bims-traimu 2023-08-06 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2023–08–06
eight papers selected by
Yantong Wan, Southern Medical University

COVID-19 inactivated and non-replicating viral vector vaccines induce regulatory training phenotype in human monocytes under epigenetic control.
Intravesical BCG in bladder cancer induces innate immune responses against SARS-CoV-2.
Immunogenicity of Bacillus Calmette-Guérin in pigs: potential as a translational model of non-specific effects of BCG.
Oral immunization with heat-inactivated Mycobacterium bovis reduces local parasite dissemination and hepatic granuloma development in mice infected with Leishmania amazonensis.
Differences between DNA vaccine and single-cycle viral vaccine in the ability of cross-protection against viral hemorrhagic septicemia virus (VHSV) and infectious hematopoietic necrosis virus (IHNV).
Sulfur metabolic response in macrophage limits excessive inflammatory response by creating a negative feedback loop.
Negative regulation of pro-apoptotic AMPK/JNK pathway by itaconate in mice with fulminant liver injury.
Artificial cells delivering itaconic acid induce anti-inflammatory memory-like macrophages to reverse acute liver failure and prevent reinjury.

Front Cell Infect Microbiol. 2023 ;13 1200789

COVID-19 inactivated and non-replicating viral vector vaccines induce regulatory training phenotype in human monocytes under epigenetic control.

Mateus da Silva Matias Antunes, Fabricia Heloisa Cavicchioli Sugiyama, Humberto Doriguetto Gravina, Ricardo Cardoso Castro, Francisco Javier Romero Mercado, Julia Oliveira de Lima, Caroline Fontanari, Fabiani Gai Frantz.

   Background: Trained immunity is the enhanced innate immune response resulting from exposure to pathogens or vaccines against an unrelated pathogen stimulus. Certain vaccines induce a memory like response in monocytes and NK cells, leading to modulation in cytokine production, metabolic changes, and modifications in histone patterns. Here, we hypothesized that vaccination against SARS-CoV-2 could induce the training of monocytes in addition to stimulating the adaptive immune response.
Methods: Therefore, we aimed to investigate the immunophenotyping, cytokine and metabolic profile of monocytes from individuals who were completely immunized with two doses of inactivated COVID-19 vaccine or non-replicating viral vector vaccine. Subsequently, we investigated the epigenetic mechanisms underlying monocyte immune training. As a model of inflammatorychallenge, to understand if the monocytes were trained by vaccination and how they were trained, cells were stimulated in vitro with the endotoxin LPS, an unrelated stimulus that would provoke the effects of training.
Results: When challenged in vitro, monocytes from vaccinated individuals produced less TNF-α and those who received inactivated vaccine produced less IL-6, whereas vaccination with non-replicating viral vector vaccine induced more IL-10. Inactivated vaccine increased classical monocyte frequency, and both groups showed higher CD163 expression, a hallmark of trained immunity. We observed increased expression of genes involved in glycolysis and reduced IRG1 expression in vaccinated subjects, a gene associated with the tolerance phenotype in monocytes. We observed that both vaccines reduced the chromatin accessibility of genes associated with the inflammatory response, the inactivated COVID-19 vaccine trained monocytes to a regulatory phenotype mediated by histone modifications in the IL6 and IL10 genes, while the non-replicating viral vector COVID-19 vaccine trained monocytes to a regulatory phenotype, mediated by histone modifications in the IL6, IL10, TNF, and CCL2 genes.
Conclusions: Our findings support the recognized importance of adopting vaccination against SARS CoV-2, which has been shown to be effective in enhancing the adaptive immune response against the virus and reducing mortality and morbidity rates. Here, we provide evidence that vaccination also modulates the innate immune response by controlling the detrimental inflammatory response to unrelated pathogen stimulation.

Keywords:  COVID-19; epigenetic; monocyte; trained immunity; vaccine

DOI:  https://doi.org/10.3389/fcimb.2023.1200789
Front Immunol. 2023 ;14 1202157

Intravesical BCG in bladder cancer induces innate immune responses against SARS-CoV-2.

Renate Pichler, Gabriel Diem, Hubert Hackl, Jiří Koutník, Laura S Mertens, David D Andrea, Benjamin Pradere, Francesco Soria, Andrea Mari, Ekaterina Laukhtina, Wojciech Krajewski, Jeremy Yuen-Chun Teoh, Francesco Del Guidice, Marco Moschini, Martin Thurnher, Wilfried Posch.

