bims-traimu Biomed News
on Trained immunity
Issue of 2023–12–10
eight papers selected by
Yantong Wan, Southern Medical University
  1. Mucosal recombinant BCG vaccine induces lung-resident memory macrophages and enhances trained immunity via mTORC2/HK1-mediated metabolic rewiring.
  2. Helicobacter pylori induces a novel form of innate immune memory via accumulation of NF-кB proteins.
  3. Bacteria-derived nanovesicles enhance tumour vaccination by trained immunity.
  4. Nanovaccines for Advancing Long-Lasting Immunity against Infectious Diseases.
  5. Innate Allorecognition in Transplantation: Ancient Mechanisms With Modern Impact.
  6. IL-15-dependent immune crosstalk between natural killer cells and dendritic cells in HIV-1 elite controllers.
  7. Metabolite itaconate in host immunoregulation and defense.
  8. Oral magnesium prevents acetaminophen-induced acute liver injury by modulating microbial metabolism.
  1. J Biol Chem. 2023 Nov 30. pii: S0021-9258(23)02546-2. [Epub ahead of print] 105518
    Mucosal recombinant BCG vaccine induces lung-resident memory macrophages and enhances trained immunity via mTORC2/HK1-mediated metabolic rewiring.
    Xiaofei Peng, Yuting Zhou, Baoying Zhang, Xiaotong Liang, Jingyu Feng, Yuejun Huang, Shufeng Weng, Ying Xu, Haibo Su.
      Bacillus Calmette-Guérin (BCG) vaccination induces a type of immune memory known as "trained immunity", characterized by the immunometabolic and epigenetic changes in innate immune cells. However, the molecular mechanism underlying the strategies for inducing and/or boosting trained immunity in alveolar macrophages remains unknown. Here, we found that mucosal vaccination with the recombinant strain rBCGPPE27 significantly augmented the trained immune response in mice, facilitating a superior protective response against Mycobacterium tuberculosis and non-related bacterial reinfection in mice when compared to BCG. Mucosal immunization with rBCGPPE27 enhanced innate cytokine production by alveolar macrophages associated with promoted glycolytic metabolism, typical of trained immunity. Deficiency of the mammalian target of rapamycin complex 2 and hexokinase 1 abolished the immunometabolic and epigenetic rewiring in mouse alveolar macrophages after mucosal rBCGPPE27 vaccination. Most noteworthy, utilizing rBCGPPE27's higher-up trained effects: The single mucosal immunization with rBCGPPE27-adjuvanted coronavirus disease (CoV-2) vaccine raised the rapid development of virus-specific immunoglobulin G antibodies, boosted pseudovirus neutralizing antibodies, and augmented T helper type 1-biased cytokine release by vaccine-specific T cells, compared to BCG/CoV-2 vaccine. These findings revealed that mucosal recombinant BCG vaccine induces lung-resident memory macrophages and enhances trained immunity via reprogramming mTORC2- and HK-1-mediated aerobic glycolysis, providing new vaccine strategies for improving tuberculosis (TB) or coronavirus variant vaccinations, and targeting innate immunity via mucosal surfaces.
    Keywords:  Bacille Calmette-Guerin; Trained immunity; glycolysis; innate immune memory; mucosal vaccination
    DOI:  https://doi.org/10.1016/j.jbc.2023.105518
  2. Front Immunol. 2023 ;14 1290833
    Helicobacter pylori induces a novel form of innate immune memory via accumulation of NF-кB proteins.
    Tobias Frauenlob, Theresa Neuper, Christof Regl, Veronika Schaepertoens, Michael S Unger, Anna-Lena Oswald, Hieu-Hoa Dang, Christian G Huber, Fritz Aberger, Silja Wessler, Jutta Horejs-Hoeck.
      Helicobacter pylori is a widespread Gram-negative pathogen involved in a variety of gastrointestinal diseases, including gastritis, ulceration, mucosa-associated lymphoid tissue (MALT) lymphoma and gastric cancer. Immune responses aimed at eradication of H. pylori often prove futile, and paradoxically play a crucial role in the degeneration of epithelial integrity and disease progression. We have previously shown that H. pylori infection of primary human monocytes increases their potential to respond to subsequent bacterial stimuli - a process that may be involved in the generation of exaggerated, yet ineffective immune responses directed against the pathogen. In this study, we show that H. pylori-induced monocyte priming is not a common feature of Gram-negative bacteria, as Acinetobacter lwoffii induces tolerance to subsequent Escherichia coli lipopolysaccharide (LPS) challenge. Although the increased reactivity of H. pylori-infected monocytes seems to be specific to H. pylori, it appears to be independent of its virulence factors Cag pathogenicity island (CagPAI), cytotoxin associated gene A (CagA), vacuolating toxin A (VacA) and γ-glutamyl transferase (γ-GT). Utilizing whole-cell proteomics complemented with biochemical signaling studies, we show that H. pylori infection of monocytes induces a unique proteomic signature compared to other pro-inflammatory priming stimuli, namely LPS and the pathobiont A. lwoffii. Contrary to these tolerance-inducing stimuli, H. pylori priming leads to accumulation of NF-кB proteins, including p65/RelA, and thus to the acquisition of a monocyte phenotype more responsive to subsequent LPS challenge. The plasticity of pro-inflammatory responses based on abundance and availability of intracellular signaling molecules may be a heretofore underappreciated form of regulating innate immune memory as well as a novel facet of the pathobiology induced by H. pylori.
