bims-traimu Biomed News
on Trained immunity
Issue of 2024–03–10
seven papers selected by
Yantong Wan, Southern Medical University
  1. C. albicans N-linked mannans potentiate the induction of trained immunity via Dectin-2.
  2. Leishmania braziliensis enhances monocyte responses to promote anti-tumor activity.
  3. Altered DNA methylation underlies monocyte dysregulation and immune exhaustion memory in sepsis.
  4. The plasticity of immune memory in invertebrates.
  5. The bacterial lysate OM-85 engages Toll-like receptors 2 and 4 triggering an immunomodulatory gene signature in human myeloid cells.
  6. Single-Cell Sequencing Reveals MYOF-Enriched Monocyte/Macrophage Subcluster as a Favorable Prognostic Factor in Sepsis.
  7. The transcription factor NF-κB orchestrates nucleosome remodeling during the primary response to Toll-like receptor 4 signaling.
  1. J Infect Dis. 2024 Mar 06. pii: jiae112. [Epub ahead of print]
    C. albicans N-linked mannans potentiate the induction of trained immunity via Dectin-2.
    Diletta Rosati, Arnab Pradhan, Julia I P van Heck, Leonie Helder, Martin Jaeger, Neil A R Gow, Leo A B Joosten, David L Williams, Alistair J P Brown, Mariolina Bruno, Mihai G Netea.
      The interaction between the Candida albicans cell wall and pattern recognition receptors is crucial for the initiation of host immune responses which, ultimately, contribute to the clearance of this pathogenic fungus. In the present study, we investigate the ability of C. albicans mannans to modulate immune response and induce innate immune memory (also termed trained immunity). Using mutants of C. albicans that are defective in, or lack mannosyl residues, we show that alterations in the mannosylation of the C. albicans cell wall affect the innate cytokine response and strongly reduce the secretion of T cell-derived cytokines. Subsequently, we demonstrate that the branching of N-linked mannan, but not O-linked mannan, is essential to potentiate the induction of trained immunity, a process mediated by Dectin-2. In conclusion, N-linked mannan is needed, in addition to β-glucans, for an effective induction of trained immunity by C. albicans.
    Keywords:   Candida albicans ; cell wall; innate immune memory; mannans; trained immunity
    DOI:  https://doi.org/10.1093/infdis/jiae112
  2. Cell Rep. 2024 Mar 07. pii: S2211-1247(24)00260-2. [Epub ahead of print]43(3): 113932
    Leishmania braziliensis enhances monocyte responses to promote anti-tumor activity.
    Jéssica Cristina Dos Santos, María Moreno, Lisa U Teufel, Sofía Chilibroste, Samuel T Keating, Laszlo Groh, Jorge Domínguez-Andrés, David L Williams, Zuchao Ma, Douglas W Lowman, Harry E Ensley, Boris Novakovic, Fátima Ribeiro-Dias, Mihai G Netea, José A Chabalgoity, Leo A B Joosten.
      Innate immune cells can undergo long-term functional reprogramming after certain infections, a process called trained immunity (TI). Here, we focus on antigens of Leishmania braziliensis, which induced anti-tumor effects via trained immunity in human monocytes. We reveal that monocytes exposed to promastigote antigens of L. braziliensis develop an enhanced response to subsequent exposure to Toll-like receptor (TLR)2 or TLR4 ligands. Mechanistically, the induction of TI in monocytes by L. braziliensis is mediated by multiple pattern recognition receptors, changes in metabolism, and increased deposition of H3K4me3 at the promoter regions of immune genes. The administration of L. braziliensis exerts potent anti-tumor capabilities by delaying tumor growth and prolonging survival of mice with non-Hodgkin lymphoma. Our work reveals mechanisms of TI induced by L. braziliensis in vitro and identifies its potential for cancer immunotherapy.
    Keywords:  CP: Cancer; CP: Immunology; Leishmania braziliensis; anti-tumor activities; enhanced cytokines responsiveness; human monocytes; non-Hodgkin lymphoma; trained immunity
    DOI:  https://doi.org/10.1016/j.celrep.2024.113932
  3. Cell Rep. 2024 Mar 04. pii: S2211-1247(24)00222-5. [Epub ahead of print]43(3): 113894
    Altered DNA methylation underlies monocyte dysregulation and immune exhaustion memory in sepsis.
