bims-bac4me 2024-07-14 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2024‒07‒14
43 papers selected by
Chun-Chi Chang, University Hospital Zurich

Nasal commensals reduce Staphylococcus aureus proliferation by restricting siderophore availability.
The innate memory response of macrophages to Mycobacterium tuberculosis is shaped by the nature of the antigenic stimuli.
Uremic toxin indoxyl sulfate induces trained immunity via the AhR-dependent arachidonic acid pathway in end-stage renal disease (ESRD).
Clinical and in vitro models identify distinct adaptations enhancing Staphylococcus aureus pathogenesis in human macrophages.
Blocking HXA 3 -mediated neutrophil elastase release during S. pneumoniae lung infection limits pulmonary epithelial barrier disruption and bacteremia.
High-throughput screen identifies non inflammatory small molecule inducers of trained immunity.
Seasonal variation in BCG-induced trained immunity.
Bacillus subtilis-derived peptides disrupt quorum sensing and biofilm assembly in multidrug-resistant Staphylococcus aureus.
Single-cell view into the role of microbiota shaping host immunity in the larynx.
Exploring the Potential of Glycolytic Modulation in Myeloid-Derived Suppressor Cells for Immunotherapy and Disease Management.
Interferon α and β induce differential transcriptional and functional metabolic phenotypes in human macrophages and blunt glycolysis in response to antigenic stimuli.
Glucose transporter 1 is essential for the resolution of methicillin-resistant S. aureus skin and soft tissue infections.
Implications of inflammatory cell death-PANoptosis in health and disease.
A specialized population of monocyte-derived tracheal macrophages promote airway epithelial regeneration through a CCR2-dependent mechanism.
A fungal metabolic regulator underlies infectious synergism during Candida albicans-Staphylococcus aureus intra-abdominal co-infection.
IL-10 inhibition during immunization improves vaccine-induced protection against Staphylococcus aureus infection.
Tolerance to Haemophilus influenzae infection in human epithelial cells: Insights from a primary cell-based model.
Skin deep: Epithelial cell metabolism and chronic skin inflammation.
Are secondary bacterial pneumonia mortalities increased because of insufficient pro-resolving mediators?
Antimicrobial peptides: Opportunities and challenges in overcoming resistance.
Heterogeneity in lung macrophage control of Mycobacterium tuberculosis is modulated by T cells.
Platelet transcription factors license the pro-inflammatory cytokine response of human monocytes.
Microbiome-derived bacterial lipids regulate gene expression of proinflammatory pathway inhibitors in systemic monocytes.
IL-1 Receptor Dynamics in Immune Cells: Orchestrating Immune Precision and Balance.
Altered ontogeny and transcriptomic signatures of tissue-resident pulmonary interstitial macrophages ameliorate allergic airway hyperresponsiveness.
Metabolic reprograming mediated by tumor cell-intrinsic type I IFN signaling is required for CD47-SIRPα blockade efficacy.
Classical monocyte ontogeny dictates their functions and fates as tissue macrophages.
Probiotics for oral health: a critical evaluation of bacterial strains.
Compartmentalized mitochondrial ferroptosis converges with optineurin-mediated mitophagy to impact airway epithelial cell phenotypes and asthma outcomes.
Exopolysaccharide from Lacticaseibacillus paracasei alleviates gastritis in Helicobacter pylori-infected mice by regulating gastric microbiota.
Unconventional posttranslational modification in innate immunity.
Palmitoylation at a conserved cysteine residue facilitates gasdermin D-mediated pyroptosis and cytokine release.
Intrinsic antimicrobial resistance: Molecular biomaterials to combat microbial biofilms and bacterial persisters.
Bacterial single-cell RNA sequencing captures biofilm transcriptional heterogeneity and differential responses to immune pressure.
Airway basal stem cells are necessary for the maintenance of functional intraepithelial airway macrophages.
CircCDC42-encoded CDC42-165aa regulates macrophage pyroptosis in Klebsiella pneumoniae infection through Pyrin inflammasome activation.
Pseudomonas aeruginosa impairs mitochondrial function and metabolism during infection of corneal epithelial cells.
Rescue of pyrimidine-defective Pseudomonas aeruginosa through metabolic complementation.
Mitochondrial Quality Control Processes at the Crossroads of Cell Death and Survival: Mechanisms and Signaling Pathways.
Regulation of Type I Interferon and Autophagy in Immunity against Mycobacterium Tuberculosis: Role of CGAS and STING1.
The pros and confs of IL-18 activation.
HIF-1 mediated metabolic reprogramming in cancer: Mechanisms and therapeutic implications.
Proteomic and metabolomic profiling of methicillin resistant versus methicillin sensitive Staphylococcus aureus using a simultaneous extraction protocol.

ISME J. 2024 Jul 11. pii: wrae123. [Epub ahead of print]

Nasal commensals reduce Staphylococcus aureus proliferation by restricting siderophore availability.

Yanfeng Zhao, Alina Bitzer, Jeffrey John Power, Darya Belikova, Benjamin Orlando Torres Salazar, Lea Antje Adolf, David Leon Gerlach, Bernhard Krismer, Simon Heilbronner.

  The human microbiome is critically associated with human health and disease. One aspect of this is that antibiotic-resistant opportunistic bacterial pathogens such as methicillin-resistant Staphylococcus aureus can reside within the nasal microbiota which increases the risk of infections. Epidemiological studies of the nasal microbiome have revealed positive and negative correlations between non-pathogenic species and S. aureus, but the underlying molecular mechanisms remain poorly understood. The nasal cavity is iron-limited and bacteria are known to produce iron-scavenging siderophores to proliferate in such environments. Siderophores are public goods that can be consumed by all members of a bacterial community. Accordingly, siderophores are known to mediate bacterial competition and collaboration but their role in the nasal microbiome is unknown. Here we show that siderophore acquisition is crucial for S. aureus nasal colonization in vivo. We screened 94 nasal bacterial strains from seven genera for their capacity to produce siderophores as well as to consume the siderophores produced by S. aureus. We found that 80% of the strains engaged in siderophore mediated interactions with S. aureus. Non-pathogenic corynebacterial species were found to be prominent consumers of S. aureus siderophores. In co-culture experiments, consumption of siderophores by competitors reduced S. aureus growth in an iron dependent fashion. Our data show a wide network of siderophore mediated interactions between the species of the human nasal microbiome and provide mechanistic evidence for inter-species competition and collaboration impacting pathogen proliferation. This opens avenues for designing nasal probiotics to displace S. aureus from the nasal cavity of humans.

Keywords:  Staphylococcus aureus; inter-species competition; iron limitation; nasal microbiome; siderophore

DOI:  https://doi.org/10.1093/ismejo/wrae123
Microbiol Spectr. 2024 Jul 09. e0047324

The innate memory response of macrophages to Mycobacterium tuberculosis is shaped by the nature of the antigenic stimuli.

Ranjeet Kumar, Afsal Kolloli, Pooja Singh, Lanbo Shi, Andreas Kupz, Selvakumar Subbian.

  Innate immune cells, such as macrophages, mount an immune response upon exposure to antigens and pathogens. Emerging evidence shows that macrophages exposed to an antigen can generate a "memory-like" response (a.k.a. trained immunity), which confers a non-specific and enhanced response upon subsequent stimulation with a second antigen/microbe. This trained immunity has been implicated in the enhanced response of macrophages against several invading pathogens. However, the association between the nature of the antigen and the corresponding immune correlate of elicited trained immunity is not fully understood. Similarly, the response of macrophages trained and restimulated with homologous stimulants to subsequent infection by pathogenic Mycobacterium tuberculosis (Mtb) remains unexplored. Here, we report the immune and metabolic profiles of trained immunity in human THP-1-derived macrophages after homologous training and restimulation with BCG, LPS, purified protein Derivative (PPD), heat-killed Mtb strains HN878 (hk-HN), and CDC1551 (hk-CDC). Furthermore, the impact of training on the autophagic and antimicrobial responses of macrophages with or without subsequent infection by clinical Mtb isolates HN878 and CDC1551 was evaluated. Results show that repeated stimulation of macrophages with different antigens displays distinct pro-inflammatory, metabolic, antimicrobial, and autophagy induction profiles. These macrophages also induce a differential antimicrobial response upon infection with clinical Mtb HN878 and CDC1551 isolates. A significantly reduced intracellular bacterial load was noted in the stimulated macrophages, which was augmented by the addition of rapamycin, an autophagy inducer. These observations suggest that the nature of the antigen and the mode of stimulation shape the magnitude and breadth of macrophage innate memory response, which impacts subsequent response to Mtb infection.IMPORTANCE: Trained immunity (a.k.a. innate memory response) is a novel concept that has been rapidly emerging as a mechanism underpinning the non-specific immunity of innate immune cells, such as macrophages. However, the association between the nature of the stimuli and the corresponding immune correlate of trained immunity is not fully understood. Similarly, the kinetics of immunological and metabolic characteristics of macrophages upon "training" by the same antigen as primary and secondary stimuli (homologous stimulation) are not fully characterized. Furthermore, the ability of antigens such as purified protein derivative (PPD) and heat-killed-Mtb to induce trained immunity remains unknown. Similarly, the response of macrophages primed and trained by homologous stimulants to subsequent infection by pathogenic Mtb is yet to be reported. In this study, we evaluated the hypothesis that the nature of the stimuli impacts the depth and breadth of trained immunity in macrophages, which differentially affects their response to Mtb infection.

Keywords:  autophagy; immunometabolism; inflammation; trained immunity; tuberculosis

DOI:  https://doi.org/10.1128/spectrum.00473-24
Elife. 2024 Jul 09. pii: RP87316. [Epub ahead of print]12

Uremic toxin indoxyl sulfate induces trained immunity via the AhR-dependent arachidonic acid pathway in end-stage renal disease (ESRD).

Hee Young Kim, Yeon Jun Kang, Dong Hyun Kim, Jiyeon Jang, Su Jeong Lee, Gwanghun Kim, Hee Byung Koh, Ye Eun Ko, Hyun Mu Shin, Hajeong Lee, Tae-Hyun Yoo, Won-Woo Lee.

