bims-traimu Biomed News
on Trained immunity
Issue of 2023–05–14
eleven papers selected by
Yantong Wan, Southern Medical University
  1. Subcutaneous BCG vaccination protects against streptococcal pneumonia via regulating innate immune responses in the lung.
  2. A single-cell view on host immune transcriptional response to in vivo BCG-induced trained immunity.
  3. Effect of MMR Vaccination to Mitigate Severe Sequelae Associated With COVID-19: Challenges and Lessons Learned.
  4. Metabolic reprogramming of immune cells following vaccination: from metabolites to personalized vaccinology.
  5. Author Correction: Parenteral BCG vaccine induces lung-resident memory macrophages and trained immunity via the gut-lung axis.
  6. The glycolysis/HIF-1α axis defines the inflammatory role of IL-4-primed macrophages.
  7. Rapid glycolytic activation accompanying innate immune responses: mechanisms and function.
  8. Randomized clinical trials of COVID-19 vaccines: Do adenovirus-vector vaccines have beneficial non-specific effects?
  9. The immune hunger games: the effects of fasting on monocytes.
  10. No evidence for trans-generational immune priming in Drosophila melanogaster.
  11. The role of efferocytosis-fueled macrophage metabolism in the resolution of inflammation.
  1. EMBO Mol Med. 2023 May 09. e17084
    Subcutaneous BCG vaccination protects against streptococcal pneumonia via regulating innate immune responses in the lung.
    Alisha Kang, Gluke Ye, Ramandeep Singh, Sam Afkhami, Jegarubee Bavananthasivam, Xiangqian Luo, Maryam Vaseghi-Shanjani, Fatemah Aleithan, Anna Zganiacz, Mangalakumari Jeyanathan, Zhou Xing.
      Bacillus Calmette-Guérin (BCG) still remains the only licensed vaccine for TB and has been shown to provide nonspecific protection against unrelated pathogens. This has been attributed to the ability of BCG to modulate the innate immune system, known as trained innate immunity (TII). Trained innate immunity is associated with innate immune cells being in a hyperresponsive state leading to enhanced host defense against heterologous infections. Both epidemiological evidence and prospective studies demonstrate cutaneous BCG vaccine-induced TII provides enhanced innate protection against heterologous pathogens. Regardless of the extensive progress made thus far, the effect of cutaneous BCG vaccination against heterologous respiratory bacterial infections and the underlying mechanisms still remain unknown. Here, we show that s.c. BCG vaccine-induced TII provides enhanced heterologous innate protection against pulmonary Streptococcus pneumoniae infection. We further demonstrate that this enhanced innate protection is mediated by enhanced neutrophilia in the lung and is independent of centrally trained circulating monocytes. New insight from this study will help design novel effective vaccination strategies against unrelated respiratory bacterial pathogens.
    Keywords:  Streptococcus pneumoniae infection; lung; subcutaneous BCG vaccine; tissue-resident macrophages; trained innate immunity
    DOI:  https://doi.org/10.15252/emmm.202217084
  2. Cell Rep. 2023 May 07. pii: S2211-1247(23)00498-9. [Epub ahead of print]42(5): 112487
    A single-cell view on host immune transcriptional response to in vivo BCG-induced trained immunity.
    Wenchao Li, Simone J C F M Moorlag, Valerie A C M Koeken, Rutger J Röring, L Charlotte J de Bree, Vera P Mourits, Manoj K Gupta, Bowen Zhang, Jianbo Fu, Zhenhua Zhang, Inge Grondman, Krista E van Meijgaarden, Liang Zhou, Ahmed Alaswad, Leo A B Joosten, Reinout van Crevel, Cheng-Jian Xu, Mihai G Netea, Yang Li.
      Bacillus Calmette-Guérin (BCG) vaccination is a prototype model for the study of trained immunity (TI) in humans, and results in a more effective response of innate immune cells upon stimulation with heterologous stimuli. Here, we investigate the heterogeneity of TI induction by single-cell RNA sequencing of immune cells collected from 156 samples. We observe that both monocytes and CD8+ T cells show heterologous transcriptional responses to lipopolysaccharide, with an active crosstalk between these two cell types. Furthermore, the interferon-γ pathway is crucial in BCG-induced TI, and it is upregulated in functional high responders. Data-driven analyses and functional experiments reveal STAT1 to be one of the important transcription factors for TI shared in all identified monocyte subpopulations. Finally, we report the role of type I interferon-related and neutrophil-related TI transcriptional programs in patients with sepsis. These findings provide comprehensive insights into the importance of monocyte heterogeneity during TI in humans.
