bims-bac4me 2023-12-10 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2023–12–10
29 papers selected by
Chun-Chi Chang, University Hospital Zurich

The microbiome: an integral player in immune homeostasis and inflammation in the respiratory tract.
Measurement of Accumulation of Antibiotics to Staphylococcus aureus in Phagosomes of Live Macrophages.
Editorial: The development and plasticity of myeloid immunity in the lung.
Apoptotic signaling clears engineered Salmonella in an organ-specific manner.
Mucosal recombinant BCG vaccine induces lung-resident memory macrophages and enhances trained immunity via mTORC2/HK1-mediated metabolic rewiring.
Bifidobacterium mechanisms of immune modulation and tolerance.
Post-transcriptional regulation of myeloid cell-mediated inflammatory responses.
Immunometabolism of dendritic cells in health and disease.
Microbial interaction-induced siderophore dynamics lead to phenotypic differentiation of Staphylococcus aureus.
Helicobacter pylori induces a novel form of innate immune memory via accumulation of NF-кB proteins.
The Relationship Between the Microbiome and Antimicrobial Resistance.
Staphylococcus aureus β-hemolysin causes skin inflammation by acting as an agonist of epidermal growth factor receptor.
Microbial interactions and the homeostasis of the gut microbiome: the role of Bifidobacterium.
Video Introduction to "The Microbiome and Human Health Perspective".
Mutual Regulation of Transcriptomes Between Murine Pneumocytes and Fibroblasts Mediates Alveolar Regeneration in Air-Liquid Interface Cultures.
Editorial: Innate immunity and cross-talk with microflora in the regulation of immune recognition and polarization during immune-related diseases.
Metabolite itaconate in host immunoregulation and defense.
A computational framework for resolving the microbiome diversity conundrum.
Host-derived oxidized phospholipids initiate effector-triggered immunity fostering lethality upon microbial encounter.
Advancements in Novel Live Biotherapeutic Products for Clostridioides difficile Infection Prevention.
Dual-specificity phosphatase 5-mediated fatty acid oxidation promotes Mycobacterium bovis BCG -induced inflammatory responses.
Making friends: active selection of symbionts and rejection of pathogens by the neonatal immune system.
A CRISPRi-based genetic resource to study essential Staphylococcus aureus genes.
Rapamycin Exacerbates Staphylococcus aureus Pneumonia by Inhibiting mTOR-RPS6 in Macrophages.
Lack of a transcriptional response of primary bronchial epithelial cells from asthma patients and controls to IL-33.
A need to consider divergence in definition of Staphylococcus aureus bacteraemia too.
Tobacco smoke exposure recruits inflammatory airspace monocytes that establish permissive lung niches for Mycobacterium tuberculosis.
Dying to Defend: Neutrophil Death Pathways and their Implications in Immunity.
Probiotic colonization dynamics after oral consumption of VSL#3® by antibiotic-treated mice.

Physiol Rev. 2023 Dec 07.

The microbiome: an integral player in immune homeostasis and inflammation in the respiratory tract.

Olaf Perdijk, Rossana Azzoni, Benjamin J Marsland.

  The last decade of microbiome research has highlighted its fundamental role in systemic immune and metabolic homeostasis. The microbiome plays a prominent role during gestation and into early life when maternal lifestyle factors shape immune development of the newborn. Breast milk further shapes gut colonisation, supporting the development of tolerance to commensal bacteria and harmless antigens while preventing outgrowth of pathogens. Environmental microbial and lifestyle factors that disrupt this process can dysregulate immune homeostasis, predisposing infants to atopic disease and childhood asthma. In health, the low biomass lung microbiome, together with inhaled environmental microbial constituents, establishes the immunological setpoint that is necessary to maintain pulmonary immune defence. However, in disease, perturbations to immunological and physiological processes allow the upper respiratory tract to act as a reservoir of pathogenic bacteria, which can colonise the diseased lung and cause severe inflammation. Studying these host-microbe interactions in respiratory diseases holds great promise to stratify patients for suitable treatment regimens and biomarker discovery to predict disease progression. Preclinical studies show that commensal gut microbes are in a constant flux of cell division and death, releasing microbial constituents, metabolic byproducts, and vesicles that shape the immune system and can protect against respiratory diseases. The next major advances may come from testing and utilizing these microbial factors for clinical benefit and exploiting the predictive power of the microbiome by employing multi-omics analysis approaches.

Keywords:  gut-lung axis; microbial metabolites; microbiome

DOI:  https://doi.org/10.1152/physrev.00020.2023
Angew Chem Int Ed Engl. 2023 Dec 05. e202313870

Measurement of Accumulation of Antibiotics to Staphylococcus aureus in Phagosomes of Live Macrophages.

Joey J Kelly, Brianna E Dalesandro, Zichen Liu, Mahendra D Chordia, George M Ongwae, Marcos Moura Pires.

  Staphylococcus aureus (S. aureus) has evolved the ability to persist after uptake into host immune cells. This intracellular niche enables S. aureus to potentially escape host immune responses and survive the lethal actions of antibiotics. While the elevated tolerance of S. aureus to small-molecule antibiotics is likely to be multifactorial, we pose that there may be contributions related to permeation of antibiotics into phagocytic vacuoles, which would require translocation across two mammalian bilayers. To empirically test this, we adapted our recently developed permeability assay to determine the accumulation of FDA-approved antibiotics into phagocytic vacuoles of live macrophages. Bioorthogonal reactive handles were metabolically anchored within the surface of S. aureus, and complementary tags were chemically added to antibiotics. Following phagocytosis of tagged S. aureus cells, we were able to specifically analyze the arrival of antibiotics within the phagosomes of infected macrophages. Our findings enabled the determination of permeability differences between extra- and intracellular S. aureus, thus providing a roadmap to dissect the contribution of antibiotic permeability to intracellular pathogens.

