bims-traimu Biomed News
on Trained immunity
Issue of 2024–07–28
thirteen papers selected by
Yantong Wan, Southern Medical University
  1. Metabolic Regulation in the Induction of Trained Immunity.
  2. Trained Immunity Generated by the Recombinant Zoster Vaccine.
  3. Long-Lasting Enhanced Cytokine Responses Following SARS-CoV-2 BNT162b2 mRNA Vaccination.
  4. Innate immune memory after brain injury drives inflammatory cardiac dysfunction.
  5. Immune cell population dynamics following neonatal BCG vaccination and aerosol BCG revaccination in rhesus macaques.
  6. Modulation of Human Macrophages by Plasma from COVID-19 Patients Following BCG Vaccination: BATTLE Trial.
  7. Innate immune training restores pro-reparative myeloid functions to promote remyelination in the aged central nervous system.
  8. Atf3-mediated metabolic reprogramming in hepatic macrophage orchestrates metabolic dysfunction-associated steatohepatitis.
  9. Metabolism and immune memory in invertebrates: are they dissociated?
  10. An early regulatory mechanism of hyperinflammation by restricting monocyte contribution.
  11. Iron regulatory protein 2 contributes to antimicrobial immunity by preserving lysosomal function in macrophages.
  12. Metabolic Messengers: itaconate.
  13. Toll-like receptor 4 (TLR4) is the major pattern recognition receptor triggering the protective effect of a Candida albicans extracellular vesicle-based vaccine prototype in murine systemic candidiasis.
  1. Semin Immunopathol. 2024 Jul 25. 46(3-4): 7
    Metabolic Regulation in the Induction of Trained Immunity.
    Anaisa V Ferreira, Jorge Domínguez-Andrés, Laura M Merlo Pich, Leo A B Joosten, Mihai G Netea.
      The innate immune system exhibits features of memory, termed trained immunity, which promote faster and more robust responsiveness to heterologous challenges. Innate immune memory is sustained through epigenetic modifications, affecting gene accessibility, and promoting a tailored gene transcription for an enhanced immune response. Alterations in the epigenetic landscape are intertwined with metabolic rewiring. Here, we review the metabolic pathways that underscore the induction and maintenance of trained immunity, including glycolysis, oxidative phosphorylation, the tricarboxylic acid cycle, and amino acid and lipid metabolism. The intricate interplay of these pathways is pivotal for establishing innate immune memory in distinct cellular compartments. We explore in particular the case of resident lung alveolar macrophages. We propose that leveraging the memory of the innate immune system may present therapeutic potential. Specifically, targeting the metabolic programs of innate immune cells is an emerging strategy for clinical interventions, either to boost immune responses in immunosuppressed conditions or to mitigate maladaptive activation in hyperinflammatory diseases.
    Keywords:  Epigenetics; Metabolism; Therapy; Trained immunity
    DOI:  https://doi.org/10.1007/s00281-024-01015-8
  2. Res Sq. 2024 Jul 10. pii: rs.3.rs-4607744. [Epub ahead of print]
    Trained Immunity Generated by the Recombinant Zoster Vaccine.
    Adriana Weinberg, Michael Johnson, Megan Crotteau, Debashis Ghosh, Thao Vu, Myron J Levin.
      Trained immunity may play a role in vaccine-induced protection against infections. We showed that the highly efficacious recombinant VZV-gE zoster vaccine (RZV) generated trained immunity in monocytes, natural killer (NK) cells, and dendritic cells (DCs) and that the less efficacious live zoster vaccine did not. RZV stimulated ex vivo gE-specific monocyte, DC and NK cell responses that did not correlate with CD4 + T-cell responses. These responses were also elicited in purified monocyte and NK cell cocultures stimulated with VZV-gE and persisted above prevaccination levels for ≥ 4 years post-RZV administration. RZV administration also increased ex vivo heterologous monocyte and NK cell responses to herpes simplex and cytomegalovirus antigens. ATAC-seq analysis and ex vivo TGFβ1 supplementation and inhibition experiments demonstrated that decreased tgfβ1 transcription resulting from RZV-induced chromatin modifications may explain the development of monocyte trained immunity. The role of RZV-trained immunity in protection against herpes zoster and other infections should be further studied.
