bims-traimu 2022-11-13 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2022–11–13
eight papers selected by
Yantong Wan, Southern Medical University

Βeta-glucan stimulation induces trained immunity markers in common carp, Cyprinus carpio.
Drosophila melanogaster as a model to study innate immune memory.
Direct Binding of Bovine IgG-Containing Immune Complexes to Human Monocytes and Their Putative Role in Innate Immune Training.
Temperature dependent cellular, and epigenetic regulatory mechanisms underlying the antiviral immunity in sevenband grouper to nervous necrosis virus infection.
Transcriptomics and quantitative proteomics reveal changes after second stimulation of bone marrow-derived macrophages from lupus-prone MRL/lpr mice.
VPM1002 as Prophylaxis Against Severe Respiratory Tract Infections Including COVID-19 in the Elderly: a phase III randomised, double-blind, placebo-controlled, multicenter clinical study.
CD1d-dependent rewiring of lipid metabolism in macrophages regulates innate immune responses.
Role of metabolic reprogramming in pro-inflammatory cytokine secretion from LPS or silica-activated macrophages.

Fish Shellfish Immunol. 2022 Nov 03. pii: S1050-4648(22)00745-8. [Epub ahead of print]131 855-861

Βeta-glucan stimulation induces trained immunity markers in common carp, Cyprinus carpio.

David Waikhom, Jeena Kezhedath, Rahul Krishnan, Tincy Varghese, Pani Prasad Kurcheti, Rajendran Kooloth Valappil.

  Trained immunity refers to the memory acquired by innate immune cells, leading to cross-protection and non-specific responses to subsequent infection, thereby improving host survival. Trained immunity induction is a combined effect of immune signaling, metabolic changes, and epigenetic modifications. The present study evaluated the induction of markers of the phenomenon of trained immunity in common carp, which is trained using β-glucan. The mammalian target of rapamycin (mtor) and hypoxia-inducible factor (hif1α), the metabolic basis of trained immunity; the histone deacetylase (hdac7), one of the markers of epigenetic modifications, metabolic activity of activated cells and expression profiles of proinflammatory cytokines viz. il6a, tnfαa2, and ifnγ were targeted in the study and analyzed in vivo. Besides in vivo analysis, in vitro analysis of mtorc2, hif1α, hdac7, and ifnγ were analyzed. In vitro analyses were performed on head kidney macrophages isolated and maintained in L-15 media and double trained with β-glucan at 100μg/mL. The culture supernatant was collected at different time intervals and processed for expression studies. Healthy common carp were injected with β-glucan at 20 mg/kg body weight for training followed by a resting phase for 6 days and were restimulated with the same dose. Head kidney was collected from the fish post-induction as well as post-restimulation. The expression profile of mtorc2, hdac7, and hif1α were found elevated post-stimulation of β-glucan. Further, a significantly upregulated expression profile of proinflammatory cytokines (ifnγ, il6a and tnfαa2) was observed. Increased glycolysis in the cells post-β-glucan stimulation was confirmed by the high lactate and LDH production detected in the cell culture supernatant. Overall, the study revealed the expression profile of the trained immunity markers and the increased metabolic activity in cells induced with β-glucan, which further validates that the action of trained immunity is indispensable in fish on encounter with a potential ligand. The study supports the existing reports on trained immunity in teleost fish with evidence at the genomic level. However, further studies are required to understand the responses and actions of trained immune cells during infection in detail.

Keywords:  Epigenetic modifications; Macrophages; hif1α, lactate and LDH; mtor

DOI:  https://doi.org/10.1016/j.fsi.2022.10.069
Front Microbiol. 2022 ;13 991678

Drosophila melanogaster as a model to study innate immune memory.

Marta Arch, Maria Vidal, Romina Koiffman, Solomon Tibebu Melkie, Pere-Joan Cardona.

  Over the last decades, research regarding innate immune responses has gained increasing importance. A growing body of evidence supports the notion that the innate arm of the immune system could show memory traits. Such traits are thought to be conserved throughout evolution and provide a survival advantage. Several models are available to study these mechanisms. Among them, we find the fruit fly, Drosophila melanogaster. This non-mammalian model has been widely used for innate immune research since it naturally lacks an adaptive response. Here, we aim to review the latest advances in the study of the memory mechanisms of the innate immune response using this animal model.

