bims-traimu Biomed News
on Trained immunity
Issue of 2022‒09‒11
thirteen papers selected by
Yantong Wan
Southern Medical University

  1. Mucosal Immunol. 2022 Sep 05.
      Immunological memory of innate immune cells, also termed "trained immunity", allows for cross-protection against distinct pathogens, but may also drive chronic inflammation. Recent studies have shown that memory responses associated with type 2 immunity do not solely rely on adaptive immune cells, such as T- and B cells, but also involve the innate immune system and epithelial cells. Memory responses have been described for monocytes, macrophages and airway epithelial cells of asthmatic patients as well as for macrophages and group 2 innate lymphoid cells (ILC2) from allergen-sensitized or helminth-infected mice. The metabolic and epigenetic mechanisms that mediate allergen- or helminth-induced reprogramming of innate immune cells are only beginning to be uncovered. Trained immunity has been implicated in helminth-driven immune regulation and allergen-specific immunotherapy, suggesting its exploitation in future therapies. Here, we discuss recent advances and key remaining questions regarding the mechanisms and functions of trained type 2 immunity in infection and inflammation.
  2. Expert Rev Clin Immunol. 2022 Sep 05.
      INTRODUCTION: Trained Immunity (TI) refers to the long-term modulation of the innate immune response, based on previous interactions with microbes, microbial ligands or endogenous substances. Through metabolic and epigenetic reprogramming, monocytes, macrophages and neutrophils develop an enhanced capacity to mount innate immune responses to subsequent stimuli and this is persistent due to alterations at the myeloid progenitor compartment.AREAS COVERED: The purpose of this article is to review the current understanding of the TI process and discuss about its potential clinical implications in the near future. We address the evidence of TI involvement in various diseases, the currently developed new therapy, and discuss how TI may lead to new clinical tools to improve existing standards of care.
    EXPERT OPINION: The state of art in this domain has made considerable progress, linking TI-related mechanisms in multiple immune-mediated pathologies, starting with infections to autoimmune disorders and cancers. As a relatively new area of immunology, it has seen fast progress with many of its applications ready to be investigated in clinical settings.
    Keywords:  Atherosclerosis; cancer; inflammation; trained immunity; transplantation; vaccination
  3. Front Immunol. 2022 ;13 943667
      Bacillus Calmette-Guérin (BCG) is a licensed prophylactic vaccine against tuberculosis (TB). Current TB vaccine efforts focus on improving BCG effects through recombination or genetic attenuation and/or boost with different vaccines. Recent years, it was revealed that BCG could elicit non-specific heterogeneous protection against other pathogens such as viruses through a process termed trained immunity. Previously, we constructed a recombinant BCG (rBCG-DisA) with elevated c-di-AMP as endogenous adjuvant by overexpressing di-adenylate cyclase of Mycobacterium tuberculosis DisA, and found that rBCG-DisA induced enhanced immune responses by subcutaneous route in mice after M. tuberculosis infection. In this study, splenocytes from rBCG-DisA immunized mice by intravenous route (i.v) elicited greater proinflammatory cytokine responses to homologous and heterologous re-stimulations than BCG. After M. tuberculosis infection, rBCG-DisA immunized mice showed hallmark responses of trained immunity including potent proinflammatory cytokine responses, enhanced epigenetic changes, altered lncRNA expressions and metabolic rewiring in bone marrow cells and other tissues. Moreover, rBCG-DisA immunization induced higher levels of antibodies and T cells responses in the lung and spleen of mice after M. tuberculosis infection. It was found that rBCG-DisA resided longer than BCG in the lung of M. tuberculosis infected mice implying prolonged duration of vaccine efficacy. Then, we found that rBCG-DisA boosting could prolong survival of BCG-primed mice over 90 weeks against M. tuberculosis infection. Our findings provided in vivo experimental evidence that rBCG-DisA with c-di-AMP as endogenous adjuvant induced enhanced trained immunity and adaptive immunity. What's more, rBCG-DisA showed promising potential in prime-boost strategy against M. tuberculosis infection in adults.
