bims-traimu 2022-10-23 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2022–10–23
seven papers selected by
Yantong Wan, Southern Medical University

Trained immunity - basic concepts and contributions to immunopathology.
Enriched dietary saturated fatty acids induce trained immunity via ceramide production that enhances severity of endotoxemia and clearance of infection.
Transcriptome features of innate immune memory in Drosophila.
Evidence for the heterologous benefits of prior BCG vaccination on COVISHIELD™ vaccine-induced immune responses in SARS-CoV-2 seronegative young Indian adults.
Editorial: Endothelial cells as innate immune cells.
Targeting dendritic cells with TLR-2 ligand-coated nanoparticles loaded with Mycobacterium tuberculosis epitope induce anti-tuberculosis immunity.
Toll-like receptor agonists, poly(I:C) and flagellin, lead to IL-36γ induction with divergent release kinetics and differentially alter autophagy in primary human keratinocytes

Nat Rev Nephrol. 2022 Oct 17.

Trained immunity - basic concepts and contributions to immunopathology.

Jordi Ochando, Willem J M Mulder, Joren C Madsen, Mihai G Netea, Raphaël Duivenvoorden.

Trained immunity is a functional state of the innate immune response and is characterized by long-term epigenetic reprogramming of innate immune cells. This concept originated in the field of infectious diseases - training of innate immune cells, such as monocytes, macrophages and/or natural killer cells, by infection or vaccination enhances immune responses against microbial pathogens after restimulation. Although initially reported in circulating monocytes and tissue macrophages (termed peripheral trained immunity), subsequent findings indicate that immune progenitor cells in the bone marrow can also be trained (that is, central trained immunity), which explains the long-term innate immunity-mediated protective effects of vaccination against heterologous infections. Although trained immunity is beneficial against infections, its inappropriate induction by endogenous stimuli can also lead to aberrant inflammation. For example, in systemic lupus erythematosus and systemic sclerosis, trained immunity might contribute to inflammatory activity, which promotes disease progression. In organ transplantation, trained immunity has been associated with acute rejection and suppression of trained immunity prolonged allograft survival. This novel concept provides a better understanding of the involvement of the innate immune response in different pathological conditions, and provides a new framework for the development of therapies and treatment strategies that target epigenetic and metabolic pathways of the innate immune system.

DOI: https://doi.org/10.1038/s41581-022-00633-5
Elife. 2022 Oct 20. pii: e76744. [Epub ahead of print]11

Enriched dietary saturated fatty acids induce trained immunity via ceramide production that enhances severity of endotoxemia and clearance of infection.

Amy L Seufert, James W Hickman, Ste K Traxler, Rachael M Peterson, Trent A Waugh, Sydney J Lashley, Natalia Shulzhenko, Ruth J Napier, Brooke A Napier.

  Trained immunity is an innate immune memory response that is induced by primary microbial or sterile stimuli that sensitizes monocytes and macrophages to a secondary pathogenic challenge, reprogramming the host response to infection and inflammatory disease. Nutritional components, such as dietary fatty acids, can act as inflammatory stimuli, but it is unknown if they can act as the primary stimuli in the context of innate immune memory. Here we find mice fed a diet enriched exclusively in saturated fatty acids (SFAs; ketogenic diet; KD) confer a hyper-inflammatory response to systemic lipopolysaccharide (LPS) and increased mortality, independent of diet-induced microbiome and glycemic modulation. We find KD mediates the composition of the hematopoietic stem cell (HSC) compartment, and macrophages derived from the bone marrow of mice fed KD do not have altered baseline inflammation, but enhanced responses to a secondary inflammatory challenge. Lipidomics identified enhanced free palmitic acid (PA) and PA-associated lipids in KD-fed mice serum. We found pre-treatment with physiologically relevant concentrations of PA alone reprograms macrophages to induce a hyper-inflammatory response to secondary challenge with LPS. This response was found to be dependent on the synthesis of ceramide, and reversible when treated with a ceramide synthase inhibitor. In vivo, we found systemic PA confers enhanced inflammation and mortality during an acute inflammatory response to systemic LPS, and this phenotype was not reversible for up to 7 days post-PA-exposure. While PA-treatment is harmful for endotoxemia outcome, we find PA exposure enhanced clearance of Candida albicans in Rag1-/- mice. Further, we show that oleic acid (OA), a mono-unsaturated FA that depletes intracellular ceramide, reverses the PA-induced hyper-inflammatory response shown in macrophages treated with LPS, and reduces severity and mortality of LPS endotoxin stimulation, highlighting the plasticity of SFA-dependent enhanced endotoxemia severity in vivo. These are the first data to implicate enriched dietary SFAs, and specifically PA, in the induction of long-lived innate immune memory that is detrimental during an acute inflammatory response, but beneficial for clearance of pathogens.