  Trained immunity is the long-term functional reprogramming of innate immune cells, which results in altered responses toward a secondary challenge. Despite indoxyl sulfate (IS) being a potent stimulus associated with chronic kidney disease (CKD)-related inflammation, its impact on trained immunity has not been explored. Here, we demonstrate that IS induces trained immunity in monocytes via epigenetic and metabolic reprogramming, resulting in augmented cytokine production. Mechanistically, the aryl hydrocarbon receptor (AhR) contributes to IS-trained immunity by enhancing the expression of arachidonic acid (AA) metabolism-related genes such as arachidonate 5-lipoxygenase (ALOX5) and ALOX5 activating protein (ALOX5AP). Inhibition of AhR during IS training suppresses the induction of IS-trained immunity. Monocytes from end-stage renal disease (ESRD) patients have increased ALOX5 expression and after 6 days training, they exhibit enhanced TNF-α and IL-6 production to lipopolysaccharide (LPS). Furthermore, healthy control-derived monocytes trained with uremic sera from ESRD patients exhibit increased production of TNF-α and IL-6. Consistently, IS-trained mice and their splenic myeloid cells had increased production of TNF-α after in vivo and ex vivo LPS stimulation compared to that of control mice. These results provide insight into the role of IS in the induction of trained immunity, which is critical during inflammatory immune responses in CKD patients.

Keywords:  aryl hydrocarbon receptor; chronic kidney disease; epigenetic; human; immunology; indoxyl sulfate; inflammation; metabolic reprogramming; trained immunity

DOI:  https://doi.org/10.7554/eLife.87316
PLoS Pathog. 2024 Jul 11. 20(7): e1012394

Clinical and in vitro models identify distinct adaptations enhancing Staphylococcus aureus pathogenesis in human macrophages.

Dustin R Long, Elizabeth A Holmes, Hsin-Yu Lo, Kelsi Penewit, Jared Almazan, Taylor Hodgson, Nova F Berger, Zoe H Bishop, Janessa D Lewis, Adam Waalkes, Daniel J Wolter, Stephen J Salipante.

Staphylococcus aureus is a facultative intracellular pathogen of human macrophages, which facilitates chronic infection. The genotypes, pathways, and mutations influencing that phenotype remain incompletely explored. Here, we used two distinct strategies to ascertain S. aureus gene mutations affecting pathogenesis in macrophages. First, we analyzed isolates collected serially from chronic cystic fibrosis (CF) respiratory infections. We found that S. aureus strains evolved greater macrophage invasion capacity during chronic human infection. Bacterial genome-wide association studies (GWAS) identified 127 candidate genes for which mutation was significantly associated with macrophage pathogenesis in vivo. In parallel, we passaged laboratory S. aureus strains in vitro to select for increased infection of human THP-1 derived macrophages, which identified 15 candidate genes by whole-genome sequencing. Functional validation of candidate genes using isogenic transposon mutant knockouts and CRISPR interference (CRISPRi) knockdowns confirmed virulence contributions from 37 of 39 tested genes (95%) implicated by in vivo studies and 7 of 10 genes (70%) ascertained from in vitro selection, with one gene in common to the two strategies. Validated genes included 17 known virulence factors (39%) and 27 newly identified by our study (61%), some encoding functions not previously associated with macrophage pathogenesis. Most genes (80%) positively impacted macrophage invasion when disrupted, consistent with the phenotype readily arising from loss-of-function mutations in vivo. This work reveals genes and mechanisms that contribute to S. aureus infection of macrophages, highlights differences in mutations underlying convergent phenotypes arising from in vivo and in vitro systems, and supports the relevance of S. aureus macrophage pathogenesis during chronic respiratory infection in CF. Additional studies will be needed to illuminate the exact mechanisms by which implicated mutations affect their phenotypes.

DOI: https://doi.org/10.1371/journal.ppat.1012394
bioRxiv. 2024 Jun 25. pii: 2024.06.25.600637. [Epub ahead of print]

Blocking HXA 3 -mediated neutrophil elastase release during S. pneumoniae lung infection limits pulmonary epithelial barrier disruption and bacteremia.

Shuying Xu, Shumin Tan, Patricia Romanos, Jennifer L Reedy, Yihan Zhang, Michael K Mansour, Jatin M Vyas, Joan Mecsas, Hongmei Mou, John M Leong.

Streptococcus pneumoniae ( Sp ), a leading cause of community-acquired pneumonia, can spread from the lung into the bloodstream to cause septicemia and meningitis, with a concomitant three-fold increase in mortality. Limitations in vaccine efficacy and a rise in antimicrobial resistance have spurred searches for host-directed therapies that target pathogenic immune processes. Polymorphonuclear leukocytes (PMNs) are essential for infection control but can also promote tissue damage and pathogen spread. The major Sp virulence factor, pneumolysin (PLY), triggers acute inflammation by stimulating the 12-lipoxygenase (12-LOX) eicosanoid synthesis pathway in epithelial cells. This pathway is required for systemic spread in a mouse pneumonia model and produces a number of bioactive lipids, including hepoxilin A3 (HXA 3 ), a hydroxy epoxide PMN chemoattractant that has been hypothesized to facilitate breach of mucosal barriers. To understand how 12-LOX-dependent inflammation promotes dissemination during Sp lung infection and dissemination, we utilized bronchial stem cell-derived air-liquid interface (ALI) cultures that lack this enzyme to show that HXA 3 methyl ester (HXA 3 -ME) is sufficient to promote basolateral-to-apical PMN transmigration, monolayer disruption, and concomitant Sp barrier breach. In contrast, PMN transmigration in response to the non-eicosanoid chemoattractant fMLP did not lead to epithelial disruption or bacterial translocation. Correspondingly, HXA 3 -ME but not fMLP increased release of neutrophil elastase (NE) from Sp -infected PMNs. Pharmacologic blockade of NE secretion or activity diminished epithelial barrier disruption and bacteremia after pulmonary challenge of mice. Thus, HXA 3 promotes barrier disrupting PMN transmigration and NE release, pathological events that can be targeted to curtail systemic disease following pneumococcal pneumonia.Importance: Streptococcus pneumoniae ( Sp ), a leading cause of pneumonia, can spread from the lung into the bloodstream to cause systemic disease. Limitations in vaccine efficacy and a rise in antimicrobial resistance have spurred searches for host-directed therapies that limit pathologic host immune responses to Sp . Excessive polymorphonuclear leukocyte (PMN) infiltration into Sp -infected airways promotes systemic disease. Using stem cell-derived respiratory cultures that reflect bona fide lung epithelium, we identified the eicosanoid hepoxilin A3 as a critical pulmonary PMN chemoattractant that is sufficient to drive PMN-mediated epithelial damage by inducing the release of neutrophil elastase. Inhibition of the release or activity of this protease in mice limited epithelial barrier disruption and bacterial dissemination, suggesting a new host-directed treatment for Sp lung infection.

DOI: https://doi.org/10.1101/2024.06.25.600637
Proc Natl Acad Sci U S A. 2024 Jul 16. 121(29): e2400413121

High-throughput screen identifies non inflammatory small molecule inducers of trained immunity.

Hannah Riley Knight, Ellen Ketter, Trevor Ung, Adam Weiss, Jainu Ajit, Qing Chen, Jingjing Shen, Ka Man Ip, Chun-Yi Chiang, Luis Barreiro, Aaron Esser-Kahn.

  Trained immunity is characterized by epigenetic and metabolic reprogramming in response to specific stimuli. This rewiring can result in increased cytokine and effector responses to pathogenic challenges, providing nonspecific protection against disease. It may also improve immune responses to established immunotherapeutics and vaccines. Despite its promise for next-generation therapeutic design, most current understanding and experimentation is conducted with complex and heterogeneous biologically derived molecules, such as β-glucan or the Bacillus Calmette-Guérin (BCG) vaccine. This limited collection of training compounds also limits the study of the genes most involved in training responses as each molecule has both training and nontraining effects. Small molecules with tunable pharmacokinetics and delivery modalities would both assist in the study of trained immunity and its future applications. To identify small molecule inducers of trained immunity, we screened a library of 2,000 drugs and drug-like compounds. Identification of well-defined compounds can improve our understanding of innate immune memory and broaden the scope of its clinical applications. We identified over two dozen small molecules in several chemical classes that induce a training phenotype in the absence of initial immune activation-a current limitation of reported inducers of training. A surprising result was the identification of glucocorticoids, traditionally considered immunosuppressive, providing an unprecedented link between glucocorticoids and trained innate immunity. We chose seven of these top candidates to characterize and establish training activity in vivo. In this work, we expand the number of compounds known to induce trained immunity, creating alternative avenues for studying and applying innate immune training.

Keywords:  inflammation; innate immune memory; macrophages; metabolism; trained immunity

DOI:  https://doi.org/10.1073/pnas.2400413121
Vaccine. 2024 Jul 08. pii: S0264-410X(24)00751-5. [Epub ahead of print]

Seasonal variation in BCG-induced trained immunity.

Gizem Kilic, Priya A Debisarun, Ahmed Alaswad, Marijke P Baltissen, Lieke A Lamers, L Charlotte J de Bree, Christine S Benn, Peter Aaby, Helga Dijkstra, Heidi Lemmers, Joost H A Martens, Jorge Domínguez-Andrés, Reinout van Crevel, Yang Li, Cheng-Jian Xu, Mihai G Netea.

  The Bacille Calmette-Guerin (BCG) vaccine is a well-established inducer of innate immune memory (also termed trained immunity), causing increased cytokine production upon heterologous secondary stimulation. Innate immune responses are known to be influenced by season, but whether seasons impact induction of trained immunity is not known. To explore the influence of season on innate immune memory induced by the BCG vaccine, we vaccinated healthy volunteers with BCG either during winter or spring. Three months later, we measured the ex vivo cytokine responses against heterologous stimuli, analyzed gene expressions and epigenetic signatures of the immune cells, and compared these with the baseline before vaccination. BCG vaccination during winter induced a stronger increase in the production of pro-inflammatory cytokines by peripheral blood mononuclear cells (PBMCs) upon stimulation with different bacterial and fungal stimuli, compared to BCG vaccination in spring. In contrast, winter BCG vaccination resulted in lower IFNγ release in PBMCs compared to spring BCG vaccination. Furthermore, NK cells of the winter-vaccinated people had a greater pro-inflammatory cytokine and IFNγ production capacity upon heterologous stimulation. BCG had only minor effects on the transcriptome of monocytes 3 months later. In contrast, we identified season-dependent epigenetic changes in monocytes and NK cells induced by vaccination, partly explaining the higher immune cell reactivity in the winter BCG vaccination group. These results suggest that BCG vaccination during winter is more prone to induce a robust trained immunity response by activating and reprogramming the immune cells, especially NK cells. (Dutch clinical trial registry no. NL58219.091.16).

