bims-bac4me 2024-09-22 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2024–09–22
29 papers selected by
Chun-Chi Chang, Universitäts Spital Zürich

Trained innate immunity: concept, nomenclature and future perspectives.
Strategy against super-resistant bacteria: Curdlan-induced trained immunity combined with multi-epitope subunit vaccine.
Effect of Staphylococcus aureus colonization and immune defects on the pathogenesis of atopic dermatitis.
Microbiome modulation of antigen presentation in tolerance and inflammation.
Glycan-specific IgM is critical for human immunity to Staphylococcus aureus.
Integrated metabolic-transcriptomic network identifies immunometabolic modulations in human macrophages.
Inducible antibacterial responses in macrophages.
TGFβ primes alveolar-like macrophages to induce type I IFN following TLR2 activation.
To combat antimicrobial resistance, invest in test-to-treat strategies.
Striking a balance: new perspectives on homeostatic dendritic cell maturation.
Topical adjunctive treatment with flagellin augments pulmonary neutrophil responses and reduces bacterial dissemination in multidrug-resistant K. pneumoniae infection.
Functional and Proteomic Dissection of the Contributions of CodY, SigB and the Hibernation Promoting Factor HPF to Interactions of Staphylococcus aureus USA300 with Human Lung Epithelial Cells.
Butyrate and propionate are microbial danger signals that activate the NLRP3 inflammasome in human macrophages upon TLR stimulation.
Regulation of immune responses to food by commensal microbes.
The developing pig respiratory microbiome harbors strains antagonistic to common respiratory pathogens.
Gut microbiota-derived butyrate improved acute leptospirosis in hamster via promoting macrophage ROS mediated by HDAC3 inhibition.
The interplay between mobilome and resistome in Staphylococcus aureus.
Blockade of the CCR3 receptor reduces neutrophil recruitment to the lung during acute inflammation.
Intranasal vaccination with engineered BCG expressing CCL2 induces a stronger immune barrier against Mycobacterium tuberculosis than BCG.
Iron content of commercial mucin contributes to compositional stability of a cystic fibrosis airway synthetic microbiota community.
Role for IRAK-4 and p38 in Neutrophil Signaling in Response to Bacterial Lipoproteins from Staphylococcus aureus.
Activation induces shift in nutrient utilization that differentially impacts cell functions in human neutrophils.
Chitinase 3-like-1 Inhibits Innate Antitumor and Tissue Remodeling Immune Responses by Regulating CD47-SIRPα- and CD24-Siglec10-Mediated Phagocytosis.
Human transferrin and lactoferrin cooperatively support Neisseria meningitidis colonization in the murine nasopharynx.
Stop delaying action on antimicrobial resistance - it is achievable and affordable.
The interplay between probiotics and host autophagy: mechanisms of action and emerging insights.
Antigen presentation for central tolerance induction.
Activation of the NLRP1B inflammasome by caspase-8.
Chicoric acid acts as an ALOX15 inhibitor to prevent ferroptosis in asthma.

J Allergy Clin Immunol. 2024 Sep 13. pii: S0091-6749(24)00943-6. [Epub ahead of print]

Trained innate immunity: concept, nomenclature and future perspectives.

Mihai G Netea, Leo A B Joosten.

  During the past decade, compelling evidence has accumulated demonstrating that innate immune cells can mount adaptive characteristics, leading to long-term changes in their function. This de-facto innate immune memory has been termed trained immunity. Trained immunity is mediated through extensive metabolic rewiring and epigenetic modifications, and has important effects in human diseases. While the upregulation of trained immunity by certain vaccines provides heterologous protection against infections, the inappropriate activation of trained immunity by endogenous stimuli contributes to the pathogenesis of inflammatory and neurodegenerative disorders. Development of vaccines that can induce both classical adaptive immunity and trained immunity may lead to a new generation of vaccines with increased efficacy. Activation of trained immunity can also lead to novel strategies for the treatment of cancer, while modulation of trained immunity can provide new approaches for the treatment of inflammatory diseases.

Keywords:  Trained immunity; epigenetics; inflammation; innate immune memory

DOI:  https://doi.org/10.1016/j.jaci.2024.09.005
Int J Biol Macromol. 2024 Sep 14. pii: S0141-8130(24)06471-7. [Epub ahead of print]280(Pt 1): 135663

Strategy against super-resistant bacteria: Curdlan-induced trained immunity combined with multi-epitope subunit vaccine.

Hai Li, Lingdi Niu, Jiaqing Wang, Qingru Chang, Shuhe Zhang, Jiaqi Wang, Jiankai Zeng, Mingchun Gao, Junwei Ge.

  Methicillin-resistant Staphylococcus aureus (MRSA) is rapidly spreading worldwide, emerging as a leading cause of bacterial infections in healthcare and community settings. This poses serious risks to human health. The shortage of novel antibiotics and the absence of effective vaccines make MRSA particularly challenging to treat. Existing vaccine development strategies often fail to provide early protection against infections, highlighting the urgent need for solutions. Herein, we propose a novel strategy combining trained immunity with a multi-epitope subunit vaccine to combat MRSA infections. We comprehensively evaluated the trained immune phenotypes induced by β-glucan from barley and curdlan. Macrophages trained with curdlan exhibited a more balanced inflammatory response compared to β-glucan from barley, expressing higher levels of IL-1β, IFN-β, TGF-β, and CCL2 upon secondary stimulation. Furthermore, curdlan-induced trained immunity rapidly provided excellent protection against S. aureus infection in mice. RNA-sequencing analysis revealed that curdlan modulates the Wnt signaling pathway in macrophages, resolves inflammation, and promotes tissue repair. When combined with one or two doses of S. aureus multivalent epitope antigen against MRSA infection, curdlan-induced trained immunity enhanced early protection and promoted recovery. Our study demonstrates the feasibility of combining trained immunity with vaccine protection against MRSA, providing a strategy against multi-drug resistant bacteria.

Keywords:  Curdlan; Methicillin-resistant Staphylococcus aureus; Trained immunity

DOI:  https://doi.org/10.1016/j.ijbiomac.2024.135663
Arch Microbiol. 2024 Sep 20. 206(10): 410

Effect of Staphylococcus aureus colonization and immune defects on the pathogenesis of atopic dermatitis.

Evrim Özdemіr, Lütfiye Öksüz.