    Keywords:  BCG; CP: Immunology; IFN-γ; STAT1; in vivo training; monocyte heterogeneity; single-cell RNA-seq; trained immunity
    DOI:  https://doi.org/10.1016/j.celrep.2023.112487
  3. Med Res Arch. 2023 Feb;pii: 3598. [Epub ahead of print]11(2):
    Effect of MMR Vaccination to Mitigate Severe Sequelae Associated With COVID-19: Challenges and Lessons Learned.
    Mairi C Noverr, Junko Yano, Michael E Hagensee, Hui-Yi Lin, Mary C Meyaski, Erin Meyaski, Jennifer Cameron, Judd Shellito, Amber Trauth, Paul L Fidel.
      Mortality in COVID-19 cases was strongly associated with progressive lung inflammation and eventual sepsis. There is mounting evidence that live attenuated vaccines commonly administered during childhood, also provide beneficial non-specific immune effects, including reduced mortality and hospitalization due to unrelated infections. It has been proposed that live attenuated vaccine-associated non-specific effects are a result of inducing trained innate immunity to function more effectively against broader infections. In support of this, our laboratory has reported that immunization with a live attenuated fungal strain induces a novel form of trained innate immunity which provides protection against various inducers of sepsis in mice via myeloid-derived suppressor cells. Accordingly, we initiated a randomized control clinical trial with the live attenuated Measles, Mumps, Rubella (MMR) vaccine in healthcare workers in the greater New Orleans area aimed at preventing/reducing severe lung inflammation/sepsis associated with COVID-19 (ClinicalTrials.gov Identifier: NCT04475081). Included was an outcome to evaluate the myeloid-derived suppressor cell populations in blood between those administered the MMR vaccine vs placebo. The unanticipated emergency approval of several COVID-19 vaccines in the midst of the MMR clinical trials eliminated the ability to examine effects of the MMR vaccine on COVID-19-related health status. Unfortunately, we were also unable to show any impact of the MMR vaccine on peripheral blood myeloid-derived suppressor cells due to several inherent limitations (low percentages of blood leukocytes, small sample size), that also included a collaboration with a similar trial (CROWN CORONATION; ClinicalTrials.gov Identifier: NCT04333732) in St. Louis, MO. In contrast, monitoring the COVID-19 vaccine response in trial participants revealed that high COVID-19 antibody titers occurred more often in those who received the MMR vaccine vs placebo. While the trial was largely inconclusive, lessons learned from addressing several trial-associated challenges may aid future studies that test the non-specific beneficial immune effects of live attenuated vaccines.
    DOI:  https://doi.org/10.18103/mra.v11i2.3598
  4. Curr Med Chem. 2023 May 09.
    Metabolic reprogramming of immune cells following vaccination: from metabolites to personalized vaccinology.
    Michele Mussap, Melania Puddu, Vassilios Fanos.
      Identifying metabolic signatures induced by the immune response to vaccines allows to discriminate vaccinated from non-vaccinated subjects and decipher the molecular mechanisms associated with the host immune response. This review illustrates and discusses the results of metabolomics-based studies on the innate and adaptive immune response to vaccines, long-term functional reprogramming (immune memory), and adverse reactions. Glycolysis is not overexpressed by vaccines, suggesting that the immune cell response to vaccinations does not require rapid energy availability as that is necessary during an infection. Vaccines strongly impact lipids metabolism, including saturated or unsaturated fatty acids, inositol phosphate, and cholesterol. Cholesterol is strategic for synthesizing 25-hydroxycholesterol in activated macrophages and dendritic cells and stimulates the conversion of macrophages and T cells in M2 macrophage and Treg, respectively. In conclusion, the large-scale application of metabolomics enables the identification of candidate predictive biomarkers of vaccine efficacy/tolerability.
