bims-traimu Biomed News
on Trained immunity
Issue of 2024–08–18
eight papers selected by
Yantong Wan, Southern Medical University
  1. Induction of trained immunity in broiler chickens following delivery of oligodeoxynucleotide containing CpG motifs to protect against Escherichia coli septicemia.
  2. Trained immunity suppression determines kidney allograft survival.
  3. BCG vaccination of healthcare workers for protection against COVID-19: 12-month outcomes from an international randomised controlled trial.
  4. A single-cell analysis of the NK-cell landscape reveals that dietary restriction boosts NK cell antitumor immunity via Eomesdermin.
  5. Broad-spectrum antibiotics disrupt homeostatic efferocytosis.
  6. Prior Fc receptor activation primes macrophages for increased sensitivity to IgG via long-term and short-term mechanisms.
  7. Hypoxia-induced downregulation of PGK1 crotonylation promotes tumorigenesis by coordinating glycolysis and the TCA cycle.
  8. ACOD1 mediates Staphylococcus aureus-induced inflammatory response via the TLR4/NF-κB signaling pathway.
  1. Sci Rep. 2024 08 14. 14(1): 18882
    Induction of trained immunity in broiler chickens following delivery of oligodeoxynucleotide containing CpG motifs to protect against Escherichia coli septicemia.
    Iresha Subhasinghe, Khawaja Ashfaque Ahmed, Lisanework E Ayalew, Hemlata Gautam, Shelly Popowich, Ayumi Matsuyama-Kato, Betty Chow-Lockerbie, Suresh K Tikoo, Philip Griebel, Susantha Gomis.
      Oligodeoxynucleotides containing CpG motifs (CpG-ODN) can promote antimicrobial immunity in chickens by enriching immune compartments and activating immune cells. Innate memory, or trained immunity, has been demonstrated in humans and mice, featuring the absence of specificity to the initial stimulus and subsequently cross-protection against pathogens. We hypothesize that CpG-ODN can induce trained immunity in chickens. We delivered single or multiple administrations of CpG-ODN to birds and mitochondrial oxidative phosphorylation (OXPHOS) and glycolysis of peripheral blood mononuclear cells were quantified using Seahorse XFp. Next, chickens were administered with CpG-ODN twice at 1 and 4 day of age and challenged with Escherichia coli at 27 days of age. The CpG-ODN administered groups had significantly higher mitochondrial OXPHOS until 21 days of age while cellular glycolysis gradually declined by 14 days of age. The group administered with CpG-ODN twice at 1 and 4 days of age had significantly higher survival, lower clinical score and bacterial load following challenge with E. coli at 27 d of age. This study demonstrated the induction of trained immunity in broiler chickens following administration of CpG-ODN twice during the first 4 days of age to protect birds against E. coli septicemia at 27 days of age.
    Keywords:  Broiler chicken; Cellular glycolysis; CpG-ODN; Innate immune memory; Mitochondrial OXPHOS; Trained immunity
    DOI:  https://doi.org/10.1038/s41598-024-69781-x
  2. Am J Transplant. 2024 Aug 13. pii: S1600-6135(24)00492-1. [Epub ahead of print]
    Trained immunity suppression determines kidney allograft survival.
    Inge Jonkman, Maaike M E Jacobs, Yutaka Negishi, Cansu Yanginlar, Joost H A Martens, Marijke Baltissen, Michiel Vermeulen, Martijn W F van den Hoogen, Marije Baas, Johan van der Vlag, Zahi A Fayad, Abraham J P Teunissen, Joren C Madsen, Jordi Ochando, Leo A B Joosten, Mihai G Netea, Willem J M Mulder, Musa M Mhlanga, Luuk B Hilbrands, Nils Rother, Raphaël Duivenvoorden.
      The innate immune system plays an essential role in regulating the immune responses to kidney transplantation, but the mechanisms through which innate immune cells influence long-term graft survival are unclear. The current study highlights the vital role of trained immunity in kidney allograft survival. Trained immunity describes the epigenetic and metabolic changes that innate immune cells undergo following an initial stimulus, allowing them have a stronger inflammatory response to subsequent stimuli. We stimulated healthy peripheral blood mononuclear cells (PBMCs) with pre- and post-transplantation serum of kidney transplant patients, and immunosuppressive drugs in an in vitro trained immunity assay and measured tumor necrosis factor (TNF) and interleukin-6 (IL-6) cytokine levels in the supernatant as a readout for trained immunity. We show that the serum of kidney transplant recipients collected one week after transplantation can suppress trained immunity. Importantly, we found that kidney transplant recipients whose serum most strongly suppressed trained immunity, rarely experienced graft loss. This suppressive effect of post-transplant serum is likely mediated, by previously unreported effects of immunosuppressive drugs. Our findings provide mechanistic insights into the role of innate immunity in kidney allograft survival, uncovering trained immunity as a potential therapeutic target for improving graft survival.