Keywords:  immunology; inflammation; mouse

DOI:  https://doi.org/10.7554/eLife.76744
PLoS Genet. 2022 Oct 17. 18(10): e1010005

Transcriptome features of innate immune memory in Drosophila.

Naoyuki Fuse, Chisaki Okamori, Ryoma Okaji, Chang Tang, Kikuko Hirai, Shoichiro Kurata.

Immune memory is the ability of organisms to elicit potentiated immune responses at secondary infection. Current studies have revealed that similar to adaptive immunity, innate immunity exhibits memory characteristics (called "innate immune memory"). Although epigenetic reprogramming plays an important role in innate immune memory, the underlying mechanisms have not been elucidated, especially at the individual level. Here, we established experimental systems for detecting innate immune memory in Drosophila melanogaster. Training infection with low-pathogenic bacteria enhanced the survival rate of the flies at subsequent challenge infection with high-pathogenic bacteria. Among low-pathogenic bacteria, Micrococcus luteus (Ml) and Salmonella typhimurium (St) exerted apparent training effects in the fly but exhibited different mechanisms of action. Ml exerted training effects even after its clearance from flies, while live St persisted in the flies for a prolonged duration. RNA sequencing (RNA-Seq) analysis revealed that Ml training enhanced the expression of the immune-related genes under the challenge condition but not under the non-challenge condition. In contrast, St training upregulated the expression of the immune-related genes independent of challenge. These results suggest that training effects with Ml and St are due to memory and persistence of immune responses, respectively. Furthermore, we searched for the gene involved in immune memory, and identified a candidate gene, Ada2b, which encodes a component of the histone modification complex. The Ada2b mutant suppressed Ml training effects on survival and disrupted the expression of some genes under the training + challenge condition. These results suggest that the gene expression regulated by Ada2b may contribute to innate immune memory in Drosophila.

DOI: https://doi.org/10.1371/journal.pgen.1010005
Front Immunol. 2022 ;13 985938

Evidence for the heterologous benefits of prior BCG vaccination on COVISHIELD™ vaccine-induced immune responses in SARS-CoV-2 seronegative young Indian adults.

Srabanti Rakshit, Vasista Adiga, Asma Ahmed, Chaitra Parthiban, Nirutha Chetan Kumar, Pratibha Dwarkanath, Sudarshan Shivalingaiah, Srishti Rao, George D'Souza, Mary Dias, Thomas J A Maguire, Katie J Doores, Martijn Zoodsma, Busranur Geckin, Prokar Dasgupta, Sudhir Babji, Krista E van Meijgaarden, Simone A Joosten, Tom H M Ottenhoff, Yang Li, Mihai G Netea, Kenneth D Stuart, Stephen C De Rosa, M Juliana McElrath, Annapurna Vyakarnam.

  This proof-of-concept study tested if prior BCG revaccination can qualitatively and quantitively enhance antibody and T-cell responses induced by Oxford/AstraZeneca ChAdOx1nCoV-19 or COVISHIELD™, an efficacious and the most widely distributed vaccine in India. We compared COVISHIELD™ induced longitudinal immune responses in 21 BCG re-vaccinees (BCG-RV) and 13 BCG-non-revaccinees (BCG-NRV), all of whom were BCG vaccinated at birth; latent tuberculosis negative and SARS-CoV-2 seronegative prior to COVISHIELD™ vaccination. Compared to BCG-NRV, BCG-RV displayed significantly higher and persistent spike-specific neutralizing (n) Ab titers and polyfunctional CD4+ and CD8+ T-cells for eight months post COVISHIELD™ booster, including distinct CD4+IFN-γ+ and CD4+IFN-γ- effector memory (EM) subsets co-expressing IL-2, TNF-α and activation induced markers (AIM) CD154/CD137 as well as CD8+IFN-γ+ EM,TEMRA (T cell EM expressing RA) subset combinations co-expressing TNF-α and AIM CD137/CD69. Additionally, elevated nAb and T-cell responses to the Delta mutant in BCG-RV highlighted greater immune response breadth. Mechanistically, these BCG adjuvant effects were associated with elevated markers of trained immunity, including higher IL-1β and TNF-α expression in CD14+HLA-DR+monocytes and changes in chromatin accessibility highlighting BCG-induced epigenetic changes. This study provides first in-depth analysis of both antibody and memory T-cell responses induced by COVISHIELD™ in SARS-CoV-2 seronegative young adults in India with strong evidence of a BCG-induced booster effect and therefore a rational basis to validate BCG, a low-cost and globally available vaccine, as an adjuvant to enhance heterologous adaptive immune responses to current and emerging COVID-19 vaccines.

Keywords:  BCG; SARS-CoV-2; T cell; antibodies; trained immunity

DOI:  https://doi.org/10.3389/fimmu.2022.985938
Front Immunol. 2022 ;13 1035497

Editorial: Endothelial cells as innate immune cells.

