bims-traimu 2022-10-30 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2022–10–30
nine papers selected by
Yantong Wan, Southern Medical University

Trained Immunity Provides Long-Term Protection against Bacterial Infections in Channel Catfish.
Do bacterial vaccines/adjuvants prevent wheezing episodes in children?
Trained immunity is induced in humans after immunization with an adenoviral vector COVID-19 vaccine.
BCG and SARS-CoV-2-What Have We Learned?
BCG Vaccine-The Road Not Taken.
β-Glucan "Trained Immunity" Immunomodulatory Properties Potentiate Tissue Wound Management and Accelerate Fitness Recover.
Role of Glycolysis and Fatty Acid Synthesis in the Activation and T Cell-Modulating Potential of Dendritic Cells Stimulated with a TLR5-Ligand Allergen Fusion Protein.
Consecutive BNT162b2 mRNA vaccination induces short-term epigenetic memory in innate immune cells.
Assessment of the Impact of a Toll-like Receptor 2 Agonist Synthetic Lipopeptide on Macrophage Susceptibility and Responses to African Swine Fever Virus Infection.

Pathogens. 2022 Oct 02. pii: 1140. [Epub ahead of print]11(10):

Trained Immunity Provides Long-Term Protection against Bacterial Infections in Channel Catfish.

Lora Petrie-Hanson, Ann E Beth Peterman.

  Beta glucan exposure induced trained immunity in channel catfish that conferred long-term protection against Edwardsiella ictaluri and Edwardsiella piscicida infections one month post exposure. Flow cytometric analyses demonstrated that isolated macrophages and neutrophils phagocytosed higher amounts of E. ictaluri and E. piscicida. Beta glucan induced changes in the distribution of histone modifications in the monomethylation and trimethylation of H3K4 and modifications in the acetylation and trimethylation of H3K27. KEGG pathway analyses revealed that these modifications affected expressions of genes controlling phagocytosis, phagosome functions and enhanced immune cell signaling. These analyses correlate the histone modifications with gene functions and to the observed enhanced phagocytosis and to the increased survival following bacterial challenge in channel catfish. These data suggest the chromatin reconfiguration that directs trained immunity as demonstrated in mammals also occurs in channel catfish. Understanding the mechanisms underlying trained immunity can help us design prophylactic and non-antibiotic based therapies and develop broad-based vaccines to limit bacterial disease outbreaks in catfish production.

Keywords:  ChIP-seq; Edwardsiella; beta glucan; channel catfish; histone modifications; phagocytosis; trained immunity

DOI:  https://doi.org/10.3390/pathogens11101140
Curr Opin Allergy Clin Immunol. 2022 Dec 01. 22(6): 380-386

Do bacterial vaccines/adjuvants prevent wheezing episodes in children?

Antonio Nieto, María Nieto, Laura Conejero, José Luis Subiza.

PURPOSE OF REVIEW: To discuss recently discovered mechanisms of action of some bacterial vaccines that may account for their clinical benefit in the prevention of recurrent wheezing and asthma exacerbations in infants and early childhood.
RECENT FINDINGS: Trained immunity has been shown to confer innate immune cells with a quite long-term nonspecific protection against a broad spectrum of pathogens. Inducers of trained immunity include some bacterial vaccines. Trained immunity-based vaccines (TIbV) of bacterial origin have the capability to induce nonspecific responses to a variety of pathogens, including respiratory viruses, in addition to their nominal bacterial antigens. Clinical data, from epidemiological surveys to well designed randomized clinical trials, indicate that TIbV formulated with bacteria prevent respiratory tract infections of viral cause, such as those associated with recurrent wheezing or asthma exacerbation, in children. Administration of these vaccines by the mucosal route may be important for their outcome in respiratory infections.
SUMMARY: Mucosal bacterial immunotherapy, including certain TIbV, confer protection against a broad spectrum of pathogens, such as viruses, through a mechanism mediated by trained immunity. Clinical studies on the use of these preparations against recurrent wheezing reflect these mechanistic effects. These findings open a new avenue for the development of new strategies for this condition.