Keywords:  bacterial cell wall metabolic labeling staphylococcus aureus phagocytic vacuole

DOI:  https://doi.org/10.1002/anie.202313870
Front Immunol. 2023 ;14 1332852

Editorial: The development and plasticity of myeloid immunity in the lung.

Sjoerd T T Schetters, Floris Dammeijer, Christophe J Desmet.



Keywords:  ARDS (acute respiratory disease syndrome); alveolar macrophage; asthma; innate immunity; lung immune cells; myeloid plasticity; respiratory viral and bacterial infections

DOI:  https://doi.org/10.3389/fimmu.2023.1332852
Elife. 2023 Dec 06. pii: RP89210. [Epub ahead of print]12

Apoptotic signaling clears engineered Salmonella in an organ-specific manner.

Taylor J Abele, Zachary P Billman, Lupeng Li, Carissa K Harvest, Alexia K Bryan, Gabrielle R Magalski, Joseph P Lopez, Heather N Larson, Xiao-Ming Yin, Edward A Miao.

  Pyroptosis and apoptosis are two forms of regulated cell death that can defend against intracellular infection. When a cell fails to complete pyroptosis, backup pathways will initiate apoptosis. Here, we investigated the utility of apoptosis compared to pyroptosis in defense against an intracellular bacterial infection. We previously engineered Salmonella enterica serovar Typhimurium to persistently express flagellin, and thereby activate NLRC4 during systemic infection in mice. The resulting pyroptosis clears this flagellin-engineered strain. We now show that infection of caspase-1 or gasdermin D deficient macrophages by this flagellin-engineered S. Typhimurium induces apoptosis in vitro. Additionally, we engineered S. Typhimurium to translocate the pro-apoptotic BH3 domain of BID, which also triggers apoptosis in macrophages in vitro. During mouse infection, the apoptotic pathway successfully cleared these engineered S. Typhimurium from the intestinal niche but failed to clear the bacteria from the myeloid niche in the spleen or lymph nodes. In contrast, the pyroptotic pathway was beneficial in defense of both niches. To clear an infection, cells may have specific tasks that they must complete before they die; different modes of cell death could initiate these 'bucket lists' in either convergent or divergent ways.

Keywords:  Salmonella; apoptosis; extrusion; immunology; infectious disease; inflammation; microbiology; mouse; pyroptosis; regulated cell death

DOI:  https://doi.org/10.7554/eLife.89210
J Biol Chem. 2023 Nov 30. pii: S0021-9258(23)02546-2. [Epub ahead of print] 105518

Mucosal recombinant BCG vaccine induces lung-resident memory macrophages and enhances trained immunity via mTORC2/HK1-mediated metabolic rewiring.

Xiaofei Peng, Yuting Zhou, Baoying Zhang, Xiaotong Liang, Jingyu Feng, Yuejun Huang, Shufeng Weng, Ying Xu, Haibo Su.

  Bacillus Calmette-Guérin (BCG) vaccination induces a type of immune memory known as "trained immunity", characterized by the immunometabolic and epigenetic changes in innate immune cells. However, the molecular mechanism underlying the strategies for inducing and/or boosting trained immunity in alveolar macrophages remains unknown. Here, we found that mucosal vaccination with the recombinant strain rBCGPPE27 significantly augmented the trained immune response in mice, facilitating a superior protective response against Mycobacterium tuberculosis and non-related bacterial reinfection in mice when compared to BCG. Mucosal immunization with rBCGPPE27 enhanced innate cytokine production by alveolar macrophages associated with promoted glycolytic metabolism, typical of trained immunity. Deficiency of the mammalian target of rapamycin complex 2 and hexokinase 1 abolished the immunometabolic and epigenetic rewiring in mouse alveolar macrophages after mucosal rBCGPPE27 vaccination. Most noteworthy, utilizing rBCGPPE27's higher-up trained effects: The single mucosal immunization with rBCGPPE27-adjuvanted coronavirus disease (CoV-2) vaccine raised the rapid development of virus-specific immunoglobulin G antibodies, boosted pseudovirus neutralizing antibodies, and augmented T helper type 1-biased cytokine release by vaccine-specific T cells, compared to BCG/CoV-2 vaccine. These findings revealed that mucosal recombinant BCG vaccine induces lung-resident memory macrophages and enhances trained immunity via reprogramming mTORC2- and HK-1-mediated aerobic glycolysis, providing new vaccine strategies for improving tuberculosis (TB) or coronavirus variant vaccinations, and targeting innate immunity via mucosal surfaces.

Keywords:  Bacille Calmette-Guerin; Trained immunity; glycolysis; innate immune memory; mucosal vaccination

DOI:  https://doi.org/10.1016/j.jbc.2023.105518
Gut Microbes. 2023 Dec;15(2): 2291164

Bifidobacterium mechanisms of immune modulation and tolerance.

Samuel J Gavzy, Allison Kensiski, Zachariah L Lee, Emmanuel F Mongodin, Bing Ma, Jonathan S Bromberg.

  Bifidobacterium is a widely distributed commensal bacterial genus that displays beneficial pro-homeostatic and anti-inflammatory immunomodulatory properties. Depletion or absence of Bifidobacterium in humans and model organisms is associated with autoimmune responses and impaired immune homeostasis. At the cellular level, Bifidobacterium upregulates suppressive regulatory T cells, maintains intestinal barrier function, modulates dendritic cell and macrophage activity, and dampens intestinal Th2 and Th17 programs. While there has been a large volume of literature characterizing the probiotic properties of various Bifidobacterial species, the likely multifactorial mechanisms underlying these effects remain elusive, in particular, its immune tolerogenic effect. However, recent work has shed light on Bifidobacterium surface structural polysaccharide and protein elements, as well as its metabolic products, as commensal mediators of immune homeostasis. This review aims to discuss several mechanisms Bifidobacterium utilizes for immune modulation as well as their indirect impact on the regulation of gut microbiome structure and function, from structural molecules to produced metabolites. These mechanisms are pertinent to an increasingly networked understanding of immune tolerance and homeostasis in health and disease.