  Atopic dermatitis (AD) is a common and recurrent skin disease characterized by skin barrier dysfunction, inflammation and chronic pruritus, with wide heterogeneity in terms of age of onset, clinical course and persistence over the lifespan. Although the pathogenesis of the disease are unclear, epidermal barrier dysfunction, immune and microbial dysregulation, and environmental factors are known to be critical etiologies in AD pathology. The skin microbiota represents an ecosystem consisting of numerous microbial species that interact with each other as well as host epithelial cells and immune cells. Although the skin microbiota benefits the host by supporting the basic functions of the skin and preventing the colonization of pathogens, disruption of the microbial balance (dysbiosis) can cause skin diseases such as AD. Although AD is a dermatological disease, recent evidence has shown that changes in microbiota composition in the skin and intestine contribute to the pathogenesis of AD. Environmental factors that contribute to skin barrier dysfunction and microbial dysbiosis in AD include allergens, diet, irritants, air pollution, epigenetics and microbial exposure. Knowing the microbial combination of intestin, as well as the genetic and epigenetic determinants associated with the development of autoantibodies, may help elucidate the pathophysiology of the disease. The skin of patients with AD is characterized by microbial dysbiosis as a result of reduced microbial diversity and overgrowth of the pathogens such as Staphylococcus aureus. Recent studies have revealed the importance of building a strong immune response against microorganisms during childhood and new mechanisms of microbial community dynamics in modulating the skin microbiome. Numerous microorganisms are reported to modulate host response through communication with keratinocytes, specific immune cells and adipocytes to improve skin health and barrier function. This growing insight into bioactive substances in the skin microbiota has led to novel biotherapeutic approaches targeting the skin surface for the treatment of AD. This review will provide an updated overview of the skin microbiota in AD and its complex interaction with immune response mechanisms, as well as explore possible underlying mechanisms in the pathogenesis of AD and provide insights into new therapeutic developments for the treatment of AD. It also focuses on restoring skin microbial homeostasis, aiming to reduce inflammation by repairing the skin barrier.

Keywords:   Staphylococcus aureus ; Atopic dermatitis; Immune defects; Skin microbiota

DOI:  https://doi.org/10.1007/s00203-024-04134-w
Curr Opin Immunol. 2024 Sep 13. pii: S0952-7915(24)00061-X. [Epub ahead of print]91 102471

Microbiome modulation of antigen presentation in tolerance and inflammation.

Yiming He, Gayatree Mohapatra, Sahana Asokan, Samuel Philip Nobs, Eran Elinav.

The microbiome regulates mammalian immune responses from early life to adulthood. Antigen presentation, orchestrating these responses, integrates commensal and pathogenic signals. However, the temporal and spatial specificity of microbiome impacts on antigen presentation and downstream tolerance versus inflammation remain incompletely understood. Herein, we review the influences of antigen presentation of microbiome-related epitopes on immunity; impacts of microbiome-based modulation of antigen presentation on innate and adaptive immune responses; and their ramifications on homeostasis and immune-related disease, ranging from auto-inflammation to tumorigenesis. We highlight mechanisms driving these influences, such as 'molecular mimicry', in which microbiome auto-antigen presentation aberrantly triggers an immune response driving autoimmunity or influences conferred by microbiome-derived metabolites on antigen-presenting cells in inflammatory bowel disease. We discuss unknowns, controversies, and challenges associated with the study of microbiome regulation of antigen presentation while demonstrating how increasing knowledge may contribute to the development of microbiome-based therapeutics modulating immune responses in a variety of clinical contexts.

DOI: https://doi.org/10.1016/j.coi.2024.102471
Cell Rep Med. 2024 Sep 17. pii: S2666-3791(24)00464-6. [Epub ahead of print]5(9): 101734

Glycan-specific IgM is critical for human immunity to Staphylococcus aureus.

Astrid Hendriks, Priscilla F Kerkman, Meri R J Varkila, Jelle L G Haitsma Mulier, Sara Ali, Thijs Ten Doesschate, Thomas W van der Vaart, Carla J C de Haas, Piet C Aerts, Olaf L Cremer, Marc J M Bonten, Victor Nizet, George Y Liu, Jeroen D C Codée, Suzan H M Rooijakkers, Jos A G van Strijp, Nina M van Sorge.

  Staphylococcus aureus is a major human pathogen, yet the immune factors that protect against infection remain elusive. High titers of opsonic IgG antibodies, achieved in preclinical animal immunization studies, have consistently failed to provide protection in humans. Here, we investigate antibody responses to the conserved S. aureus surface glycan wall teichoic acid (WTA) and detect the presence of WTA-specific IgM and IgG antibodies in the plasma of healthy individuals. Functionally, WTA-specific IgM outperforms IgG in opsonophagocytic killing of S. aureus and protects against disseminated S. aureus bacteremia through passive immunization. In a clinical setting, patients with S. aureus bacteremia have significantly lower WTA-specific IgM but similar IgG levels compared to healthy controls. Importantly, low WTA-IgM levels correlate with disease mortality and impaired bacterial opsonization. Our findings may guide risk stratification of hospitalized patients and inform future design of antibody-based therapies and vaccines against serious S. aureus infection.

Keywords:  IgM; Staphylococcus aureus; WTA; antibody; bacteremia; glycan; opsonic; protective immunity; protein A; wall teichoic acid

DOI:  https://doi.org/10.1016/j.xcrm.2024.101734
Cell Rep. 2024 Sep 13. pii: S2211-1247(24)01092-1. [Epub ahead of print]43(9): 114741

Integrated metabolic-transcriptomic network identifies immunometabolic modulations in human macrophages.

Hung-Jen Chen, Daniel C Sévin, Guillermo R Griffith, Johanna Vappiani, Lee M Booty, Cindy P A A van Roomen, Johan Kuiper, Jeroen den Dunnen, Wouter J de Jonge, Rab K Prinjha, Palwinder K Mander, Paola Grandi, Beata S Wyspianska, Menno P J de Winther.

  Macrophages exhibit diverse phenotypes and respond flexibly to environmental cues through metabolic remodeling. In this study, we present a comprehensive multi-omics dataset integrating intra- and extracellular metabolomes with transcriptomic data to investigate the metabolic impact on human macrophage function. Our analysis establishes a metabolite-gene correlation network that characterizes macrophage activation. We find that the concurrent inhibition of tryptophan catabolism by IDO1 and IL4I1 inhibitors suppresses the macrophage pro-inflammatory response, whereas single inhibition leads to pro-inflammatory activation. We find that a subset of anti-inflammatory macrophages activated by Fc receptor signaling promotes glycolysis, challenging the conventional concept of reduced glycolysis preference in anti-inflammatory macrophages. We demonstrate that cholesterol accumulation suppresses macrophage IFN-γ responses. Our integrated network enables the discovery of immunometabolic features, provides insights into macrophage functional metabolic reprogramming, and offers valuable resources for researchers exploring macrophage immunometabolic characteristics and potential therapeutic targets for immune-related disorders.