DOI: https://doi.org/10.1097/ACI.0000000000000854
J Clin Invest. 2022 Oct 25. pii: e162581. [Epub ahead of print]

Trained immunity is induced in humans after immunization with an adenoviral vector COVID-19 vaccine.

Dearbhla M Murphy, Donal J Cox, Sarah A Connolly, Eamon P Breen, Aenea Ai Brugman, James J Phelan, Joseph Keane, Sharee A Basdeo.

   BACKGROUND: Heterologous effects of vaccines are mediated by 'trained immunity' whereby myeloid cells are metabolically and epigenetically reprogrammed resulting in heightened responses to subsequent insults. Adenovirus vaccine vector has been reported to induce trained immunity in mice. Therefore, we sought to determine if the ChAdOx1 nCoV-19 vaccine (AZD1222), which uses an adenoviral vector, could induce trained immunity in vivo in humans.
METHODS: Ten healthy volunteers donated blood on the day before receiving the ChAdOx1 nCoV-19 vaccine and on day 14, 56 and 90 post vaccination. Monocytes were purified from PBMC; cell phenotype was determined by flow cytometry, expression of metabolic enzymes were quantified by RT-qPCR and production of cytokines and chemokine in response to stimulation ex vivo were analyzed by multiplex ELISA.
RESULTS: Monocyte frequency and count were increased in peripheral blood up to 3 months post vaccination compared with their own pre-vaccine control. Expression of HLA-DR, CD40 and CD80 was enhanced on monocytes for up to 3 months following vaccination. Moreover, monocytes had increased expression of glycolysis-associated enzymes 2 months post vaccination. Upon stimulation ex vivo with unrelated antigens, monocytes produced increased IL-1β, IL-6, IL-10, CXCL1, and MIP-1α, and decreased TNF, compared with pre-vaccine controls. Resting monocytes produced more IFN-γ, IL-18, and MCP-1 up to 3 months post vaccination compared with pre-vaccine controls.
CONCLUSION: These data provide evidence for the induction of trained immunity following a single dose of the ChAdOx1 nCoV-19 vaccine.
FUNDING: This work was funded by The Health Research Board (EIA-2019-010) and Science Foundation Ireland Strategic Partnership Programme (Proposal ID 20/SPP/3685).

Keywords:  COVID-19; Cytokines; Glucose metabolism; Monocytes; Vaccines

DOI:  https://doi.org/10.1172/JCI162581
Vaccines (Basel). 2022 Sep 30. pii: 1641. [Epub ahead of print]10(10):

BCG and SARS-CoV-2-What Have We Learned?

Jakub Kulesza, Ewelina Kulesza, Piotr Koziński, Wojciech Karpik, Marlena Broncel, Marek Fol.

  Despite controversy over the protective effect of the BCG (Bacille Calmette-Guérin) vaccine in preventing pulmonary tuberculosis (TB) in adults, it has been used worldwide since 1921. Although the first reports in the 1930s had noted a remarkable decrease in child mortality after BCG immunization, this could not be explained solely by a decrease in mortality from TB. These observations gave rise to the suggestion of nonspecific beneficial effects of BCG vaccination, beyond the desired protection against M. tuberculosis. The existence of an innate immunity-training mechanism based on epigenetic changes was demonstrated several years ago. The emergence of the pandemic caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2) in 2019 revived the debate about whether the BCG vaccine can affect the immune response against the virus or other unrelated pathogens. Due to the mortality of the coronavirus disease (COVID-19), it is important to verify each factor that may have a potential protective value against the severe course of COVID-19, complications, and death. This paper reviews the results of numerous retrospective studies and prospective trials which shed light on the potential of a century-old vaccine to mitigate the pandemic impact of the new virus. It should be noted, however, that although there are numerous studies intending to verify the hypothesis that the BCG vaccine may have a beneficial effect on COVID-19, there is no definitive evidence on the efficacy of the BCG vaccine against SARS-CoV-2.