Keywords:  BCG; NK cells; Seasonality; Trained immunity; Vaccines

DOI:  https://doi.org/10.1016/j.vaccine.2024.07.010
mSystems. 2024 Jul 11. e0071224

Bacillus subtilis-derived peptides disrupt quorum sensing and biofilm assembly in multidrug-resistant Staphylococcus aureus.

Kyle R Leistikow, Daniel S May, Won Se Suh, Gabriel Vargas Asensio, Adam J Schaenzer, Cameron R Currie, Krassimira R Hristova.

  Multidrug-resistant Staphylococcus aureus is one of the most clinically important pathogens in the world, with infections leading to high rates of morbidity and mortality in both humans and animals. The ability of S. aureus to form biofilms protects cells from antibiotics and promotes the transfer of antibiotic resistance genes; therefore, new strategies aimed at inhibiting biofilm growth are urgently needed. Probiotic species, including Bacillus subtilis, are gaining interest as potential therapies against S. aureus for their ability to reduce S. aureus colonization and virulence. Here, we search for strains and microbially derived compounds with strong antibiofilm activity against multidrug-resistant S. aureus by isolating and screening Bacillus strains from a variety of agricultural environments. From a total of 1,123 environmental isolates, we identify a single strain B. subtilis 6D1, with a potent ability to inhibit biofilm growth, disassemble mature biofilm, and improve antibiotic sensitivity of S. aureus biofilms through an Agr quorum sensing interference mechanism. Biochemical and molecular networking analysis of an active organic fraction revealed multiple surfactin isoforms, and an uncharacterized peptide was driving this antibiofilm activity. Compared with commercial high-performance liquid chromatography grade surfactin obtained from B. subtilis, we show these B. subtilis 6D1 peptides are significantly better at inhibiting biofilm formation in all four S. aureus Agr backgrounds and preventing S. aureus-induced cytotoxicity when applied to HT29 human intestinal cells. Our study illustrates the potential of exploring microbial strain diversity to discover novel antibiofilm agents that may help combat multidrug-resistant S. aureus infections and enhance antibiotic efficacy in clinical and veterinary settings.IMPORTANCE: The formation of biofilms by multidrug-resistant bacterial pathogens, such as Staphylococcus aureus, increases these microorganisms' virulence and decreases the efficacy of common antibiotic regimens. Probiotics possess a variety of strain-specific strategies to reduce biofilm formation in competing organisms; however, the mechanisms and compounds responsible for these phenomena often go uncharacterized. In this study, we identified a mixture of small probiotic-derived peptides capable of Agr quorum sensing interference as one of the mechanisms driving antibiofilm activity against S. aureus. This collection of peptides also improved antibiotic killing and protected human gut epithelial cells from S. aureus-induced toxicity by stimulating an adaptive cytokine response. We conclude that purposeful strain screening and selection efforts can be used to identify unique probiotic strains that possess specially desired mechanisms of action. This information can be used to further improve our understanding of the ways in which probiotic and probiotic-derived compounds can be applied to prevent bacterial infections or improve bacterial sensitivity to antibiotics in clinical and agricultural settings.

Keywords:  Bacillus subtilis; Staphylococcus aureus; antibiotic resistance; biofilm; peptide; postbiotic; probiotic; quorum sensing interference

DOI:  https://doi.org/10.1128/msystems.00712-24
iScience. 2024 Jun 21. 27(6): 110156

Single-cell view into the role of microbiota shaping host immunity in the larynx.

Ran An, Zijian Ni, Elliott Xie, Federico E Rey, Christina Kendziorski, Susan L Thibeault.

  Microbiota play a critical role in the development and training of host innate and adaptive immunity. We present the cellular landscape of the upper airway, specifically the larynx, by establishing a reference single-cell atlas, while dissecting the role of microbiota in cell development and function at single-cell resolution. We highlight the larynx's cellular heterogeneity with the identification of 16 cell types and 34 distinct subclusters. Our data demonstrate that commensal microbiota have extensive impact on the laryngeal immune system by regulating cell differentiation, increasing the expression of genes associated with host defense, and altering gene regulatory networks. We uncover macrophages, innate lymphoid cells, and multiple secretory epithelial cells, whose cell proportions and expressions vary with microbial exposure. These cell types play pivotal roles in maintaining laryngeal and upper airway health and provide specific guidance into understanding the mechanism of immune system regulation by microbiota in laryngeal health and disease.

Keywords:  Immunity; Microbiome; Transcriptomics

DOI:  https://doi.org/10.1016/j.isci.2024.110156
Immune Netw. 2024 Jun;24(3): e26

Exploring the Potential of Glycolytic Modulation in Myeloid-Derived Suppressor Cells for Immunotherapy and Disease Management.

Jisu Kim, Jee Yeon Choi, Hyeyoung Min, Kwang Woo Hwang.

  Recent advancements in various technologies have shed light on the critical role of metabolism in immune cells, paving the way for innovative disease treatment strategies through immunometabolism modulation. This review emphasizes the glucose metabolism of myeloid-derived suppressor cells (MDSCs), an emerging pivotal immunosuppressive factor especially within the tumor microenvironment. MDSCs, an immature and heterogeneous myeloid cell population, act as a double-edged sword by exacerbating tumors or mitigating inflammatory diseases through their immune-suppressive functions. Numerous recent studies have centered on glycolysis of MDSC, investigating the regulation of altered glycolytic pathways to manage diseases. However, the specific changes in MDSC glycolysis and their exact functions continue to be areas of ongoing discussion yet. In this paper, we review a range of current findings, including the latest research on the alteration of glycolysis in MDSCs, the consequential functional alterations in these cells, and the outcomes of attempts to modulate MDSC functions by regulating glycolysis. Ultimately, we will provide insights into whether these research efforts could be translated into clinical applications.

Keywords:  Glycolysis; Immunomodulation; Metabolic reprogramming; Myeloid-derived suppressor cell

DOI:  https://doi.org/10.4110/in.2024.24.e26
Eur J Immunol. 2024 Jul 11. e2451032

Interferon α and β induce differential transcriptional and functional metabolic phenotypes in human macrophages and blunt glycolysis in response to antigenic stimuli.

Gina Leisching, Anjali Yennemadi, Karl Gogan, Joseph Keane.

  The impact of chronic exposure to type I interferons (IFN)-α2a, 2b, and β on macrophage metabolism, intimately linked to macrophage function, is not well understood. This study assesses the nuanced host responses induced by type I IFN cytokines, offering insights into potential therapeutic approaches in diseases associated with these cytokines. Employing a combination of transcriptional profiling and real-time functional analysis, we delineated metabolic reprogramming in response to chronic IFN exposure. Our results reveal distinct transcriptional metabolic profiles between macrophages chronically exposed to IFN-α and IFN-β. IFN-β significantly diminishes the oxygen consumption rate and glycolytic proton extrusion rate in macrophages. Conversely, IFN-α2b decreased parameters of mitochondrial fitness and induced a shift toward glutamine oxidation. Assessing the ability of macrophages to induce glycolysis in response to antigenic stimuli (LPS and iH37Rv), we found that chronic exposure to all IFN subtypes limited glycolytic induction. This study addresses a critical oversight in the literature, where individual roles of IFN subtypes are frequently amalgamated and lack distinction. These findings not only provide novel insights into the divergent effects of IFN-α2a, α2b, and β on macrophage metabolism but also highlight their potential implications for developing targeted therapeutic strategies.

Keywords:  Glycolysis; LPS; M. tuberculosis; Macrophage; Metabolism; Oxidative phosphorylation; Transcriptomics; Type I interferons

DOI:  https://doi.org/10.1002/eji.202451032
Cell Rep. 2024 Jul 10. pii: S2211-1247(24)00815-5. [Epub ahead of print]43(7): 114486

Glucose transporter 1 is essential for the resolution of methicillin-resistant S. aureus skin and soft tissue infections.

Srijon K Banerjee, Lance R Thurlow, Kartik Kannan, Anthony R Richardson.

  Skin/soft tissue infections (SSTIs) caused by methicillin-resistant Staphylococcus aureus (MRSA) pose a major healthcare burden. Distinct inflammatory and resolution phases comprise the host immune response to SSTIs. Resolution is a myeloid PPARγ-dependent anti-inflammatory phase that is essential for the clearance of MRSA. However, the signals activating PPARγ to induce resolution remain unknown. Here, we demonstrate that myeloid glucose transporter 1 (GLUT-1) is essential for the onset of resolution. MRSA-challenged macrophages are unsuccessful in generating an oxidative burst or immune radicals in the absence of GLUT-1 due to a reduction in the cellular NADPH pool. This translates in vivo as a significant reduction in lipid peroxidation products required for the activation of PPARγ in MRSA-infected mice lacking myeloid GLUT-1. Chemical induction of PPARγ during infection circumvents this GLUT-1 requirement and improves resolution. Thus, GLUT-1-dependent oxidative burst is essential for the activation of PPARγ and subsequent resolution of SSTIs.

Keywords:  CP: Metabolism; CP: Microbiology; aureus; immunometabolism

DOI:  https://doi.org/10.1016/j.celrep.2024.114486
Arch Pharm Res. 2024 Jul 10.

Implications of inflammatory cell death-PANoptosis in health and disease.

Hyun Bae, Yeonseo Jang, Rajendra Karki, Joo-Hui Han.

  Regulated cell death (RCD) pathways, such as pyroptosis, apoptosis, and necroptosis, are essential for maintaining the body's balance, defending against pathogens, and eliminating abnormal cells that could lead to diseases like cancer. Although these pathways operate through distinct mechanisms, recent genetic and pharmacological studies have shown that they can interact and influence each other. The concept of "PANoptosis" has emerged, highlighting the interplay between pyroptosis, apoptosis, and necroptosis, especially during cellular responses to infections. This article provides a concise overview of PANoptosis and its molecular mechanisms, exploring its implications in various diseases. The review focuses on the extensive interactions among different RCD pathways, emphasizing the role of PANoptosis in infections, cytokine storms, inflammatory diseases, and cancer. Understanding PANoptosis is crucial for developing novel treatments for conditions involving infections, sterile inflammations, and cancer.