    DOI:  https://doi.org/10.21203/rs.3.rs-4607744/v1
  3. Vaccines (Basel). 2024 Jul 03. pii: 736. [Epub ahead of print]12(7):
    Long-Lasting Enhanced Cytokine Responses Following SARS-CoV-2 BNT162b2 mRNA Vaccination.
    Georgiana Cabău, Medeea Badii, Andreea M Mirea, Orsolya I Gaal, Liesbeth van Emst, Radu A Popp, Tania O Crișan, Leo A B Joosten.
      The mRNA vaccine against COVID-19 protects against severe disease by the induction of robust humoral and cellular responses. Recent studies have shown the capacity of some vaccines to induce enduring non-specific innate immune responses by the induction of trained immunity, augmenting protection against unrelated pathogens. This study aimed to assess whether the mRNA vaccine BNT162b2 can induce lasting non-specific immune responses in myeloid cells following a three-dose vaccination scheme. In a sample size consisting of 20 healthy individuals from Romania, we assessed inflammatory proteins using the Olink® Target 96 Inflammation panel, as well as ex vivo cytokine responses following stimulations with unrelated PRR ligands. We assessed the vaccine-induced non-specific systemic inflammation and functional adaptations of myeloid cells. Our results revealed the induction of a stimulus- and cytokine-dependent innate immune memory phenotype that became apparent after the booster dose and was maintained eight months later in the absence of systemic inflammation.
    Keywords:  cytokine responses; inflammatory responses; innate immune memory; mRNA vaccine; proteomics
    DOI:  https://doi.org/10.3390/vaccines12070736
  4. Cell. 2024 Jul 12. pii: S0092-8674(24)00702-5. [Epub ahead of print]
    Innate immune memory after brain injury drives inflammatory cardiac dysfunction.
    Alba Simats, Sijia Zhang, Denise Messerer, Faye Chong, Sude Beşkardeş, Aparna Sharma Chivukula, Jiayu Cao, Simon Besson-Girard, Felipe A Montellano, Caroline Morbach, Olga Carofiglio, Alessio Ricci, Stefan Roth, Gemma Llovera, Rashween Singh, Yiming Chen, Severin Filser, Nikolaus Plesnila, Christian Braun, Hannah Spitzer, Ozgun Gokce, Martin Dichgans, Peter U Heuschmann, Kinta Hatakeyama, Eduardo Beltrán, Sebastian Clauss, Boyan Bonev, Christian Schulz, Arthur Liesz.
      The medical burden of stroke extends beyond the brain injury itself and is largely determined by chronic comorbidities that develop secondarily. We hypothesized that these comorbidities might share a common immunological cause, yet chronic effects post-stroke on systemic immunity are underexplored. Here, we identify myeloid innate immune memory as a cause of remote organ dysfunction after stroke. Single-cell sequencing revealed persistent pro-inflammatory changes in monocytes/macrophages in multiple organs up to 3 months after brain injury, notably in the heart, leading to cardiac fibrosis and dysfunction in both mice and stroke patients. IL-1β was identified as a key driver of epigenetic changes in innate immune memory. These changes could be transplanted to naive mice, inducing cardiac dysfunction. By neutralizing post-stroke IL-1β or blocking pro-inflammatory monocyte trafficking with a CCR2/5 inhibitor, we prevented post-stroke cardiac dysfunction. Such immune-targeted therapies could potentially prevent various IL-1β-mediated comorbidities, offering a framework for secondary prevention immunotherapy.
    Keywords:  brain ischemia; cardiac fibrosis; cenicriviroc; innate immune memory; interleukin-1; myeloid cells; stroke; systemic inflammation; trained immunity
    DOI:  https://doi.org/10.1016/j.cell.2024.06.028
  5. Sci Rep. 2024 Jul 23. 14(1): 16993
    Immune cell population dynamics following neonatal BCG vaccination and aerosol BCG revaccination in rhesus macaques.
    Laura Sibley, Charlotte Sarfas, Alexandra L Morrison, Jessica Williams, Konstantinos Gkolfinos, Adam Mabbutt, William Eckworth, Steve Lawrence, Mike Dennis, Andrew White, Sally Sharpe.