    Blake A Caldwell, Yajun Wu, Jing Wang, Liwu Li.
      Monocytes can develop an exhausted memory state characterized by reduced differentiation, pathogenic inflammation, and immune suppression that drives immune dysregulation during sepsis. Chromatin alterations, notably via histone modifications, underlie innate immune memory, but the contribution of DNA methylation remains poorly understood. Using an ex vivo sepsis model, we show altered DNA methylation throughout the genome of exhausted monocytes, including genes implicated in immune dysregulation during sepsis and COVID-19 infection (e.g., Plac8). These changes are recapitulated in septic mice induced by cecal slurry injection. Methylation profiles developed in septic mice are maintained during ex vivo culture, supporting the involvement of DNA methylation in stable monocyte exhaustion memory. Methylome reprogramming is driven in part by Wnt signaling inhibition in exhausted monocytes and can be reversed with DNA methyltransferase inhibitors, Wnt agonists, or immune training molecules. Our study demonstrates the significance of altered DNA methylation in the maintenance of stable monocyte exhaustion memory.
    Keywords:  CP: Immunology; DNA methylation; TICAM2; Wnt signaling; epigenetics; innate immune memory; monocyte exhaustion; sepsis
    DOI:  https://doi.org/10.1016/j.celrep.2024.113894
  4. J Exp Biol. 2024 Mar 07. pii: jeb246158. [Epub ahead of print]227(Suppl_1):
    The plasticity of immune memory in invertebrates.
    Humberto Lanz-Mendoza, Dumas Gálvez, Jorge Contreras-Garduño.
      Whether specific immune protection after initial pathogen exposure (immune memory) occurs in invertebrates has long been uncertain. The absence of antibodies, B-cells and T-cells, and the short lifespans of invertebrates led to the hypothesis that immune memory does not occur in these organisms. However, research in the past two decades has supported the existence of immune memory in several invertebrate groups, including Ctenophora, Cnidaria, Nematoda, Mollusca and Arthropoda. Interestingly, some studies have demonstrated immune memory that is specific to the parasite strain. Nonetheless, other work does not provide support for immune memory in invertebrates or offers only partial support. Moreover, the expected biphasic immune response, a characteristic of adaptive immune memory in vertebrates, varies within and between invertebrate species. This variation may be attributed to the influence of biotic or abiotic factors, particularly parasites, on the outcome of immune memory. Despite its critical importance for survival, the role of phenotypic plasticity in immune memory has not been systematically examined in the past two decades. Additionally, the features of immune responses occurring in diverse environments have yet to be fully characterized.
    Keywords:  Ecoimmunology; Host–parasite relationship; Immune response; Phenotypic plasticity; Trained immunity
    DOI:  https://doi.org/10.1242/jeb.246158
  5. Mucosal Immunol. 2024 Mar 04. pii: S1933-0219(24)00019-9. [Epub ahead of print]
    The bacterial lysate OM-85 engages Toll-like receptors 2 and 4 triggering an immunomodulatory gene signature in human myeloid cells.
    Hanif J Khameneh, Marco Bolis, Pedro Ventura, Giada A Cassanmagnago, Berenice A Fischer, Alessandro Zenobi, Jessica Guerra, Irene Buzzago, Maurizio Bernasconi, Guido J R Zaman, Andrea Rinaldi, Simone G Moro, Federica Sallusto, Edouard Baulier, Christian Pasquali, Greta Guarda.
      OM-85 is a bacterial lysate used in clinical practice to reduce duration and frequency of recurrent respiratory tract infections. Whereas knowledge on its regulatory effects in vivo has substantially advanced, the mechanisms of OM-85 sensing remain inadequately addressed. Here, we show that the immune response to OM-85 in the mouse is largely mediated by myeloid immune cells through Toll-like receptor (TLR) 4 in vitro and in vivo. Instead, in human immune cells, TLR2 and TLR4 orchestrate the response to OM-85, which binds to both receptors as shown by surface plasmon resonance assay. RNA-sequencing analyses of human monocyte-derived dendritic cells reveal that OM-85 triggers a proinflammatory signature and a unique gene set, which is not induced by canonical agonists of TLR2 or TLR4 and comprises tolerogenic genes. A largely overlapping TLR2/4-dependent gene signature, was observed in individual subsets of primary human airway myeloid cells, highlighting the robust effects of OM-85. Collectively, our results suggest caution should be taken when relating murine studies on bacterial lysates to humans. Furthermore, our data shed light on how a standardized bacterial lysate shapes the response through TLR2 and TLR4, which are crucial for immune response, trained immunity, and tolerance.