    Keywords:  Trained immunity; graft survival; innate immunity; kidney transplantation
    DOI:  https://doi.org/10.1016/j.ajt.2024.08.006
  3. J Infect. 2024 Aug 08. pii: S0163-4453(24)00179-8. [Epub ahead of print] 106245
    BCG vaccination of healthcare workers for protection against COVID-19: 12-month outcomes from an international randomised controlled trial.
    BRACE Trial Consortium Group
       OBJECTIVES: Bacille Calmette-Guérin (BCG) vaccine has immunomodulatory effects that may provide protection against unrelated infectious diseases. We aimed to determine whether BCG vaccination protects adults against COVID-19.
    DESIGN: Phase III double blind randomised controlled trial.
    SETTING: Healthcare centres in Australia, Brazil, the Netherlands, Spain, and the United Kingdom during the COVID-19 pandemic.
    PARTICIPANTS: 3988 healthcare workers with no prior COVID-19 and no contraindication to BCG.
    INTERVENTION: Randomised 1:1 using a web-based procedure to receive a single 0.1mL intradermal dose of BCG-Denmark (BCG group, n=1999) or saline (placebo group, n=1989).
    MAIN OUTCOME MEASURES: Difference in incidence of (i) symptomatic and (ii) severe COVID-19 during the 12-months following randomisation in the modified intention to treat (mITT) population (confirmed SARS-CoV-2 naïve at inclusion).
    RESULTS: Of the 3988 participants randomised, 3386 had a negative baseline SARS-CoV-2 test and were included in the mITT population. The 12-month adjusted estimated risk of symptomatic COVID-19 was higher in the BCG group (22.6%; 95% confidence interval [CI] 20.6% to 24.5%) compared with the placebo group (19.6%; 95%CI 17.6% to 21.5%); adjusted difference +3.0 percentage points (95%CI 0.2% to 5.8%; p=0.04). The 12-month adjusted estimated risk of severe COVID-19 (mainly comprising those reporting being unable to work for ≥3 consecutive days) was 11.0% in the BCG group (95%CI 9.5% to 12.4%) compared with 9.6% in the placebo group (95%CI 8.3% to 11.1%); adjusted difference +1.3 percentage points (95%CI -0.7% to 3.3%, p=0.2). Breakthrough COVID-19 (post COVID-19 vaccination), and asymptomatic SARS-CoV-2 infections were similar in the two groups. There were 18 hospitalisations due to COVID-19 (11 in BCG group, 7 in placebo group; adjusted hazard ratio 1.56, 95%CI 0.60 to 4.02, p=0.4) and two deaths due to COVID-19, both in the placebo group.
    CONCLUSIONS: Compared to placebo, vaccination with BCG-Denmark increased the risk of symptomatic COVID-19 over 12 months among health care workers and did not decrease the risk of severe COVID-19 or post-vaccination breakthrough COVID-19.
    TRIAL REGISTRATION: ClinicalTrials.gov NCT04327206.
    Keywords:  Bacille Calmette-Guérin (BCG) Vaccine; Breakthrough infection; COVID-19; Immunity; Randomised controlled trial
    DOI:  https://doi.org/10.1016/j.jinf.2024.106245
  4. Cancer Immunol Res. 2024 Aug 16.
    A single-cell analysis of the NK-cell landscape reveals that dietary restriction boosts NK cell antitumor immunity via Eomesdermin.
    Junming He, Donglin Chen, Wei Xiong, Yuande Wang, Shasha Chen, Meixiang Yang, Zhongjun Dong.