      The BCG vaccine is given to millions of children globally but efficacy wanes over time and differences in the immune systems between infants and adults can influence vaccine efficacy. To this end, 34 rhesus macaques were vaccinated with BCG within seven days of birth and blood samples were collected over 88 weeks for quantification of blood cell populations. Overall, the composition of cell populations did not change significantly between BCG vaccinated and unvaccinated groups, and that BCG vaccination did not perturb normal development. In comparison to adult macaques, higher numbers of CD4+ T-cells, Tregs and NK cells were measured in the infant age group, suggesting a potential bias towards immunosuppressive and innate immune populations. Antigen-specific IFNγ secreting cell frequencies in infant BCG vaccinated animals were detectable in peripheral blood samples for 36 weeks after vaccination but declined following this. To evaluate the long-term impact of infant BCG vaccination on subsequent revaccination with BCG, a pilot study of three adult macaques received an aerosol BCG revaccination approximately 3 years after their initial BCG vaccination as infants. This induced an increase in PPD-specific IFNγ secreting cells, and increased secretion of the cytokines IFNγ and IL-1β, following stimulation with other microorganisms, which are signals associated with trained innate immunity.
    DOI:  https://doi.org/10.1038/s41598-024-67861-6
  6. Int J Gen Med. 2024 ;17 3107-3117
    Modulation of Human Macrophages by Plasma from COVID-19 Patients Following BCG Vaccination: BATTLE Trial.
    Keini Buosi, Mehrsa Jalalizadeh, Aline Rosa Maia, Joseane Morari, Licio Augusto Velloso, Leonardo Oliveira Reis.
       Purpose: To analyze the interfering effect of plasma from COVID-19 convalescent adults vaccinated or not with intradermal Bacillus Calmette-Guérin (BCG) on human macrophages.
    Methods: The BATTLE clinical trial (NCT04369794) was initiated in the 2020 SARS-CoV-2 pandemic to study the safety and efficacy of BCG revaccination of COVID-19 convalescent adults. We measured the expression induction of eleven COVID-19-related genes in human macrophages cultured in plasma taken from 22 BCG vaccinated and 17 placebo patients at baseline and 45 days post-intervention. Subgroup analysis was based on gender, age, job type (healthcare worker [HCW] vs non-HCW), and the presence of anosmia/dysgeusia.
    Results: Compared to plasma from placebo counterparts, the plasma of BCG vaccinated patients increased the expression induction of interferon (IFN)β-1b (p = 0.042) in human macrophages. This increase was more pronounced in females and in healthcare workers (HCW) (p = 0.007 and 0.001, respectively). Interferon-induced transmembrane protein 3 (IFITM3) expression induction was increased by plasma from BCG vaccinated females, young age group, and HCWs (p = 0.004, 0.011, and 0.040, respectively). Interleukin (IL)-10 induction increased by the plasma of young BCG recipients (p = 0.008). Induction of IL-6 expression increased by non-HCW BCG recipients plasma but decreased by HCW BCG recipients plasma (p = 0.005). Baseline plasma of patients who presented with anosmia/dysgeusia at the time of admission induced lower angiotensin-converting enzyme 2 (ACE2) compared to those without the symptom (0.76 vs 0.97, p = 0.004). ACE2 expression induction significantly increased by plasma of BCG recipients if they had anosmia/dysgeusia on admission (p = 0.028).
    Conclusion: The expressions of IFNβ-1b, IFITM3, IL-6, and IL-10 in human macrophages incubated with the plasma of COVID-19 convalescent patients were modulated by BCG. These modulations depended on subject-specific characteristics, including gender, age, clinical presentation (anosmia/dysgeusia), job type, and previous exposure to mycobacteria.
    Keywords:  ACE2; BCG; COVID; IFNs; age; gender; healthcare worker; trained immunity
    DOI:  https://doi.org/10.2147/IJGM.S468047
  7. Immunity. 2024 Jul 19. pii: S1074-7613(24)00348-0. [Epub ahead of print]
    Innate immune training restores pro-reparative myeloid functions to promote remyelination in the aged central nervous system.
