugs; Epigenetic modifications; Gene alteration; Gene transcription; Histone acetylation; Histone methylation; Histone modifications; Matrix metalloproteinase (MMP); Mycobacterium tuberculosis; Phagocytosis; RNA interference; Tuberculosis; miRNA

DOI:  https://doi.org/10.1016/j.micres.2023.127400
Cytometry A. 2023 May 17.

OMIP-92: Characterization of rat macrophage subsets, lymphocytes, and granulocytes in bronchoalveolar lavage fluid.

Karine Bouchard, Dany Patoine, Elyse Y Bissonnette, Jean-Francois Lauzon-Joset.

  Airway inflammation is a defense mechanism against inhaled agents characterized by infiltration of circulating immune cells. Given the inconsistent cellular identification across pre-clinical rat model, we have developed a flow cytometry panel of six colors to characterize macrophages subsets, lymphocytes and granulocytes in bronchoalveolar lavage fluid (BAL). Rats were challenged with intratracheal instillation of lipopolysaccharide (LPS). BAL were harvested 24 h after one LPS exposure in rats. This flow cytometry panel involve the description of macrophage subsets, T and B lymphocytes and neutrophils, which are central to airway immune responses, as based on scientific literature. By using a relatively small number of parameters to identify multiple cell types, additional parameters can be used for project/disease-specific activation markers.

Keywords:  ARDS; airway inflammation; flow cytometry; lung; lymphocytes; macrophages; neutrophils

DOI:  https://doi.org/10.1002/cyto.a.24739
Cells. 2023 04 07. pii: 1104. [Epub ahead of print]12(8):

Inflammation as a Regulator of the Airway Surface Liquid pH in Cystic Fibrosis.

Tayyab Rehman, Michael J Welsh.

  The airway surface liquid (ASL) is a thin sheet of fluid that covers the luminal aspect of the airway epithelium. The ASL is a site of several first-line host defenses, and its composition is a key factor that determines respiratory fitness. Specifically, the acid-base balance of ASL has a major influence on the vital respiratory defense processes of mucociliary clearance and antimicrobial peptide activity against inhaled pathogens. In the inherited disorder cystic fibrosis (CF), loss of cystic fibrosis transmembrane conductance regulator (CFTR) anion channel function reduces HCO3- secretion, lowers the pH of ASL (pHASL), and impairs host defenses. These abnormalities initiate a pathologic process whose hallmarks are chronic infection, inflammation, mucus obstruction, and bronchiectasis. Inflammation is particularly relevant as it develops early in CF and persists despite highly effective CFTR modulator therapy. Recent studies show that inflammation may alter HCO3- and H+ secretion across the airway epithelia and thus regulate pHASL. Moreover, inflammation may enhance the restoration of CFTR channel function in CF epithelia exposed to clinically approved modulators. This review focuses on the complex relationships between acid-base secretion, airway inflammation, pHASL regulation, and therapeutic responses to CFTR modulators. These factors have important implications for defining optimal ways of tackling CF airway inflammation in the post-modulator era.

Keywords:  airway epithelium; airway surface liquid; cystic fibrosis; host defense; inflammation; pH

DOI:  https://doi.org/10.3390/cells12081104
Adv Exp Med Biol. 2023 ;1413 73-106

Basic Science Perspective on Engineering and Modeling the Large Airways.

Lalit K Gautam, Noa C Harriott, Adrian M Caceres, Amy L Ryan.

  The airway epithelium provides a physical and biochemical barrier playing a key role in protecting the lung from infiltration of pathogens and irritants and is, therefore, crucial in maintaining tissue homeostasis and regulating innate immunity. Due to continual inspiration and expiration of air during breathing, the epithelium is exposed to a plethora of environmental insults. When severe or persistent, these insults lead to inflammation and infection. The effectiveness of the epithelium as a barrier is reliant upon its capacity for mucociliary clearance, immune surveillance, and regeneration upon injury. These functions are accomplished by the cells that comprise the airway epithelium and the niche in which they reside. Engineering of new physiological and pathological models of the proximal airways requires the generation of complex structures comprising the surface airway epithelium, submucosal gland epithelium, extracellular matrix, and niche cells, including smooth muscle cells, fibroblasts, and immune cells. This chapter focuses on the structure-function relationships in the airways and the challenges of developing complex engineered models of the human airway.