Keywords:  CP: Immunology; CP: Metabolism; Fc receptor; IDO1; IL4I1; cholesterol; glycolysis; immunometabolism; interferon; macrophage; metabolomics; tryptophan metabolism

DOI:  https://doi.org/10.1016/j.celrep.2024.114741
Nat Rev Immunol. 2024 Sep 18.

Inducible antibacterial responses in macrophages.

Matthew J Sweet, Divya Ramnath, Amit Singhal, Ronan Kapetanovic.

Macrophages destroy bacteria and other microorganisms through phagocytosis-coupled antimicrobial responses, such as the generation of reactive oxygen species and the delivery of hydrolytic enzymes from lysosomes to the phagosome. However, many intracellular bacteria subvert these responses, escaping to other cellular compartments to survive and/or replicate. Such bacterial subversion strategies are countered by a range of additional direct antibacterial responses that are switched on by pattern-recognition receptors and/or host-derived cytokines and other factors, often through inducible gene expression and/or metabolic reprogramming. Our understanding of these inducible antibacterial defence strategies in macrophages is rapidly evolving. In this Review, we provide an overview of the broad repertoire of antibacterial responses that can be engaged in macrophages, including LC3-associated phagocytosis, metabolic reprogramming and antimicrobial metabolites, lipid droplets, guanylate-binding proteins, antimicrobial peptides, metal ion toxicity, nutrient depletion, autophagy and nitric oxide production. We also highlight key inducers, signalling pathways and transcription factors involved in driving these different antibacterial responses. Finally, we discuss how a detailed understanding of the molecular mechanisms of antibacterial responses in macrophages might be exploited for developing host-directed therapies to combat antibiotic-resistant bacterial infections.

DOI: https://doi.org/10.1038/s41577-024-01080-y
bioRxiv. 2024 Sep 08. pii: 2024.09.04.611226. [Epub ahead of print]

TGFβ primes alveolar-like macrophages to induce type I IFN following TLR2 activation.

Sean M Thomas, Laurisa M Ankley, Kayla N Conner, Alexander W Rapp, Abigail P McGee, Francois LeSage, Christopher D Tanner, Taryn E Vielma, Eleanor C Scheeres, Joshua J Obar, Andrew J Olive.

Alveolar macrophages (AMs) are key mediators of lung function and are potential targets for therapies during respiratory infections. TGFβ is an important regulator of AM differentiation and maintenance, but how TGFβ directly modulates the innate immune responses of AMs remains unclear. This shortcoming prevents effective targeting of AMs to improve lung function in health and disease. Here we leveraged an optimized ex vivo AM model system, fetal-liver derived alveolar-like macrophages (FLAMs), to dissect the role of TGFβ in AMs. Using transcriptional analysis, we first globally defined how TGFβ regulates gene expression of resting FLAMs. We found that TGFβ maintains the baseline metabolic state of AMs by driving lipid metabolism through oxidative phosphorylation and restricting inflammation. To better understand inflammatory regulation in FLAMs, we next directly tested how TGFβ alters the response to TLR2 agonists. While both TGFβ (+) and TGFβ (-) FLAMs robustly responded to TLR2 agonists, we found an unexpected activation of type I interferon (IFN) responses in FLAMs and primary AMs in a TGFβ-dependent manner. Surprisingly, mitochondrial antiviral signaling protein and the interferon regulator factors 3 and 7 were required for IFN production by TLR2 agonists. Together, these data suggest that TGFβ modulates AM metabolic networks and innate immune signaling cascades to control inflammatory pathways in AMs.

DOI: https://doi.org/10.1101/2024.09.04.611226
Nature. 2024 Sep;633(8030): 525

To combat antimicrobial resistance, invest in test-to-treat strategies.

Rachel A McKendry, Elliott Rogers, Mervyn Singer, Colin S Brown.



Keywords:  Antibiotics; Health care; Infection; Policy

DOI:  https://doi.org/10.1038/d41586-024-03022-z
Nat Rev Immunol. 2024 Sep 17.

Striking a balance: new perspectives on homeostatic dendritic cell maturation.

Victor Bosteels, Sophie Janssens.

Dendritic cells (DCs) are crucial gatekeepers of the balance between immunity and tolerance. They exist in two functional states, immature or mature, that refer to an information-sensing versus an information-transmitting state, respectively. Historically, the term DC maturation was used to describe the acquisition of immunostimulatory capacity by DCs following their triggering by pathogens or tissue damage signals. As such, immature DCs were proposed to mediate tolerance, whereas mature DCs were associated with the induction of protective T cell immunity. Later studies have challenged this view and unequivocally demonstrated that two distinct modes of DC maturation exist, homeostatic and immunogenic DC maturation, each with a distinct functional outcome. Therefore, the mere expression of maturation markers cannot be used to predict immunogenicity. How DCs become activated in homeostatic conditions and maintain tolerance remains an area of intense debate. Several recent studies have shed light on the signals driving the homeostatic maturation programme, especially in the conventional type 1 DC (cDC1) compartment. Here, we highlight our growing understanding of homeostatic DC maturation and the relevance of this process for immune tolerance.

DOI: https://doi.org/10.1038/s41577-024-01079-5
Front Immunol. 2024 ;15 1450486

Topical adjunctive treatment with flagellin augments pulmonary neutrophil responses and reduces bacterial dissemination in multidrug-resistant K. pneumoniae infection.

Christine C A van Linge, Robert F J Kullberg, Osoul Chouchane, Joris J T H Roelofs, Wil H F Goessens, Cornelis van 't Veer, Jean-Claude Sirard, Alex F de Vos, Tom van der Poll.

   Objective: Antimicrobial resistance is an emerging problem and multi-drug resistant (MDR) Klebsiella pneumoniae (K. pneumoniae) represents an enormous risk of failing therapy in hospital-acquired pneumonia. The current study aimed to determine the immunomodulatory effect of topical flagellin in addition to antibiotic treatment during respiratory infection evoked by hypervirulent antibiotic-susceptible and antibiotic-resistant K. pneumoniae in mice.
Methods: C57BL6 mice were inoculated intranasally with hypervirulent K. pneumoniae (K2:O1) which was either antibiotic-susceptible or multi-drug resistant. Six hours after infection, mice were treated with antibiotics intraperitoneally and flagellin or vehicle intranasally. Mice were sacrificed 24 hours after infection. Samples were analyzed for bacterial loads and for inflammatory and coagulation markers.
Results: Flagellin therapy induced neutrophil influx in the lung during antibiotic-treated pneumonia evoked by either antibiotic-susceptible or -resistant K. pneumoniae. The pulmonary neutrophil response was matched by elevated levels of neutrophil-attracting chemokines, neutrophil degranulation products, and local coagulation activation. The combined therapy of effective antibiotics and flagellin did not impact K. pneumoniae outgrowth in the lung, but decreased bacterial counts in distant organs. Neutrophil depletion abrogated the flagellin-mediated effect on bacterial dissemination and local coagulation responses.
Conclusion: Topical flagellin administration as an adjunctive to antibiotic treatment augments neutrophil responses during pneumonia evoked by MDR-K. pneumoniae, thereby reducing bacterial dissemination to distant organs.