    Vini Tiwari, Bharat Prajapati, Yaw Asare, Alkmini Damkou, Hao Ji, Lu Liu, Nawraa Naser, Garyfallia Gouna, Katarzyna B Leszczyńska, Jakub Mieczkowski, Martin Dichgans, Qing Wang, Riki Kawaguchi, Zechuan Shi, Vivek Swarup, Daniel H Geschwind, Marco Prinz, Ozgun Gokce, Mikael Simons.
      The reduced ability of the central nervous system to regenerate with increasing age limits functional recovery following demyelinating injury. Previous work has shown that myelin debris can overwhelm the metabolic capacity of microglia, thereby impeding tissue regeneration in aging, but the underlying mechanisms are unknown. In a model of demyelination, we found that a substantial number of genes that were not effectively activated in aged myeloid cells displayed epigenetic modifications associated with restricted chromatin accessibility. Ablation of two class I histone deacetylases in microglia was sufficient to restore the capacity of aged mice to remyelinate lesioned tissue. We used Bacillus Calmette-Guerin (BCG), a live-attenuated vaccine, to train the innate immune system and detected epigenetic reprogramming of brain-resident myeloid cells and functional restoration of myelin debris clearance and lesion recovery. Our results provide insight into aging-associated decline in myeloid function and how this decay can be prevented by innate immune reprogramming.
    Keywords:  aging; innate immunity; microglia; myelin; remyelination
    DOI:  https://doi.org/10.1016/j.immuni.2024.07.001
  8. Sci Adv. 2024 Jul 26. 10(30): eado3141
    Atf3-mediated metabolic reprogramming in hepatic macrophage orchestrates metabolic dysfunction-associated steatohepatitis.
    Shuwei Hu, Rui Li, Dongxu Gong, Pei Hu, Jitu Xu, Yingjie Ai, Xiaojie Zhao, Chencheng Hu, Minghuan Xu, Chenxi Liu, Shuyu Chen, Jie Fan, Zhonghua Zhao, Zhigang Zhang, Huijuan Wu, Yanyong Xu.
      Metabolic dysfunction-associated steatohepatitis (MASH) is regulated by complex interplay between the macrophages and surrounding cells in the liver. Here, we show that Atf3 regulates glucose-fatty acid cycle in macrophages attenuates hepatocyte steatosis, and fibrogenesis in hepatic stellate cells (HSCs). Overexpression of Atf3 in macrophages protects against the development of MASH in Western diet-fed mice, whereas Atf3 ablation has the opposite effect. Mechanistically, Atf3 improves the reduction of fatty acid oxidation induced by glucose via forkhead box O1 (FoxO1) and Cd36. Atf3 inhibits FoxO1 activity via blocking Hdac1-mediated FoxO1 deacetylation at K242, K245, and K262 and increases Zdhhc4/5-mediated CD36 palmitoylation at C3, C7, C464, and C466; furthermore, macrophage Atf3 decreases hepatocytes lipogenesis and HSCs activation via retinol binding protein 4 (Rbp4). Anti-Rbp4 can prevent MASH progression that is induced by Atf3 deficiency in macrophages. This study identifies Atf3 as a regulator of glucose-fatty acid cycle. Targeting macrophage Atf3 or Rbp4 may be a plausible therapeutic strategy for MASH.
    DOI:  https://doi.org/10.1126/sciadv.ado3141
  9. Front Immunol. 2024 ;15 1379471
    Metabolism and immune memory in invertebrates: are they dissociated?
    Texca T Méndez-López, Julio César Carrero, Humberto Lanz-Mendoza, Alejandra Ochoa-Zarzosa, Krishnendu Mukherjee, Jorge Contreras-Garduño.
      Since the discovery of specific immune memory in invertebrates, researchers have investigated its immune response to diverse microbial and environmental stimuli. Nevertheless, the extent of the immune system's interaction with metabolism, remains relatively enigmatic. In this mini review, we propose a comprehensive investigation into the intricate interplay between metabolism and specific immune memory. Our hypothesis is that cellular endocycles and epigenetic modifications play pivotal roles in shaping this relationship. Furthermore, we underscore the importance of the crosstalk between metabolism and specific immune memory for understanding the evolutionary costs. By evaluating these costs, we can gain deeper insights into the adaptive strategies employed by invertebrates in response to pathogenic challenges. Lastly, we outline future research directions aimed at unraveling the crosstalk between metabolism and specific immune memory. These avenues of inquiry promise to illuminate fundamental principles governing host-pathogen interactions and evolutionary trade-offs, thus advancing our understanding of invertebrate immunology.