    Keywords:  Bacillus Calmette-Guérin; Mycobacterium tuberculosis; adjuvant; cyclic di-AMP; trained immunity
  4. Dev Comp Immunol. 2022 Sep 03. pii: S0145-305X(22)00190-2. [Epub ahead of print] 104528
      Invertebrates' immune priming or innate immune memory is an analogous response to the vertebrates' adaptive memory. We investigated if honey bees have immune memory. We compared survival and immune response between bees that were: 1) manipulated (Naïve), 2) challenged twice with the same pathogen Escherichia coli (Memory), 3) challenged twice with different pathogens (Staphylococcus aureus versus E. coli, Micrococcus lysodeikticus versus E. coli), or 4) with PBS (the diluent of bacteria) versus E. coli (heterologous challenge; Control). Results indicate better survival in the Memory than the Control group, and the Memory group showed a similar survival than Naïve insects. The Memory group had higher lytic activity but lower prophenoloxidase, phenoloxidase activity, and hemocyte count than the Control and Naïve groups. No differences were found in relative expression of defensin-1. This first demonstration of immune memory opens the questions about its molecular mechanisms and whether, immune memory could be used against natural parasites that affect honey bees, hence, if they could be "vaccinated" against some natural parasites.
    Keywords:  Colony collapse disorder; Ecoimmunology; Host-parasite relationship; Immune priming; Innate immunity; Trained immunity
  5. Microbes Infect. 2022 Sep 06. pii: S1286-4579(22)00113-7. [Epub ahead of print] 105043
      2021 was the year of the 100th anniversary of the first administration of the Bacillus Calmette-Guérin (BCG) to a human being. It was the start of a long journey of the world's most widely used vaccine and the oldest vaccine still in use. More than 4 billion children have been vaccinated with BCG for protection against tuberculosis. However, over the years it became apparent that BCG also has beneficial non-specific effects. As such, it provides protection against various heterologous infectious and non-infectious diseases and is used to treat non-muscle-invasive bladder cancer. As BCG was developed at the Institut Pasteur de Lille by Albert Calmette and Camille Guérin, the Institute has celebrated this important anniversary with an international scientific symposium on all aspects of BCG, held from November 17 to 19, 2021 at the Institut Pasteur de Lille. It covered BCG against tuberculosis and described novel vaccine approaches, the effect of BCG against heterologous infections, including BCG and COVID-19, the effect of BCG against cancer, and BCG against auto-immune and inflammatory diseases. To discuss these areas, the symposium gathered close to 200 participants from all five continents, 2/3 on-line. This article presents the highlights of this 3rd International Symposium on BCG.
    Keywords:  COVID-19; Tuberculosis; allergy; cancer; diabetes; trained innate immunity
  6. STAR Protoc. 2022 Sep 16. 3(3): 101652
      Vaccination route dictates the quality and localization of immune responses within tissues. Intranasal vaccination seeds tissue-resident adaptive immunity, alongside trained innate responses within the lung/airways, critical for superior protection against SARS-CoV-2. This protocol encompasses intranasal vaccination in mice, step-by-step bronchoalveolar lavage for both cellular and acellular airway components, lung mononuclear cell isolation, and detailed flow cytometric characterization of lung tissue-resident memory T cell responses, and airway macrophage-trained innate immunity. For complete details on the use and execution of this protocol, please refer to Afkhami et al. (2022).
    Keywords:  Cell isolation; Flow Cytometry/Mass Cytometry; Immunology
  7. Int J Mol Sci. 2022 Aug 31. pii: 9880. [Epub ahead of print]23(17):
      Vaccination, being able to prevent millions of cases of infectious diseases around the world every year, is the most effective medical intervention ever introduced. However, immunosenescence makes vaccines less effective in providing protection to older people. Although most studies explain that this is mainly due to the immunosenescence of T and B cells, the immunosenescence of innate immunity can also be a significant contributing factor. Alterations in function, number, subset, and distribution of blood neutrophils, monocytes, and natural killer and dendritic cells are detected in aging, thus potentially reducing the efficacy of vaccines in older individuals. In this paper, we focus on the immunosenescence of the innate blood immune cells. We discuss possible strategies to counteract the immunosenescence of innate immunity in order to improve the response to vaccination. In particular, we focus on advances in understanding the role and the development of new adjuvants, such as TLR agonists, considered a promising strategy to increase vaccination efficiency in older individuals.