Keywords:  Klebsiella pneumoniae; antimicrobial resistance; flagellin; pneumonia; respiratory infection

DOI:  https://doi.org/10.3389/fimmu.2024.1450486
J Proteome Res. 2024 Sep 20.

Functional and Proteomic Dissection of the Contributions of CodY, SigB and the Hibernation Promoting Factor HPF to Interactions of Staphylococcus aureus USA300 with Human Lung Epithelial Cells.

Xiaofang Li, Larissa M Busch, Sjouke Piersma, Min Wang, Lei Liu, Manuela Gesell Salazar, Kristin Surmann, Ulrike Mäder, Uwe Völker, Girbe Buist, Jan Maarten van Dijl.

  Staphylococcus aureus is a leading cause of severe pneumonia. Our recent proteomic investigations into S. aureus invasion of human lung epithelial cells revealed three key adaptive responses: activation of the SigB and CodY regulons and upregulation of the hibernation-promoting factor SaHPF. Therefore, our present study aimed at a functional and proteomic dissection of the contributions of CodY, SigB and SaHPF to host invasion using transposon mutants of the methicillin-resistant S. aureus USA300. Interestingly, disruption of codY resulted in a "small colony variant" phenotype and redirected the bacteria from (phago)lysosomes into the host cell cytoplasm. Furthermore, we show that CodY, SigB and SaHPF contribute differentially to host cell adhesion, invasion, intracellular survival and cytotoxicity. CodY- or SigB-deficient bacteria experienced faster intracellular clearance than the parental strain, underscoring the importance of these regulators for intracellular persistence. We also show an unprecedented role of SaHPF in host cell adhesion and invasion. Proteomic analysis of the different mutants focuses attention on the CodY-perceived metabolic state of the bacteria and the SigB-perceived environmental cues in bacterial decision-making prior and during infection. Additionally, it underscores the impact of the nutritional status and bacterial stress on the initiation and progression of staphylococcal lung infections.

Keywords:  CodY; SaHPF; SigB; Staphylococcus aureus; human lung epithelial cells

DOI:  https://doi.org/10.1021/acs.jproteome.4c00724
Cell Rep. 2024 Sep 13. pii: S2211-1247(24)01087-8. [Epub ahead of print]43(9): 114736

Butyrate and propionate are microbial danger signals that activate the NLRP3 inflammasome in human macrophages upon TLR stimulation.

Wei Wang, Alesja Dernst, Bianca Martin, Lucia Lorenzi, Maria Cadefau-Fabregat, Kshiti Phulphagar, Antonia Wagener, Christina Budden, Neil Stair, Theresa Wagner, Harald Färber, Andreas Jaensch, Rainer Stahl, Fraser Duthie, Susanne V Schmidt, Rebecca C Coll, Felix Meissner, Sergi Cuartero, Eicke Latz, Matthew S J Mangan.

  Short-chain fatty acids (SCFAs) are immunomodulatory compounds produced by the microbiome through dietary fiber fermentation. Although generally considered beneficial for gut health, patients suffering from inflammatory bowel disease (IBD) display poor tolerance to fiber-rich diets, suggesting that SCFAs may have contrary effects under inflammatory conditions. To investigate this, we examined the effect of SCFAs on human macrophages in the presence of Toll-like receptor (TLR) agonists. In contrast to anti-inflammatory effects under steady-state conditions, we found that butyrate and propionate activated the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome in the presence of TLR agonists. Mechanistically, these SCFAs prevented transcription of FLICE-like inhibitory protein (cFLIP) and interleukin-10 (IL-10) through histone deacetylase (HDAC) inhibition, triggering caspase-8-dependent NLRP3 inflammasome activation. SCFA-driven NLRP3 activation was potassium efflux independent and did not result in cell death but rather triggered hyperactivation and IL-1β release. Our findings demonstrate that butyrate and propionate are bacterially derived danger signals that regulate NLRP3 inflammasome activation through epigenetic modulation of the inflammatory response.

Keywords:  CP: Immunology; HDAC; IL-10; NLRP3; SCFA; acetylation; butyrate; cFLIP; caspase-8; inflammasome; propionate

DOI:  https://doi.org/10.1016/j.celrep.2024.114736
Immunol Rev. 2024 Sep 16.

Regulation of immune responses to food by commensal microbes.

Samuel H Light, Cathryn R Nagler.

  The increasing prevalence of immune-mediated non-communicable chronic diseases, such as food allergies, has prompted a deeper investigation into the role of the gut microbiome in modulating immune responses. Here, we explore the complex interactions between commensal microbes and the host immune system, highlighting the critical role of gut bacteria in maintaining immune homeostasis. We examine how modern lifestyle practices and environmental factors have disrupted co-evolved host-microbe interactions and discuss how changes in microbiome composition impact epithelial barrier function, responses to food allergens, and susceptibility to allergic diseases. Finally, we examine the potential of bioengineered microbiome-based therapies, and live biotherapeutic products, for reestablishing immune homeostasis to prevent or treat food allergies.

Keywords:  butyrate; commensal bacteria; food allergy; live biotherapeutic products; microbiome

DOI:  https://doi.org/10.1111/imr.13396
mSystems. 2024 Sep 17. e0062624

The developing pig respiratory microbiome harbors strains antagonistic to common respiratory pathogens.

Abel A Vlasblom, Birgitta Duim, Shriram Patel, Roosmarijn E C Luiken, Daniel Crespo-Piazuelo, Julia Eckenberger, Chloe E Huseyin, Peadar G Lawlor, Christian Elend, Jaap A Wagenaar, Marcus J Claesson, Aldert L Zomer.