    Keywords:  ecoimmunology; host-parasite relationship; immune priming; immunometabolism; innate immune response; specific memory; trade-offs
    DOI:  https://doi.org/10.3389/fimmu.2024.1379471
  10. Front Immunol. 2024 ;15 1398153
    An early regulatory mechanism of hyperinflammation by restricting monocyte contribution.
    Megumi Akiyama, Masashi Kanayama, Yoshihiro Umezawa, Toshikage Nagao, Yuta Izumi, Masahide Yamamoto, Toshiaki Ohteki.
      Innate immune cells play a key role in inflammation as a source of pro-inflammatory cytokines. However, it remains unclear how innate immunity-mediated inflammation is fine-tuned to minimize tissue damage and assure the host's survival at the early phase of systemic inflammation. The results of this study with mouse models demonstrate that the supply of monocytes is restricted depending on the magnitude of inflammation. During the acute phase of severe inflammation, monocytes, but not neutrophils, were substantially reduced by apoptosis and the remaining monocytes were dysfunctional in the bone marrow. Monocyte-specific ablation of Casp3/7 prevented monocyte apoptosis but promoted monocyte necrosis in the bone marrow, leading to elevated levels of pro-inflammatory cytokines and the increased mortality of mice during systemic inflammation. Importantly, the limitation of monocyte supply was dependent on pro-inflammatory cytokines in vivo. Consistently, a reduction of monocytes was observed in the peripheral blood during cytokine-release syndrome (CRS) patients, a pathogen-unrelated systemic inflammation induced by chimeric antigen receptor-T cell (CAR-T cell) therapy. Thus, monocytes act as a safety valve to alleviate tissue damage caused by inflammation and ensure host survival, which may be responsible for a primitive immune-control mechanism that does not require intervention by acquired immunity.
    Keywords:  CRS - cytokine release syndrome; apoptosis; cytokine; inflammation; monocyte
    DOI:  https://doi.org/10.3389/fimmu.2024.1398153
  11. Proc Natl Acad Sci U S A. 2024 Jul 30. 121(31): e2321929121
    Iron regulatory protein 2 contributes to antimicrobial immunity by preserving lysosomal function in macrophages.
    Chen Cheng, Zhiyao Xing, Wenxin Zhang, Lei Zheng, Hongting Zhao, Xiao Zhang, Yibing Ding, Tong Qiao, Yi Li, Esther G Meyron-Holtz, Fanis Missirlis, Zhiwen Fan, Kuanyu Li.
      Colorectal cancer and Crohn's disease patients develop pyogenic liver abscesses due to failures of immune cells to fight off bacterial infections. Here, we show that mice lacking iron regulatory protein 2 (Irp2), globally (Irp2-/-) or myeloid cell lineage (Lysozyme 2 promoter-driven, LysM)-specifically (Irp2ΔLysM), are highly susceptible to liver abscesses when the intestinal tissue was injured with dextran sodium sulfate treatment. Further studies demonstrated that Irp2 is required for lysosomal acidification and biogenesis, both of which are crucial for bacterial clearance. In Irp2-deficient liver tissue or macrophages, the nuclear location of transcription factor EB (Tfeb) was remarkably reduced, leading to the downregulation of Tfeb target genes that encode critical components for lysosomal biogenesis. Tfeb mislocalization was reversed by hypoxia-inducible factor 2 inhibitor PT2385 and, independently, through inhibition of lactic acid production. These experimental findings were confirmed clinically in patients with Crohn's disease and through bioinformatic searches in databases from Crohn's disease or ulcerative colitis biopsies showing loss of IRP2 and transcription factor EB (TFEB)-dependent lysosomal gene expression. Overall, our study highlights a mechanism whereby Irp2 supports nuclear translocation of Tfeb and lysosomal function, preserving macrophage antimicrobial activity and protecting the liver against invading bacteria during intestinal inflammation.
    Keywords:  HIF2; IRP2; TFEB localization; lactic acid; lysosomal function
    DOI:  https://doi.org/10.1073/pnas.2321929121
  12. Nat Metab. 2024 Jul 26.
    Metabolic Messengers: itaconate.