      Abnormal metabolism in tumor cells represents a potential target for tumor therapy. In this regard, dietary restriction (DR) or its combination with anticancer drugs is of interest as it can impede the growth of tumor cells. In addition to its effects on tumor cell, DR also plays an extrinsic role in restricting tumor growth by regulating immune cells. Natural killer (NK) cells are innate immune cells involved in tumor immunosurveillance. However, it remains uncertain whether DR can assist NK cells in controlling tumor growth. Herein, we demonstrate that DR effectively inhibits metastasis of melanoma cells to the lung. Consistent with this, the regression of tumors induced by DR was minimal in mice lacking NK cells. Single-cell RNA sequencing analysis revealed that DR enriched a rejuvenated subset of CD27+CD11b+ NK cells. Mechanistically, DR activated a regulatory network involving the transcription factor Eomesodermin (Eomes), which is essential for NK-cell development. Firstly, DR promoted the expression of Eomes by optimizing mTORC1 signaling. The upregulation of Eomes revived the subset of functional CD27+CD11b+ NK cells by counteracting the expression of T-bet and downstream Zeb2. Moreover, DR enhanced the function and chemotaxis of NK cells by increasing the accessibility of Eomes to chromatin, leading to elevated expression of adhesion molecules and chemokines. Consequently, we conclude that DR therapy enhances tumor immunity through non-tumor autonomous mechanisms, including promoting NK-cell tumor immunosurveillance and activation.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-23-0944
  5. Nat Metab. 2024 Aug 09.
    Broad-spectrum antibiotics disrupt homeostatic efferocytosis.
    Pedro H V Saavedra, Alissa J Trzeciak, Allie Lipshutz, Andrew W Daman, Anya J O'Neal, Zong-Lin Liu, Zhaoquan Wang, Jesús E Romero-Pichardo, Waleska Saitz Rojas, Giulia Zago, Marcel R M van den Brink, Steven Z Josefowicz, Christopher D Lucas, Christopher J Anderson, Alexander Y Rudensky, Justin S A Perry.
      The clearance of apoptotic cells, termed efferocytosis, is essential for tissue homeostasis and prevention of autoimmunity1. Although past studies have elucidated local molecular signals that regulate homeostatic efferocytosis in a tissue2,3, whether signals arising distally also regulate homeostatic efferocytosis remains elusive. Here, we show that large peritoneal macrophage (LPM) display impairs efferocytosis in broad-spectrum antibiotics (ABX)-treated, vancomycin-treated and germ-free mice in vivo, all of which have a depleted gut microbiota. Mechanistically, the microbiota-derived short-chain fatty acid butyrate directly boosts efferocytosis efficiency and capacity in mouse and human macrophages, and rescues ABX-induced LPM efferocytosis defects in vivo. Bulk messenger RNA sequencing of butyrate-treated macrophages in vitro and single-cell messenger RNA sequencing of LPMs isolated from ABX-treated and butyrate-rescued mice reveals regulation of efferocytosis-supportive transcriptional programmes. Specifically, we find that the efferocytosis receptor T cell immunoglobulin and mucin domain containing 4 (TIM-4, Timd4) is downregulated in LPMs of ABX-treated mice but rescued by oral butyrate. We show that TIM-4 is required for the butyrate-induced enhancement of LPM efferocytosis capacity and that LPM efferocytosis is impaired beyond withdrawal of ABX. ABX-treated mice exhibit significantly worse disease in a mouse model of lupus. Our results demonstrate that homeostatic efferocytosis relies on distal metabolic signals and suggest that defective homeostatic efferocytosis may explain the link between ABX use and inflammatory disease4-7.
    DOI:  https://doi.org/10.1038/s42255-024-01107-7
  6. Dev Cell. 2024 Aug 09. pii: S1534-5807(24)00457-X. [Epub ahead of print]
    Prior Fc receptor activation primes macrophages for increased sensitivity to IgG via long-term and short-term mechanisms.
    Annalise Bond, Sareen Fiaz, Kirstin Rollins, Jazz Elaiza Q Nario, Erika T Snyder, Dixon J Atkins, Samuel J Rosen, Alyssa Granados, Siddharth S Dey, Maxwell Z Wilson, Meghan A Morrissey.