    Keywords:  immune cells; metabolic reprogramming; metabolomics; system vaccinology; trained immunity; vaccines
    DOI:  https://doi.org/10.2174/0929867330666230509110108
  5. Nat Immunol. 2023 May 09.
    Author Correction: Parenteral BCG vaccine induces lung-resident memory macrophages and trained immunity via the gut-lung axis.
    Mangalakumari Jeyanathan, Maryam Vaseghi-Shanjani, Sam Afkhami, Jensine A Grondin, Alisha Kang, Michael R D'Agostino, Yushi Yao, Shreya Jain, Anna Zganiacz, Zachary Kroezen, Meera Shanmuganathan, Ramandeep Singh, Anna Dvorkin-Gheva, Philip Britz-McKibbin, Waliul I Khan, Zhou Xing.
      
    DOI:  https://doi.org/10.1038/s41590-023-01525-x
  6. Cell Rep. 2023 May 06. pii: S2211-1247(23)00482-5. [Epub ahead of print]42(5): 112471
    The glycolysis/HIF-1α axis defines the inflammatory role of IL-4-primed macrophages.
    Buyun Dang, Qingxiang Gao, Lishan Zhang, Jia Zhang, Hanyi Cai, Yanhui Zhu, Qiumei Zhong, Junqiao Liu, Yujia Niu, Kairui Mao, Nengming Xiao, Wen-Hsien Liu, Shu-Hai Lin, Jialiang Huang, Stanley Ching-Cheng Huang, Ping-Chih Ho, Shih-Chin Cheng.
      T helper type 2 (Th2) cytokine-activated M2 macrophages contribute to inflammation resolution and wound healing. This study shows that IL-4-primed macrophages exhibit a stronger response to lipopolysaccharide stimulation while maintaining M2 signature gene expression. Metabolic divergence between canonical M2 and non-canonical proinflammatory-prone M2 (M2INF) macrophages occurs after the IL-4Rα/Stat6 axis. Glycolysis supports Hif-1α stabilization and proinflammatory phenotype of M2INF macrophages. Inhibiting glycolysis blunts Hif-1α accumulation and M2INF phenotype. Wdr5-dependent H3K4me3 mediates the long-lasting effect of IL-4, with Wdr5 knockdown inhibiting M2INF macrophages. Our results also show that the induction of M2INF macrophages by IL-4 intraperitoneal injection and transferring of M2INF macrophages confer a survival advantage against bacterial infection in vivo. In conclusion, our findings highlight the previously neglected non-canonical role of M2INF macrophages and broaden our understanding of IL-4-mediated physiological changes. These results have immediate implications for how Th2-skewed infections could redirect disease progression in response to pathogen infection.
    Keywords:  CP: Immunology; CP: Metabolism; Hif1α; IL-4; M2 macrophage; epigenetics; glycolysis; trained immunity
    DOI:  https://doi.org/10.1016/j.celrep.2023.112471
  7. Front Immunol. 2023 ;14 1180488
    Rapid glycolytic activation accompanying innate immune responses: mechanisms and function.
    Dmitry Namgaladze, Bernhard Brüne.
      Innate immune responses to pathogens, mediated by activation of pattern recognition receptors and downstream signal transduction cascades, trigger rapid transcriptional and epigenetic changes to support increased expression of pro-inflammatory cytokines and other effector molecules. Innate immune cells also rapidly rewire their metabolism. The most prominent metabolic alteration following innate immune activation is rapid up-regulation of glycolysis. In this mini-review, we summarize recent advances regarding the mechanisms of rapid glycolytic activation in innate immune cells, highlighting the relevant signaling components. We also discuss the impact of glycolytic activation on inflammatory responses, including the recently elucidated links of metabolism and epigenetics. Finally, we highlight unresolved mechanistic details of glycolytic activation and possible avenues of future research in this area.
    Keywords:  dendritic cell; glycolysis; inflammation; macrophage; metabolism; pattern recognition receptors
    DOI:  https://doi.org/10.3389/fimmu.2023.1180488
  8. iScience. 2023 May 19. 26(5): 106733
    Randomized clinical trials of COVID-19 vaccines: Do adenovirus-vector vaccines have beneficial non-specific effects?