  BCG is the most efficient adjuvant therapy for high-risk, non-muscle-invasive bladder cancer (NMIBC). Both innate and adaptive immune responses have been implicated in BCG-mediated effects. BCG vaccination can boost innate immune responses via trained immunity (TI), resulting in an increased resistance to respiratory viral infections. Here we evaluated for the first time whether intravesical application of BCG triggers increased immunity against SARS-CoV-2 in patients with high-risk NMIBC. Serum and peripheral blood mononuclear cells (PBMCs) from heparinized whole blood samples of 11 unvaccinated SARS-CoV-2-naïve high-risk NMIBC patients were collected at baseline and during BCG treatment in a pre-COVID-19 era. To examine B-cell or T cell-dependent adaptive immunity against SARS-CoV-2, sera were tested for the presence of SARS-CoV-2 neutralizing antibodies. Using a SARS-CoV-2 peptide pool, virus-specific T cells were quantified via IFNγ ELISpot assays. To analyze innate immune responses, mRNA and protein expression levels of pro- and anti-inflammatory cytokines were measured after a 24-hour stimulation of PBMCs with either BCG or SARS-CoV-2 wildtype. ATAC- sequencing was performed to identify a potential epigenetic reprogramming in immune cells. We neither identified SARS-CoV-2 neutralizing antibodies nor SARS-CoV-2- reactive T cells, indicating that intravesical BCG did not induce adaptive immunity against SARS-CoV-2. However, a significant increase in mRNA as well as protein expression of IL-1β, IL-6 and TNFα, which are key cytokines of trained immunity, could be observed after at least four intravesical BCG instillations. Genomic regions in the proximity of TI genes (TLR2, IGF1R, AKT1, MTOR, MAPK14, HSP90AA1) were more accessible during BCG compared to baseline. Although intravesical BCG did not induce adaptive immune responses, repetitive intravesical instillations of BCG induced circulating innate immune cells that produce TI cytokines also in response to SARS-CoV-2.

Keywords:  BCG; COVID-19; SARS-CoV-2; bladder cancer; trained immunity; viral infections

DOI:  https://doi.org/10.3389/fimmu.2023.1202157
Front Immunol. 2023 ;14 1219006

Immunogenicity of Bacillus Calmette-Guérin in pigs: potential as a translational model of non-specific effects of BCG.

Kristoffer Jarlov Jensen, Mette Sif Hansen, Kerstin Skovgaard, Erik Svensson, Lars Erik Larsen, Peter M H Heegaard, Christine Stabell Benn, Gregers Jungersen.

   Background: Clinical and immunological studies in humans show that the live attenuated Bacillus Calmette-Guérin (BCG) vaccine has beneficial non-specific effects, increasing resistance against diseases other than tuberculosis. The underlying mechanisms are currently being explored. The pig exhibits considerable physiological similarity to humans in anatomy and physiology, suggesting that similar responses to BCG could be expected. Studies of the non-specific effects of BCG in pigs are scarce. We investigated the feasibility of using pigs as a large animal model to investigate the non-specific immunological effects of BCG.
Methods: In a series of experiments, we randomized newborn or young piglets from conventional farms to receiving BCG or placebo and investigated the persistence of live BCG bacteria in various tissues, the immunogenicity of BCG in ex vivo blood and in vitro stimulation assays, and the acute phase protein and clinical responses to heterologous infectious challenge with influenza A virus or Actinobacillus pleuropneumoniae.
Results: The BCG vaccine was generally well tolerated. In contrast to humans, no skin reaction in the form of abscesses, ulcers, or scars was observed. Live BCG was recovered from draining lymph nodes in 2/13 animals 20 weeks after vaccination. Specific in vitro responses of IFN-γ to antigen-specific re-stimulation with mycobacterial antigen were increased but not TNF-responses to TLR2 or TLR4 agonists. A few genes were differentially expressed in blood after vaccination, including the antiviral genes RIG-I and CSF1, although the effect disappeared after correction for multiple testing. Clinical symptoms after heterologous bacterial or viral respiratory infections did not differ, nor did virus copies in nasopharyngeal samples after the challenge. However, the acute phase protein response was significantly reduced in BCG-vaccinated animals after influenza challenge but not after A. pleuropneumoniae challenge.
Discussion: BCG was safe in pigs, inducing specific immunological responses, but our model did not corroborate the innate immunological responsiveness to BCG seen in humans. The dose of BCG or the bacterial and viral challenges may have been sub-optimal. Even so, the acute phase protein response to influenza infection was significantly reduced in BCG-vaccinated animals.

Keywords:  Actinobacillus pleuropneumoniae; BCG; heterologous immunity; influenza virus; non-specific effects; pigs

DOI:  https://doi.org/10.3389/fimmu.2023.1219006
Res Vet Sci. 2023 Jul 26. pii: S0034-5288(23)00214-X. [Epub ahead of print]162 104963

Oral immunization with heat-inactivated Mycobacterium bovis reduces local parasite dissemination and hepatic granuloma development in mice infected with Leishmania amazonensis.