Keywords:  Bifidobacteria; gut microbiome; immune homeostasis; live biotherapeutics; metabolites; tolerogenic immune responses

DOI:  https://doi.org/10.1080/19490976.2023.2291164
Adv Immunol. 2023 ;pii: S0065-2776(23)00029-9. [Epub ahead of print]160 59-82

Post-transcriptional regulation of myeloid cell-mediated inflammatory responses.

Xingxian Liu, Weidong Han, Xiaoyu Hu.

  Myeloid cells, particularly macrophages, act as the frontline responders to infectious agents and initiate inflammation. While the molecular mechanisms driving inflammatory responses have primarily focused on pattern recognition by myeloid cells and subsequent transcriptional events, it is crucial to note that post-transcriptional regulation plays a pivotal role in this process. In addition to the transcriptional regulation of innate immune responses, additional layers of intricate network of post-transcriptional mechanisms critically determine the quantity and duration of key inflammatory products and thus the outcome of immune responses. A multitude of mechanisms governing post-transcriptional regulation in innate immunity have been uncovered, encompassing RNA alternative splicing, mRNA stability, and translational regulation. This review encapsulates the current insights into the post-transcriptional regulation of inflammatory genes within myeloid cells, with particular emphasis on translational regulation during inflammation. While acknowledging the advancements, we also shed light on the existing gaps in immunological research pertaining to post-transcriptional levels and propose perspectives that controlling post-transcriptional process may serve as potential targets for therapeutic interventions in inflammatory diseases.

Keywords:  Inflammation; Innate immunity; Macrophage; Myeloid cell; Post-transcriptional regulation; Translation regulation

DOI:  https://doi.org/10.1016/bs.ai.2023.09.001
Adv Immunol. 2023 ;pii: S0065-2776(23)00032-9. [Epub ahead of print]160 83-116

Immunometabolism of dendritic cells in health and disease.

Chuansheng Guo, Hongbo Chi.

Dendritic cells (DCs) are crucial mediators that bridge the innate and adaptive immune responses. Cellular rewiring of metabolism is an emerging regulator of the activation, migration, and functional specialization of DC subsets in specific microenvironments and immunological conditions. DCs undergo metabolic adaptation to exert immunogenic or tolerogenic effects in different contexts. Also, beyond their intracellular metabolic and signaling roles, metabolites and nutrients mediate the intercellular crosstalk between DCs and other cell types, and such crosstalk orchestrates DC function and immune responses. Here, we provide a comprehensive review of the metabolic regulation of DC biology in various contexts and summarize the current understanding of such regulation in directing immune homeostasis and inflammation, specifically with respect to infections, autoimmunity, tolerance, cancer, metabolic diseases, and crosstalk with gut microbes. Understanding context-specific metabolic alterations in DCs may identify mechanisms for physiological and pathological functions of DCs and yield potential opportunities for therapeutic targeting of DC metabolism in many diseases.

DOI: https://doi.org/10.1016/bs.ai.2023.10.002
Front Cell Infect Microbiol. 2023 ;13 1277176

Microbial interaction-induced siderophore dynamics lead to phenotypic differentiation of Staphylococcus aureus.

Soundarya Rajapitamahuni, Eun Sun Lyou, Bo Ram Kang, Tae Kwon Lee.

  This study investigated the impact of microbial interactions on siderophore dynamics and phenotypic differentiation of Staphylococcus aureus under iron-deficient conditions. Optimization of media demonstrated that the glycerol alanine salts medium was best suited for analyzing the dynamics of siderophore production because of its stable production of diverse siderophore types. The effects of pH and iron concentration on siderophore yield revealed a maximum yield at neutral pH and low iron concentration (10 µg). Microbial interaction studies have highlighted variations in siderophore production when different strains (Staphylococcus epidermidis, Pseudomonas aeruginosa, and Escherichia coli) are co-cultured with S. aureus. Co-culture of S. aureus with P. aeruginosa eliminated siderophore production in S. aureus, while co-culture of S. aureus with E. coli and S. epidermidis produced one or two siderophores, respectively. Raman spectroscopy revealed that microbial interactions and siderophore dynamics play a crucial role in directing the phenotypic differentiation of S. aureus, especially under iron-deficient conditions. Our results suggest that microbial interactions profoundly influence siderophore dynamics and phenotypic differentiation and that the study of these interactions could provide valuable insights for understanding microbial survival strategies in iron-limited environments.

Keywords:  Raman spectroscopy; iron deficiency; microbial interactions; phenotype; siderophores

DOI:  https://doi.org/10.3389/fcimb.2023.1277176
Front Immunol. 2023 ;14 1290833

Helicobacter pylori induces a novel form of innate immune memory via accumulation of NF-кB proteins.

Tobias Frauenlob, Theresa Neuper, Christof Regl, Veronika Schaepertoens, Michael S Unger, Anna-Lena Oswald, Hieu-Hoa Dang, Christian G Huber, Fritz Aberger, Silja Wessler, Jutta Horejs-Hoeck.