    Keywords:  adjuvants; aging; dendritic cells; immunosenescence; immunostimulation; innate immunity; trained immunity; vaccines
  8. Nat Rev Nephrol. 2022 Sep 05.
      Mortality among patients with chronic kidney disease (CKD) is largely a consequence of cardiovascular disease (CVD) and is a particular concern given the increasing prevalence of CKD. Sterile inflammation triggered by activation of the innate immune system is an important driver of both CKD and associated CVD. Several endogenous mediators, including lipoproteins, crystals such as silica, urate and cholesterol crystals, or compounds released from dying cells interact with pattern recognition receptors expressed on a variety of different cell types, leading to the release of pro-inflammatory cytokines. Disturbed regulation of the haematopoietic system by damage-associated molecular patterns, or as a consequence of clonal haematopoiesis or trained innate immunity, also contributes to the development of inflammation. In observational and genetic association studies, inflammation is linked to the progression of CKD and cardiovascular events. In 2017, the CANTOS trial of canakinumab provided evidence that inhibiting inflammation driven by NLRP3-IL-1-IL-6-mediated signalling significantly reduced cardiovascular event rates in individuals with and without CKD. Other approaches to target innate immune pathways are now under investigation for their ability to reduce cardiovascular events and slow disease progression among patients with atherosclerosis and stage 3 and 4 CKD. This Review summarizes current understanding of the role of inflammation in the pathogenesis of CKD and its associated CVD, and how this knowledge may translate into novel therapeutics.
  9. Front Immunol. 2022 ;13 914598
      Malaria is the cause of 600.000 deaths annually. However, these deaths represent only a tiny fraction of total malaria cases. Repeated natural infections with the causative agent, Plasmodium sp. parasites, induce protection from severe disease but not sterile immunity. Thus, immunity to Plasmodium is incomplete. Conversely, immunization with attenuated sporozoite stage parasites can induce sterile immunity albeit after multiple vaccinations. These different outcomes are likely to be influenced strongly by the innate immune response to different stages of the parasite lifecycle. Even small numbers of sporozoites can induce a robust proinflammatory type I interferon response, which is believed to be driven by the sensing of parasite RNA. Moreover, induction of innate like gamma-delta cells contributes to the development of adaptive immune responses. Conversely, while blood stage parasites can induce a strong proinflammatory response, regulatory mechanisms are also triggered. In agreement with this, intact parasites are relatively weakly sensed by innate immune cells, but isolated parasite molecules, notably DNA and RNA can induce strong responses. Thus, the innate response to Plasmodium parasite likely represents a trade-off between strong pro-inflammatory responses that may potentiate immunity and regulatory processes that protect the host from cytokine storms that can induce life threatening illness.
    Keywords:  Plasmodium; blood stages; innate immunity; malaria; pathogen-associated molecular patterns; pattern recognition receptors; sporozoites
  10. Biomed Res Int. 2022 ;2022 5396628
      Background: Natural killer (NK) cells are cytotoxic lymphocytes of the innate immune system, capable of killing viral-infected and cancerous cells. NK cell-mediated immunotherapy has remarkably changed the current paradigm of cancer treatment in recent years. It emerged as a safe and effective therapeutic approach for patients with advanced-stage leukemia. Several immune-escape mechanisms can be enacted by cancer cells to avoid NK-mediated killing. Exosomes released by NK cells that carry proteins and miRNAs can exert an antitumor effect. In the present study, we hypothesized that maybe exosomes derived from trained natural killer cells show more antitumor effect in comparison to non-trained one.Methods: PBMC was separated by the Ficoll method and cultured with IL-2 for 21 days to expand NK cells. The NK cells were co-cultured with K562 for 72 hours and exosome-derived co-cultured (as trained) and natural killer cell-derived exosomes (as non-trained) were extracted by Exo kit. The exosomes were confirmed by dynamic light scattering (DLS), transmission electron microscopy (TEM), flow cytometry, and western blotting. The K562 cells were separately treated by trained and non-trained exosomes and MTT assay, apoptosis, and real-time PCR were performed.
