bims-traimu Biomed News
on Trained immunity
Issue of 2024–06–09
thirteen papers selected by
Yantong Wan, Southern Medical University
  1. Multifaceted roles of trained immunity in diverse pathological contexts.
  2. Yeast β-glucan promotes antiviral type I interferon response via dectin-1.
  3. Neutrophils and galectin-3 defend mice from lethal bacterial infection and humans from acute respiratory failure.
  4. Trained immunity: A link between risk factors and cardiovascular disease.
  5. Bacillus Calmette-Guérin immunotherapy induces an efficient antitumor response to control murine melanoma depending on MyD88 signaling.
  6. BCG priming followed by a novel interleukin combination activates Natural Killer cells to selectively proliferate and become anti-tumour long-lived effectors.
  7. Absence of c-Maf and IL-10 enables Type I IFN enhancement of innate responses to low-dose LPS in alveolar macrophages.
  8. SARS-CoV-2 envelope protein regulates innate immune tolerance.
  9. Neuropathological lesions in intravenous BCG-stimulated K18-hACE2 mice challenged with SARS-CoV-2.
  10. Macrophage fate: to kill or not to kill?
  11. Stimulus-response signaling dynamics characterize macrophage polarization states.
  12. Collaboration between distinct SWI/SNF chromatin remodeling complexes directs enhancer selection and activation of macrophage inflammatory genes.
  13. Opposing tumor-cell-intrinsic and -extrinsic roles of the IRF1 transcription factor in antitumor immunity.
  1. BMB Rep. 2024 Jun 05. pii: 6218. [Epub ahead of print]
    Multifaceted roles of trained immunity in diverse pathological contexts.
    Hyo Jin Park, Su Min Kim, Un Yung Choi, Lark Kyun Kim.
      Trained immunity, an innate immune response characterized by enhanced cellular responsiveness, exhibits a profound memory akin to adaptive immunity. This phenomenon involves intricate metabolic and epigenetic reprogramming triggered by stimuli such as β-glucan and BCG, shaping innate immune memory. Following elucidation of the background on trained immunity, it is important to explore its multifaceted roles in various pathological contexts. In this review, we delve into the specific contributions of trained immunity in the intricate landscape of viral infections, tumorigenesis, and diverse inflammatory diseases, shedding light on its potential as a therapeutic target, and offering comprehensive understanding of its broader immunological implications.
  2. Vet Microbiol. 2024 May 09. pii: S0378-1135(24)00129-9. [Epub ahead of print]295 110107
    Yeast β-glucan promotes antiviral type I interferon response via dectin-1.
    Jiaqi Wang, Xuemin Jin, Shihan Yan, Haoran Zhao, Daxin Pang, Hongsheng Ouyang, Xiaochun Tang.
      Pseudorabies virus (PRV), an alphaherpesvirus, is a neglected zoonotic pathogen. Dectin-1 sensing of β-glucan (BG) induces trained immunity, which can possibly form a new strategy for the prevention of viral infection. However, alphaherpesvirus including PRV have received little to no investigation in the context of trained immunity. Here, we found that BG pretreatment improved the survival rate, weight loss outcomes, alleviated histological injury and decreased PRV copy number of tissues in PRV-infected mice. Type I interferons (IFNs) including IFN-α/β levels in serum were significantly increased by BG. However, these effects were abrogated in the presence of Dectin-1 antagonist. Dectin-1-mediated effect of BG was also confirmed in porcine and murine macrophages. These results suggested that BG have effects on type I IFNs with antiviral property involved in Dectin-1. In piglets, oral or injected immunization with BG and PRV vaccine could significantly elevated the level of PRV-specific IgG and type I IFNs. And it also increased the antibody levels of porcine reproductive and respiratory syndrome virus vaccine and classical swine fever vaccine that were later immunized, indicating a broad-spectrum effect on improving vaccine immunity. On the premise that the cost was greatly reducing, the immunological effect of oral was better than injection administration. Our findings highlighted that BG induced type I IFNs related antiviral effect against PRV involved in Dectin-1 and potential application value as a feed additive to help control the spread of PRV and future emerging viruses.