    Keywords:  BALF; Bacterial lysate; Myeloid cells; TLR2; TLR4
    DOI:  https://doi.org/10.1016/j.mucimm.2024.02.010
  6. Adv Biol (Weinh). 2024 Mar 08. e2300673
    Single-Cell Sequencing Reveals MYOF-Enriched Monocyte/Macrophage Subcluster as a Favorable Prognostic Factor in Sepsis.
    Yi-Fan Zhang, Zhu-Jun Yi, Wen-Feng Zhang, Lian Yang, Feng Qi, Ting Yu, Zhu Zhu, Ming-Jie Li, Yao Cheng, Lei Zhao, Jian-Ping Gong, Pei-Zhi Li.
      This research utilized single-cell RNA sequencing to map the immune cell landscape in sepsis, revealing 28 distinct cell clusters and categorizing them into nine major types. Delving into the monocyte/macrophage subclusters, 12 unique subclusters are identified and pathway enrichment analyses are conducted using KEGG and GO, discovering enriched pathways such as oxidative phosphorylation and antigen processing. Further GSVA and AUCell assessments show varied activation of interferon pathways, especially in subclusters 4 and 11. The clinical correlation analysis reveals genes significantly linked to survival outcomes. Additionally, cellular differentiation in these subclusters is explored. Building on these insights, the differential gene expression within these subclusters is specifically scrutinized, which reveal MYOF as a key gene with elevated expression levels in the survivor group. This finding is further supported by in-depth pathway enrichment analysis and the examination of cellular differentiation trajectories, where MYOF's role became evident in the context of immune response regulation and sepsis progression. Validating the role of the MYOF gene in sepsis, a dose-dependent response to LPS in THP-1 cells and C57 mice is observed. Finally, inter-cellular communications are analyzed, particularly focusing on the MYOF+Mono/Macro subcluster, which indicates a pivotal role in immune regulation and potential therapeutic targeting.
    Keywords:  MYOF; monocytes and macrophages; peripheral blood mononuclear cells (PBMCs); prognostic marker; sepsis; single-cell analysis
    DOI:  https://doi.org/10.1002/adbi.202300673
  7. Immunity. 2024 Feb 28. pii: S1074-7613(24)00080-3. [Epub ahead of print]
    The transcription factor NF-κB orchestrates nucleosome remodeling during the primary response to Toll-like receptor 4 signaling.
    An-Chieh Feng, Brandon J Thomas, Prabhat K Purbey, Filipe Menegatti de Melo, Xin Liu, Allison E Daly, Fei Sun, Jerry Hung-Hao Lo, Lijing Cheng, Michael F Carey, Philip O Scumpia, Stephen T Smale.
      Inducible nucleosome remodeling at hundreds of latent enhancers and several promoters shapes the transcriptional response to Toll-like receptor 4 (TLR4) signaling in macrophages. We aimed to define the identities of the transcription factors that promote TLR-induced remodeling. An analysis strategy based on ATAC-seq and single-cell ATAC-seq that enriched for genomic regions most likely to undergo remodeling revealed that the transcription factor nuclear factor κB (NF-κB) bound to all high-confidence peaks marking remodeling during the primary response to the TLR4 ligand, lipid A. Deletion of NF-κB subunits RelA and c-Rel resulted in the loss of remodeling at high-confidence ATAC-seq peaks, and CRISPR-Cas9 mutagenesis of NF-κB-binding motifs impaired remodeling. Remodeling selectivity at defined regions was conferred by collaboration with other inducible factors, including IRF3- and MAP-kinase-induced factors. Thus, NF-κB is unique among TLR4-activated transcription factors in its broad contribution to inducible nucleosome remodeling, alongside its ability to activate poised enhancers and promoters assembled into open chromatin.
    Keywords:  IRF3; NF-κB; chromatin; macrophages; nucleosome remodeling; transcription
    DOI:  https://doi.org/10.1016/j.immuni.2024.02.004
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