Keywords:  Apoptosis; Cancer; Cell death; Cytokine release syndrome; Infection; Inflammatory disease; Necroptosis; PANoptosis; Pyroptosis

DOI:  https://doi.org/10.1007/s12272-024-01506-0
iScience. 2024 Jul 19. 27(7): 110169

A specialized population of monocyte-derived tracheal macrophages promote airway epithelial regeneration through a CCR2-dependent mechanism.

Alexandra B Ysasi, Anna E Engler, Pushpinder Singh Bawa, Feiya Wang, Regan D Conrad, Anthony K Yeung, Jason R Rock, Jennifer Beane-Ebel, Sarah A Mazzilli, Ruth A Franklin, Joseph P Mizgerd, George J Murphy.

  Macrophages are critical for maintenance and repair of mucosal tissues. While functionally distinct subtypes of macrophage are known to have important roles in injury response and repair in the lungs, little is known about macrophages in the proximal conducting airways. Single-cell RNA sequencing and flow cytometry demonstrated murine tracheal macrophages are largely monocyte-derived and are phenotypically distinct from lung macrophages at homeostasis. Following sterile airway injury, monocyte-derived macrophages are recruited to the trachea and activate a pro-regenerative phenotype associated with wound healing. Animals lacking the chemokine receptor CCR2 have reduced numbers of circulating monocytes and tracheal macrophages, deficient pro-regenerative macrophage activation and defective epithelial repair. Together, these studies indicate that recruitment and activation of monocyte-derived tracheal macrophages is CCR2-dependent and is required for normal airway epithelial regeneration.

Keywords:  Immunity; Molecular biology; Physiology

DOI:  https://doi.org/10.1016/j.isci.2024.110169
Nat Commun. 2024 Jul 09. 15(1): 5746

A fungal metabolic regulator underlies infectious synergism during Candida albicans-Staphylococcus aureus intra-abdominal co-infection.

Saikat Paul, Olivia A Todd, Kara R Eichelberger, Christine Tkaczyk, Bret R Sellman, Mairi C Noverr, James E Cassat, Paul L Fidel, Brian M Peters.

Candida albicans and Staphylococcus aureus are two commonly associated pathogens that cause nosocomial infections with high morbidity and mortality. Our prior and current work using a murine model of polymicrobial intra-abdominal infection (IAI) demonstrates that synergistic lethality is driven by Candida-induced upregulation of functional S. aureus α-toxin leading to polymicrobial sepsis and organ damage. In order to determine the candidal effector(s) mediating enhanced virulence, an unbiased screen of C. albicans transcription factor mutants was undertaken revealing that zcf13Δ/Δ fails to drive augmented α-toxin or lethal synergism during co-infection. A combination of transcriptional and phenotypic profiling approaches shows that ZCF13 regulates genes involved in pentose metabolism, including RBK1 and HGT7 that contribute to fungal ribose catabolism and uptake, respectively. Subsequent experiments reveal that ribose inhibits the staphylococcal agr quorum sensing system and concomitantly represses toxicity. Unlike wild-type C. albicans, zcf13Δ/Δ did not effectively utilize ribose during co-culture or co-infection leading to exogenous ribose accumulation and agr repression. Forced expression of RBK1 and HGT7 in the zcf13Δ/Δ mutant fully restores pathogenicity during co-infection. Collectively, our results detail the interwoven complexities of cross-kingdom interactions and highlight how intermicrobial metabolism impacts polymicrobial disease pathogenesis with devastating consequences for the host.

DOI: https://doi.org/10.1038/s41467-024-50058-w
JCI Insight. 2024 May 28. pii: e178216. [Epub ahead of print]9(13):

IL-10 inhibition during immunization improves vaccine-induced protection against Staphylococcus aureus infection.

Alanna M Kelly, Karen N McCarthy, Tracey J Claxton, Simon R Carlile, Eoin C O'Brien, Emilio G Vozza, Kingston Hg Mills, Rachel M McLoughlin.

  Staphylococcus aureus is a major human pathogen. An effective anti-S. aureus vaccine remains elusive as the correlates of protection are ill-defined. Targeting specific T cell populations is an important strategy for improving anti-S. aureus vaccine efficacy. Potential bottlenecks that remain are S. aureus-induced immunosuppression and the impact this might have on vaccine-induced immunity. S. aureus induces IL-10, which impedes effector T cell responses, facilitating persistence during both colonization and infection. Thus, it was hypothesized that transient targeting of IL-10 might represent an innovative way to improve vaccine efficacy. In this study, IL-10 expression was elevated in the nares of persistent carriers of S. aureus, and this was associated with reduced systemic S. aureus-specific Th1 responses. This suggests that systemic responses are remodeled because of commensal exposure to S. aureus, which negatively implicates vaccine function. To provide proof of concept that targeting immunosuppressive responses during immunization may be a useful approach to improve vaccine efficacy, we immunized mice with T cell-activating vaccines in combination with IL-10-neutralizing antibodies. Blocking IL-10 during vaccination enhanced effector T cell responses and improved bacterial clearance during subsequent systemic and subcutaneous infection. Taken together, these results reveal a potentially novel strategy for improving anti-S. aureus vaccine efficacy.

Keywords:  Bacterial infections; Bacterial vaccines; Immunology; T cells; Vaccines

DOI:  https://doi.org/10.1172/jci.insight.178216
PLoS Pathog. 2024 Jul;20(7): e1012282

Tolerance to Haemophilus influenzae infection in human epithelial cells: Insights from a primary cell-based model.

Ulrike Kappler, Anna Henningham, Marufa Nasreen, Ayaho Yamamoto, Andrew H Buultjens, Timothy P Stinear, Peter Sly, Emmanuelle Fantino.

Haemophilus influenzae is a human respiratory pathogen and inhabits the human respiratory tract as its only niche. Despite this, the molecular mechanisms that allow H. influenzae to establish persistent infections of human epithelia are not well understood. Here, we have investigated how H. influenzae adapts to the host environment and triggers the host immune response using a human primary cell-based infection model that closely resembles human nasal epithelia (NHNE). Physiological assays combined with dualRNAseq revealed that NHNE from five healthy donors all responded to H. influenzae infection with an initial, 'unproductive' inflammatory response that included a strong hypoxia signature but did not produce pro-inflammatory cytokines. Subsequently, an apparent tolerance to large extracellular and intraepithelial burdens of H. influenzae developed, with NHNE transcriptional profiles resembling the pre-infection state. This occurred in parallel with the development of intraepithelial bacterial populations, and appears to involve interruption of NFκB signalling. This is the first time that large-scale, persistence-promoting immunomodulatory effects of H. influenzae during infection have been observed, and we were able to demonstrate that only infections with live, but not heat-killed H. influenzae led to immunomodulation and reduced expression of NFκB-controlled cytokines such as IL-1β, IL-36γ and TNFα. Interestingly, NHNE were able to re-activate pro-inflammatory responses towards the end of the 14-day infection, resulting in release of IL-8 and TNFα. In addition to providing first molecular insights into mechanisms enabling persistence of H. influenzae in the host, our data further indicate the presence of infection stage-specific gene expression modules, highlighting fundamental similarities between immune responses in NHNE and canonical immune cells, which merit further investigation.

DOI: https://doi.org/10.1371/journal.ppat.1012282
Immunity. 2024 Jul 09. pii: S1074-7613(24)00310-8. [Epub ahead of print]57(7): 1451-1453

Skin deep: Epithelial cell metabolism and chronic skin inflammation.

Eliana R Solis, Julie M Jameson.

Skin inflammation is potentiated by coordinated epithelial and immune cell metabolism. In this issue of Immunity, Subudhi and Konieczny et al. delineate how HIF1α regulates epithelial cell glycolysis during psoriasis. In turn, lactate is a byproduct that augments type 17 γδ T cell responses to sustain inflammatory skin disease.

DOI: https://doi.org/10.1016/j.immuni.2024.06.004
J Infect Chemother. 2024 Jul 06. pii: S1341-321X(24)00184-3. [Epub ahead of print]

Are secondary bacterial pneumonia mortalities increased because of insufficient pro-resolving mediators?

Kevin Roe.

  Respiratory viral infections, including respiratory syncytial virus (RSV), parainfluenza viruses and type A and B influenza viruses, can have severe outcomes. Bacterial infections frequently follow viral infections, and influenza or other viral epidemics periodically have higher mortalities from secondary bacterial pneumonias. Most secondary bacterial infections can cause lung immunosuppression by fatty acid mediators which activate cellular receptors to manipulate neutrophils, macrophages, natural killer cells, dendritic cells and other lung immune cells. Bacterial infections induce synthesis of inflammatory mediators including prostaglandins and leukotrienes, then eventually also special pro-resolving mediators, including lipoxins, resolvins, protectins and maresins, which normally resolve inflammation and immunosuppression. Concurrent viral and secondary bacterial infections are more dangerous, because viral infections can cause inflammation and immunosuppression before the secondary bacterial infections worsen inflammation and immunosuppression. Plausibly, the higher mortalities of secondary bacterial pneumonias are caused by the overwhelming inflammation and immunosuppression, which the special pro-resolving mediators might not resolve.

Keywords:  Bacterial Pneumonia; Immunosuppression; Influenza; Respiratory Pathogens; Special Pro-Resolving Mediators

DOI:  https://doi.org/10.1016/j.jiac.2024.07.006
Microbiol Res. 2024 Jun 26. pii: S0944-5013(24)00223-4. [Epub ahead of print]286 127822

Antimicrobial peptides: Opportunities and challenges in overcoming resistance.

Cezara Bucataru, Corina Ciobanasu.

  Antibiotic resistance represents a global health threat, challenging the efficacy of traditional antimicrobial agents and necessitating innovative approaches to combat infectious diseases. Among these alternatives, antimicrobial peptides have emerged as promising candidates against resistant pathogens. Unlike traditional antibiotics with only one target, these peptides can use different mechanisms to destroy bacteria, with low toxicity to mammalian cells compared to many conventional antibiotics. Antimicrobial peptides (AMPs) have encouraging antibacterial properties and are currently employed in the clinical treatment of pathogen infection, cancer, wound healing, cosmetics, or biotechnology. This review summarizes the mechanisms of antimicrobial peptides against bacteria, discusses the mechanisms of drug resistance, the limitations and challenges of AMPs in peptide drug applications for combating drug-resistant bacterial infections, and strategies to enhance their capabilities.