  In the global efforts to combat antimicrobial resistance and reduce antimicrobial use in pig production, there is a continuous search for methods to prevent and/or treat infections. Within this scope, we explored the relationship between the developing piglet nasal microbiome and (zoonotic) bacterial pathogens from birth until 10 weeks of life. The nasal microbiome of 54 pigs was longitudinally studied over 16 timepoints on 9 farms in 3 European countries (Germany, Ireland, and the Netherlands) using amplicon sequencing targeting the V3-V4 16S rRNA region as well as the tuf gene for its staphylococcal discrimination power. The piglets' age, the farm, and the litter affected the nasal microbiome, with piglets' age explaining 19% of the variation in microbial composition between samples. Stabilization of the microbiome occurred around 2 weeks post-weaning. Notably, while opportunistic pathogens were ubiquitously present, they did not cause disease. The piglet nasal microbiome often carried species associated with gut, skin, or vagina, which suggests that contact with the vaginal and fecal microbiomes shapes the piglet nasal microbiome. We identified bacterial co-abundance groups of species that were present in the nasal microbiomes in all three countries over time. Anti-correlation between these species and known bacterial pathogens identified species that might be exploited for pathogen reduction. Further experimental evidence is required to confirm these findings. Overall, this study advances our understanding of the piglet nasal microbiome, the factors influencing it, and its longitudinal development, providing insights into its role in health and disease.
IMPORTANCE: Our study on the nasal microbiota development in piglets across farms in three European countries found that the microbiomes developed similarly in all locations. Additionally, we observed that the colonization of porcine pathogens was either positively or negatively associated with the presence of other bacterial species. These findings enhance our knowledge of co-colonizing species in the nasal cavity and the identified microbial interactions that can be explored for the development of interventions to control pathogens in porcine husbandry.

Keywords:  colonization; microbiome; microbiome development; nasal; porcine; respiratory pathogens

DOI:  https://doi.org/10.1128/msystems.00626-24
mBio. 2024 Sep 17. e0190624

Gut microbiota-derived butyrate improved acute leptospirosis in hamster via promoting macrophage ROS mediated by HDAC3 inhibition.

Xi Chen, Xufeng Xie, Ni Sun, Xin Liu, Jiuxi Liu, Wenlong Zhang, Yongguo Cao.

  Leptospirosis is a re-emerging worldwide zoonotic disease. Infected patients and animals often exhibit intestinal symptoms. Mounting evidence suggests that host immune responses to bacterial infection are closely associated with intestinal homeostasis. Our previous research has shown that the gut microbiota can protect the host from acute leptospirosis, while the specific bacterial metabolic mediators participating in the pathogenesis remain to be identified. Short-chain fatty acids (SCFAs) are metabolites produced mainly by the gut microbiota that play a role in immune regulation. However, whether SCFAs are the key to protecting the host against leptospirosis and the underlying regulatory mechanisms are unknown. In this study, our results showed that the SCFA butyrate is involved in ameliorating leptospirosis. The depletion of SCFAs by antibiotic cocktail treatment reduced survival time after Leptospira infection while supplementation with butyrate but not acetate or propionate significantly amelioration of leptospirosis. In vitro experiments showed that butyrate treatment enhanced the intracellular bactericidal activity mediated by reactive oxygen species (ROS) production. Mechanistically, butyrate functions as a histone deacetylase 3 inhibitor (HDAC3i) to promote ROS production via monocarboxylate transporter (MCT). The protection of butyrate against acute leptospirosis mediated by ROS was also proven in vivo. Collectively, our data provide evidence that the butyrate-MCT-HDAC3i-ROS signaling axis is a potential therapeutic target for acute leptospirosis. Our work not only interprets the microbial metabolite signaling involved in transkingdom interactions between the host and gut microbiota but also provides a possible target for developing a prevention strategy for acute leptospirosis.
IMPORTANCE: Leptospirosis is a worldwide zoonotic disease caused by Leptospira. An estimated 1 million people are infected with leptospirosis each year. Studies have shown that healthy gut microbiota can protect the host against leptospirosis but the mechanism is not clear. This work elucidated the mechanism of gut microbiota protecting the host against acute leptospirosis. Here, we find that butyrate, a metabolite of gut microbiota, can improve the survival rate of hamsters with leptospirosis by promoting the bactericidal activity of macrophages. Mechanistically, butyrate upregulates reactive oxygen species (ROS) levels after macrophage infection with Leptospira by inhibiting HDAC3. This work confirms the therapeutic potential of butyrate in preventing acute leptospirosis and provides evidence for the benefits of the macrophage-HDAC3i-ROS axis.

Keywords:  HDAC3; ROS; butyrate; leptospirosis; macrophage

DOI:  https://doi.org/10.1128/mbio.01906-24
mBio. 2024 Sep 17. e0242824

The interplay between mobilome and resistome in Staphylococcus aureus.

Rachel Contarin, Antoine Drapeau, Pauline François, Jean-Yves Madec, Marisa Haenni, Emilie Dordet-Frisoni.

  Antibiotic resistance genes (ARGs) in Staphylococcus aureus can disseminate vertically through successful clones, but also horizontally through the transfer of genes conveyed by mobile genetic elements (MGEs). Even though underexplored, MGE/ARG associations in S. aureus favor the emergence of multidrug-resistant clones, which are challenging therapeutic success in both human and animal health. This study investigated the interplay between the mobilome and the resistome of more than 10,000 S. aureus genomes from human and animal origin. The analysis revealed a remarkable diversity of MGEs and ARGs, with plasmids and transposons being the main carriers of ARGs. Numerous MGE/ARG associations were identified, suggesting that MGEs play a critical role in the dissemination of resistance. A high degree of similarity was observed in MGE/ARG associations between human and animal isolates, highlighting the potential for unrestricted spread of ARGs between hosts. Our results showed that in parallel to clonal expansion, MGEs and their associated ARGs can spread across different strain types sequence types (STs), favoring the evolution of these clones and their adaptation in selective environments. The high variability of MGE/ARG associations within individual STs and their spread across several STs highlight the crucial role of MGEs in shaping the S. aureus resistome. Overall, this study provides valuable insights into the complex interplay between MGEs and ARGs in S. aureus, emphasizing the need to elucidate the mechanisms governing the epidemic success of MGEs, particularly those implicated in ARG transfer.IMPORTANCEThe research presented in this article highlights the importance of understanding the interactions between mobile genetic elements (MGEs) and antibiotic resistance genes (ARGs) carried by Staphylococcus aureus, a versatile bacterium that can be both a harmless commensal and a dangerous pathogen for humans and animals. S. aureus has a great capacity to acquire and disseminate ARGs, enabling efficient adaption to various environmental or clinical conditions. By analyzing a large data set of S. aureus genomes, we highlighted the substantial role of MGEs, particularly plasmids and transposons, in disseminating ARGs within and between S. aureus populations, bypassing host barriers. Given that multidrug-resistant S. aureus strains are classified as a high-priority pathogen by global health organizations, this knowledge is crucial for understanding the complex dynamics of transmission of antibiotic resistance in this species.

Keywords:  Staphylococcus aureus; antimicrobial resistance; horizontal gene transfer; mobile genetic elements; mobilome; plasmids; resistome; transposons

DOI:  https://doi.org/10.1128/mbio.02428-24
J Leukoc Biol. 2024 Sep 19. pii: qiae203. [Epub ahead of print]

Blockade of the CCR3 receptor reduces neutrophil recruitment to the lung during acute inflammation.