    Keywords:  H. pylori; NF-кB; inflammation; innate immune memory; innate immunity; monocytes; tolerance; trained immunity
    DOI:  https://doi.org/10.3389/fimmu.2023.1290833
  3. Nat Nanotechnol. 2023 Dec 05.
    Bacteria-derived nanovesicles enhance tumour vaccination by trained immunity.
    Guangna Liu, Nana Ma, Keman Cheng, Qingqing Feng, Xiaotu Ma, Yale Yue, Yao Li, Tianjiao Zhang, Xiaoyu Gao, Jie Liang, Lizhuo Zhang, Xinwei Wang, Zhenhua Ren, Yang-Xin Fu, Xiao Zhao, Guangjun Nie.
      Trained immunity enhances the responsiveness of immune cells to subsequent infections or vaccinations. Here we demonstrate that pre-vaccination with bacteria-derived outer-membrane vesicles, which contain large amounts of pathogen-associated molecular patterns, can be used to potentiate, and enhance, tumour vaccination by trained immunity. Intraperitoneal administration of these outer-membrane vesicles to mice activates inflammasome signalling pathways and induces interleukin-1β secretion. The elevated interleukin-1β increases the generation of antigen-presenting cell progenitors. This results in increased immune response when tumour antigens are delivered, and increases tumour-antigen-specific T-cell activation. This trained immunity increased protection from tumour challenge in two distinct cancer models.
    DOI:  https://doi.org/10.1038/s41565-023-01553-6
  4. ACS Nano. 2023 Dec 06.
    Nanovaccines for Advancing Long-Lasting Immunity against Infectious Diseases.
    Xinglong Gao, Xinlian Wang, Shilin Li, Muhammad Saif Ur Rahman, Shanshan Xu, Ying Liu.
      Infectious diseases, particularly life-threatening pathogens such as small pox and influenza, have substantial implications on public health and global economies. Vaccination is a key approach to combat existing and emerging pathogens. Immunological memory is an essential characteristic used to evaluate vaccine efficacy and durability and the basis for the long-term effects of vaccines in protecting against future infections; however, optimizing the potency, improving the quality, and enhancing the durability of immune responses remains challenging and a focus for research involving investigation of nanovaccine technologies. In this review, we describe how nanovaccines can address the challenges for conventional vaccines in stimulating adaptive immune memory responses to protect against reinfection. We discuss protein and nonprotein nanoparticles as useful antigen platforms, including those with highly ordered and repetitive antigen array presentation to enhance immunogenicity through cross-linking with multiple B cell receptors, and with a focus on antigen properties. In addition, we describe how nanoadjuvants can improve immune responses by providing enhanced access to lymph nodes, lymphnode targeting, germinal center retention, and long-lasting immune response generation. Nanotechnology has the advantage to facilitate vaccine induction of long-lasting immunity against infectious diseases, now and in the future.
    Keywords:  antigen platforms; immunological memory; infectious diseases; long-lasting immune response; lymph node; lymphatic trafficking; nanoadjuvants; nanoparticles; nanotechnology; trained immunity
    DOI:  https://doi.org/10.1021/acsnano.3c07741
  5. Transplantation. 2023 Dec 05.
    Innate Allorecognition in Transplantation: Ancient Mechanisms With Modern Impact.
    Zeping Gui, Mouhamad Al Moussawy, Steven M Sanders, Khodor I Abou-Daya.
      Through the effective targeting of the adaptive immune system, solid organ transplantation became a life-saving therapy for organ failure. However, beyond 1 y of transplantation, there is little improvement in transplant outcomes. The adaptive immune response requires the activation of the innate immune system. There are no modalities for the specific targeting of the innate immune system involvement in transplant rejection. However, the recent discovery of innate allorecognition and innate immune memory presents novel targets in transplantation that will increase our understanding of organ rejection and might aid in improving transplant outcomes. In this review, we look at the latest developments in the study of innate allorecognition and innate immune memory in transplantation.
    DOI:  https://doi.org/10.1097/TP.0000000000004847
  6. Cell Rep. 2023 Dec 02. pii: S2211-1247(23)01542-5. [Epub ahead of print]42(12): 113530
    IL-15-dependent immune crosstalk between natural killer cells and dendritic cells in HIV-1 elite controllers.
    Ciputra Adijaya Hartana, Melanie Lancien, Ce Gao, Yelizaveta Rassadkina, Mathias Lichterfeld, Xu G Yu.