Elisa Ferreras-Colino, Inmaculada Moreno, Christian Gortázar, Iker Sevilla, Irene Agulló-Ros, Lucas Domínguez, Ramón Juste, Maria A Risalde, Mercedes Domínguez.

  Aiming to explore whether oral immunization with heat-inactivated Mycobacterium bovis (HIMB) protects mice against Leishmania infection, 18 female BALB/c mice were randomly assigned to the immunized group, that received oral HIMB, or the control group, and were infected by inoculation of 10,000 Leishmania amazonensis promastigotes in the footpad. Spleen culture was positive in 55.55% of immunized mice and in 100% of control mice (p = 0.082). The number of immunolabeled amastigotes number in the popliteal lymph node was lower in the immunized group (p = 0.009). The immunized group presented fewer mature granulomas in the liver (p = 0.005) and more Lys + macrophages (p = 0.002) and fewer CD3+ T lymphocytes (p < 0.001) per hepatic granuloma. We conclude that immunization with HIMB via the oral route limited local parasite dissemination and hepatic granuloma development in mice challenged with Leishmania amazonensis through stimulation of macrophages, which is compatible with trained immunity.

Keywords:  Heat-inactivated Mycobacterium bovis; Leishmania; Liver; Macrophages; Trained immunity

DOI:  https://doi.org/10.1016/j.rvsc.2023.104963
Vaccine. 2023 Jul 28. pii: S0264-410X(23)00889-7. [Epub ahead of print]

Differences between DNA vaccine and single-cycle viral vaccine in the ability of cross-protection against viral hemorrhagic septicemia virus (VHSV) and infectious hematopoietic necrosis virus (IHNV).

So Yeon Kim, Kyung Min Lee, Ki Hong Kim.

  Vaccination procedures can be stressful for fish and can bring severe side effects. Therefore, vaccines that can minimize the number of administrations and maximize cross-protection against multiple serotypes, genotypes, or even different species would be highly advantageous. In the present study, we investigated the cross-protective ability of two types of vaccines - viral hemorrhagic septicemia virus (VHSV) G protein-expressing DNA vaccine and G gene-deleted single-cycle VHSV genotype IVa (rVHSV-ΔG) vaccine - against both VHSV genotype Ia and infectious hematopoietic necrosis virus (IHNV) in rainbow trout (Oncorhynchus mykiss). The results showed that rainbow trout immunized with VHSV genotype Ia G gene- or IVa G gene-expressing DNA vaccine were significantly protected against VHSV genotype Ia, but were not protected against IHNV. In contrast to the DNA vaccine, the single-cycle VHSV IVa vaccine induced significant protection against not only VHSV Ia but also IHNV. Considering no significant increase in ELISA titer and serum neutralization activity against IHNV in fish immunized with single-cycle VHSV IVa, the protection might be independent of humoral adaptive immunity. The scarcity of cytotoxic T cell epitopes between VHSV and IHNV suggested that the possibility of involvement of cytotoxic T cell-mediated cellular adaptive immunity would be low. The role of trained immunity (innate immune memory) in cross-protection should be further investigated.

Keywords:  Cross-protection; Novirhabdoviruses; Rainbow trout; Single-cycle VHSV

DOI:  https://doi.org/10.1016/j.vaccine.2023.07.058
Redox Biol. 2023 Jul 29. pii: S2213-2317(23)00235-5. [Epub ahead of print]65 102834

Sulfur metabolic response in macrophage limits excessive inflammatory response by creating a negative feedback loop.

Haruna Takeda, Shohei Murakami, Zun Liu, Tomohiro Sawa, Masatomo Takahashi, Yoshihiro Izumi, Takeshi Bamba, Hideyo Sato, Takaaki Akaike, Hiroki Sekine, Hozumi Motohashi.

  The excessive inflammatory response of macrophages plays a vital role in the pathogenesis of various diseases. The dynamic metabolic alterations in macrophages, including amino acid metabolism, are known to orchestrate their inflammatory phenotype. To explore a new metabolic pathway that regulates the inflammatory response, we examined metabolome changes in mouse peritoneal macrophages (PMs) in response to lipopolysaccharide (LPS) and found a coordinated increase of cysteine and its related metabolites, suggesting an enhanced demand for cysteine during the inflammatory response. Because Slc7a11, which encodes a cystine transporter xCT, was remarkably upregulated upon the pro-inflammatory challenge and found to serve as a major channel of cysteine supply, we examined the inflammatory behavior of Slc7a11 knockout PMs (xCT-KO PMs) to clarify an impact of the increased cysteine demand on inflammation. The xCT-KO PMs exhibited a prolonged upregulation of pro-inflammatory genes, which was recapitulated by cystine depletion in the culture media of wild-type PMs, suggesting that cysteine facilitates the resolution of inflammation. Detailed analysis of the sulfur metabolome revealed that supersulfides, such as cysteine persulfide, were increased in PMs in response to LPS, which was abolished in xCT-KO PMs. Supplementation of N-acetylcysteine tetrasulfide (NAC-S2), a supersulfide donor, attenuated the pro-inflammatory gene expression in xCT-KO PMs. Thus, activated macrophages increase cystine uptake via xCT and produce supersulfides, creating a negative feedback loop to limit excessive inflammation. Our study highlights the finely tuned regulation of macrophage inflammatory response by sulfur metabolism.