    Keywords:  Dectin-1; PRV; Piglet; Type I interferon; β-glucan
    DOI:  https://doi.org/10.1016/j.vetmic.2024.110107
  3. Nat Commun. 2024 Jun 03. 15(1): 4724
    Neutrophils and galectin-3 defend mice from lethal bacterial infection and humans from acute respiratory failure.
    Sudipta Das, Tomasz W Kaminski, Brent T Schlegel, William Bain, Sanmei Hu, Akruti Patel, Sagar L Kale, Kong Chen, Janet S Lee, Rama K Mallampalli, Valerian E Kagan, Dhivyaa Rajasundaram, Bryan J McVerry, Prithu Sundd, Georgios D Kitsios, Anuradha Ray, Prabir Ray.
      Respiratory infection by Pseudomonas aeruginosa, common in hospitalized immunocompromised and immunocompetent ventilated patients, can be life-threatening because of antibiotic resistance. This raises the question of whether the host's immune system can be educated to combat this bacterium. Here we show that prior exposure to a single low dose of lipopolysaccharide (LPS) protects mice from a lethal infection by P. aeruginosa. LPS exposure trained the innate immune system by promoting expansion of neutrophil and interstitial macrophage populations distinguishable from other immune cells with enrichment of gene sets for phagocytosis- and cell-killing-associated genes. The cell-killing gene set in the neutrophil population uniquely expressed Lgals3, which encodes the multifunctional antibacterial protein, galectin-3. Intravital imaging for bacterial phagocytosis, assessment of bacterial killing and neutrophil-associated galectin-3 protein levels together with use of galectin-3-deficient mice collectively highlight neutrophils and galectin-3 as central players in LPS-mediated protection. Patients with acute respiratory failure revealed significantly higher galectin-3 levels in endotracheal aspirates (ETAs) of survivors compared to non-survivors, galectin-3 levels strongly correlating with a neutrophil signature in the ETAs and a prognostically favorable hypoinflammatory plasma biomarker subphenotype. Taken together, our study provides impetus for harnessing the potential of galectin-3-expressing neutrophils to protect from lethal infections and respiratory failure.
    DOI:  https://doi.org/10.1038/s41467-024-48796-y
  4. Br J Pharmacol. 2024 Jun 02.
    Trained immunity: A link between risk factors and cardiovascular disease.
    Mingqi Chen, Xuya Kang, Yan Zhang, Yahan Liu.
      Cardiovascular diseases are significant contributors to human mortality, closely associated with inflammation. With the changing living conditions and the extension of human lifespan, greater attention has been directed towards understanding the impact of early, long-term events on the development of cardiovascular events. Lifestyle factors such as stress, unhealthy diet and physical inactivity can increase the risk of cardiovascular diseases. Interestingly, even if the risk factors are addressed later, their influence may persist. Recently, the concept of trained innate immunity (TRIM), defined as sustained alterations in the function of innate immunocyte that promote a more robust response to downstream stimuli, has been proposed to be involved in cardiovascular diseases. It is hypothesized that TRIM may serve as a mediator bridging the impacts of aforementioned risk factors. This review aims to elucidate the role of TRIM in cardiovascular diseases and highlight its significance in uncovering new mechanisms and therapeutic targets.
    Keywords:  cadiovascular diseases; risk factors; therapeutics; trained innate immunity (TRIM)
    DOI:  https://doi.org/10.1111/bph.16472
  5. Front Immunol. 2024 ;15 1380069
    Bacillus Calmette-Guérin immunotherapy induces an efficient antitumor response to control murine melanoma depending on MyD88 signaling.
    Vinícius M Borges, Fábio V Marinho, Christiane V A Caldeira, Nina M G P de Queiroz, Sergio C Oliveira.