Fatima Lopez-Leal, Tecilli Cabellos-Avelar, Diego A Correa-Becerril, Brenda Juarez-Macias, Rodrigo Cervantes-Diaz, Raul F Reyes-Huerta, Guillermo Juarez-Vega, Daniel Gutierrez-Castaneda, Tannya Karen Castro-Jimenez, Jose Bustos-Arriaga, Jose Luis Maravillas-Montero, Araceli Perez-Lopez.

  Neutrophils represent one of the host's first lines of defense against invading pathogens. However, an aberrant activation can cause damage to the host. In the case of respiratory infections with viral or bacterial pathogens, one of the most common complications is the development of acute respiratory distress syndrome (ARDS), in which neutrophil infiltration into the lung is a hallmark. Neutrophils gain expression of chemokine receptors under inflammatory conditions, and their activation can amplify the neutrophil responses. Earlier studies showed that neutrophils recruited to the lung mucosa during bacterial infection upregulate expression of CCR3 and ex vivo stimulation of CCR3 results in an increased neutrophil activation. Therefore, the modulation of effector functions or migration of neutrophils to target sites through chemokine receptors constitutes an opportunity for pharmacological intervention. We aimed to determine whether the blockade of the CCR3 using the specific antagonist SB-328437 reduces neutrophil recruitment and inflammation in the lung in the LPS-induced lung injury model and influenza infection in mice. We found that neutrophils acquire CCR3 expression in the lung alveolar space. The intraperitoneal administration of SB-328437 reduced neutrophil recruitment to the lung alveolar space and reduced tissue damage in both the LPS-induced lung injury model and influenza infection. Moreover, treatment with SB-328437 reduced the percentage of neutrophils producing TNFα and neutrophil activation in the alveolar space. Together, these data suggest that CCR3 blockade might be a pharmacological strategy to prevent the aberrant neutrophil activation that results detrimental for the host but preserves sufficient effector response to control the pathogen.

Keywords:  CCR3; Influenza A; Neutrophils; inflammation

DOI:  https://doi.org/10.1093/jleuko/qiae203
Mol Ther. 2024 Sep 17. pii: S1525-0016(24)00609-9. [Epub ahead of print]

Intranasal vaccination with engineered BCG expressing CCL2 induces a stronger immune barrier against Mycobacterium tuberculosis than BCG.

Shaohua Guo, Jiangshan Ouyang, Zhiming Hu, Ting Cao, Chunxu Huang, Jun Mou, Xinxia Gu, Jie Liu.

  Intradermal Mycobacterium bovis Bacillus Calmette-Guérin (BCG) vaccination is currently the only licensed strategy for preventing tuberculosis (TB). It provides limited protection against pulmonary TB. To enhance the efficacy of BCG, we developed a recombinant BCG expressing exogenous monocyte chemoattractant CC chemokine ligand 2 (CCL2), termed rBCG-CCL2. Co-culturing macrophages with rBCG-CCL2 enhances their abilities in migration, phagocytosis, and effector molecules expression. In the mouse model, intranasal vaccination with rBCG-CCL2 induced greater immune cells infiltration and a more extensive innate immune responses in lung compared to vaccination with parental BCG, as determined by multiparameter flow cytometry, transcriptomic analysis, and pathological assessments. Moreover, rBCG-CCL2 induced a high frequency of activated macrophages and antigen-specific Th1 and Th17 T cells in lungs. The enhanced immune microenvironment responded more effectively to intravenous challenge with Mycobacterium tuberculosis (Mtb) H37Ra, leading to significant reductions in H37Ra burden and pathological damage to the lungs and spleen. Intranasal rBCG-CCL2 vaccinated mice rapidly initiated pro-inflammatory Th1 cytokine release and reduced pathological damage to the lungs and spleen during the early stage of H37Ra challenge. The finding that co-expression of CCL2 synergistically enhances the immune barrier induced by BCG provides a model for defining immune correlates and mechanisms of vaccine-elicited protection against TB.

Keywords:  BCG; CCL2; Intranasal vaccination; Macrophage; T cell immunity

DOI:  https://doi.org/10.1016/j.ymthe.2024.09.021
bioRxiv. 2024 Sep 06. pii: 2024.09.06.611695. [Epub ahead of print]

Iron content of commercial mucin contributes to compositional stability of a cystic fibrosis airway synthetic microbiota community.

Emily Giedraitis, Rachel L Neve, Vanessa V Phelan.

In vitro culture models of mucosal environments are used to elucidate the mechanistic roles of the microbiota in human health. These models often include commercial mucins to reflect the in-situ role of mucins as an attachment site and nutrient source for the microbiota. Two types of mucins are commercially available: porcine gastric mucin (PGM) and bovine submaxillary mucin (BSM). These commercial mucins have been shown to contain iron, an essential element required by the microbiota as a co-factor for a variety of metabolic functions. In these mucin preparations, the concentration of available iron can exceed physiological concentrations present in the native environment. This unexpected source of iron influences experimental outcomes, including shaping the interactions between co-existing microbes in synthetic microbial communities used to elucidate the multispecies interactions within native microbiota. In this work, we leveraged the well-characterized iron-dependent production of secondary metabolites by the opportunistic pathogen Pseudomonas aeruginosa to aid in the development of a simple, low-cost, reproducible workflow to remove iron from commercial mucins. Using the mucosal environment of the cystic fibrosis (CF) airway as a model system, we show that P. aeruginosa is canonically responsive to iron concentration in the chemically defined synthetic CF medium complemented with semi-purified PGM, and community composition of a clinically relevant, synthetic CF airway microbial community is modulated, in part, by iron concentration in PGM.

DOI: https://doi.org/10.1101/2024.09.06.611695
Inflammation. 2024 Sep 20.

Role for IRAK-4 and p38 in Neutrophil Signaling in Response to Bacterial Lipoproteins from Staphylococcus aureus.

Jessica S Hook, Austin D Matheis, Jeffrey S Kavanaugh, Alexander R Horswill, Jessica G Moreland.