Keywords:  Drosophila melanogaster; infection; innate immune memory; resistance; tolerance; trained immunity

DOI:  https://doi.org/10.3389/fmicb.2022.991678
Nutrients. 2022 Oct 22. pii: 4452. [Epub ahead of print]14(21):

Direct Binding of Bovine IgG-Containing Immune Complexes to Human Monocytes and Their Putative Role in Innate Immune Training.

Mojtaba Porbahaie, Huub F J Savelkoul, Cornelis A M de Haan, Malgorzata Teodorowicz, R J Joost van Neerven.

  Bovine milk IgG (bIgG) was shown to bind to and neutralize the human respiratory synovial virus (RSV). In animal models, adding bIgG prevented experimental RSV infection and increased the number of activated T cells. This enhanced activation of RSV-specific T cells may be explained by receptor-mediated uptake and antigen presentation after binding of bIgG-RSV immune complexes (ICs) with FcγRs (primarily CD32) on human immune cells. This indirect effect of bIgG ICs on activation of RSV-specific T cells was confirmed previously in human T cell cultures. However, the direct binding of ICs to antigen-presenting cells has not been addressed. As bovine IgG can induce innate immune training, we hypothesized that this effect could be caused more efficiently by ICs. Therefore, we characterized the expression of CD16, CD32, and CD64 on (peripheral blood mononuclear cells (PBMCs), determined the optimal conditions to form ICs of bIgG with the RSV preF protein, and demonstrated the direct binding of these ICs to human CD14+ monocytes. Similarly, bIgG complexed with a murine anti-bIgG mAb also bound efficiently to the monocytes. To evaluate whether the ICs could induce innate immune training more efficiently than bIgG itself, the resulted ICs, as well as bIgG, were used in an in vitro innate immune training model. Training with the ICs containing bIgG and RSV preF protein-but not the bIgG alone-induced significantly higher TNF-α production upon LPS and R848 stimulation. However, the preF protein itself nonsignificantly increased cytokine production as well. This may be explained by its tropism to the insulin-like growth factor receptor 1 (IGFR1), as IGF has been reported to induce innate immune training. Even so, these data suggest a role for IgG-containing ICs in inducing innate immune training after re-exposure to pathogens. However, as ICs of bIgG with a mouse anti-bIgG mAb did not induce this effect, further research is needed to confirm the putative role of bIgG ICs in enhancing innate immune responses in vivo.

Keywords:  RSV; bovine IgG; immune complex; preF protein; trained immunity

DOI:  https://doi.org/10.3390/nu14214452
Fish Shellfish Immunol. 2022 Nov 02. pii: S1050-4648(22)00744-6. [Epub ahead of print]

Temperature dependent cellular, and epigenetic regulatory mechanisms underlying the antiviral immunity in sevenband grouper to nervous necrosis virus infection.

Rahul Krishnan, Yo-Seb Jang, Jong-Oh Kim, Su-Young Yoon, Rahul Rajendran, Myung-Joo Oh.

  Changes in the thermal optima of fish impacts changes in the physiology and immune response associated with infections. The present study showed that at suboptimal temperatures (17 °C), the host tries to evade viral infection by downregulating the inflammatory response through enhanced neuronal protection. There was significantly less abundance of IgM + B cells in the 17 °C group compared to that in the 25 °C group. An increased macrophage population (Iba1+) during the survival phase in fish challenged at 25 °C demonstrated inflammation. Optimal temperature challenge activated virus-induced senescence in brain cells, demonstrated with a heterochromatin-associated H3K9me3 histone mark. There was an abundant expression of anti-inflammatory cytokines in the brain of fish at the suboptimal challenge. Besides the cytokines, the expression of BDNF was significantly higher in the suboptimally challenged group, suggesting that its neuronal protection activity following NNV infection is mediated through TGFβ. The suboptimal challenge resulted in H3k9ac displaying transcriptional competency, activation of trained immunity H3K4me3, and enrichment of H3 histone-lysine-4 monomethylation (H3K4me1), resulting in a robust re-stimulatory immune response. The observations from the H4 modifications showed that besides H4K12ac and H4K20m3, all the assayed modifications were significantly higher in suboptimal convalescent fishes. The suboptimally challenged fish acquired more methylation along cytosine residues than the optimally infected fish. Together, these observations suggest that optimal temperature results in an immune priming effect, whereas the protection enabled in suboptimal convalescent fishes is operated through epigenetically controlled trained immune functions.