    Results: Based on flow cytometry, CD56 marker was 89.7% and 40.1% for NK cells and NK-derived exosomes, respectively. CD63 and CD9 were positive for exosomes by western blotting. The morphology of exosome was confirmed by TEM. Treated K562 cells by trained exosomes indicated the diminished cell viability and higher apoptosis. Furthermore, the trained exosomes showed up-regulation in both P53 and caspase3 genes as compared with non-trained sample. Discussion. Trained Exos showed a potent inhibitory effect on proliferation and induced apoptosis on K562 cell lines compared to the same dose of non-trained Exos. According to the results of qRT-PCR, trained Exos exerted an antitumor activity through up-regulation of caspase 3 and P53 in the apoptotic signaling pathway in tumor cells. Our findings indicate an effective action of trained Exos against cancer cells.
  11. Front Immunol. 2022 ;13 947320
      To explore the effects of SARS-CoV-2-mRNA vaccines on innate immune responses we enrolled 58 individuals who received 3 doses of the BNT162b2 vaccine in a longitudinal study; 45 of these individuals had never been SARS-CoV-2 infected. Results showed that vaccination significantly increased: 1) classical and intermediate inflammatory monocytes, 2) CD56bright, CD56dim, and CD56dim/CD16dim NK cells, and 3) IFN-γ+ ;production as well as perforin and granzyme content by NK cells. Vaccination also reduced expression of the NK inhibitory receptor ILT-2, increasing that of the stimulatory molecule 2DS2. These effects were long-lasting and were boosted by every vaccine dose. Notably, ILT-2 expressing NK cells were reduced even more robustly in COVID-19-recovereed vaccines. BNT162b1 mRNA vaccine is known to induce potent adaptive immune responses; results herein show its ability to modulate innate immune responses as well, offering further support to the indication to proceed with worldwide vaccination efforts to end the SARS-CoV-2 pandemic.
    Keywords:  IFN-γ; KIR; innate immunity; mRNA vaccine; natural killer
  12. Front Immunol. 2022 ;13 916491
      Background: Recently, bacterial components were shown to enhance immune responses by shifting immune cell metabolism towards glycolysis and lactic acid production, also known as the Warburg Effect. Currently, the effect of allergen products for immunotherapy (AIT) and commercial vaccines on immune cell metabolism is mostly unknown.Objective: To investigate the effect of AIT products (adjuvanted with either MPLA or Alum) on myeloid dendritic cell (mDC) metabolism and activation.
    Methods: Bone marrow-derived mDCs were stimulated with five allergoid-based AIT products (one adjuvanted with MPLA, four adjuvanted with Alum) and two MPLA-adjuvanted vaccines and analyzed for their metabolic activation, expression of cell surface markers, and cytokine secretion by ELISA. mDCs were pre-incubated with either immunological or metabolic inhibitors or cultured in glucose- or glutamine-free culture media and subsequently stimulated with the MPLA-containing AIT product (AIT product 1). mDCs were co-cultured with allergen-specific CD4+ T cells to investigate the contribution of metabolic pathways to the T cell priming capacity of mDCs stimulated with AIT product 1.
    Results: Both the MPLA-containing AIT product 1 and commercial vaccines, but not the Alum-adjuvanted AIT products, activated Warburg metabolism and TNF-α secretion in mDCs. Further experiments focused on AIT product 1. Metabolic analysis showed that AIT product 1 increased glycolytic activity while also inducing the secretion of IL-1β, IL-10, IL-12, and TNF-α. Both rapamycin (mTOR-inhibitor) and SP600125 (SAP/JNK MAPK-inhibitor) dose-dependently suppressed the AIT product 1-induced Warburg Effect, glucose consumption, IL-10-, and TNF-α secretion. Moreover, both glucose- and glutamine deficiency suppressed secretion of all investigated cytokines (IL-1β, IL-10, and TNF-α). Glucose metabolism in mDCs was also critical for the (Th1-biased) T cell priming capacity of AIT product 1-stimulated mDCs, as inhibition of mTOR signaling abrogated their ability to induce Th1-responses.
    Conclusion: The AIT product and commercial vaccines containing the adjuvant MPLA were shown to modulate the induction of immune responses by changing the metabolic state of mDCs. Better understanding the mechanisms underlying the interactions between cell metabolism and immune responses will allow us to further improve vaccine development and AIT.
    Keywords:  MPLA: monophosphoryl lipid A; Warburg Effect; allergen specific immunotherapy; immune metabolism; vaccine