      Bacillus Calmette-Guérin (BCG) is the first line treatment for bladder cancer and it is also proposed for melanoma immunotherapy. BCG modulates the tumor microenvironment (TME) inducing an antitumor effective response, but the immune mechanisms involved still poorly understood. The immune profile of B16-F10 murine melanoma cells was assessed by infecting these cells with BCG or stimulating them with agonists for different innate immune pathways such as TLRs, inflammasome, cGAS-STING and type I IFN. B16-F10 did not respond to any of those stimuli, except for type I IFN agonists, contrasting with bone marrow-derived macrophages (BMDMs) that showed high production of proinflammatory cytokines. Additionally, we confirmed that BCG is able to infect B16-F10, which in turn can activate macrophages and spleen cells from mice in co-culture experiments. Furthermore, we established a subcutaneous B16-F10 melanoma model for intratumoral BCG treatment and compared wild type mice to TLR2-/-, TLR3-/-, TLR4-/-, TLR7-/-, TLR3/7/9-/-, caspase 1-/-, caspase 11-/-, IL-1R-/-, cGAS-/-, STING-/-, IFNAR-/-, MyD88-/-deficient animals. These results in vivo demonstrate that MyD88 signaling is important for BCG immunotherapy to control melanoma in mice. Also, BCG fails to induce cytokine production in the co-culture experiments using B16-F10 and BMDMs or spleen cells derived from MyD88-/- compared to wild-type (WT) animals. Immunotherapy with BCG was not able to induce the recruitment of inflammatory cells in the TME from MyD88-/- mice, impairing tumor control and IFN-γ production by T cells. In conclusion, MyD88 impacts on both innate and adaptive responses to BCG leading to an efficient antitumor response against melanoma.
    Keywords:  Bacillus Calmette-Guérin (BCG); MyD88; TLRs; cGAS-STING; cancer immunotherapy; innate immune pathways; melanoma
    DOI:  https://doi.org/10.3389/fimmu.2024.1380069
  6. Sci Rep. 2024 Jun 07. 14(1): 13133
    BCG priming followed by a novel interleukin combination activates Natural Killer cells to selectively proliferate and become anti-tumour long-lived effectors.
    María-José Felgueres, Gloria Esteso, Álvaro F García-Jiménez, Ana Dopazo, Nacho Aguiló, Carmen Mestre-Durán, Luis Martínez-Piñeiro, Antonio Pérez-Martínez, Hugh T Reyburn, Mar Valés-Gómez.
      The short-lived nature and heterogeneity of Natural Killer (NK) cells limit the development of NK cell-based therapies, despite their proven safety and efficacy against cancer. Here, we describe the biological basis, detailed phenotype and function of long-lived anti-tumour human NK cells (CD56highCD16+), obtained without cell sorting or feeder cells, after priming of peripheral blood cells with Bacillus Calmette-Guérin (BCG). Further, we demonstrate that survival doses of a cytokine combination, excluding IL18, administered just weekly to BCG-primed NK cells avoids innate lymphocyte exhaustion and leads to specific long-term proliferation of innate cells that exert potent cytotoxic function against a broad range of solid tumours, mainly through NKG2D. Strikingly, a NKG2C+CD57-FcεRIγ+ NK cell population expands after BCG and cytokine stimulation, independently of HCMV serology. This strategy was exploited to rescue anti-tumour NK cells even from the suppressor environment of cancer patients' bone marrow, demonstrating that BCG confers durable anti-tumour features to NK cells.
    Keywords:  BCG; Cancer immunology; Cell immunotherapy; Cytokine activation; NK cells
    DOI:  https://doi.org/10.1038/s41598-024-62968-2
  7. bioRxiv. 2024 May 26. pii: 2024.05.22.594428. [Epub ahead of print]
    Absence of c-Maf and IL-10 enables Type I IFN enhancement of innate responses to low-dose LPS in alveolar macrophages.
    Pamelia N Lim, Maritza M Cervantes, Linh K Pham, Sydney Doherty, Ankita Tufts, Divya Dubey, Dat Mai, Alan Aderem, Alan H Diercks, Alissa C Rothchild.