Keywords:  Epigenetics; Nervous necrosis virus; Sevenband grouper; Trained immunity; Virus-induced senescence

DOI:  https://doi.org/10.1016/j.fsi.2022.10.068
Front Immunol. 2022 ;13 1004232

Transcriptomics and quantitative proteomics reveal changes after second stimulation of bone marrow-derived macrophages from lupus-prone MRL/lpr mice.

Keyue Chen, Tiyun Wu, Danyan Wang, Rong Li, Xiangfeng Shen, Ting Zhao, Keiko Ozato, Rongqun Li.

  Innate immune memory can cause the occurrence and exacerbation of autoimmune diseases, and it is as well as being strongly associated with the pathogenesis of systemic lupus erythematosus (SLE), however, the specific mechanism remains to be further studied. We learned that IFN-γ stimulation generated innate immune memory in bone marrow-derived macrophages (BMDMs) and activated memory interferon-stimulated genes (ISGs). This research used IFN-γ and lipopolysaccharide (LPS) to treat BMDMs with lupus-prone MRL/lpr mice and showed that particular memory ISGs were substantially elevated in prestimulated macrophages. In order to identify the differentially expressed genes (DEGs), researchers turned to RNA-seq. GO and KEGG analysis showed that up-regulated DEGs were enriched in defense and innate immune responses, and were related to the expression of pattern recognition receptors (PRRs)-related pathways in macrophages. TMT-based proteome analysis revealed differentially expressed proteins (DEPs) up-regulated in BMDMs were abundant in metabolic pathways such as glucose metabolism. Our study found that after the secondary stimulation of MRL/lpr mice, the expression of PRRs in innate immune cells was changed, and IFN-related pathways were activated to release a large number of ISGs to promote the secondary response. At the same time, related metabolic modes such as glycolysis were enhanced, and epigenetic changes may occur. Therefore, SLE is brought on, maintained, and worsened by a variety of factors that work together to produce innate immune memory.

Keywords:  MRL/lpr mice; RNA-seq; innate immune memory; proteome; systemic lupus erythematosus

DOI:  https://doi.org/10.3389/fimmu.2022.1004232
Clin Infect Dis. 2022 Nov 11. pii: ciac881. [Epub ahead of print]

VPM1002 as Prophylaxis Against Severe Respiratory Tract Infections Including COVID-19 in the Elderly: a phase III randomised, double-blind, placebo-controlled, multicenter clinical study.

Alexandra M Blossey, Sina Brückner, Marcus May, Gerald P Parzmair, Hitt Sharma, Umesh Shaligram, Leander Grode, Stefan H E Kaufmann, Mihai G Netea, Christoph Schindler.

   BACKGROUND: Bacille Calmette-Guérin (BCG) vaccination can potentially reduce the rate of respiratory infections in vulnerable populations. This study evaluates the safety and efficacy of VPM1002 (a genetically modified BCG) as prophylaxis against severe respiratory tract infections including COVID-19 in an elderly population.
METHODS: In this phase III, randomized, double-blind, placebo-controlled, multicenter clinical trial, healthy elderly volunteers (n = 2064) were enrolled, randomized (1:1) to receive either VPM1002 or placebo, and followed up remotely for 240 days. The primary outcome was the mean number of days with severe respiratory infections at hospital and/or at home. Secondary endpoints included the incidence of self-reported fever, number of hospital and ICU admissions, and number of adverse events.
RESULTS: A total of 31 participants in the VPM1002 group reported at least 1 day with severe respiratory disease and a mean number of days with severe respiratory disease of 9.39 ± 9.28 days while in the placebo group, 38 participants reported a mean of 14.29 ± 16.25 days with severe respiratory disease. The incidence of self-reported fever was lower in the VPM1002 group (odds ratio: 0.46; 95% CI: 0.28 to 0.74; p-value: 0.001) and consistent trends to less hospitalization and ICU admissions due to COVID-19 were observed after VPM1002-vaccination. Local reactions typical for BCG were observed in the VPM1002-vaccinated group, which were mostly of mild intensity.
CONCLUSIONS: Vaccination with VPM1002 is well tolerated and seems to have a prophylactic effect against severe respiratory diseases in the elderly. (ClinicalTrials.gov: NCT04435379).