      As the principal effector cell population of the innate immune system, natural killer (NK) cells may make critical contributions to natural, immune-mediated control of HIV-1 replication. Using genome-wide assessments of activating and inhibitory chromatin features, we demonstrate here that cytotoxic NK (cNK) cells from elite controllers (ECs) display elevated activating histone modifications at the interleukin 2 (IL-2)/IL-15 receptor β chain and the BCL2 gene loci. These histone changes translate into increased responsiveness of cNK cells to paracrine IL-15 secretion, which coincides with higher levels of IL-15 transcription by myeloid dendritic cells in ECs. The distinct immune crosstalk between these innate immune cell populations results in improved IL-15-dependent cNK cell survival and cytotoxicity, paired with a metabolic profile biased toward IL-15-mediated glycolytic activities. Together, these results suggest that cNK cells from ECs display a programmed IL-15 response signature and support the emerging role of innate immune pathways in natural, drug-free control of HIV-1.
    Keywords:  CP: Immunology; HIV infection; IL-15; NK cells; chromatin modifications; cytotoxicity; elite controllers; metabolism; trained innate immunity
    DOI:  https://doi.org/10.1016/j.celrep.2023.113530
  7. Cell Mol Biol Lett. 2023 Dec 02. 28(1): 100
    Metabolite itaconate in host immunoregulation and defense.
    Wenchang Yang, Yaxin Wang, Kaixiong Tao, Ruidong Li.
      Metabolic states greatly influence functioning and differentiation of immune cells. Regulating the metabolism of immune cells can effectively modulate the host immune response. Itaconate, an intermediate metabolite derived from the tricarboxylic acid (TCA) cycle of immune cells, is produced through the decarboxylation of cis-aconitate by cis-aconitate decarboxylase in the mitochondria. The gene encoding cis-aconitate decarboxylase is known as immune response gene 1 (IRG1). In response to external proinflammatory stimulation, macrophages exhibit high IRG1 expression. IRG1/itaconate inhibits succinate dehydrogenase activity, thus influencing the metabolic status of macrophages. Therefore, itaconate serves as a link between macrophage metabolism, oxidative stress, and immune response, ultimately regulating macrophage function. Studies have demonstrated that itaconate acts on various signaling pathways, including Keap1-nuclear factor E2-related factor 2-ARE pathways, ATF3-IκBζ axis, and the stimulator of interferon genes (STING) pathway to exert antiinflammatory and antioxidant effects. Furthermore, several studies have reported that itaconate affects cancer occurrence and development through diverse signaling pathways. In this paper, we provide a comprehensive review of the role IRG1/itaconate and its derivatives in the regulation of macrophage metabolism and functions. By furthering our understanding of itaconate, we intend to shed light on its potential for treating inflammatory diseases and offer new insights in this field.
    Keywords:  Defense; Immunometabolism; Itaconate; Itaconate derivative
    DOI:  https://doi.org/10.1186/s11658-023-00503-3
  8. Cell Host Microbe. 2023 Dec 01. pii: S1931-3128(23)00456-0. [Epub ahead of print]
    Oral magnesium prevents acetaminophen-induced acute liver injury by modulating microbial metabolism.
    Dongping Li, Yu Chen, Meijuan Wan, Fengyi Mei, Fangzhao Wang, Peng Gu, Xianglong Zhang, Rongjuan Wei, Yunong Zeng, Hanzhao Zheng, Bangguo Chen, Qingquan Xiong, Tao Xue, Tianshan Guan, Jiayin Guo, Yuanxin Tian, Li-Yan Zeng, Zhanguo Liu, Hang Yuan, Ling Yang, Hongbin Liu, Lei Dai, Yao Yu, Yifeng Qiu, Peng Wu, Sanda Win, Tin Aung Than, Riqing Wei, Bernd Schnabl, Neil Kaplowitz, Yong Jiang, Qiang Ma, Peng Chen.
      Acetaminophen overuse is a common cause of acute liver failure (ALF). During ALF, toxins are metabolized by enzymes such as CYP2E1 and transformed into reactive species, leading to oxidative damage and liver failure. Here, we found that oral magnesium (Mg) alleviated acetaminophen-induced ALF through metabolic changes in gut microbiota that inhibit CYP2E1. The gut microbiota from Mg-supplemented humans prevented acetaminophen-induced ALF in mice. Mg exposure modulated Bifidobacterium metabolism and enriched indole-3-carboxylic acid (I3C) levels. Formate C-acetyltransferase (pflB) was identified as a key Bifidobacterium enzyme involved in I3C generation. Accordingly, a Bifidobacterium pflB knockout showed diminished I3C generation and reduced the beneficial effects of Mg. Conversely, treatment with I3C or an engineered bacteria overexpressing Bifidobacterium pflB protected against ALF. Mechanistically, I3C bound and inactivated CYP2E1, thus suppressing formation of harmful reactive intermediates and diminishing hepatocyte oxidative damage. These findings highlight how interactions between Mg and gut microbiota may help combat ALF.
    Keywords:  Bifidobacterium; acute liver failure; gut microbiota; indole-3-carboxylic acid; magnesium
    DOI:  https://doi.org/10.1016/j.chom.2023.11.006
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