  Neutrophils, polymorphonuclear leukocytes (PMN), express numerous pattern recognition receptors, including TLRs, capable of recognizing a wide variety of pathogens. Receptor engagement initiates a cascade of PMN responses with some occurring in seconds, and some requiring de novo protein synthesis over the course of many hours. Although numerous species of bacteria and bacterial products have been shown to activate PMN via TLRs, the signaling intermediates required for distinct PMN responses have not been well-defined in human PMN. Given the potential for host tissue damage by overexuberant PMN activity, a better understanding of neutrophil signaling is needed to generate effective therapies. We hypothesized that PMN responses to a lipoprotein-containing cell membrane preparation from methicillin-resistant S. aureus (MRSA-CMP) would activate signaling via IRAK4 and p38, with potentially distinct pathways for early vs. late responses. Using human PMN we investigated MRSA-CMP-elicited reactive oxygen species (ROS) production, elastase activity, NET formation, IL-8 production, and the role of IRAK4 and p38 activation. MRSA-CMP elicited ROS in a concentration and lipoprotein-dependent manner. MRSA-CMP elicited phosphorylation of p38 MAPK, and MRSA-CMP-elicited ROS production was partially dependent on p38 MAPK and IRAK4 activation. Inhibition of IRAK4 resulted in a reduction of p38 phosphorylation. MRSA-CMP-elicited elastase activity and NET formation was partially dependent on p38 MAPK activation, but independent of IRAK4 activation. MRSA-CMP-elicited IL-8 production required both p38 and IRAK4 activation. In conclusion, MRSA-CMP elicits PMN responses via distinct signaling pathways. There is potential to target components of the neutrophil inflammatory response without compromising critical pathogen-specific immune functions.

Keywords:  Inflammation; Neutrophil; Sepsis; Signaling

DOI:  https://doi.org/10.1007/s10753-024-02147-7
Proc Natl Acad Sci U S A. 2024 Sep 24. 121(39): e2321212121

Activation induces shift in nutrient utilization that differentially impacts cell functions in human neutrophils.

Emily C Britt, Xin Qing, James A Votava, Jorgo Lika, Andrew S Wagner, Simone Shen, Nicholas L Arp, Hamidullah Khan, Stefan M Schieke, Christopher D Fletcher, Anna Huttenlocher, Jing Fan.

  Neutrophils utilize a variety of metabolic sources to support their crucial functions as the first responders in innate immunity. Here, through in vivo and ex vivo isotopic tracing, we examined the contributions of different nutrients to neutrophil metabolism under specific conditions. Human peripheral blood neutrophils, in contrast to a neutrophil-like cell line, rely on glycogen storage as a major metabolic source under resting state but rapidly switch to primarily using extracellular glucose upon activation with various stimuli. This shift is driven by a substantial increase in glucose uptake, enabled by rapidly increased GLUT1 on cell membrane, that dominates the simultaneous increase in gross glycogen cycling capacity. Shifts in nutrient utilization impact neutrophil functions in a function-specific manner: oxidative burst depends on glucose utilization, whereas NETosis and phagocytosis can be flexibly supported by either glucose or glycogen, and neutrophil migration and fungal control are enhanced by the shift from glycogen utilization to glucose utilization. This work provides a quantitative and dynamic understanding of fundamental features in neutrophil metabolism and elucidates how metabolic remodeling shapes neutrophil functions, which has broad health relevance.

Keywords:  immunometabolism; neutrophil; nutrient dependence; nutrient preference switch

DOI:  https://doi.org/10.1073/pnas.2321212121
J Immunol. 2024 Sep 18. pii: ji2400035. [Epub ahead of print]

Chitinase 3-like-1 Inhibits Innate Antitumor and Tissue Remodeling Immune Responses by Regulating CD47-SIRPα- and CD24-Siglec10-Mediated Phagocytosis.

Bing Ma, Suchitra Kamle, Takayuki Sadanaga, Chang-Min Lee, Joyce H Lee, Daniel C Yee, Zhou Zhu, Edwin K Silverman, Dawn L DeMeo, Augustine M K Choi, Chun Geun Lee, Jack A Elias.

Innate immune responses such as phagocytosis are critically linked to the generation of adaptive immune responses against the neoantigens in cancer and the efferocytosis that is essential for homeostasis in diseases characterized by lung injury, inflammation, and remodeling as in chronic obstructive pulmonary disease (COPD). Chitinase 3-like-1 (CHI3L1) is induced in many cancers where it inhibits adaptive immune responses by stimulating immune checkpoint molecules (ICPs) and portends a poor prognosis. CHI3L1 is also induced in COPD where it regulates epithelial cell death. In this study, we demonstrate that pulmonary melanoma metastasis inhibits macrophage phagocytosis by stimulating the CD47-SIRPα and CD24-Siglec10 phagocytosis checkpoint pathways while inhibiting macrophage "eat me" signals from calreticulin and HMGB1. We also demonstrate that these effects on macrophage phagocytosis are associated with CHI3L1 stimulation of the SHP-1 and SHP-2 phosphatases and inhibition of the accumulation and phosphorylation of cytoskeleton-regulating nonmuscle myosin IIa. This inhibition of innate immune responses such as phagocytosis provides a mechanistic explanation for the ability of CHI3L1 to stimulate ICPs and inhibit adaptive immune responses in cancer and diseases such as COPD. The ability of CHI3L1 to simultaneously inhibit innate immune responses, stimulate ICPs, inhibit T cell costimulation, and regulate a number of other oncogenic and inflammation pathways suggests that CHI3L1-targeted therapeutics are promising interventions in cancer, COPD, and other disorders.

DOI: https://doi.org/10.4049/jimmunol.2400035
bioRxiv. 2024 Sep 07. pii: 2024.09.07.611816. [Epub ahead of print]

Human transferrin and lactoferrin cooperatively support Neisseria meningitidis colonization in the murine nasopharynx.

Isaac S Lee, Jamie E Fegan, Elissa G Currie, Anna Bojagora, Nelly Y Leung, Derrick Rancourt, Muhamed-Kheir Taha, Anthony B Schryvers, Scott D Gray-Owen.

Neisseria meningitidis is a human-restricted bacteria that is a normal nasopharyngeal resident, yet it can also disseminate, causing invasive meningococcal disease. Meningococci are highly adapted to life in humans, with human-specific virulence factors contributing to bacterial adhesion, nutrient acquisition and immune evasion. While these factors have been explored in isolation, their relative contribution during infection has not been considered due to their absence in small animal models and their expression by different human cell types not readily combined in either in vitro or ex vivo systems. Herein, we show that transgenic expression of the iron-binding glycoproteins human transferrin and lactoferrin can each facilitate N. meningitidis replication in mouse serum but that transferrin was required to support infection-induced sepsis. While these host proteins are insufficient to allow nasopharyngeal colonization alone, mice co-expressing these and human CEACAM1 support robust colonization. In this case, meningococcal colonization elicits an acute elevation in both transferrin and lactoferrin levels within the upper respiratory mucosa, with transferrin levels remaining elevated while lactoferrin returns to basal levels after establishment of infection. Competitive infection of triple transgenic animals with transferrin- and lactoferrin- binding protein mutants selects for bacteria expressing the transferrin receptor, implicating the critical contribution of transferrin-based iron acquisition to support colonization. These transgenic animals have thus allowed us to disentangle the relative contribution of three virulence factors during colonization and invasive disease, and provides a novel in vivo model that can support extended meningococcal colonization, opening a new avenue to explore the meningococcal lifestyle within its primary niche.