Keywords:  Basal cells; Epithelium; Extracellular matrix; Inflammation; Mesenchyme; Regeneration

DOI:  https://doi.org/10.1007/978-3-031-26625-6_5
Eur J Immunol. 2023 May 12. e2250135

Exopolysaccharide from Lacticaseibacillus rhamnosus induces IgA production in airways and alleviates allergic airway inflammation in mouse model.

Dagmar Srutkova, Hana Kozakova, Tereza Novotna, Sabina Gorska, Petra Petr Hermanova, Tomas Hudcovic, Tereza Svabova, Marek Sinkora, Martin Schwarzer.

  The currently observed high prevalence of allergic diseases has been associated with changes in microbial exposure in industrialized countries. Defined bacterial components represent a new strategy for modulating the allergic immune response. We show that intranasal administration of exopolysaccharide isolated from Lacticaseibacillus (L.) rhamnosus LOCK900 (EPS) induces TGF-β1, IgA, and regulatory FoxP3 T cells in the lungs of naive mice. Using the ovalbumin mouse model, we demonstrate that intranasal administration of EPS downregulates the development of allergic airway inflammation and the Th2 cytokine response in sensitized individuals. At the same time, EPS treatment of sensitized mice, similar to EPS-induced responses in naive mice, significantly increased the level of total, OVA-specific and also bacteria-specific IgA in bronchoalveolar lavage and the number of IgA-producing B cells in the lung tissue of these mice. Thus, EPS derived from L. rhamnosus LOCK900 can be considered a safe candidate for preventing the development of allergic symptoms in the lungs of sensitized individuals upon exposure to an allergen. This article is protected by copyright. All rights reserved.

Keywords:  Airway allergic inflammation; Exopolysaccharide; IgA antibody; Immunomodulation; Lacticaseibacillus

DOI:  https://doi.org/10.1002/eji.202250135
bioRxiv. 2023 May 03. pii: 2023.05.03.539199. [Epub ahead of print]

A modified BCG with depletion of enzymes associated with peptidoglycan amidation induces enhanced protection against tuberculosis in mice.

Moagi T Shaku, Peter Um, Karl L Ocius, Alexis J Apostolos, Marcos M Pires, William R Bishai, Bavesh D Kana.

Mechanisms by which Mycobacterium tuberculosis (Mtb) evades pathogen recognition receptor activation during infection may offer insights for the development of improved tuberculosis (TB) vaccines. Whilst Mtb elicits NOD-2 activation through host recognition of its peptidoglycan-derived muramyl dipeptide (MDP), it masks the endogenous NOD-1 ligand through amidation of glutamate at the second position in peptidoglycan sidechains. As the current BCG vaccine is derived from pathogenic mycobacteria, a similar situation prevails. To alleviate this masking ability and to potentially improve efficacy of the BCG vaccine, we used CRISPRi to inhibit expression of the essential enzyme pair, MurT-GatD, implicated in amidation of peptidoglycan sidechains. We demonstrate that depletion of these enzymes results in reduced growth, cell wall defects, increased susceptibility to antibiotics and altered spatial localization of new peptidoglycan. In cell culture experiments, training of monocytes with this recombinant BCG yielded improved control of Mtb growth. In the murine model of TB infection, we demonstrate that depletion of MurT-GatD in BCG, resulting in unmasking of the D-glutamate diaminopimelate (iE-DAP) NOD-1 ligand, yields superior prevention of TB disease compared to the standard BCG vaccine. This work demonstrates the feasibility of gene regulation platforms such as CRISPRi to alter antigen presentation in BCG in a bespoke manner that tunes immunity towards more effective protection against TB disease.

DOI: https://doi.org/10.1101/2023.05.03.539199
NPJ Biofilms Microbiomes. 2023 May 18. 9(1): 26

Antibiotic treatment can exacerbate biofilm-associated infection by promoting quorum cheater development.

Lei He, Huiying Lv, Yanan Wang, Feng Jiang, Qian Liu, Feiyang Zhang, Hua Wang, Hao Shen, Michael Otto, Min Li.