Keywords:  COVID-19; SARS-COV-2; VPM1002; respiratory tract infections; trained immunity

DOI:  https://doi.org/10.1093/cid/ciac881
Nat Commun. 2022 Nov 07. 13(1): 6723

CD1d-dependent rewiring of lipid metabolism in macrophages regulates innate immune responses.

Phillip M Brailey, Lauren Evans, Juan Carlos López-Rodríguez, Anthony Sinadinos, Victoria Tyrrel, Gavin Kelly, Valerie O'Donnell, Peter Ghazal, Susan John, Patricia Barral.

Alterations in cellular metabolism underpin macrophage activation, yet little is known regarding how key immunological molecules regulate metabolic programs in macrophages. Here we uncover a function for the antigen presenting molecule CD1d in the control of lipid metabolism. We show that CD1d-deficient macrophages exhibit a metabolic reprogramming, with a downregulation of lipid metabolic pathways and an increase in exogenous lipid import. This metabolic rewiring primes macrophages for enhanced responses to innate signals, as CD1d-KO cells show higher signalling and cytokine secretion upon Toll-like receptor stimulation. Mechanistically, CD1d modulates lipid import by controlling the internalization of the lipid transporter CD36, while blocking lipid uptake through CD36 restores metabolic and immune responses in macrophages. Thus, our data reveal CD1d as a key regulator of an inflammatory-metabolic circuit in macrophages, independent of its function in the control of T cell responses.

DOI: https://doi.org/10.1038/s41467-022-34532-x
Front Immunol. 2022 ;13 936167

Role of metabolic reprogramming in pro-inflammatory cytokine secretion from LPS or silica-activated macrophages.

Antonella Marrocco, Luis A Ortiz.

  In the lungs, macrophages constitute the first line of defense against pathogens and foreign bodies and play a fundamental role in maintaining tissue homeostasis. Activated macrophages show altered immunometabolism and metabolic changes governing immune effector mechanisms, such as cytokine secretion characterizing their classic (M1) or alternative (M2) activation. Lipopolysaccharide (LPS)-stimulated macrophages demonstrate enhanced glycolysis, blocked succinate dehydrogenase (SDH), and increased secretion of interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α). Glycolysis suppression using 2 deoxyglucose in LPS-stimulated macrophages inhibits IL-1β secretion, but not TNF-α, indicating metabolic pathway specificity that determines cytokine production. In contrast to LPS, the nature of the immunometabolic responses induced by non-organic particles, such as silica, in macrophages, its contribution to cytokine specification, and disease pathogenesis are not well understood. Silica-stimulated macrophages activate pattern recognition receptors (PRRs) and NLRP3 inflammasome and release IL-1β, TNF-α, and interferons, which are the key mediators of silicosis pathogenesis. In contrast to bacteria, silica particles cannot be degraded, and the persistent macrophage activation results in an increased NADPH oxidase (Phox) activation and mitochondrial reactive oxygen species (ROS) production, ultimately leading to macrophage death and release of silica particles that perpetuate inflammation. In this manuscript, we reviewed the effects of silica on macrophage mitochondrial respiration and central carbon metabolism determining cytokine specification responsible for the sustained inflammatory responses in the lungs.

Keywords:  M1 macrophages; complex II; electron transport chain; macrophage immunometabolism; macrophage metabolic adaptation; mitochondria; respirable crystalline silica

DOI:  https://doi.org/10.3389/fimmu.2022.936167