DOI: https://doi.org/10.1101/2024.09.07.611816
Nature. 2024 Sep;633(8030): 495

Stop delaying action on antimicrobial resistance - it is achievable and affordable.

Ramanan Laxminarayan.



Keywords:  Antibiotics; Developing world; Health care

DOI:  https://doi.org/10.1038/d41586-024-02993-3
Autophagy. 2024 Sep 18.

The interplay between probiotics and host autophagy: mechanisms of action and emerging insights.

Zahra Sadeghloo, Ali Nabavi-Rad, Mohammad Reza Zali, Daniel J Klionsky, Abbas Yadegar.

  Autophagy, a lysosome-dependent protein degradation mechanism, is a highly conserved catabolic process seen in all eukaryotes. This cell protection system, which is present in all tissues and functions at a basic level, can be up- or downregulated in response to various stresses. A disruption in the natural route of the autophagy process is frequently followed by an interruption in the inherent operation of the body's cells and organs. Probiotics are live bacteria that protect the host through various mechanisms. One of the processes through which probiotics exert their beneficial effects on various cells and tissues is autophagy. Autophagy can assist in maintaining host homeostasis by stimulating the immune system and affecting numerous physiological and pathological responses. In this review, we particularly focus on autophagy impairments occurring in several human illnesses and investigate how probiotics affect the autophagy process under various circumstances.

Keywords:  Autophagy; cancer; infectious diseases; neurological diseases; obesity; postbiotics; prebiotics; probiotics

DOI:  https://doi.org/10.1080/15548627.2024.2403277
Nat Rev Immunol. 2024 Sep 18.

Antigen presentation for central tolerance induction.

Ludger Klein, Elisabetta Petrozziello.

The extent of central T cell tolerance is determined by the diversity of self-antigens that developing thymocytes 'see' on thymic antigen-presenting cells (APCs). Here, focusing on insights from the past decade, we review the functional adaptations of medullary thymic epithelial cells, thymic dendritic cells and thymic B cells for the purpose of tolerance induction. Their distinct cellular characteristics range from unconventional phenomena, such as promiscuous gene expression or mimicry of peripheral cell types, to strategic positioning in distinct microenvironments and divergent propensities to preferentially access endogenous or exogenous antigen pools. We also discuss how 'tonic' inflammatory signals in the thymic microenvironment may extend the intrathymically visible 'self' to include autoantigens that are otherwise associated with highly immunogenic peripheral environments.

DOI: https://doi.org/10.1038/s41577-024-01076-8
Commun Biol. 2024 Sep 17. 7(1): 1164

Activation of the NLRP1B inflammasome by caspase-8.

Justin J Meade, Sarah Stuart, Jana Neiman-Zenevich, Christian Krustev, Stephen E Girardin, Jeremy Mogridge.

Cleavage of the innate immune receptor NLRP1B by various microbial proteases causes the proteasomal degradation of its N-terminal fragment and the subsequent release of a C-terminal fragment that forms an inflammasome. We reported previously that metabolic stress caused by intracellular bacteria triggers NLRP1B activation, but the mechanism by which this occurs was not elucidated. Here we demonstrate that TLR4 signaling in metabolically stressed macrophages promotes the formation of a TRIF/RIPK1/caspase-8 complex. Caspase-8 activity, induced downstream of this TLR4 pathway or through a distinct TNF receptor pathway, causes cleavage and activation of NLRP1B, which facilitates the maturation of both pro-caspase-1 and pro-caspase-8. Thus, our findings indicate that caspase-8 and NLRP1B generate a positive feedback loop that amplifies cell death processes and promotes a pro-inflammatory response through caspase-1. The ability of NLRP1B to detect caspase-8 activity suggests that this pattern recognition receptor may play a role in the defense against a variety of pathogens that induce apoptosis.

DOI: https://doi.org/10.1038/s42003-024-06882-3
Int Immunopharmacol. 2024 Sep 18. pii: S1567-5769(24)01709-0. [Epub ahead of print]142(Pt B): 113187

Chicoric acid acts as an ALOX15 inhibitor to prevent ferroptosis in asthma.

Lianxiang Luo, Kangdi Liu, Liyan Deng, Wenjian Wang, Tianli Lai, Xiaoling Li.

   BACKGROUND: Chicoric acid (CA) is a crucial immunologically active compound found in chicory and echinacea, possessing a range of biological activities. Ferroptosis, a type of iron-dependent cell death induced by lipid peroxidation, plays a key role in the development and advancement of asthma. Targeting ferroptosis could be a potential therapeutic strategy for treating asthma.
PURPOSE: The purpose of this study was to explore the screening of ALOX15, a pivotal target of ferroptosis in asthma, and potential therapeutic agents, as well as to investigate the promising potential of CA as an ALOX15 inhibitor for modulating ferroptosis in asthma.
METHODS: Through high-throughput data processing of bronchial epithelial RNA from asthma patients using bioinformatics and machine learning, the key target of ferroptosis in asthma, ALOX15, was identified. An inhibitor of ALOX15 was then obtained through high-throughput molecular docking and molecular dynamics simulation tests. In vitro experiments were conducted using a 16HBE cell model induced by house dust mite (HDM) and lipopolysaccharide (LPS), which were treated with the ALOX15 inhibitor (PD146176), CA treatment, or ALOX15 knockdown. In vivo experiments were also carried out using a mouse model induced by HDM and LPS.
RESULTS: The composite model of ALOX15 and CA in molecular dynamics simulations shows good stability and flexibility. Network pharmacological analysis reveals that CA regulates ferroptosis through ALOX15 in treating asthma. In vitro studies show that ALOX15 is highly expressed in HDM and LPS treatments, while CA inhibits HDM and LPS-induced ferroptosis in 16HBE cells by reducing ALOX15 expression. Knockdown of ALOX15 has the opposite effect. Metabolomics analysis identifies key compounds associated with ferroptosis, including L-Targinine, eicosapentaenoic acid, 16-hydroxy hexadecanoic acid, and succinic acid. In vivo experiments demonstrate that CA suppresses ALOX15 expression, inhibits ferroptosis, and improves asthma symptoms in mice.
CONCLUSION: Our research initially identified CA as a promising asthma treatment that effectively blocks ferroptosis by specifically targeting ALOX15. This study not only highlights CA as a potential therapeutic agent for asthma but also introduces novel targets and treatment options for this condition, along with innovative approaches for utilizing natural compounds to target diseases associated with ferroptosis.

Keywords:  ALOX15; Asthma; Chicoric acid (CA); Ferroptosis; Ferroptosis inhibitor

DOI:  https://doi.org/10.1016/j.intimp.2024.113187