Quorum cheating, a socio-microbiological process that is based on mutations in cell density-sensing (quorum-sensing) systems, has emerged as an important contributor to biofilm-associated infection in the leading human pathogen Staphylococcus aureus. This is because inactivation of the staphylococcal Agr quorum-sensing system leads to pronounced biofilm formation, increasing resistance to antibiotics and immune defense mechanisms. Since biofilm infections in the clinic usually progress under antibiotic treatment, we here investigated whether such treatment promotes biofilm infection via the promotion of quorum cheating. Quorum cheater development was stimulated by several antibiotics used in the treatment of staphylococcal biofilm infections more strongly in biofilm than in the planktonic mode of growth. Sub-inhibitory concentrations of levofloxacin and vancomycin were investigated for their impact on biofilm-associated (subcutaneous catheter-associated and prosthetic joint-associated infection), where in contrast to a non-biofilm-associated subcutaneous skin infection model, a significant increase of the bacterial load and development of agr mutants was observed. Our results directly demonstrate the development of Agr dysfunctionality in animal biofilm-associated infection models and reveal that inappropriate antibiotic treatment can be counterproductive for such infections as it promotes quorum cheating and the associated development of biofilms.

DOI: https://doi.org/10.1038/s41522-023-00394-4
J Clin Med. 2023 Apr 29. pii: 3216. [Epub ahead of print]12(9):

Metabolic Support in Acute Respiratory Distress Syndrome: A Narrative Review.

Michele Umbrello, John J Marini, Paolo Formenti.

  Nutritional support for acute respiratory distress syndrome (ARDS) patients shares metabolic notions common to other critically ill conditions. Nevertheless, it generates specific concern regarding the primary limitation of oxygen supply and the complications of carbon dioxide elimination, as well as the significant metabolic alterations due to the body's response to illness. In the present narrative review, after briefly summarizing the pathophysiology of critical illness stress response and patients' metabolic requirements, we focus on describing the characteristics of metabolic and artificial nutrition in patients with acute respiratory failure. In patients with ARDS, several aspects of metabolism assume special importance. The physiological effects of substrate metabolism are described for this setting, particularly regarding energy consumption, diet-induced thermogenesis, and the price of their clearance, transformation, and storage. Moreover, we review the possible direct effects of macronutrients on lung tissue viability during ARDS. Finally, we summarize the noteworthy characteristics of metabolic control in critically ill patients with ARDS and offer a suggestion as to the ideal methods of metabolic support for this problem.

Keywords:  acute respiratory distress syndrome; artificial nutrition; metabolic support

DOI:  https://doi.org/10.3390/jcm12093216
J Immunol. 2023 May 15. pii: ji2200615. [Epub ahead of print]

Hippo Kinase MST1-Mediated Cell Metabolism Reprograms the Homeostasis and Differentiation of Granulocyte Progenitor Cells.

Anna Jia, Yufei Wang, Qiuli Yang, Yuexin Wang, Yijin Huang, Yujing Bi, Guangwei Liu.

The mechanism of the development of granulocyte progenitor cells into neutrophils under steady-state and pathological conditions remains unclear. In this study, our results showed that with the development of neutrophils from hematopoietic stem cells to mature neutrophils, the expression level of the Hippo kinase MST1 gradually increased. Mst1-specific deficiency in myeloid cells caused neutrophilia, with an expanded granulocytic compartment resulting from a cell-autonomous increase in the number of granulocyte-macrophage progenitors under steady-state conditions and during Listeria monocytogenes infection. Mechanistically, mTOR and HIF1α signaling are required for regulating the balance between glycolysis and succinate dehydrogenase-mediated oxidative phosphorylation, which is crucial for Mst1-/--induced proliferation of granulocyte-monocyte progenitors, lineage-decision factor C/EBPα expression, and granulopoiesis. HIF1α directly regulated C/EBPα promoter activities. Blocking mTOR and HIF1α or adjusting the balance between glycolysis and succinate dehydrogenase-mediated oxidative phosphorylation reversed the granulopoiesis induced by Mst1-/- under steady-state conditions or infection in mice. Thus, our findings identify a previously unrecognized interplay between Hippo kinase MST1 signaling and mTOR-HIF1α metabolic reprogramming in granulocyte progenitor cells that underlies granulopoiesis.

DOI: https://doi.org/10.4049/jimmunol.2200615