Yifan Lu, Yu Sun, Keman Xu, Ying Shao, Fatma Saaoud, Nathaniel W Snyder, Ling Yang, Jun Yu, Sheng Wu, Wenhui Hu, Jianxin Sun, Hong Wang, Xiaofeng Yang.



Keywords:  aorta as immune organ; endothelial cells as immune cells; secretome; trained immunity; vascular inflammation

DOI:  https://doi.org/10.3389/fimmu.2022.1035497
J Biol Chem. 2022 Oct 15. pii: S0021-9258(22)01039-0. [Epub ahead of print] 102596

Targeting dendritic cells with TLR-2 ligand-coated nanoparticles loaded with Mycobacterium tuberculosis epitope induce anti-tuberculosis immunity.

Deepjyoti Kumar Das, Mohammad Adeel Zafar, Sidhanta Nanda, Sanpreet Singh, Taruna Lamba, Hilal Bashir, Pargat Singh, Sudeep Kumar Maurya, Sajid Nadeem, Sharvan Sehrawat, Vijayender Bhalla, Javed Naim Agrewala.

  Novel vaccination strategies are crucial to efficiently control tuberculosis, as proposed by WHO under its flagship program 'End TB Strategy'. However, the emergence of drug-resistant strains of Mycobacterium tuberculosis (Mtb), particularly in those co-infected with HIV-AIDS, constitutes a major impediment to achieving this goal. We report here a novel vaccination strategy that involves synthesizing a formulation of an immunodominant peptide derived from the Acr1 protein of Mtb. This nanoformulation additionally displayed a toll-like receptor-2 (TLR-2) ligand to offer to target dendritic cells (DCs). Our results showed an efficient uptake of such a concoction by DCs in a predominantly TLR-2-dependent pathway. These dendritic cells produced elevated levels of nitric oxide, pro-inflammatory cytokines IL-6, IL-12, and TNF-α, and upregulated the surface expression of class MHC II molecules, as well as costimulatory molecules such as CD80 and CD86. Animals injected with such a vaccine mounted a significantly higher response of effector and memory Th1 cells and Th17 cells. Furthermore, we noticed a reduction in the bacterial load in the lungs of animals challenged with aerosolized live Mtb. Therefore, our findings indicated that the described vaccine triggered protective anti-Mtb immunity to control the TB infection.

Keywords:  Mycobacterium tuberculosis; nanotechnology; peptides; toll‐like receptor-2 (TLR-2); vaccine

DOI:  https://doi.org/10.1016/j.jbc.2022.102596
Eur Cytokine Netw. 2022 06 01. 33(2): 19-29

Toll-like receptor agonists, poly(I:C) and flagellin, lead to IL-36γ induction with divergent release kinetics and differentially alter autophagy in primary human keratinocytes

Christopher J Papayannakos, Daniel Zhu, Bongseok Jung, Ali A Rana, James A DeVoti, Allan L Abramson, Vincent R Bonagura, Bettie M Steinberg.

  IL-36γ, a pro-inflammatory member of the IL-1 cytokine superfamily, can be induced and secreted by normal human foreskin keratinocytes (HFKs) in response to pathogenic stimuli, however, the mechanisms underlying the secretion are unknown. In this study, we demonstrate that stimulation with the TLR3 agonist, poly (I:C), led to a delayed secretion of IL-36γ compared to stimulation with the TLR5 agonist, flagellin, despite equal levels of the cytokine (p = 0.006). IL-36γ was shown to be released from HFKs in its inactive, uncleaved form, based on western blotting. Moreover, recombinant IL-36γ in its activated, cleaved form induced endogenous IL-36γ 10-fold (p = 0.004) and CXCL8 five-fold (p = 0.003) over baseline levels compared to unactivated full-length recombinant IL-36γ. The ratio of LC3b-II/LC3b-I was significantly higher in poly(I:C)-treated cells compared to flagellin-treated and unstimulated controls without a change in SQSTM1/p62 after 24 hours of stimulation (p = 0.043). Under fluorescence microscopy, poly(I:C) led to a two-fold increase at eight hours and four-fold increase at 24 hours in accumulated autophagosomes post-stimulation (p = 0.032). In contrast, autophagosomes were unchanged relative to baseline in response to flagellin. Bafilomycin A1 treatment enhanced poly(I:C)-mediated IL-36γ secretion (p = 0.044) while rapamycin led to a noticeable, but non-significant, increase in flagellin-mediated IL-36γ secretion, indicating that interrupting autophagic flux can alter IL-3γ grelease from HFKs. Finally, we show that, compared to clinically normal laryngeal tissue, there were significantly higher levels of LC3b-II in HPV-infected respiratory papilloma tissue, indicating a higher number of autophagosomes; a signature of disrupted autophagic flux.

Keywords:  interleukin-36γ; autophagy; Toll-like receptor; LC3b; keratinocyte

DOI:  https://doi.org/10.1684/ecn.2022.0479