  Helicobacter pylori is a widespread Gram-negative pathogen involved in a variety of gastrointestinal diseases, including gastritis, ulceration, mucosa-associated lymphoid tissue (MALT) lymphoma and gastric cancer. Immune responses aimed at eradication of H. pylori often prove futile, and paradoxically play a crucial role in the degeneration of epithelial integrity and disease progression. We have previously shown that H. pylori infection of primary human monocytes increases their potential to respond to subsequent bacterial stimuli - a process that may be involved in the generation of exaggerated, yet ineffective immune responses directed against the pathogen. In this study, we show that H. pylori-induced monocyte priming is not a common feature of Gram-negative bacteria, as Acinetobacter lwoffii induces tolerance to subsequent Escherichia coli lipopolysaccharide (LPS) challenge. Although the increased reactivity of H. pylori-infected monocytes seems to be specific to H. pylori, it appears to be independent of its virulence factors Cag pathogenicity island (CagPAI), cytotoxin associated gene A (CagA), vacuolating toxin A (VacA) and γ-glutamyl transferase (γ-GT). Utilizing whole-cell proteomics complemented with biochemical signaling studies, we show that H. pylori infection of monocytes induces a unique proteomic signature compared to other pro-inflammatory priming stimuli, namely LPS and the pathobiont A. lwoffii. Contrary to these tolerance-inducing stimuli, H. pylori priming leads to accumulation of NF-кB proteins, including p65/RelA, and thus to the acquisition of a monocyte phenotype more responsive to subsequent LPS challenge. The plasticity of pro-inflammatory responses based on abundance and availability of intracellular signaling molecules may be a heretofore underappreciated form of regulating innate immune memory as well as a novel facet of the pathobiology induced by H. pylori.

Keywords:  H. pylori; NF-кB; inflammation; innate immune memory; innate immunity; monocytes; tolerance; trained immunity

DOI:  https://doi.org/10.3389/fimmu.2023.1290833
Clin Infect Dis. 2023 Dec 05. 77(Supplement_6): S479-S486

The Relationship Between the Microbiome and Antimicrobial Resistance.

Nguyen T Q Nhu, Vincent B Young.

  Antibiotics have benefitted human health since their introduction nearly a century ago. However, the rise of antibiotic resistance may portend the dawn of the "post-antibiotic age." With the narrow pipeline for novel antimicrobials, we need new approaches to deal with the rise of multidrug resistant organisms. In the last 2 decades, the role of the intestinal microbiota in human health has been acknowledged and studied widely. Of the various activities carried out by the gut microbiota, colonization resistance is a key function that helps maintain homeostasis. Therefore, re-establishing a healthy microbiota is a novel strategy for treating drug resistance organisms. Preliminary studies suggest that this is a viable approach. However, the extent of their success still needs to be examined. Herein, we will review work in this area and suggest where future studies can further investigate this method for dealing with the threat of antibiotic resistance.

Keywords:   Clostridioides difficile ; antimicrobial resistance; microbiome; microbiome therapeutics; microbiota; multidrug resistant organsisms

DOI:  https://doi.org/10.1093/cid/ciad641
Microbiol Spectr. 2023 Dec 07. e0222723

Staphylococcus aureus β-hemolysin causes skin inflammation by acting as an agonist of epidermal growth factor receptor.

Yonggen Jia, Zhangchun Guan, Chenghua Liu, Minjun Huang, Jingjing Li, Jiannan Feng, Beifen Shen, Guang Yang.

   IMPORTANCE: Staphylococcus aureus is a Gram-positive opportunistic bacterium that is responsible for the majority of skin infections in humans. Our study provides important molecular insights into the pathogenesis of S. aureus skin infections and identifies a potential therapeutic target for the treatment of these infections. Our findings also indicate that β-hemolysin (Hlb) secreted by colonized S. aureus is a risk factor for epidermal growth factor receptor (EGFR)-related diseases by acting as an agonist of EGFR. The neutralized monoclonal antibody we have developed for the first time will provide a functional inhibitor of Hlb. This study provides important insights to better understand the relationship between the skin colonization of S. aureus and inflammatory skin diseases.

Keywords:  ADAM17; EGFR; Staphylococcus aureus; skin inflammation; sphingomyelinase; β-hemolysin

DOI:  https://doi.org/10.1128/spectrum.02227-23
Microbiome Res Rep. 2023 ;2(3): 17

Microbial interactions and the homeostasis of the gut microbiome: the role of Bifidobacterium.

Alberto J M Martin, Kineret Serebrinsky-Duek, Erick Riquelme, Pedro A Saa, Daniel Garrido.

  The human gut is home to trillions of microorganisms that influence several aspects of our health. This dense microbial community targets almost all dietary polysaccharides and releases multiple metabolites, some of which have physiological effects on the host. A healthy equilibrium between members of the gut microbiota, its microbial diversity, and their metabolites is required for intestinal health, promoting regulatory or anti-inflammatory immune responses. In contrast, the loss of this equilibrium due to antibiotics, low fiber intake, or other conditions results in alterations in gut microbiota composition, a term known as gut dysbiosis. This dysbiosis can be characterized by a reduction in health-associated microorganisms, such as butyrate-producing bacteria, enrichment of a small number of opportunistic pathogens, or a reduction in microbial diversity. Bifidobacterium species are key species in the gut microbiome, serving as primary degraders and contributing to a balanced gut environment in various ways. Colonization resistance is a fundamental property of gut microbiota for the prevention and control of infections. This community competes strongly with foreign microorganisms, such as gastrointestinal pathogens, antibiotic-resistant bacteria, or even probiotics. Resistance to colonization is based on microbial interactions such as metabolic cross-feeding, competition for nutrients, or antimicrobial-based inhibition. These interactions are mediated by metabolites and metabolic pathways, representing the inner workings of the gut microbiota, and play a protective role through colonization resistance. This review presents a rationale for how microbial interactions provide resistance to colonization and gut dysbiosis, highlighting the protective role of Bifidobacterium species.

