bims-traimu Biomed News
on Trained immunity
Issue of 2023–09–03
seven papers selected by
Yantong Wan, Southern Medical University
  1. Outer Membrane Vesicle-Based Nanohybrids Target Tumor-Associated Macrophages to Enhance Trained Immunity-Related Vaccine-Generated Antitumor Activity.
  2. Sepsis induces non-classic innate immune memory in granulocytes.
  3. Mycobacterium tuberculosis infection associated immune perturbations correlate with antiretroviral immunity.
  4. A suspension of inactivated bacteria used for vaccination against recurrent urinary tract infections increases the phagocytic activity of murine macrophages.
  5. The malate-aspartate shuttle is important for de novo serine biosynthesis.
  6. Pneumonic plague protection induced by a monophosphoryl lipid A decorated Yersinia outer-membrane-vesicle vaccine.
  7. Toll-like Receptor Agonist CBLB502 Protects Against Cisplatin-induced Liver and Kidney Damage in Mice.
  1. Adv Mater. 2023 Aug 29. e2306158
    Outer Membrane Vesicle-Based Nanohybrids Target Tumor-Associated Macrophages to Enhance Trained Immunity-Related Vaccine-Generated Antitumor Activity.
    Jie Liang, Fei Zhu, Keman Cheng, Nana Ma, Xiaotu Ma, Qingqing Feng, Chen Xu, Xiaoyu Gao, Xinwei Wang, Jian Shi, Xiao Zhao, Guangjun Nie.
      Trained immunity refers to the innate immune system building memory-like features in response to subsequent infections and vaccinations. Compared with classical tumor vaccines, trained immunity-related vaccines (TIrV) are independent of tumor-specific antigens. Bacterial outer membrane vesicles (OMVs) contain an abundance of PAMPs and have the potential to act as TIrV-inducer, but face challenges in endotoxin tolerance, systemic delivery, long-term training, and trained tumor-associated macrophage (TAM)-mediated antitumor phagocytosis. Here, we developed an OMV-based TIrV, OMV nanohybrids (OMV-SIRPα@CaP/GM-CSF) for exerting vaccine-enhanced antitumor activity. In the bone marrow, GM-CSF-assisted OMVs trained bone marrow progenitor cells and monocytes, which were inherited by TAMs. In tumor tissues, SIRPα-Fc-assisted OMVs triggered TAM-mediated phagocytosis. This TIrV can be identified by metabolic and epigenetic rewiring using transposase-accessible chromatin (ATAC) and transcriptome sequencing. Furthermore, we found that the TIrV-mediated antitumor mechanism in MC38 tumor model (TAM-hot & T cell-cold) is trained immunity and activated T cell response, whereas in B16-F10 tumor model (T cell-hot & TAM-cold) is primarily mediated by trained immunity. Our study not only developed and identified OMV-based TIrV, but also investigated the trained immunity signatures and therapeutic mechanisms, providing a basis for further vaccination strategies. This article is protected by copyright. All rights reserved.
    Keywords:  Outer membrane vesicle-based nanohybrids; antitumor mechanism; trained immunity signatures; trained immunity-related vaccines (TIrV); tumor-associated macrophages (TAMs)
    DOI:  https://doi.org/10.1002/adma.202306158
  2. Cell Rep. 2023 Aug 28. pii: S2211-1247(23)01055-0. [Epub ahead of print]42(9): 113044
    Sepsis induces non-classic innate immune memory in granulocytes.
    Beibei Wang, Liuluan Zhu, Bei Jia, Chenchen Zhao, Ju Zhang, Fangyuan Li, Jiarui Li, Nan Ding, Can Zhang, Yu Hao, Shuai Tong, Jiajia Wang, Guoli Li, Yang Fan, Henghui Zhang, Rui Li, Juan Du, Yaxian Kong, Yue Zhang, Xiaoyu Yang, Junyan Han, Zhengya Yu, Zhongtao Du, Hong Zheng, Christian Kosan, Ang Li, Chen Chen, Yaluan Ma, Hui Zeng.
      Secondary infection in patients with sepsis triggers a new wave of inflammatory response, which aggravates organ injury and increases mortality. Trained immunity boosts a potent and nonspecific response to the secondary challenge and has been considered beneficial for the host. Here, using a murine model of polymicrobial infection, we find that the primary infection reprograms granulocytes to boost enhanced inflammatory responses to the secondary infection, including the excessive production of inflammatory cytokines, respiratory burst, and augmented phagocytosis capacity. However, these reprogramed granulocytes exhibit "non-classic" characteristics of innate immune memory. Two mechanisms are independently involved in the innate immune memory of granulocytes: a metabolic shift in favor of glycolysis and fatty acid synthesis and chromatin remodeling leading to the transcriptional inactivity of genes encoding inhibitors of TLR4-initiated signaling pathways. Counteracting the deleterious effects of stressed granulocytes on anti-infection immunity might provide a strategy to fight secondary infections during sepsis.