Keywords:  Cysteine; Inflammation; LPS; Macrophage; Persulfide; xCT

DOI:  https://doi.org/10.1016/j.redox.2023.102834
Cell Death Dis. 2023 07 31. 14(7): 486

Negative regulation of pro-apoptotic AMPK/JNK pathway by itaconate in mice with fulminant liver injury.

Kerui Fan, Kun Chen, Xinyan Zan, Ying Zhi, Xue Zhang, Xinyue Zhang, Jinghuan Qiu, Gang Liu, Longjiang Li, Li Tang, Kai Hu, Jingyuan Wan, Xianqiong Gong, Yongqiang Yang, Li Zhang.

Accumulating evidence indicates that metabolic responses are deeply integrated into signal transduction, which provides novel opportunities for the metabolic control of various disorders. Recent studies suggest that itaconate, a highly concerned bioactive metabolite catalyzed by immune responsive gene 1 (IRG1), is profoundly involved in the regulation of apoptosis, but the underlying mechanisms have not been fully understood. In the present study, the molecular mechanisms responsible for the apoptosis-modulatory activities of IRG1/itaconate have been investigated in mice with lipopolysaccharide (LPS)/D-galactosamine (D-Gal)-induced apoptotic liver injury. The results indicated that LPS/D-Gal exposure upregulated the level of IRG1 and itaconate. Deletion of IRG1 resulted in exacerbated hepatocytes apoptosis and liver injury. The phospho-antibody microarray analysis and immunoblot analysis indicated that IRG1 deletion enhanced the activation of AMP-activated protein kinase (AMPK)/c-jun-N-terminal kinase (JNK) pathway in LPS/D-Gal exposed mice. Mechanistically, IRG1 deficiency impaired the anti-oxidative nuclear factor erythroid-2 related factor 2 (Nrf2) signaling and then enhanced the activation of the redox-sensitive AMPK/JNK pathway that promotes hepatocytes apoptosis. Importantly, post-insult supplementation with 4-octyl itaconate (4-OI), a cell-permeable derivate of itaconate, resulted in beneficial outcomes in fulminant liver injury. Therefore, IRG1/itaconate might function as a negative regulator that controls AMPK-induced hepatocyte apoptosis in LPS/D-Gal-induced fulminant liver injury.

DOI: https://doi.org/10.1038/s41419-023-06001-w
Cell Rep Med. 2023 Jul 26. pii: S2666-3791(23)00260-4. [Epub ahead of print] 101132

Artificial cells delivering itaconic acid induce anti-inflammatory memory-like macrophages to reverse acute liver failure and prevent reinjury.

Na Yin, Wenjun Zhang, Xiao-Xin Sun, Runxiu Wei, Qiang Yang, Fengming He, Changrui Li, Ling Guo, Min Feng.

  Hepatic macrophages represent a key cellular component of the liver and are essential for the progression of acute liver failure (ALF). We construct artificial apoptotic cells loaded with itaconic acid (AI-Cells), wherein the compositions of the synthetic plasma membrane and surface topology are rationally engineered. AI-Cells are predominantly localized to the liver and further transport to hepatic macrophages. Intravenous administration of AI-Cells modulates macrophage inflammation to protect the liver from acetaminophen-induced ALF. Mechanistically, AI-Cells act on caspase-1 to suppress NLRP3 inflammasome-mediated cleavage of pro-IL-1β into its active form in macrophages. Notably, AI-Cells specifically induce anti-inflammatory memory-like hepatic macrophages in ALF mice, which prevent constitutive overproduction of IL-1β when liver reinjury occurs. In light of AI-Cells' precise delivery and training of memory-like hepatic macrophages, they offer promising therapeutic potential in reversing ALF by finely controlling inflammatory responses and orchestrating liver homeostasis, which potentially affect the treatment of various types of liver failure.

Keywords:  IL-1β; acute liver failure; artificial cells; itaconic acid; memory-like hepatic macrophages

DOI:  https://doi.org/10.1016/j.xcrm.2023.101132