      Macrophages measure the "eat-me" signal immunoglobulin G (IgG) to identify targets for phagocytosis. We tested whether prior encounters with IgG influence macrophage appetite. IgG is recognized by the Fc receptor. To temporally control Fc receptor activation, we engineered an Fc receptor that is activated by the light-induced oligomerization of Cry2, triggering phagocytosis. Using this tool, we demonstrate that subthreshold Fc receptor activation primes mouse bone-marrow-derived macrophages to be more sensitive to IgG in future encounters. Macrophages that have previously experienced subthreshold Fc receptor activation eat more IgG-bound human cancer cells. Increased phagocytosis occurs by two discrete mechanisms-a short- and long-term priming. Long-term priming requires new protein synthesis and Erk activity. Short-term priming does not require new protein synthesis and correlates with an increase in Fc receptor mobility. Our work demonstrates that IgG primes macrophages for increased phagocytosis, suggesting that therapeutic antibodies may become more effective after initial priming doses.
    Keywords:  Fc receptor; IgG; antibodies; immune priming; macrophage; optogenetics; phagocytosis
    DOI:  https://doi.org/10.1016/j.devcel.2024.07.017
  7. Nat Commun. 2024 Aug 12. 15(1): 6915
    Hypoxia-induced downregulation of PGK1 crotonylation promotes tumorigenesis by coordinating glycolysis and the TCA cycle.
    Zihao Guo, Yang Zhang, Haoyue Wang, Liming Liao, Lingdi Ma, Yiliang Zhao, Ronghui Yang, Xuexue Li, Jing Niu, Qiaoyun Chu, Yanxia Fu, Binghui Li, Chuanzhen Yang.
      Protein post-translational modifications (PTMs) are crucial for cancer cells to adapt to hypoxia; however, the functional significance of lysine crotonylation (Kcr) in hypoxia remains unclear. Herein we report a quantitative proteomics analysis of global crotonylome under normoxia and hypoxia, and demonstrate 128 Kcr site alterations across 101 proteins in MDA-MB231 cells. Specifically, we observe a significant decrease in K131cr, K156cr and K220cr of phosphoglycerate kinase 1 (PGK1) upon hypoxia. Enoyl-CoA hydratase 1 (ECHS1) is upregulated and interacts with PGK1, leading to the downregulation of PGK1 Kcr under hypoxia. Abolishment of PGK1 Kcr promotes glycolysis and suppresses mitochondrial pyruvate metabolism by activating pyruvate dehydrogenase kinase 1 (PDHK1). A low PGK1 K131cr level is correlated with malignancy and poor prognosis of breast cancer. Our findings show that PGK1 Kcr is a signal in coordinating glycolysis and the tricarboxylic acid (TCA) cycle and may serve as a diagnostic indicator for breast cancer.
    DOI:  https://doi.org/10.1038/s41467-024-51232-w
  8. Int Immunopharmacol. 2024 Aug 11. pii: S1567-5769(24)01445-0. [Epub ahead of print]140 112924
    ACOD1 mediates Staphylococcus aureus-induced inflammatory response via the TLR4/NF-κB signaling pathway.
    Fan Dai, Xuyang Zhang, Guilan Ma, Wu Li.
      Staphylococcus aureus (SA) is a common Gram-positive bacterium that activates inflammatory cells, expressing various cytokines and inducing an inflammatory response. Recent research revealed aconitate decarboxylase 1 (ACOD1) as a regulator of the immune response through various metabolic pathways, playing a dual role in the inflammatory response. However, the mechanism by which ACOD1 participates in the regulation of SA-induced inflammatory responses in macrophages remains unknown. Therefore, this study aims to investigate the function and underlying regulatory mechanisms of ACOD1 in SA-induced inflammatory response. This study reveals that SA induced a macrophage inflammatory response and upregulated ACOD1 expression. ACOD1 knockdown significantly inhibited SA-induced macrophage inflammatory response, attenuated SA-induced nuclear envelope wrinkling, and plasma membrane rupture, and suppressed the TLR4/NF-κB signaling pathway. Furthermore, ACOD1 knockdown reduced the inflammatory response and alleviated lung tissue injury and cellular damage, leading to decreased bacterial loads in the lungs of SA-infected mice. Collectively, these findings demonstrate that SA induces an inflammatory response in macrophages and increases ACOD1 expression. ACOD1 enhances SA-induced inflammatory responses via the TLR4/NF-κB signaling pathway. Our findings highlight the significant role of ACOD1 in mediating the inflammatory response in SA-infected macrophages and elucidate its molecular mechanism in regulating the SA-induced inflammatory response.
    Keywords:  ACOD1; C57BL/6J mice; Inflammatory response; Macrophage; Staphylococcus aureus
    DOI:  https://doi.org/10.1016/j.intimp.2024.112924
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