    Keywords:  CP: Immunology; granulocyte; immune memory; secondary infection; sepsis
    DOI:  https://doi.org/10.1016/j.celrep.2023.113044
  3. bioRxiv. 2023 Jul 18. pii: 2023.07.14.548872. [Epub ahead of print]
    Mycobacterium tuberculosis infection associated immune perturbations correlate with antiretroviral immunity.
    Swiss HIV Cohort Study
      Infection with Mycobacterium tuberculosis (MTB) remains one of the most important opportunistic infections in people with HIV-1 (PWH). While it is well accepted that active Tuberculosis (TB) leads to rapid progression of immunodeficiency in PWH, the interaction between MTB and HIV-1 during the asymptomatic phase of both infections remains poorly understood. Here, we show in a well-matched cohort of PWH with suppressed HIV-1 viral load that MTB infection is associated with a baseline transcriptional profile away from a Type 1 Interferon towards a proinflammatory cytokine response. The transcriptional changes are conserved during HIV-1 viremia and are inversely correlated with HIV-1 viral load, suggesting that MTB infection-associated perturbations of the innate immune system improve HIV-1 control. In line with these findings, the transcriptional profile of individuals with MTB infection overlaps with that of HIV-1 long term non-progressors. Conversely, during active TB, the transcriptional pattern is reversed, indicating loss of immune control and suggesting a shared immunological mechanism of control and progression for both HIV-1 and MTB infection. In conclusion, our data show that MTB infection is associated with a shift in the activation state of the immune system. This shift contributes to lower HIV-1 viral load in MTB/HIV-1 co- infection and is lost during disease progression.
    Significance statement: Mycobacterium tuberculosis (MTB) affects 23% of the human population, but little is known about its impact on human biology. MTB infection is associated with better HIV-1 control and fewer opportunistic infections, but with an increased risk of non-communicable diseases such as diabetes. To understand why this is the case, we studied individuals co-infected with HIV-1 and MTB infection and found that MTB infection affects the innate immune system, improving the control of HIV-1 replication. Animal and BCG vaccination studies also support the idea that MTB affects the innate immune system and provides immunity against other diseases. Overall, this study advances our understanding of how MTB infection can have unexpected effects on host responses and sheds light on its complex nature.Highlights: In people with HIV-1 (PWH), MTB infection is associated with a perturbation of the PBMC transcriptome independently of re-exposure to MTB specific antigen.MTB infection is associated with a shift away from Type 1 Interferon towards a trained immunity type phenotype.The perturbations associated with MTB infection correlate with improved retroviral control and are lost during progression to active tuberculosis.
    DOI:  https://doi.org/10.1101/2023.07.14.548872
  4. Front Immunol. 2023 ;14 1180785
    A suspension of inactivated bacteria used for vaccination against recurrent urinary tract infections increases the phagocytic activity of murine macrophages.
    Anja Eggers, Melissa Ballüer, Belal A Mohamed, Roland Nau, Jana Seele.
       Background: Urinary tract infections are a major cause of the consumption of antibiotics in humans.
    Methods: We studied the effect of a vaccine (StroVac®, containing inactivated bacteria and used to prevent recurrent urinary tract infections) licensed in Germany on the release of pro-inflammatory cytokines and the phagocytosis of Escherichia (E.) coli in primary murine macrophages and the macrophage cell line J774A.1.
    Results: StroVac® increased the release of the cytokines TNF-α, IL-6, IL-12/23 p40, and IL-1β and stimulated the phagocytosis of E. coli in a dose-dependent manner. This effect was independent of LPS as shown by the use of macrophages isolated from LPS-resistant C3H/HeJ mice. At concentrations up to 30 mg/l it was not toxic to bacteria or eukaryotic cells.
    Conclusion: StroVac® does not only act via the adaptive but also by stimulating the innate immune system. This stimulation may help to build trained innate immunity against bacterial pathogens involved in recurrent urinary tract infections.
    Keywords:  cytokine induction; innate immune response; phagocytosis; urinary tract infections; vaccine
    DOI:  https://doi.org/10.3389/fimmu.2023.1180785
  5. Cell Rep. 2023 Aug 29. pii: S2211-1247(23)01054-9. [Epub ahead of print]42(9): 113043
    The malate-aspartate shuttle is important for de novo serine biosynthesis.
    Melissa H Broeks, Nils W F Meijer, Denise Westland, Marjolein Bosma, Johan Gerrits, Hannah M German, Jolita Ciapaite, Clara D M van Karnebeek, Ronald J A Wanders, Fried J T Zwartkruis, Nanda M Verhoeven-Duif, Judith J M Jans.