      Alveolar macrophages (AMs) are lower-airway resident myeloid cells and are among the first to respond to inhaled pathogens. Here, we interrogate AM innate sensing to Pathogen Associated Molecular Patterns (PAMPs) and determine AMs have decreased responses to low- dose LPS compared to other macrophages, as measured by TNF, IL-6, Ifnb , and Ifit3 . We find the reduced response to low-dose LPS correlates with minimal TLR4 and CD14 surface expression, despite sufficient internal expression of TLR4. Additionally, we find that AMs do not produce IL-10 in response to a variety of PAMPs due to low expression of transcription factor c- Maf and that lack of IL-10 production contributes to an enhancement of pro-inflammatory responses by Type I IFN. Our findings demonstrate that AMs have cell-intrinsic dampened responses to LPS, which is enhanced by type I IFN exposure. These data implicate conditions where AMs may have reduced or enhanced sentinel responses to bacterial infections.
    HIGHLIGHTS: Alveolar macrophages (AMs) do not produce TNF or IL-6 in response to low-dose LPS due to minimal surface expression of TLR4 and CD14Lack of AM IL-10 production is dependent on low c-Maf expressionExogenous c-Maf expression increases AM IL-10 productionIFNβ enhances AM TNF and IL-6 responses to low-dose LPS and this is dependent on a lack of IL-10.
    DOI:  https://doi.org/10.1101/2024.05.22.594428
  8. iScience. 2024 Jun 21. 27(6): 109975
    SARS-CoV-2 envelope protein regulates innate immune tolerance.
    Eric S Geanes, Rebecca McLennan, Stephen H Pierce, Heather L Menden, Oishi Paul, Venkatesh Sampath, Todd Bradley.
      Severe COVID-19 often leads to secondary infections and sepsis that contribute to long hospital stays and mortality. However, our understanding of the precise immune mechanisms driving severe complications after SARS-CoV-2 infection remains incompletely understood. Here, we provide evidence that the SARS-CoV-2 envelope (E) protein initiates innate immune inflammation, via toll-like receptor 2 signaling, and establishes a sustained state of innate immune tolerance following initial activation. Monocytes in this tolerant state exhibit reduced responsiveness to secondary stimuli, releasing lower levels of cytokines and chemokines. Mice exposed to E protein before secondary lipopolysaccharide challenge show diminished pro-inflammatory cytokine expression in the lung, indicating that E protein drives this tolerant state in vivo. These findings highlight the potential of the SARS-CoV-2 E protein to induce innate immune tolerance, contributing to long-term immune dysfunction that could lead to susceptibility to subsequent infections, and uncovers therapeutic targets aimed at restoring immune function following SARS-CoV-2 infection.
    Keywords:  components of the immune system; immunity; molecular biology; transcriptomics; virology
    DOI:  https://doi.org/10.1016/j.isci.2024.109975
  9. Vet Res. 2024 May 31. 55(1): 71
    Neuropathological lesions in intravenous BCG-stimulated K18-hACE2 mice challenged with SARS-CoV-2.
    Lidia Sánchez-Morales, Néstor Porras, Teresa García-Seco, Marta Pérez-Sancho, Fátima Cruz, Blanca Chinchilla, Sandra Barroso-Arévalo, Marta Diaz-Frutos, Aránzazu Buendía, Inmaculada Moreno, Víctor Briones, María de Los Ángeles Risalde, José de la Fuente, Ramón Juste, Joseba Garrido, Ana Balseiro, Christian Gortázar, Antonio Rodríguez-Bertos, Mercedes Domínguez, Lucas Domínguez.