Keywords:  Bifidobacterium; colonization resistance; gut dysbiosis; microbial interactions

DOI:  https://doi.org/10.20517/mrr.2023.10
Clin Infect Dis. 2023 Dec 05. 77(Supplement_6): e1

Video Introduction to "The Microbiome and Human Health Perspective".

DOI: https://doi.org/10.1093/cid/ciad650
Am J Respir Cell Mol Biol. 2023 Dec 05.

Mutual Regulation of Transcriptomes Between Murine Pneumocytes and Fibroblasts Mediates Alveolar Regeneration in Air-Liquid Interface Cultures.

Yiwen Yao, Sarah Miethe, Kathrin Kattler, Betül Colakoglu, Jörn Walter, Nicole Schneider-Daum, Christian Herr, Holger Garn, Felix Ritzmann, Robert Bals, Christoph Beisswenger.

  Alveolar type 2 (AT2) and club cells are part of the stem cell niche of the lung and their differentiation is required for pulmonary homeostasis and tissue regeneration. A disturbed crosstalk between fibroblasts and epithelial cells contributes to the loss of lung structure in chronic lung diseases. Therefore, it is important to understand how fibroblasts and lung epithelial cells interact during regeneration. Here we analyzed the interaction of fibroblasts and the alveolar epithelium modelled in air-liquid interface cultures. Single-cell transcriptomics showed that co-cultivation with fibroblasts leads to increased expression of type 2 markers in pneumocytes, activation of regulons associated with maintenance of alveolar type 2 cells (e.g. Etv5), and trans-differentiation of club cells towards pneumocytes. This was accompanied by an intensified transepithelial barrier. Vice versa, activation of NFκB pathways and the CEBPB regulon as well as the expression of IL-6 and other differentiation factors (e.g. FGFs) were increased in fibroblasts co-cultured with epithelial cells. Recombinant IL-6 enhanced epithelial barrier formation. Therefore, in our co-culture model, regulatory loops were identified by which lung epithelial cells mediate regeneration and differentiation of the alveolar epithelium in a cooperative manner with the mesenchymal compartment.

Keywords:  alveolar regeneration,; differentiation; fibroblasts; pneumocytes; single-cell

DOI:  https://doi.org/10.1165/rcmb.2023-0078OC
Front Immunol. 2023 ;14 1335238

Editorial: Innate immunity and cross-talk with microflora in the regulation of immune recognition and polarization during immune-related diseases.

Haitao Zhu, Zhongwei Liu.



Keywords:  cross talk; immune polarization; immune recognition; innate immunity; microbiota

DOI:  https://doi.org/10.3389/fimmu.2023.1335238
Cell Mol Biol Lett. 2023 Dec 02. 28(1): 100

Metabolite itaconate in host immunoregulation and defense.

Wenchang Yang, Yaxin Wang, Kaixiong Tao, Ruidong Li.

  Metabolic states greatly influence functioning and differentiation of immune cells. Regulating the metabolism of immune cells can effectively modulate the host immune response. Itaconate, an intermediate metabolite derived from the tricarboxylic acid (TCA) cycle of immune cells, is produced through the decarboxylation of cis-aconitate by cis-aconitate decarboxylase in the mitochondria. The gene encoding cis-aconitate decarboxylase is known as immune response gene 1 (IRG1). In response to external proinflammatory stimulation, macrophages exhibit high IRG1 expression. IRG1/itaconate inhibits succinate dehydrogenase activity, thus influencing the metabolic status of macrophages. Therefore, itaconate serves as a link between macrophage metabolism, oxidative stress, and immune response, ultimately regulating macrophage function. Studies have demonstrated that itaconate acts on various signaling pathways, including Keap1-nuclear factor E2-related factor 2-ARE pathways, ATF3-IκBζ axis, and the stimulator of interferon genes (STING) pathway to exert antiinflammatory and antioxidant effects. Furthermore, several studies have reported that itaconate affects cancer occurrence and development through diverse signaling pathways. In this paper, we provide a comprehensive review of the role IRG1/itaconate and its derivatives in the regulation of macrophage metabolism and functions. By furthering our understanding of itaconate, we intend to shed light on its potential for treating inflammatory diseases and offer new insights in this field.

Keywords:  Defense; Immunometabolism; Itaconate; Itaconate derivative

DOI:  https://doi.org/10.1186/s11658-023-00503-3
Nat Commun. 2023 Dec 02. 14(1): 7977

A computational framework for resolving the microbiome diversity conundrum.

Itay Daybog, Oren Kolodny.

Recent empirical studies offer conflicting findings regarding the relation between host fitness and the composition of its microbiome, a conflict which we term 'the microbial β- diversity conundrum'. The microbiome is crucial for host wellbeing and survival. Surprisingly, different healthy individuals' microbiome compositions, even in the same population, often differ dramatically, contrary to the notion that a vital trait should be highly conserved. Moreover, gnotobiotic individuals exhibit highly deleterious phenotypes, supporting the view that the microbiome is paramount to host fitness. However, the introduction of almost arbitrarily selected microbiota into the system often achieves a significant rescue effect of the deleterious phenotypes. This is true even for microbiota from soil or phylogenetically distant host species, highlighting an apparent paradox. We suggest several solutions to the paradox using a computational framework, simulating the population dynamics of hosts and their microbiomes over multiple generations. The answers invoke factors such as host population size, the specific mode of microbial contribution to host fitness, and typical microbiome richness, offering solutions to the conundrum by highlighting scenarios where even when a host's fitness is determined in full by its microbiome composition, this composition has little effect on the natural selection dynamics of the population.