      The malate-aspartate shuttle (MAS) is a redox shuttle that transports reducing equivalents across the inner mitochondrial membrane while recycling cytosolic NADH to NAD+. We genetically disrupted each MAS component to generate a panel of MAS-deficient HEK293 cell lines in which we performed [U-13C]-glucose tracing. MAS-deficient cells have reduced serine biosynthesis, which strongly correlates with the lactate M+3/pyruvate M+3 ratio (reflective of the cytosolic NAD+/NADH ratio), consistent with the NAD+ dependency of phosphoglycerate dehydrogenase in the serine synthesis pathway. Among the MAS-deficient cells, those lacking malate dehydrogenase 1 (MDH1) show the most severe metabolic disruptions, whereas oxoglutarate-malate carrier (OGC)- and MDH2-deficient cells are less affected. Increasing the NAD+-regenerating capacity using pyruvate supplementation resolves most of the metabolic disturbances. Overall, we show that the MAS is important for de novo serine biosynthesis, implying that serine supplementation could be used as a therapeutic strategy for MAS defects and possibly other redox disorders.
    Keywords:  CP: Metabolism; NADH shuttle; central carbon metabolism; glycolysis; isotope-tracer analysis; malate dehydrogenase; malate-aspartate shuttle; metabolomics; serine biosynthesis
    DOI:  https://doi.org/10.1016/j.celrep.2023.113043
  6. bioRxiv. 2023 Aug 17. pii: 2023.08.17.553697. [Epub ahead of print]
    Pneumonic plague protection induced by a monophosphoryl lipid A decorated Yersinia outer-membrane-vesicle vaccine.
    Saugata Majumder, Shreya Das, Peng Li, Nicole Yang, Hazel Dellario, Haixin Sui, Ziqiang Guan, Wei Sun.
      A newly constructed Yersinia pseudotuberculosis mutant (YptbS46) carrying the lpxE insertion and pmrF-J deletion exclusively synthesized an adjuvant form of lipid A, monophosphoryl lipid A (MPLA). Outer membrane vesicles (OMVs) isolated from YptbS46 harboring an lcrV expression plasmid, pSMV13, were designated OMV 46 -LcrV, which contained MPLA and high amounts of LcrV and displayed low activation of Toll-like receptor 4 (TLR4). Similar to the previous OMV 44 -LcrV, intramuscular prime-boost immunization with 30 µg of OMV 46 -LcrV exhibited substantially reduced reactogenicity and conferred complete protection to mice against a high-dose of respiratory Y. pestis challenge. OMV 46 -LcrV immunization induced robust adaptive responses in both lung mucosal and systemic compartments and orchestrated innate immunity in the lung, which were correlated with rapid bacterial clearance and unremarkable lung damage during Y. pestis challenge. Additionally, OMV 46 -LcrV immunization conferred long-term protection. Moreover, immunization with reduced doses of OMV 46 -LcrV exhibited further lower reactogenicity and still provided great protection against pneumonic plague. Our studies strongly demonstrate the feasibility of OMV 46 -LcrV as a new type of plague vaccine candidate.
    DOI:  https://doi.org/10.1101/2023.08.17.553697
  7. In Vivo. 2023 Sep-Oct;37(5):37(5): 2044-2056
    Toll-like Receptor Agonist CBLB502 Protects Against Cisplatin-induced Liver and Kidney Damage in Mice.
    Pengzhen Niu, Wenyu Zhao, Qiong Wang, Junzhao Duan, Jie Zhu, Hanjiang Fu, Yongge Wu, Xiaofei Zheng, Daguang Zhang, Changhui Ge.
       BACKGROUND/AIM: CBLB502, a Toll-like receptor-5 agonist derived from Salmonella flagellin, exerts protective roles against irradiation and chemical drugs in mammalian tissues and stimulates tissue regeneration. This study aimed to investigate whether CBLB502 can protect against liver and kidney damage induced by the chemotherapeutic drug cisplatin (CDDP) and the underlying mechanism of the protective effect.
    MATERIALS AND METHODS: Mice were pretreated with CBLB502 [0.2 mg/kg, intraperitoneal (i.p.) injection] 0.5 h prior to administration of CDDP (20 mg/kg, i.p. injection), and analyses of the liver and kidney indices, blood biochemistry, and histopathology were performed.
    RESULTS: Pretreatment with CBLB502 alleviated CDDP-induced liver and kidney damage. RNA sequencing and bioinformatic analysis indicated that CDDP induced a similar damage-promoting gene regulation pattern in the liver and kidney. CBLB502 protected against liver and kidney damage only after CDDP treatment primarily via different pathways. However, some CBLB502-regulated genes were common between the liver and kidney, including those involved in blood coagulation, fibrinolysis, hemostasis, apoptotic regulation, NF-kappaB signaling, and response to lipopolysaccharide, suggesting a general protective effect by CBLB502.
    CONCLUSION: Our data provide insights into the protective mechanism of CBLB502 against CDDP-induced tissue damage in the liver and kidney and might provide a basis for future studies on functional genes and regulatory mechanisms that mediate protection against chemoradiotherapy-induced damage.
    Keywords:  CBLB502; TLR5 agonist; chemotherapy protection; cisplatin; kidney injury; liver injury
    DOI:  https://doi.org/10.21873/invivo.13302
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