Keywords:  Antimicrobial peptides; Antimicrobial resistance; Bacterial infection; Mechanism of action; Peptide drug

DOI:  https://doi.org/10.1016/j.micres.2024.127822
Nat Commun. 2024 Jul 08. 15(1): 5710

Heterogeneity in lung macrophage control of Mycobacterium tuberculosis is modulated by T cells.

Rocky Lai, Travis Williams, Tasfia Rakib, Jinhee Lee, Samuel M Behar.

Following Mycobacterium tuberculosis infection, alveolar macrophages are initially infected but ineffectively restrict bacterial replication. The distribution of M. tuberculosis among different cell types in the lung changes with the onset of T cell immunity when the dominant infected cellular niche shifts from alveolar to monocyte-derived macrophages (MDM). We hypothesize that changes in bacterial distribution among different cell types is driven by differences in T cell recognition of infected cells and their subsequent activation of antimicrobial effector mechanisms. We show that CD4 and CD8 T cells efficiently eliminate M. tuberculosis infection in alveolar macrophages, but they have less impact on suppressing infection in MDM, which may be a bacterial niche. Importantly, CD4 T cell responses enhance MDM recruitment to the lung. Thus, the outcome of infection depends on the interaction between the T cell subset and the infected cell; both contribute to the resolution and persistence of the infection.

DOI: https://doi.org/10.1038/s41467-024-48515-7
EMBO Mol Med. 2024 Jul 08.

Platelet transcription factors license the pro-inflammatory cytokine response of human monocytes.

Ibrahim Hawwari, Lukas Rossnagel, Nathalia Rosero, Salie Maasewerd, Matilde B Vasconcelos, Marius Jentzsch, Agnieszka Demczuk, Lino L Teichmann, Lisa Meffert, Damien Bertheloot, Lucas S Ribeiro, Sebastian Kallabis, Felix Meissner, Moshe Arditi, Asli E Atici, Magali Noval Rivas, Bernardo S Franklin.

  In humans, blood Classical CD14+ monocytes contribute to host defense by secreting large amounts of pro-inflammatory cytokines. Their aberrant activity causes hyper-inflammation and life-threatening cytokine storms, while dysfunctional monocytes are associated with 'immunoparalysis', a state of immune hypo responsiveness and reduced pro-inflammatory gene expression, predisposing individuals to opportunistic infections. Understanding how monocyte functions are regulated is critical to prevent these harmful outcomes. We reveal platelets' vital role in the pro-inflammatory cytokine responses of human monocytes. Naturally low platelet counts in patients with immune thrombocytopenia or removal of platelets from healthy monocytes result in monocyte immunoparalysis, marked by impaired cytokine response to immune challenge and weakened host defense transcriptional programs. Remarkably, supplementing monocytes with fresh platelets reverses these conditions. We discovered that platelets serve as reservoirs of key cytokine transcription regulators, such as NF-κB and MAPK p38, and pinpointed the enrichment of platelet NF-κB2 in human monocytes by proteomics. Platelets proportionally restore impaired cytokine production in human monocytes lacking MAPK p38α, NF-κB p65, and NF-κB2. We uncovered a vesicle-mediated platelet-monocyte-propagation of inflammatory transcription regulators, positioning platelets as central checkpoints in monocyte inflammation.

Keywords:  Hyperinflammation; Immune Thrombocytopenia; Immunoparalysis; Inflammasomes; Toll-like Receptors

DOI:  https://doi.org/10.1038/s44321-024-00093-3
Front Immunol. 2024 ;15 1415565

Microbiome-derived bacterial lipids regulate gene expression of proinflammatory pathway inhibitors in systemic monocytes.

Saki Mihori, Frank Nichols, Anthony Provatas, Alyssa Matz, Beiyan Zhou, Christopher N Blesso, Hunter Panier, Lauren Daddi, Yanjiao Zhou, Robert B Clark.

  How the microbiome regulates responses of systemic innate immune cells is unclear. In the present study, our purpose was to document a novel mechanism by which the microbiome mediates crosstalk with the systemic innate immune system. We have identified a family of microbiome Bacteroidota-derived lipopeptides-the serine-glycine (S/G) lipids, which are TLR2 ligands, access the systemic circulation, and regulate proinflammatory responses of splenic monocytes. To document the role of these lipids in regulating systemic immunity, we used oral gavage with an antibiotic to decrease the production of these lipids and administered exogenously purified lipids to increase the systemic level of these lipids. We found that decreasing systemic S/G lipids by decreasing microbiome Bacteroidota significantly enhanced splenic monocyte proinflammatory responses. Replenishing systemic levels of S/G lipids via exogenous administration returned splenic monocyte responses to control levels. Transcriptomic analysis demonstrated that S/G lipids regulate monocyte proinflammatory responses at the level of gene expression of a small set of upstream inhibitors of TLR and NF-κB pathways that include Trem2 and Irf4. Consistent with enhancement in proinflammatory cytokine responses, decreasing S/G lipids lowered gene expression of specific pathway inhibitors. Replenishing S/G lipids normalized gene expression of these inhibitors. In conclusion, our results suggest that microbiome-derived S/G lipids normally establish a level of buffered signaling activation necessary for well-regulated innate immune responses in systemic monocytes. By regulating gene expression of inflammatory pathway inhibitors such as Trem2, S/G lipids merit broader investigation into the potential dysfunction of other innate immune cells, such as microglia, in diseases such as Alzheimer's disease.

Keywords:  TLR; bacterial lipids; gene expression; inhibitors; innate immunity; microbiome; proinflammatory pathways

DOI:  https://doi.org/10.3389/fimmu.2024.1415565
Immune Netw. 2024 Jun;24(3): e21

IL-1 Receptor Dynamics in Immune Cells: Orchestrating Immune Precision and Balance.

Dong Hyun Kim, Won-Woo Lee.

  IL-1, a pleiotropic cytokine with profound effects on various cell types, particularly immune cells, plays a pivotal role in immune responses. The proinflammatory nature of IL-1 necessitates stringent control mechanisms of IL-1-mediated signaling at multiple levels, encompassing transcriptional and translational regulation, precursor processing, as well as the involvement of a receptor accessory protein, a decoy receptor, and a receptor antagonist. In T-cell immunity, IL-1 signaling is crucial during both the priming and effector phases of immune reactions. The fine-tuning of IL-1 signaling hinges upon two distinct receptor types; the functional IL-1 receptor (IL-1R) 1 and the decoy IL-1R2, accompanied by ancillary molecules such as the IL-1R accessory protein (IL-1R3) and IL-1R antagonist. IL-1R1 signaling by IL-1β is critical for the differentiation, expansion, and survival of Th17 cells, essential for defense against extracellular bacteria or fungi, yet implicated in autoimmune disease pathogenesis. Recent investigations emphasize the physiological importance of IL-1R2 expression, particularly in its capacity to modulate IL-1-dependent responses within Tregs. The precise regulation of IL-1R signaling is indispensable for orchestrating appropriate immune responses, as unchecked IL-1 signaling has been implicated in inflammatory disorders, including Th17-mediated autoimmunity. This review provides a thorough exploration of the IL-1R signaling complex and its pivotal roles in immune regulation. Additionally, it highlights recent advancements elucidating the mechanisms governing the expression of IL-1R1 and IL-1R2, underscoring their contributions to fine-tuning IL-1 signaling. Finally, the review briefly touches upon therapeutic strategies targeting IL-1R signaling, with potential clinical applications.

Keywords:  Autoimmunity; Interleukin-1; Receptors, Interleukin-1; Regulatory T cells; T cells

DOI:  https://doi.org/10.4110/in.2024.24.e21
Front Immunol. 2024 ;15 1371764

Altered ontogeny and transcriptomic signatures of tissue-resident pulmonary interstitial macrophages ameliorate allergic airway hyperresponsiveness.

Robert M Tighe, Anastasiya Birukova, Yuryi Malakhau, Yoshihiko Kobayashi, Aaron T Vose, Vidya Chandramohan, Jaime M Cyphert-Daly, R Ian Cumming, Helene Fradin Kirshner, Purushothama R Tata, Jennifer L Ingram, Michael D Gunn, Loretta G Que, Yen-Rei A Yu.

  Introduction: Environmental exposures and experimental manipulations can alter the ontogenetic composition of tissue-resident macrophages. However, the impact of these alterations on subsequent immune responses, particularly in allergic airway diseases, remains poorly understood. This study aims to elucidate the significance of modified macrophage ontogeny resulting from environmental exposures on allergic airway responses to house dust mite (HDM) allergen.Methods: We utilized embryonic lineage labeling to delineate the ontogenetic profile of tissue-resident macrophages at baseline and following the resolution of repeated lipopolysaccharide (LPS)-induced lung injury. We investigated differences in house dust mite (HDM)-induced allergy to assess the influence of macrophage ontogeny on allergic airway responses. Additionally, we employed single-cell RNA sequencing (scRNAseq) and immunofluorescent staining to characterize the pulmonary macrophage composition, associated pathways, and tissue localization.
Results: Our findings demonstrate that the ontogeny of homeostatic alveolar and interstitial macrophages is altered after the resolution from repeated LPS-induced lung injury, leading to the replacement of embryonic-derived by bone marrow-derived macrophages. This shift in macrophage ontogeny is associated with reduced HDM-induced allergic airway responses. Through scRNAseq and immunofluorescent staining, we identified a distinct subset of resident-derived interstitial macrophages expressing genes associated with allergic airway diseases, localized adjacent to terminal bronchi, and diminished by prior LPS exposure.
Discussion: These results suggest a pivotal role for pulmonary macrophage ontogeny in modulating allergic airway responses. Moreover, our findings highlight the implications of prior environmental exposures in shaping future immune responses and influencing the development of allergies. By elucidating the mechanisms underlying these phenomena, this study provides valuable insights into potential therapeutic targets for allergic airway diseases and avenues for further research into immune modulation and allergic disease prevention.

Keywords:  asthma; house dust mite; macrophages; ontogeny; single-cell RNA-seq

DOI:  https://doi.org/10.3389/fimmu.2024.1371764
Nat Commun. 2024 Jul 09. 15(1): 5759

Metabolic reprograming mediated by tumor cell-intrinsic type I IFN signaling is required for CD47-SIRPα blockade efficacy.