      In the wake of the COVID-19 pandemic caused by SARS-CoV-2, questions emerged about the potential effects of Bacillus Calmette-Guérin (BCG) vaccine on the immune response to SARS-CoV-2 infection, including the neurodegenerative diseases it may contribute to. To explore this, an experimental study was carried out in BCG-stimulated and non-stimulated k18-hACE2 mice challenged with SARS-CoV-2. Viral loads in tissues determined by RT-qPCR, histopathology in brain and lungs, immunohistochemical study in brain (IHC) as well as mortality rates, clinical signs and plasma inflammatory and coagulation biomarkers were assessed. Our results showed BCG-SARS-CoV-2 challenged mice presented higher viral loads in the brain and an increased frequency of neuroinvasion, with the greatest differences observed between groups at 3-4 days post-infection (dpi). Histopathological examination showed a higher severity of brain lesions in BCG-SARS-CoV-2 challenged mice, mainly consisting of neuroinflammation, increased glial cell population and neuronal degeneration, from 5 dpi onwards. This group also presented higher interstitial pneumonia and vascular thrombosis in lungs (3-4 dpi), BCG-SARS-CoV-2 mice showed higher values for TNF-α and D-dimer values, while iNOS values were higher in SARS-CoV-2 mice at 3-4 dpi. Results presented in this study indicate that BCG stimulation could have intensified the inflammatory and neurodegenerative lesions promoting virus neuroinvasion and dissemination in this experimental model. Although k18-hACE2 mice show higher hACE2 expression and neurodissemination, this study suggests that, although the benefits of BCG on enhancing heterologous protection against pathogens and tumour cells have been broadly demonstrated, potential adverse outcomes due to the non-specific effects of BCG should be considered.
    Keywords:  BCG stimulation; K18-hACE2; SARS-CoV-2; neuroinvasion
    DOI:  https://doi.org/10.1186/s13567-024-01325-7
  10. Infect Immun. 2024 Jun 03. e0047623
    Macrophage fate: to kill or not to kill?
    Armando M Marrufo, Ana Lidia Flores-Mireles.
      Macrophages are dynamic innate immune cells that either reside in tissue, serving as sentinels, or recruited as monocytes from bone marrow into inflamed and infected tissue. In response to cues in the tissue microenvironment (TME), macrophages polarize on a continuum toward M1 or M2 with diverse roles in progression and resolution of disease. M1-like macrophages exhibit proinflammatory functions with antimicrobial and anti-tumorigenic activities, while M2-like macrophages have anti-inflammatory functions that generally resolve inflammatory responses and orchestrate a tissue healing process. Given these opposite phenotypes, proper spatiotemporal coordination of macrophage polarization in response to cues within the TME is critical to effectively resolve infectious disease and regulate wound healing. However, if this spatiotemporal coordination becomes disrupted due to persistent infection or dysregulated coagulation, macrophages' inappropriate response to these cues will result in the development of diseases with clinically unfavorable outcomes. Since plasticity and heterogeneity are hallmarks of macrophages, they are attractive targets for therapies to reprogram toward specific phenotypes that could resolve disease and favor clinical prognosis. In this review, we discuss how basic science studies have elucidated macrophage polarization mechanisms in TMEs during infections and inflammation, particularly coagulation. Therefore, understanding the dynamics of macrophage polarization within TMEs in diseases is important in further development of targeted therapies.
    Keywords:  M1; M1/M2; M2; coagulation; innate immunity; macrophage polarization; macrophages; tissue microenvironment
    DOI:  https://doi.org/10.1128/iai.00476-23
  11. Cell Syst. 2024 May 31. pii: S2405-4712(24)00146-7. [Epub ahead of print]
    Stimulus-response signaling dynamics characterize macrophage polarization states.
    Apeksha Singh, Supriya Sen, Michael Iter, Adewunmi Adelaja, Stefanie Luecke, Xiaolu Guo, Alexander Hoffmann.
      The functional state of cells is dependent on their microenvironmental context. Prior studies described how polarizing cytokines alter macrophage transcriptomes and epigenomes. Here, we characterized the functional responses of 6 differentially polarized macrophage populations by measuring the dynamics of transcription factor nuclear factor κB (NF-κB) in response to 8 stimuli. The resulting dataset of single-cell NF-κB trajectories was analyzed by three approaches: (1) machine learning on time-series data revealed losses of stimulus distinguishability with polarization, reflecting canalized effector functions. (2) Informative trajectory features driving stimulus distinguishability ("signaling codons") were identified and used for mapping a cell state landscape that could then locate macrophages conditioned by an unrelated condition. (3) Kinetic parameters, inferred using a mechanistic NF-κB network model, provided an alternative mapping of cell states and correctly predicted biochemical findings. Together, this work demonstrates that a single analyte's dynamic trajectories may distinguish the functional states of single cells and molecular network states underlying them. A record of this paper's transparent peer review process is included in the supplemental information.