DOI: https://doi.org/10.1038/s41467-023-42768-4
bioRxiv. 2023 Nov 21. pii: 2023.11.21.568047. [Epub ahead of print]

Host-derived oxidized phospholipids initiate effector-triggered immunity fostering lethality upon microbial encounter.

Marco Di Gioia, Valentina Poli, Piao J Tan, Roberto Spreafico, Anne Chu, Alex G Cuenca, Philip Lsm Gordts, Laura Pandolfi, Federica Meloni, Joseph L Witztum, Janet Chou, James R Springstead, Ivan Zanoni.

Macrophages detect invading microorganisms via pattern recognition receptors that recognize pathogen-associated molecular patterns, or via sensing the activity of virulence factors that initiates effector-triggered immunity (ETI). Tissue damage that follows pathogen encounter leads to the release of host-derived factors that participate to inflammation. How these self -derived molecules are sensed by macrophages and their impact on immunity remain poorly understood. Here we demonstrate that, in mice and humans, host-derived oxidized phospholipids (oxPLs) are formed upon microbial encounter. oxPL blockade restricts inflammation and prevents the death of the host, without affecting pathogen burden. Mechanistically, oxPLs bind and inhibit AKT, a master regulator of immunity and metabolism. AKT inhibition potentiates the methionine cycle, and epigenetically dampens Il10 , a pluripotent anti-inflammatory cytokine. Overall, we found that host-derived inflammatory cues act as " self " virulence factors that initiate ETI and that their activity can be targeted to protect the host against excessive inflammation upon microbial encounter.

DOI: https://doi.org/10.1101/2023.11.21.568047
Clin Infect Dis. 2023 Dec 05. 77(Supplement_6): S447-S454

Advancements in Novel Live Biotherapeutic Products for Clostridioides difficile Infection Prevention.

Thomas Lavoie, Haley J Appaneal, Kerry L LaPlante.

  The profound impact of the human microbiome on health and disease has captivated the interest of clinical and scientific communities. The human body hosts a vast array of microorganisms collectively forming the human microbiome, which significantly influences various physiological processes and profoundly shapes overall well-being. Notably, the gut stands out as an exceptional reservoir, harboring the most significant concentration of microorganisms, akin to an organ in itself. The gut microbiome's composition and function are influenced by genetics, environment, age, underlying conditions, and antibiotic usage, leading to dysbiosis and pathogenesis, such as Clostridioides difficile infection (CDI). Conventional CDI treatment, involving antibiotics like oral vancomycin and fidaxomicin, fails to address dysbiosis and may further disrupt gut microbial communities. Consequently, emerging therapeutic strategies are focused on targeting dysbiosis and restoring gut microbiota to advance CDI therapeutics. Fecal microbiota transplantation (FMT) has demonstrated remarkable efficacy in treating recurrent CDI by transferring processed stool from a healthy donor to a recipient, restoring gut dysbiosis and enhancing bacterial diversity. Moreover, 2 newer Food and Drug Administration (FDA)-approved live biotherapeutic products (LBP), namely, Fecal Microbiota Live-JSLM and Fecal Microbiota Spores Live-BRPK, have shown promise in preventing CDI recurrence. This review explores the role of the gut microbiota in preventing and treating CDI, with an emphasis on gut-based interventions like FMT and fecal microbiota-based products that hold potential for gut restoration and prevention of CDI recurrence. Understanding the microbiome's impact on CDI prevention and treatment offers valuable insights for advancing future CDI therapeutics.

Keywords:  FMT; dysbiosis; live biotherapeutic products; microbiome; probiotics

DOI:  https://doi.org/10.1093/cid/ciad639
Exp Cell Res. 2023 Dec 02. pii: S0014-4827(23)00420-2. [Epub ahead of print] 113869

Dual-specificity phosphatase 5-mediated fatty acid oxidation promotes Mycobacterium bovis BCG -induced inflammatory responses.

Jia Luo, Zengjian Tian, Fuyang Song, Chao Ren, Wenmiao Liu.

  Mycobacterium tuberculosis (Mtb) reprograms FAs metabolism of macrophages during infection and affects inflammatory reaction eventually, however, the mechanism remains poorly understood. Here we show that Mycobacterium bovis (BCG) induces DUSP5 expression through TLR2-MAPKs signaling pathway and promotes fatty acid oxidation (FAO). Silencing DUSP5 by adeno-associated virus vector (AAV) ameliorates lung injury and DUSP5 knockdown reduces the expression of IL-1β, IL-6 and inactivated NF-κB signaling in BCG-infected macrophages. Of note, DUSP5 specific siRNA increases the content of free fatty acids (FFAs) and triglyceride (TG), but represses the expression of FAO associated enzymes such as CPT1A and PPARα, suggesting DUSP5 mediated FAO during BCG infection. Moreover, Inhibiting FAO by pharmacological manner suppresses IL-1β, IL-6, TNF-α expression and relieves lung damage. Taken together, our data indicates DUSP5 mediates FAO reprogramming and promotes inflammatory response to BCG infection.

Keywords:  BCG; Dual specificity phosphatase 5; Fatty acid oxidation; Inflammation; Macrophage

DOI:  https://doi.org/10.1016/j.yexcr.2023.113869
Front Immunol. 2023 ;14 1287518

Making friends: active selection of symbionts and rejection of pathogens by the neonatal immune system.

Colleen J Sedney, Eric T Harvill.