    Christine S Benn, Frederik Schaltz-Buchholzer, Sebastian Nielsen, Mihai G Netea, Peter Aaby.
      We examined the possible non-specific effects of novel mRNA- and adenovirus-vector COVID-19 vaccines by reviewing the randomized control trials (RCTs) of mRNA and adenovirus-vector COVID-19 vaccines. We calculated mortality risk ratios (RRs) for mRNA COVID-19 vaccines vs. placebo recipients and compared them with the RR for adenovirus-vector COVID-19 vaccine recipients vs. controls. The RR for overall mortality of mRNA vaccines vs. placebo was 1.03 (95% confidence interval [CI]: 0.63-1.71). In the adenovirus-vector vaccine RCTs, the RR for overall mortality was 0.37 (0.19-0.70). The two vaccine types differed significantly with respect to impact on overall mortality (p = 0.015). The RCTs of COVID-19 vaccines were unblinded rapidly, and controls were vaccinated. The results may therefore not be representative of the long-term effects. However, the data argue for performing RCTs of mRNA and adenovirus-vector vaccines head-to-head comparing long-term effects on overall mortality.
    Keywords:  Microbiology; Virology
    DOI:  https://doi.org/10.1016/j.isci.2023.106733
  9. Cell Mol Immunol. 2023 May 10.
    The immune hunger games: the effects of fasting on monocytes.
    Jorge Domínguez-Andrés, Holger Reinecke, Yahya Sohrabi.
      
    DOI:  https://doi.org/10.1038/s41423-023-01033-w
  10. bioRxiv. 2023 Apr 25. pii: 2023.04.25.538340. [Epub ahead of print]
    No evidence for trans-generational immune priming in Drosophila melanogaster.
    R Radhika, Brian P Lazzaro.
      Most organisms are under constant and repeated exposure to pathogens, leading to perpetual natural selection for more effective ways to fight-off infections. This could include the evolution of memory-based immunity to increase protection from repeatedly-encountered pathogens both within and across generations. There is mixed evidence for intra- and trans-generational priming in non-vertebrates, which lack the antibody-mediated acquired immunity characteristic of vertebrates. In this work, we tested for trans-generational immune priming in adult offspring of the fruit fly, Drosophila melanogaster , after maternal challenge with 10 different bacterial pathogens. We focused on natural opportunistic pathogens of Drosophila spanning a range of virulence from 10% to 100% host mortality. We infected mothers via septic injury and tested for enhanced resistance to infection in their adult offspring, measured as the ability to suppress bacterial proliferation and survive infection. We categorized the mothers into four classes for each bacterium tested: those that survived infection, those that succumbed to infection, sterile-injury controls, and uninjured controls. We found no evidence for trans-generational priming by any class of mother in response to any of the bacteria.
    DOI:  https://doi.org/10.1101/2023.04.25.538340
  11. Immunol Rev. 2023 May 09.
    The role of efferocytosis-fueled macrophage metabolism in the resolution of inflammation.
    Maaike Schilperoort, David Ngai, Santosh R Sukka, Kleopatra Avrampou, Hongxue Shi, Ira Tabas.
      The phagocytosis of dying cells by macrophages, termed efferocytosis, is a tightly regulated process that involves the sensing, binding, engulfment, and digestion of apoptotic cells. Efferocytosis not only prevents tissue necrosis and inflammation caused by secondary necrosis of dying cells, but it also promotes pro-resolving signaling in macrophages, which is essential for tissue resolution and repair following injury or inflammation. An important factor that contributes to this pro-resolving reprogramming is the cargo that is released from apoptotic cells after their engulfment and phagolysosomal digestion by macrophages. The apoptotic cell cargo contains amino acids, nucleotides, fatty acids, and cholesterol that function as metabolites and signaling molecules to bring about this re-programming. Here, we review efferocytosis-induced changes in macrophage metabolism that mediate the pro-resolving functions of macrophages. We also discuss various strategies, challenges, and future perspectives related to drugging efferocytosis-fueled macrophage metabolism as strategy to dampen inflammation and promote resolution in chronic inflammatory diseases.
    Keywords:  cell metabolism; efferocytosis; inflammation resolution; macrophages
    DOI:  https://doi.org/10.1111/imr.13214
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