Hang Zhou, Wenjun Wang, Hairong Xu, Yong Liang, Jiyu Ding, Mengjie Lv, Boyang Ren, Hua Peng, Yang-Xin Fu, Mingzhao Zhu.

Type I interferons have been well recognized for their roles in various types of immune cells during tumor immunotherapy. However, their direct effects on tumor cells are less understood. Oxidative phosphorylation is typically latent in tumor cells. Whether oxidative phosphorylation can be targeted for immunotherapy remains unclear. Here, we find that tumor cell responsiveness to type I, but not type II interferons, is essential for CD47-SIRPα blockade immunotherapy in female mice. Mechanistically, type I interferons directly reprogram tumor cell metabolism by activating oxidative phosphorylation for ATP production in an ISG15-dependent manner. ATP extracellular release is also promoted by type I interferons due to enhanced secretory autophagy. Functionally, tumor cells with genetic deficiency in oxidative phosphorylation or autophagy are resistant to CD47-SIRPα blockade. ATP released upon CD47-SIRPα blockade is required for antitumor T cell response induction via P2X7 receptor-mediated dendritic cell activation. Based on this mechanism, combinations with inhibitors of ATP-degrading ectoenzymes, CD39 and CD73, are designed and show synergistic antitumor effects with CD47-SIRPα blockade. Together, these data reveal an important role of type I interferons on tumor cell metabolic reprograming for tumor immunotherapy and provide rational strategies harnessing this mechanism for enhanced efficacy of CD47-SIRPα blockade.

DOI: https://doi.org/10.1038/s41467-024-50136-z
Immunity. 2024 Jul 09. pii: S1074-7613(24)00317-0. [Epub ahead of print]57(7): 1710-1712

Classical monocyte ontogeny dictates their functions and fates as tissue macrophages.

Sébastien Trzebanski, Jung-Seok Kim, Niss Larossi, Ayala Raanan, Daliya Kancheva, Jonathan Bastos, Montaser Haddad, Aryeh Solomon, Ehud Sivan, Dan Aizik, Jarmila Sekeresova Kralova, Mor Gross-Vered, Sigalit Boura-Halfon, Tsvee Lapidot, Ronen Alon, Kiavash Movahedi, Steffen Jung.

DOI: https://doi.org/10.1016/j.immuni.2024.06.011
Front Microbiol. 2024 ;15 1430810

Probiotics for oral health: a critical evaluation of bacterial strains.

Rachelle E Beattie.

  Oral health is critical for total body health and well-being; however, little improvement in oral health status has occurred in the U.S. over the past 20 years. Tooth decay and gum disease remain highly prevalent, with more than 90% and 50% of adults suffering from these conditions, respectively. To combat this lack of improvement, alternative approaches to dental care are now being suggested. One such alternative therapy is probiotics for oral care. In the oral cavity, probiotic strains have been shown to reduce levels of oral pathogens, inhibit the formation of dental caries, and reduce the levels of bacteria that cause halitosis. However, as the oral care probiotic market expands, many products contain bacterial species and strains with no documented health benefits leading to confusion and mistrust among consumers and clinicians. This confusion is enhanced by the regulatory status of probiotic products which puts the onus of safety and efficacy on the manufacturer rather than a central regulatory body. The overarching goal of this review is to provide consumers and clinicians with documented evidence supporting (or refuting) the health benefits of oral care probiotics marketed for sale in the United States. This includes defining what constitutes an oral care probiotic product and a strain level analysis of candidate probiotics from the genera Streptococcus, Lactobacillus, Bifidobacterium, and Bacillus. Additionally, prebiotics and postbiotics will be discussed. Finally, a set of considerations for consumers and clinicians is provided to empower probiotic product decision making. Together, this review will improve understanding of oral care probiotics marketed in the US for dental professionals and consumers.

Keywords:  Lactobacillus; Streptococcus; dentistry; oral care; prebiotic; probiotic

DOI:  https://doi.org/10.3389/fmicb.2024.1430810
Nat Commun. 2024 Jul 10. 15(1): 5818

Compartmentalized mitochondrial ferroptosis converges with optineurin-mediated mitophagy to impact airway epithelial cell phenotypes and asthma outcomes.

Kazuhiro Yamada, Claudette St Croix, Donna B Stolz, Yulia Y Tyurina, Vladimir A Tyurin, Laura R Bradley, Alexander A Kapralov, Yanhan Deng, Xiuxia Zhou, Qi Wei, Bo Liao, Nobuhiko Fukuda, Mara Sullivan, John Trudeau, Anuradha Ray, Valerian E Kagan, Jinming Zhao, Sally E Wenzel.

A stable mitochondrial pool is crucial for healthy cell function and survival. Altered redox biology can adversely affect mitochondria through induction of a variety of cell death and survival pathways, yet the understanding of mitochondria and their dysfunction in primary human cells and in specific disease states, including asthma, is modest. Ferroptosis is traditionally considered an iron dependent, hydroperoxy-phospholipid executed process, which induces cytosolic and mitochondrial damage to drive programmed cell death. However, in this report we identify a lipoxygenase orchestrated, compartmentally-targeted ferroptosis-associated peroxidation process which occurs in a subpopulation of dysfunctional mitochondria, without promoting cell death. Rather, this mitochondrial peroxidation process tightly couples with PTEN-induced kinase (PINK)-1(PINK1)-Parkin-Optineurin mediated mitophagy in an effort to preserve the pool of functional mitochondria and prevent cell death. These combined peroxidation processes lead to altered epithelial cell phenotypes and loss of ciliated cells which associate with worsened asthma severity. Ferroptosis-targeted interventions of this process could preserve healthy mitochondria, reverse cell phenotypic changes and improve disease outcomes.

DOI: https://doi.org/10.1038/s41467-024-50222-2
Front Nutr. 2024 ;11 1426358

Exopolysaccharide from Lacticaseibacillus paracasei alleviates gastritis in Helicobacter pylori-infected mice by regulating gastric microbiota.

Jianxing Yu, Ziqi Chen, Qingqing Zhou, Ping Li, Shiying Wu, Tao Zhou, Qing Gu.

  Introduction: Many probiotics have the ability to produce extracellular polysaccharides (EPS). EPS derived from these probiotics has been confirmed to regulate the host intestinal microecological balance and alleviate the symptoms of diseases caused by gastrointestinal microecological imbalance.Results: Lactic acid bacteria (LAB) strain with good exopolysaccharide (EPS) producing ability, namely, Lacticaseibacillus paracasei ZFM54 (L. paracasei ZFM54) was screened. The fermentation conditions of L. paracasei ZFM54 for EPS production were optimized. The EPS54 was characterized by chemical component and monosaccharide composition determination, UV, FT-IR and NMR spectra analysis. Cango red, SEM, AFM and XRD analysis were conducted to characterize the structure of EPS54. The EPS54 effectively reduced the colonization of Helicobacter pylori to AGS cells and recovered the cell morphology. EPS54 could also effectively alleviate the gastritis in the H. pylori-infected mice by down-regulating the mRNA expression levels of pro-inflammatory cytokines IL-6, IL-8, IL-1β and TNF-α and up-regulating the mRNA expression of inflammatory cytokine IL-10 in gastric cells. EPS54 was also found to be able to positively regulate the structure of gastric microbiota.
Conclusion: The EPS 54 from L. paracasei ZFM54 can alleviate gastritis in H. pylori-infected mice by modulating the gastric microbiota.

Keywords:  Exopolysaccharides; Gastric microbiota; Gastritis; Helicobacter pylori; Lacticaseibacillus paracasei

DOI:  https://doi.org/10.3389/fnut.2024.1426358
Cell Mol Life Sci. 2024 Jul 06. 81(1): 290

Unconventional posttranslational modification in innate immunity.

Jiaxi Chen, Dejun Qi, Haorui Hu, Xiaojian Wang, Wenlong Lin.

  Pattern recognition receptors (PRRs) play a crucial role in innate immunity, and a complex network tightly controls their signaling cascades to maintain immune homeostasis. Within the modification network, posttranslational modifications (PTMs) are at the core of signaling cascades. Conventional PTMs, which include phosphorylation and ubiquitination, have been extensively studied. The regulatory role of unconventional PTMs, involving unanchored ubiquitination, ISGylation, SUMOylation, NEDDylation, methylation, acetylation, palmitoylation, glycosylation, and myristylation, in the modulation of innate immune signaling pathways has been increasingly investigated. This comprehensive review delves into the emerging field of unconventional PTMs and highlights their pivotal role in innate immunity.

Keywords:  Innate immunity; Unconventional posttranslational modifications

DOI:  https://doi.org/10.1007/s00018-024-05319-8
Proc Natl Acad Sci U S A. 2024 Jul 16. 121(29): e2400883121

Palmitoylation at a conserved cysteine residue facilitates gasdermin D-mediated pyroptosis and cytokine release.

Zhonghua Liu, Sai Li, Chuanping Wang, Kaylynn J Vidmar, Syrena Bracey, Ling Li, Belinda Willard, Masaru Miyagi, Tong Lan, Bryan C Dickinson, Abdullah Osme, Theresa T Pizarro, Tsan Sam Xiao.

  Gasdermin D (GSDMD)-mediated pyroptotic cell death drives inflammatory cytokine release and downstream immune responses upon inflammasome activation, which play important roles in host defense and inflammatory disorders. Upon activation by proteases, the GSDMD N-terminal domain (NTD) undergoes oligomerization and membrane translocation in the presence of lipids to assemble pores. Despite intensive studies, the molecular events underlying the transition of GSDMD from an autoinhibited soluble form to an oligomeric pore form inserted into the membrane remain incompletely understood. Previous work characterized S-palmitoylation for gasdermins from bacteria, fungi, invertebrates, as well as mammalian gasdermin E (GSDME). Here, we report that a conserved residue Cys191 in human GSDMD was S-palmitoylated, which promoted GSDMD-mediated pyroptosis and cytokine release. Mutation of Cys191 or treatment with palmitoyltransferase inhibitors cyano-myracrylamide (CMA) or 2-bromopalmitate (2BP) suppressed GSDMD palmitoylation, its localization to the membrane and dampened pyroptosis or IL-1β secretion. Furthermore, Gsdmd-dependent inflammatory responses were alleviated by inhibition of palmitoylation in vivo. By contrast, coexpression of GSDMD with palmitoyltransferases enhanced pyroptotic cell death, while introduction of exogenous palmitoylation sequences fully restored pyroptotic activities to the C191A mutant, suggesting that palmitoylation-mediated membrane localization may be distinct from other molecular events such as GSDMD conformational change during pore assembly. Collectively, our study suggests that S-palmitoylation may be a shared regulatory mechanism for GSDMD and other gasdermins, which points to potential avenues for therapeutically targeting S-palmitoylation of gasdermins in inflammatory disorders.