  The neonatal immune system is generally viewed as deficient compared to adults, often attributed to its incomplete development. This view is reinforced by the extraordinary sensitivity and susceptibility of neonates to certain pathogens. Examination of the basis for this susceptibility has characterized neonatal immunity as skewed strongly toward anti-inflammatory responses, which are interpreted as the lack of full development of the strong inflammatory responses observed in adults. Here we examine the alternative explanation that neonatal immune responses are generally complete in healthy newborns but evolved and adapted to very different functions than adult immunity. Adult immunity is primarily aimed at controlling pathogens that invade the holobiont, with substantial competition and protection conferred by resident microbiota. Rather than simply repelling new invaders, the immediate and critical challenge of the neonatal immune system during the sudden transition from near sterility to microbe-rich world is the assimilation of a complex microbiota to generate a stable and healthy holobiont. This alternative view of the role of the neonatal immune system both explains its strong anti-inflammatory bias and provides a different perspective on its other unique aspects. Here we discuss recent work exploring the initial contact of newborns with microbes and their interactions with neonatal immune responses, contrasting these alternative perspectives. Understanding how the need to rapidly acquire a highly complex and rich microbiota of commensals affects interactions between the neonatal immune system and both commensals and pathogens will allow more targeted and effective collaboration with this system to quickly achieve a more disease-resistant holobiont.

Keywords:  immune system development; immunity; microbiota; neonatal; neonatal immune system

DOI:  https://doi.org/10.3389/fimmu.2023.1287518
mBio. 2023 Dec 06. e0277323

A CRISPRi-based genetic resource to study essential Staphylococcus aureus genes.

Patricia Reed, Moritz Sorg, Dominik Alwardt, Lúcia Serra, Helena Veiga, Simon Schäper, Mariana G Pinho.

   IMPORTANCE: Staphylococcus aureus is an important clinical pathogen that causes a high number of antibiotic-resistant infections. The study of S. aureus biology, and particularly of the function of essential proteins, is of particular importance to develop new approaches to combat this pathogen. We have optimized a clustered regularly interspaced short palindromic repeat interference (CRISPRi) system that allows efficient targeting of essential S. aureus genes. Furthermore, we have used that system to construct a library comprising 261 strains, which allows the depletion of essential proteins encoded by 200 genes/operons. This library, which we have named Lisbon CRISPRi Mutant Library, should facilitate the study of S. aureus pathogenesis and biology.

Keywords:  CRISPRi; Staphylococcus aureus; essential genes

DOI:  https://doi.org/10.1128/mbio.02773-23
J Inflamm Res. 2023 ;16 5715-5728

Rapamycin Exacerbates Staphylococcus aureus Pneumonia by Inhibiting mTOR-RPS6 in Macrophages.

Fang-Yi Yu, Kua Zheng, Yin-Fang Wu, Shen-Wei Gao, Qing-Yu Weng, Chen Zhu, Yan-Ping Wu, Miao Li, Zhong-Nan Qin, Jia-Fei Lou, Zhi-Hua Chen, Song-Min Ying, Hua-Hao Shen, Wen Li.

   Purpose: This study aimed to explore the effect of Rapamycin (Rapa) in Staphylococcus aureus (S. aureus) pneumonia and clarify its possible mechanism.
Methods: We investigated the effects of Rapa on S. aureus pneumonia in mouse models and in macrophages cultured in vitro. Two possible mechanisms were investigated: the mTOR-RPS6 pathway phosphorylation and phagocytosis. Furthermore, for the mechanism verification in vivo, mice with specific Mtor knockout in myeloid cells were constructed for pneumonia models.
Results: Rapa exacerbated S. aureus pneumonia in mouse models, promoting chemokines secretion and inflammatory cells infiltration in lung. In vitro, Rapa upregulated the secretion of chemokines and cytokines in macrophages induced by S. aureus. Mechanistically, the mTOR-ribosomal protein S6 (RPS6) pathway in macrophages was phosphorylated in response to S. aureus infection, and the inhibition of RPS6 phosphorylation upregulated the inflammation level. However, Rapa did not increase the phagocytic activity. Accordingly, mice with specific Mtor knockout in myeloid cells experienced more severe S. aureus pneumonia.
Conclusion: Rapa exacerbates S. aureus pneumonia by increasing the inflammatory levels of macrophages. Inhibition of mTOR-RPS6 pathway upregulates the expression of cytokines and chemokines in macrophages, thus increases inflammatory cells infiltration and exacerbates tissue damage.

Keywords:  Staphylococcus aureus; mTOR- ribosomal protein S6 signaling pathway; macrophage; pneumonia; rapamycin

DOI:  https://doi.org/10.2147/JIR.S434483
Am J Physiol Lung Cell Mol Physiol. 2023 Dec 05.

Lack of a transcriptional response of primary bronchial epithelial cells from asthma patients and controls to IL-33.

Akshaya Keerthi Saikumar Jayalatha, Marnix R Jonker, Orestes A Carpaij, Maarten van den Berge, Karen X Affleck, Gerard H Koppelman, Martijn C Nawijn.

  IL-33 and IL-1RL1 are well-replicated asthma genes that act in a single pathway towards type-2 immune responses. IL-33 is expressed by basal epithelial cell, and release of IL-33 upon epithelial damage can activate innate lymphoid cells, T helper-2 cells, basohilic granulocytes and mast cells through a receptor complex containing IL-1RL1. However, it is unkown how bronchial epithelial cells respond to IL-33, and whether this response is increased in disease. We aimed to characterize the IL-33-driven transcriptomic changes in cultured primary bronchial epithelial cells from patients with asthma and healthy controls. Primary bronchial epithelial cells (PBECs) were obtained by bronchial brushing. We cultured PBECs either as epithelial organoids or in air-liquid interface (ALI) conditions, followed by stimulation with recombinant IL-33, RNA-sequencing and differential gene expression analysis. We did not detect any genome-wide significant differentially expressed genes after stimulation of PBECs with IL-33, irrespective of growth in 3D epithelial organoids or after differentiation in ALI cultures. These results were identical between PBECs obtained from patients with asthma or from healthy control subjects. We detected very low levels of IL-1RL1 gene expression in these airway epithelial cell cultures. We conclude that bronchial epithelial cells do not have a transcriptional response to IL-33, independent of their differentiation state. Hence, the airway epithelium acts as a source of IL-33, but does not seem to contribute to the response upon release of the alarmin after epithelial damage.