    A F McGettrick, L A Bourner, F C Dorsey, L A J O'Neill.
      The metabolite itaconate has emerged as an important immunoregulator with roles in antibacterial defence, inhibition of inflammation and, more recently, as an inhibitory factor in obesity. Itaconate is one of the most upregulated metabolites in inflammatory macrophages. It is produced owing to the disturbance of the tricarboxylic acid cycle and the diversion of aconitate to itaconate via the enzyme aconitate decarboxylase 1. In immunology, initial studies concentrated on the role of itaconate in inflammatory macrophages where it was shown to be inhibitory, but this has expanded as the impact of itaconate on other cell types is starting to emerge. This review focuses on itaconate as a key immunoregulatory metabolite and describes its diverse mechanisms of action and its many impacts on the immune and inflammatory responses and in cancer. We also examine the clinical relevance of this immunometabolite and its therapeutic potential for immune and inflammatory diseases.
    DOI:  https://doi.org/10.1038/s42255-024-01092-x
  13. mSphere. 2024 Jul 22. e0046724
    Toll-like receptor 4 (TLR4) is the major pattern recognition receptor triggering the protective effect of a Candida albicans extracellular vesicle-based vaccine prototype in murine systemic candidiasis.
    Leandro Honorato, Jhon J Artunduaga Bonilla, Alessandro F Valdez, Susana Frases, Glauber Ribeiro de Sousa Araújo, Albaniza Liuane Ribeiro do Nascimento Sabino, Natalia Martins da Silva, Larissa Ribeiro, Marina da Silva Ferreira, Julio Kornetz, Marcio L Rodrigues, Iain Cunningham, Neil A R Gow, Attila Gacser, Allan J Guimarães, Fabianno F Dutra, Leonardo Nimrichter.
      Systemic candidiasis remains a significant public health concern worldwide, with high mortality rates despite available antifungal drugs. Drug-resistant strains add to the urgency for alternative therapies. In this context, vaccination has reemerged as a prominent immune-based strategy. Extracellular vesicles (EVs), nanosized lipid bilayer particles, carry a diverse array of native fungal antigens, including proteins, nucleic acids, lipids, and glycans. Previous studies from our laboratory demonstrated that Candida albicans EVs triggered the innate immune response, activating bone marrow-derived dendritic cells (BMDCs) and potentially acting as a bridge between innate and adaptive immunity. Vaccination with C. albicans EVs induced the production of specific antibodies, modulated cytokine production, and provided protection in immunosuppressed mice infected with lethal C. albicans inoculum. To elucidate the mechanisms underlying EV-induced immune activation, our study investigated pathogen-associated molecular patterns (PAMPs) and pattern recognition receptors (PRRs) involved in EVs-phagocyte engagement. EVs from wild-type and mutant C. albicans strains with truncated mannoproteins were compared for their ability to stimulate BMDCs. Our findings revealed that EV decoration with O- and N-linked mannans and the presence of β-1,3-glucans and chitin oligomers may modulate the activation of specific PRRs, in particular Toll-like receptor 4 (TLR4) and dectin-1. The protective effect of vaccination with wild-type EVs was found to be dependent on TLR4. These results suggest that fungal EVs can be harnessed in vaccine formulations to selectively activate PRRs in phagocytes, offering potential avenues for combating or preventing candidiasis.IMPORTANCESystemic candidiasis is a serious global health concern with high mortality rates and growing drug resistance. Vaccination offers a promising solution. A unique approach involves using tiny lipid-coated particles called extracellular vesicles (EVs), which carry various fungal components. Previous studies found that Candida albicans EVs activate the immune response and may bridge the gap between innate and adaptive immunity. To understand this better, we investigated how these EVs activate immune cells. We demonstrated that specific components on EV surfaces, such as mannans and glucans, interact with receptors on immune cells, including Toll-like receptor 4 (TLR4) and dectin-1. Moreover, vaccinating with these EVs led to strong immune responses and full protection in mice infected with Candida. This work shows how harnessing fungal EVs might lead to effective vaccines against candidiasis.
    Keywords:  Candida albicans; extracellular vesicles; vaccines
    DOI:  https://doi.org/10.1128/msphere.00467-24
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