Keywords:  S-palmitoylation; ZDHHC palmitoyltransferase; gasdermin D; inflammasome; pyroptosis

DOI:  https://doi.org/10.1073/pnas.2400883121
Biomaterials. 2024 Jun 28. pii: S0142-9612(24)00224-2. [Epub ahead of print]311 122690

Intrinsic antimicrobial resistance: Molecular biomaterials to combat microbial biofilms and bacterial persisters.

Swagatam Barman, Leman Buzoglu Kurnaz, Ryan Leighton, Md Waliullah Hossain, Alan W Decho, Chuanbing Tang.

  The escalating rise in antimicrobial resistance (AMR) coupled with a declining arsenal of new antibiotics is imposing serious threats to global public health. A pervasive aspect of many acquired AMR infections is that the pathogenic microorganisms exist as biofilms, which are equipped with superior survival strategies. In addition, persistent and recalcitrant infections are seeded with bacterial persister cells at infection sites. Together, conventional antibiotic therapeutics often fail in the complete treatment of infections associated with bacterial persisters and biofilms. Novel therapeutics have been attempted to tackle AMR, biofilms, and persister-associated complex infections. This review focuses on the progress in designing molecular biomaterials and therapeutics to address acquired and intrinsic AMR, and the fundamental microbiology behind biofilms and persisters. Starting with a brief introduction of AMR basics and approaches to tackling acquired AMR, the emphasis is placed on various biomaterial approaches to combating intrinsic AMR, including (1) semi-synthetic antibiotics; (2) macromolecular or polymeric biomaterials mimicking antimicrobial peptides; (3) adjuvant effects in synergy; (4) nano-therapeutics; (5) nitric oxide-releasing antimicrobials; (6) antimicrobial hydrogels; (7) antimicrobial coatings. Particularly, the structure-activity relationship is elucidated in each category of these biomaterials. Finally, illuminating perspectives are provided for the future design of molecular biomaterials to bypass AMR and cure chronic multi-drug resistant (MDR) infections.

Keywords:  Antimicrobial resistance; Biofilm; Biomaterials; Peptides; Persister

DOI:  https://doi.org/10.1016/j.biomaterials.2024.122690
bioRxiv. 2024 Jun 28. pii: 2024.06.28.601229. [Epub ahead of print]

Bacterial single-cell RNA sequencing captures biofilm transcriptional heterogeneity and differential responses to immune pressure.

Lee E Korshoj, Tammy Kielian.

Biofilm formation is an important mechanism of survival and persistence for many bacterial pathogens. These multicellular communities contain subpopulations of cells that display vast metabolic and transcriptional diversity along with high recalcitrance to antibiotics and host immune defenses. Investigating the complex heterogeneity within biofilm has been hindered by the lack of a sensitive and high-throughput method to assess stochastic transcriptional activity and regulation between bacterial subpopulations, which requires single-cell resolution. We have developed an optimized bacterial single-cell RNA sequencing method, BaSSSh-seq, to study Staphylococcus aureus diversity during biofilm growth and transcriptional adaptations following immune cell exposure. We validated the ability of BaSSSh-seq to capture extensive transcriptional heterogeneity during biofilm compared to planktonic growth. Application of new computational tools revealed transcriptional regulatory networks across the heterogeneous biofilm subpopulations and identification of gene sets that were associated with a trajectory from planktonic to biofilm growth. BaSSSh-seq also detected alterations in biofilm metabolism, stress response, and virulence that were tailored to distinct immune cell populations. This work provides an innovative platform to explore biofilm dynamics at single-cell resolution, unlocking the potential for identifying biofilm adaptations to environmental signals and immune pressure.

DOI: https://doi.org/10.1101/2024.06.28.601229
bioRxiv. 2024 Jun 26. pii: 2024.06.25.600501. [Epub ahead of print]

Airway basal stem cells are necessary for the maintenance of functional intraepithelial airway macrophages.

Tristan Kooistra, Borja Saez, Marly Roche, Alejandro Egea-Zorrilla, Dongzhu Li, Dilanjan Anketell, Nhan Nguyen, Jorge Villoria, Jacob Gillis, Eva Petri, Laura Vera, Zuriñe Blasco-Iturri, Neal P Smith, Jehan Alladina, Yanting Zhang, Vladimir Vinarsky, Manjunatha Shivaraju, Susan L Sheng, Meryem Gonzalez-Celeiro, Hongmei Mou, Avinash Waghray, Brian Lin, Azadeh Paksa, Kilangsungla Yanger, Purushotama Rao Tata, Rui Zhao, Benjamin Causton, Javier J Zulueta, Felipe Prosper, Josalyn L Cho, Alexandra-Chloe Villani, Adam Haber, Jayaraj Rajagopal, Benjamin D Medoff, Ana Pardo-Saganta.

Adult stem cells play a crucial role in tissue homeostasis and repair through multiple mechanisms. In addition to being able to replace aged or damaged cells, stem cells provide signals that contribute to the maintenance and function of neighboring cells. In the lung, airway basal stem cells also produce cytokines and chemokines in response to inhaled irritants, allergens, and pathogens, which affect specific immune cell populations and shape the nature of the immune response. However, direct cell-to-cell signaling through contact between airway basal stem cells and immune cells has not been demonstrated. Recently, a unique population of intraepithelial airway macrophages (IAMs) has been identified in the murine trachea. Here, we demonstrate that IAMs require Notch signaling from airway basal stem cells for maintenance of their differentiated state and function. Furthermore, we demonstrate that Notch signaling between airway basal stem cells and IAMs is required for antigen-induced allergic inflammation only in the trachea where the basal stem cells are located whereas allergic responses in distal lung tissues are preserved consistent with a local circuit linking stem cells to proximate immune cells. Finally, we demonstrate that IAM-like cells are present in human conducting airways and that these cells display Notch activation, mirroring their murine counterparts. Since diverse lung stem cells have recently been identified and localized to specific anatomic niches along the proximodistal axis of the respiratory tree, we hypothesize that the direct functional coupling of local stem cell-mediated regeneration and immune responses permits a compartmentalized inflammatory response.

DOI: https://doi.org/10.1101/2024.06.25.600501
Nat Commun. 2024 Jul 08. 15(1): 5730

CircCDC42-encoded CDC42-165aa regulates macrophage pyroptosis in Klebsiella pneumoniae infection through Pyrin inflammasome activation.

Nana Xu, Jiebang Jiang, Fei Jiang, Guokai Dong, Li Meng, Meng Wang, Jing Chen, Cong Li, Yongping Shi, Sisi He, Rongpeng Li.

The circular RNA (circRNA) family is a group of endogenous non-coding RNAs (ncRNAs) that have critical functions in multiple physiological and pathological processes, including inflammation, cancer, and cardiovascular diseases. However, their roles in regulating innate immune responses remain unclear. Here, we define Cell division cycle 42 (CDC42)-165aa, a protein encoded by circRNA circCDC42, which is overexpressed in Klebsiella pneumoniae (KP)-infected alveolar macrophages. High levels of CDC42-165aa induces the hyperactivation of Pyrin inflammasomes and aggravates alveolar macrophage pyroptosis, while the inhibition of CDC42-165aa reduces lung injury in mice after KP infection by inhibiting Pyrin inflammasome-mediated pyroptosis. Overall, these results demonstrate that CDC42-165aa stimulates Pyrin inflammasome by inhibiting CDC42 GTPase activation and provides a potential clinical target for pathogenic bacterial infection in clinical practice.

DOI: https://doi.org/10.1038/s41467-024-50154-x
bioRxiv. 2024 Jun 25. pii: 2024.06.24.600521. [Epub ahead of print]

Pseudomonas aeruginosa impairs mitochondrial function and metabolism during infection of corneal epithelial cells.

Rajalakshmy Ayilam Ramachandran, Joelle T Abdallah, Mahad Rehman, Hamid Baniasadi, Abigail M Blanton, Santiago Vizcaino, Danielle M Robertson.

Pseudomonas aeruginosa (PA) is a gram-negative opportunistic pathogen that can infect the cornea as a result of trauma or contact lens wear. In addition to their known energy producing role, mitochondria are important mediators of immune signaling and host defense. While certain pathogens have developed strategies to evade host defenses by modulating host mitochondrial dynamics and metabolism, the ability of PA to harness host cell mitochondria during corneal infection is unknown. Using a combination of biochemical and imaging techniques, we show that PA infection of corneal epithelial cells induced mitochondrial fission in a DRP1-dependent manner that preceded PINK1/Parkin and FUNDC1-mediated mitophagy. PA also impaired NADH-linked respiration through a reduction in complex 1. This corresponded to a decrease in metabolic pathways related to glycolysis and the TCA cycle. Metabolomics analysis further demonstrated an upregulation of the pentose phosphate pathway, arginine, purine, and pyrimidine metabolism in PA infected cells. These pathways may provide a key source of nucleotides, amino acids, and nitrogen for both the host cell and PA, in addition to antioxidant functions. Following treatment with gentamicin to kill all extracellular bacteria, metabolic flux analysis showed that corneal epithelial cells were able to restore mitochondrial function despite the continued presence of intracellular PA. Taken together, these data demonstrate that mitochondrial dysfunction and metabolic rewiring in host cells is triggered by extracellular PA, but once inside, PA requires healthy mitochondria to ensure host cell survival.

DOI: https://doi.org/10.1101/2024.06.24.600521
Microbiol Spectr. 2024 Jul 11. e0422623

Rescue of pyrimidine-defective Pseudomonas aeruginosa through metabolic complementation.

Hafij Al Mahmud, Randy Garcia, Alexsis Garcia, Jiwasmika Baishya, Catherine A Wakeman.