    Keywords:  NF-κB dynamics; inflammation; innate immunity; machine learning; macrophage; math modeling; microenvironmental context; polarization; stimulus-specific responses; trajectory data
    DOI:  https://doi.org/10.1016/j.cels.2024.05.002
  12. Immunity. 2024 May 29. pii: S1074-7613(24)00262-0. [Epub ahead of print]
    Collaboration between distinct SWI/SNF chromatin remodeling complexes directs enhancer selection and activation of macrophage inflammatory genes.
    Jingwen Liao, Josephine Ho, Mannix Burns, Emily C Dykhuizen, Diana C Hargreaves.
      Macrophages elicit immune responses to pathogens through induction of inflammatory genes. Here, we examined the role of three variants of the SWI/SNF nucleosome remodeling complex-cBAF, ncBAF, and PBAF-in the macrophage response to bacterial endotoxin (lipid A). All three SWI/SNF variants were prebound in macrophages and retargeted to genomic sites undergoing changes in chromatin accessibility following stimulation. Cooperative binding of all three variants associated with de novo chromatin opening and latent enhancer activation. Isolated binding of ncBAF and PBAF, in contrast, associated with activation and repression of active enhancers, respectively. Chemical and genetic perturbations of variant-specific subunits revealed pathway-specific regulation in the activation of lipid A response genes, corresponding to requirement for cBAF and ncBAF in inflammatory and interferon-stimulated gene (ISG) activation, respectively, consistent with differential engagement of SWI/SNF variants by signal-responsive transcription factors. Thus, functional diversity among SWI/SNF variants enables increased regulatory control of innate immune transcriptional programs, with potential for specific therapeutic targeting.
    Keywords:  ARID1A; BAF complex; BRD9; SWI/SNF complex; TLR; chromatin remodeling; enhancer; inflammation; macrophage; toll like receptor; transcriptional regulation
    DOI:  https://doi.org/10.1016/j.immuni.2024.05.008
  13. Cell Rep. 2024 Jun 02. pii: S2211-1247(24)00617-X. [Epub ahead of print]43(6): 114289
    Opposing tumor-cell-intrinsic and -extrinsic roles of the IRF1 transcription factor in antitumor immunity.
    Prabhat K Purbey, Joowon Seo, Manash K Paul, Keisuke S Iwamoto, Allison E Daly, An-Chieh Feng, Ameya S Champhekar, Justin Langerman, Katie M Campbell, Dörthe Schaue, William H McBride, Steven M Dubinett, Antoni Ribas, Stephen T Smale, Philip O Scumpia.
      Type I interferon (IFN-I) and IFN-γ foster antitumor immunity by facilitating T cell responses. Paradoxically, IFNs may promote T cell exhaustion by activating immune checkpoints. The downstream regulators of these disparate responses are incompletely understood. Here, we describe how interferon regulatory factor 1 (IRF1) orchestrates these opposing effects of IFNs. IRF1 expression in tumor cells blocks Toll-like receptor- and IFN-I-dependent host antitumor immunity by preventing interferon-stimulated gene (ISG) and effector programs in immune cells. In contrast, expression of IRF1 in the host is required for antitumor immunity. Mechanistically, IRF1 binds distinctly or together with STAT1 at promoters of immunosuppressive but not immunostimulatory ISGs in tumor cells. Overexpression of programmed cell death ligand 1 (PD-L1) in Irf1-/- tumors only partially restores tumor growth, suggesting multifactorial effects of IRF1 on antitumor immunity. Thus, we identify that IRF1 expression in tumor cells opposes host IFN-I- and IRF1-dependent antitumor immunity to facilitate immune escape and tumor growth.
    Keywords:  CP: Cancer; CP: Immunology; IRF1; PD-L1 regulation; TLR signaling; antitumor immunity; cytotoxic T lymphocytes; immune checkpoint blockade; immune evasion; interferon signaling; scRNA-seq; transcription
    DOI:  https://doi.org/10.1016/j.celrep.2024.114289
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