Keywords:  Airway; Asthma; Epithelial Cells; Genetics; Organoids

DOI:  https://doi.org/10.1152/ajplung.00298.2023
Clin Infect Dis. 2023 Dec 07. pii: ciad751. [Epub ahead of print]

A need to consider divergence in definition of Staphylococcus aureus bacteraemia too.

Paul Robertson.

DOI: https://doi.org/10.1093/cid/ciad751
Sci Transl Med. 2023 Dec 06. 15(725): eadg3451

Tobacco smoke exposure recruits inflammatory airspace monocytes that establish permissive lung niches for Mycobacterium tuberculosis.

Björn Corleis, Constantine N Tzouanas, Marc H Wadsworth, Josalyn L Cho, Alice H Linder, Abigail E Schiff, Björn Zessin, Fabian Stei, Anca Dorhoi, Amy K Dickey, Benjamin D Medoff, Alex K Shalek, Douglas S Kwon.

Tobacco smoking doubles the risk of active tuberculosis (TB) and accounts for up to 20% of all active TB cases globally. How smoking promotes lung microenvironments permissive to Mycobacterium tuberculosis (Mtb) growth remains incompletely understood. We investigated primary bronchoalveolar lavage cells from current and never smokers by performing single-cell RNA sequencing (scRNA-seq), flow cytometry, and functional assays. We observed the enrichment of immature inflammatory monocytes in the lungs of smokers compared with nonsmokers. These monocytes exhibited phenotypes consistent with recent recruitment from blood, ongoing differentiation, increased activation, and states similar to those with chronic obstructive pulmonary disease. Using integrative scRNA-seq and flow cytometry, we identified CD93 as a marker for a subset of these newly recruited smoking-associated lung monocytes and further provided evidence that the recruitment of monocytes into the lung was mediated by CCR2-binding chemokines, including CCL11. We also show that these cells exhibit elevated inflammatory responses upon exposure to Mtb and accelerated intracellular growth of Mtb compared with mature macrophages. This elevated Mtb growth could be inhibited by anti-inflammatory small molecules, providing a connection between smoking-induced pro-inflammatory states and permissiveness to Mtb growth. Our findings suggest a model in which smoking leads to the recruitment of immature inflammatory monocytes from the periphery to the lung, which results in the accumulation of these Mtb-permissive cells in the airway. This work defines how smoking may lead to increased susceptibility to Mtb and identifies host-directed therapies to reduce the burden of TB among those who smoke.

DOI: https://doi.org/10.1126/scitranslmed.adg3451
Adv Sci (Weinh). 2023 Dec 03. e2306457

Dying to Defend: Neutrophil Death Pathways and their Implications in Immunity.

Haiyue Tu, Haoyu Ren, Junjie Jiang, Changshun Shao, Yufang Shi, Peishan Li.

  Neutrophils, accounting for ≈70% of human peripheral leukocytes, are key cells countering bacterial and fungal infections. Neutrophil homeostasis involves a balance between cell maturation, migration, aging, and eventual death. Neutrophils undergo different death pathways depending on their interactions with microbes and external environmental cues. Neutrophil death has significant physiological implications and leads to distinct immunological outcomes. This review discusses the multifarious neutrophil death pathways, including apoptosis, NETosis, pyroptosis, necroptosis, and ferroptosis, and outlines their effects on immune responses and disease progression. Understanding the multifaceted aspects of neutrophil death, the intersections among signaling pathways and ramifications of immunity will help facilitate the development of novel therapeutic methods.

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

DOI:  https://doi.org/10.1002/advs.202306457
Microbiome Res Rep. 2022 ;1(4): 21

Probiotic colonization dynamics after oral consumption of VSL#3® by antibiotic-treated mice.

Casey Theriot, Rajani Thanissery, Sarah O'Flaherty, Rodolphe Barrangou.

  Background: The ability of probiotic strains to provide health benefits to the host partially hinges on the survival of gastrointestinal passage and temporary colonization of the digestive tract. This study aims to investigate the colonization profile of individual probiotic strains comprising the commercial product VSL#3® and determine their impact on the host intestinal microbiota. Methods: Using a cefoperazone-treated mouse model of antibiotic treatment, we investigated the impact of oral gavage with ~108 CFU commercial VSL#3® product on the intestinal microbiota using 16S-based amplicon sequencing over 7 days. Results: Results showed that probiotic strains in the formulation were detected in treated murine fecal samples, with early colonization by Streptococcus thermophilus and Lactiplantibacillus plantarum subsp. plantarum, and late colonization by Lacticaseibacillus paracasei subsp. paracasei, Bifidobacterium breve and Bifidobacterium animalis subsp. lactis. Overall, VSL#3® consumption is associated with increased alpha diversity in the cecal microbial community, which is important in the context of antibiotic consumption. Probiotic supplementation resulted in an expansion of Proteobacteria, Bacteroidetes, and Actinobacteria, especially Bifidobacteriaceae and Lachnospiraceae, which are associated with Clostridioides difficile resistance in the murine gut. Conclusion: This study illustrates the need for determining the ability of probiotics to colonize the host and impact the gut microbiota, and suggests that multiple doses may be warranted for extended transient colonization. In addition, follow-up studies should determine whether VSL#3® can provide resistance against C. difficile colonization and disease in a mouse model.

Keywords:  Probiotics; antibiotics; colonization; microbiota

DOI:  https://doi.org/10.20517/mrr.2022.07