  Chronic infections harbor multiple pathogens where dynamic interactions between members of the polymicrobial community play a major role in determining the infection outcome. For example, in a nutrient-rich polymicrobial infection, bacteria have the potential to undergo evolutionary changes that impair their ability to synthesize essential metabolites. This adaptation may facilitate metabolic interdependencies between neighboring pathogens and lead to difficult-to-treat chronic infections. Our research group previously demonstrated that Pseudomonas aeruginosa (PA) and Staphylococcus aureus (SA), typically considered classical competitors, can adopt a cooperative lifestyle through bi-directional purine exchange medicated by exogenous DNA (eDNA) release. To further validate our initial findings, in this study, we investigated the potential exchange of pyrimidine between PA and other pathogens, which is another constituent of DNA. In our findings, we observed that a pyrimidine-deficient transposon mutant strain of PA showed improved growth when co-cultured with wild-type PA, SA, Acinetobacter baumannii (AB), and Enterococcus faecalis (EF). Additionally, improved fitness of pyrimidine-deficient PA was further observed in chemical complementation with eDNA and uridine-5'-monophosphate. Interestingly, the rescue of PA growth through eDNA complementation is not as effective as in intact cells, such as SA, AB, EF, and wild-type PA, implying that eDNA is a lesser contributor to this metabolic complementation. Also, the exchange mechanism between pathogens involves more active mechanisms beyond simple eDNA or metabolite release. Our data further highlights the importance of cell-to-cell contact for effective and increased metabolic complementation.IMPORTANCE: This research holds crucial implications for combating chronic infections, where multiple pathogens coexist and interact within the same environment. By uncovering the dynamic exchange of pyrimidines between Pseudomonas aeruginosa (PA) and Staphylococcus aureus (SA), our study reveals a previously unrecognized aspect of interspecies cooperation. The observed enhanced growth of a pyrimidine-deficient PA strain when co-cultured with SA suggests potential avenues for understanding and disrupting bacterial metabolic interdependencies in chronic infection settings. Furthermore, our findings highlight the mechanisms involved in metabolic exchange, emphasizing the importance of cell-to-cell contact. This research explored essential metabolic interactions to address the challenges posed by difficult-to-treat chronic infections.

Keywords:  Pseudomonas aeruginosa; Staphylococcus aureus; polymicrobial interactions; pyrimidine exchange

DOI:  https://doi.org/10.1128/spectrum.04226-23
Int J Mol Sci. 2024 Jul 03. pii: 7305. [Epub ahead of print]25(13):

Mitochondrial Quality Control Processes at the Crossroads of Cell Death and Survival: Mechanisms and Signaling Pathways.

Emanuele Marzetti, Riccardo Calvani, Francesco Landi, Helio José Coelho-Júnior, Anna Picca.

  Biological aging results from an accumulation of damage in the face of reduced resilience. One major driver of aging is cell senescence, a state in which cells remain viable but lose their proliferative capacity, undergo metabolic alterations, and become resistant to apoptosis. This is accompanied by complex cellular changes that enable the development of a senescence-associated secretory phenotype (SASP). Mitochondria, organelles involved in energy provision and activities essential for regulating cell survival and death, are negatively impacted by aging. The age-associated decline in mitochondrial function is also accompanied by the development of chronic low-grade sterile inflammation. The latter shares some features and mediators with the SASP. Indeed, the unloading of damage-associated molecular patterns (DAMPs) at the extracellular level can trigger sterile inflammatory responses and mitochondria can contribute to the generation of DAMPs with pro-inflammatory properties. The extrusion of mitochondrial DNA (mtDNA) via mitochondrial outer membrane permeabilization under an apoptotic stress triggers senescence programs. Additional pathways can contribute to sterile inflammation. For instance, pyroptosis is a caspase-dependent inducer of systemic inflammation, which is also elicited by mtDNA release and contributes to aging. Herein, we overview the molecular mechanisms that may link mitochondrial dyshomeostasis, pyroptosis, sterile inflammation, and senescence and discuss how these contribute to aging and could be exploited as molecular targets for alleviating the cell damage burden and achieving healthy longevity.

Keywords:  DAMPs; SASP; cell death; extracellular vesicles; inflammaging; interleukin; mitochondrial quality control; mitochondrial-derived vesicles; mtDNA; pyroptosis

DOI:  https://doi.org/10.3390/ijms25137305
Adv Biol (Weinh). 2024 Jul 08. e2400174

Regulation of Type I Interferon and Autophagy in Immunity against Mycobacterium Tuberculosis: Role of CGAS and STING1.

Asrar Ahmad Malik, Mohd Shariq, Javaid Ahmad Sheikh, Haleema Fayaz, Gauri Srivastava, Deeksha Thakuri, Yashika Ahuja, Saquib Ali, Anwar Alam, Nasreen Z Ehtesham, Seyed E Hasnain.

  Mycobacterium tuberculosis (M. tb) is a significant intracellular pathogen responsible for numerous infectious disease-related deaths worldwide. It uses ESX-1 T7SS to damage phagosomes and to enter the cytosol of host cells after phagocytosis. During infection, M. tb and host mitochondria release dsDNA, which activates the CGAS-STING1 pathway. This pathway leads to the production of type I interferons and proinflammatory cytokines and activates autophagy, which targets and degrades bacteria within autophagosomes. However, the role of type I IFNs in immunity against M. tb is controversial. While previous research has suggested a protective role, recent findings from cgas-sting1 knockout mouse studies have contradicted this. Additionally, a study using knockout mice and non-human primate models uncovered a new mechanism by which neutrophils recruited to lung infections form neutrophil extracellular traps. Activating plasmacytoid dendritic cells causes them to produce type I IFNs, which interfere with the function of interstitial macrophages and increase the likelihood of tuberculosis. Notably, M. tb uses its virulence proteins to disrupt the CGAS-STING1 signaling pathway leading to enhanced pathogenesis. Investigating the CGAS-STING1 pathway can help develop new ways to fight tuberculosis.

Keywords:  IRF3; M. tb; TBK1; Type‐I IFNs; dsDNA; mtDNA; phosphodiesterase

DOI:  https://doi.org/10.1002/adbi.202400174
Immunity. 2024 Jul 09. pii: S1074-7613(24)00312-1. [Epub ahead of print]57(7): 1445-1448

The pros and confs of IL-18 activation.

Danielle M Clancy, Julie Andries, Savvas N Savvides.

Interleukin-1 (IL-1) family cytokines are key immunological regulators that achieve their signaling prowess after post-translational proteolytic processing. In this issue of Immunity, Dong et al. reveal the structural consequences of this process on proinflammatory IL-18, demonstrating that pro-IL-18 and mature IL-18 are structurally distinct.

DOI: https://doi.org/10.1016/j.immuni.2024.06.006
Life Sci. 2024 Jul 04. pii: S0024-3205(24)00480-6. [Epub ahead of print]352 122890

HIF-1 mediated metabolic reprogramming in cancer: Mechanisms and therapeutic implications.

Nikita Taneja, Akansha Chauhan, Ritu Kulshreshtha, Sandhya Singh.

  Cancer cells undergo metabolic reprogramming to survive in hypoxic conditions and meet the elevated energy demands of the cancer microenvironment. This metabolic alteration is orchestrated by hypoxia-inducible factor 1 (HIF-1), regulating various processes within cancer cells. The intricate metabolic modifications induced by hypoxia underscore the significance of HIF-1-induced metabolic reprogramming in promoting each aspect of cancer progression. The complex interactions between HIF-1 signalling and cellular metabolic processes in response to hypoxia are examined in this study, focusing on the metabolism of carbohydrates, nucleotides, lipids, and amino acids. Comprehending the various regulatory mechanisms controlled by HIF-1 in cellular metabolism sheds light on the intricate biology of cancer growth and offers useful insights for developing targeted treatments.

Keywords:  Cancer metabolism; Cancer therapeutics; Hypoxia inducible factor (HIF-1); Metabolic reprogramming

DOI:  https://doi.org/10.1016/j.lfs.2024.122890
Front Microbiol. 2024 ;15 1402796

Proteomic and metabolomic profiling of methicillin resistant versus methicillin sensitive Staphylococcus aureus using a simultaneous extraction protocol.

Syrine Boucherabine, Alexander Giddey, Rania Nassar, Hamza M Al-Hroub, Lobna Mohamed, Mohammad Harb, Nelson Cruz Soares, Abiola Senok.

  Background: Understanding the biology of methicillin resistant Staphylococcus aureus (MRSA) is crucial to unlocking insights for new targets in our fight against this antimicrobial resistant priority pathogen. Although proteomics and metabolomic profiling offer the potential to elucidating such biological markers, reports of methodological approaches for carrying this out in S. aureus isolates remain limited. We describe the use of a dual-functionality methanol extraction method for the concurrent extraction of protein and metabolites from S. aureus and report on the comparative analysis of the proteomic and metabolomic profiles of MRSA versus methicillin sensitive S. aureus (MSSA).Methods: Bacterial reference strains MRSA ATCC43300 and MSSA ATCC25923 were used. The conventional urea methodology was used for protein extraction and a methanol based method was used for concurrent proteins and metabolites extraction. Proteomic and metabolomic profiling was carried out using TimsTOF mass spectrometry. Data processing was carried out using the MaxQuant version 2.1.4.0.
Results: This study represents the first report on the utilization of the methanol extraction method for concurrent protein and metabolite extraction in Gram positive bacteria. Our findings demonstrate good performance of the method for the dual extraction of proteins and metabolites from S. aureus with demonstration of reproducibility. Comparison of MRSA and MSSA strains revealed 407 proteins with significantly different expression levels. Enrichment analysis of those proteins revealed distinct pathways involved in fatty acid degradation, metabolism and beta-lactam resistance. Penicillin-binding protein PBP2a, the key determinant of MRSA resistance, exhibited distinct expression patterns in MRSA isolates. Metabolomic analysis identified 146 metabolites with only one exclusive to the MRSA. The enriched pathways identified were related to arginine metabolism and biosynthesis.
Conclusion: Our findings demonstrate the effectiveness of the methanol-based dual-extraction method, providing simultaneous insights into the proteomic and metabolomic landscapes of S. aureus strains. These findings demonstrate the utility of proteomic and metabolomic profiling for elucidating the biological basis of antimicrobial resistance.

Keywords:  Staphylococcus aureus; gram positive bacteria; mass spectrometry; metabolomics; proteomics

DOI:  https://doi.org/10.3389/fmicb.2024.1402796