Keywords:  COVID-19; Mycobacterium bovis bacillus Calmette-Guérin (BCG); SARS-CoV-2; immunity; non-specific protection; trained immunity; vaccination

DOI:  https://doi.org/10.3390/vaccines10101641
Microorganisms. 2022 Sep 27. pii: 1919. [Epub ahead of print]10(10):

BCG Vaccine-The Road Not Taken.

Coad Thomas Dow, Laith Kidess.

  The Bacillus Calmette-Guérin (BCG) vaccine has been used for over one hundred years to protect against the most lethal infectious agent in human history, tuberculosis. Over four billion BCG doses have been given and, worldwide, most newborns receive BCG. A few countries, including the United States, did not adopt the WHO recommendation for routine use of BCG. Moreover, within the past several decades, most of Western Europe and Australia, having originally employed routine BCG, have discontinued its use. This review article articulates the impacts of those decisions. The suggested consequences include increased tuberculosis, increased infections caused by non-tuberculous mycobacteria (NTM), increased autoimmune disease (autoimmune diabetes and multiple sclerosis) and increased neurodegenerative disease (Parkinson's disease and Alzheimer's disease). This review also offers an emerged zoonotic pathogen, Mycobacteriumavium ss. paratuberculosis (MAP), as a mostly unrecognized NTM that may have a causal role in some, if not all, of these diseases. Current clinical trials with BCG for varied infectious, autoimmune and neurodegenerative diseases have brought this century-old vaccine to the fore due to its presumed immuno-modulating capacity. With its historic success and strong safety profile, the new and novel applications for BCG may lead to its universal use-putting the Western World back onto the road not taken.

Keywords:  Alzheimer’s disease; Bacillus Calmette-Guérin (BCG); Mycobacterium avium ss. paratuberculosis (MAP); Parkinson’s disease; global burden of disease; molecular mimicry; multiple sclerosis; non-tuberculous mycobacteria (NTM); nonspecific effects; trained immunity; tuberculosis; type 1 diabetes

DOI:  https://doi.org/10.3390/microorganisms10101919
Immunotargets Ther. 2022 ;11 67-73

β-Glucan "Trained Immunity" Immunomodulatory Properties Potentiate Tissue Wound Management and Accelerate Fitness Recover.

Guilherme Renke, Thomaz Baesso, Raphaela Paes, Aline Renke.

   Introduction: It is well established that moderate physical activity can improve the immune status, rather excess or high-intensity physical exercise can cause damage to the immune system. In addition, muscle injuries resulting from increased frequency and intensity of exercises compromise innate immune activity and may decrease tissue regeneration. Thus, β-glucans, a natural compound, may represent an important substance with strong immunomodulatory properties acting as an immunostimulant therapy known as "trained immunity". This immune stimulating therapeutic is an immunological memory phenomenon linked to the innate immune system, triggering cellular changes at epigenetic, transcriptional, and functional levels, to regulate the immune system and recover its homeostasis with clinical benefits.
Conclusion: This narrative review works with the current evidence regarding β-glucans as a possible alternative therapy for wound healing and its safety and efficacy in the treatment of muscle injuries and physical recovery including other chronic conditions and diseases.

Keywords:  beta-glucans; innate immunity; metabolic-inflammation; muscle recovery; tissue regeneration; trained immunity; wound healing

DOI:  https://doi.org/10.2147/ITT.S381145
Int J Mol Sci. 2022 Oct 21. pii: 12695. [Epub ahead of print]23(20):

Role of Glycolysis and Fatty Acid Synthesis in the Activation and T Cell-Modulating Potential of Dendritic Cells Stimulated with a TLR5-Ligand Allergen Fusion Protein.

Alexandra Goretzki, Yen-Ju Lin, Jennifer Zimmermann, Hannah Rainer, Ann-Christine Junker, Sonja Wolfheimer, Stefan Vieths, Stephan Scheurer, Stefan Schülke.

  Trained immune responses, based on metabolic and epigenetic changes in innate immune cells, are de facto innate immune memory and, therefore, are of great interest in vaccine development. In previous studies, the recombinant fusion protein rFlaA:Betv1, combining the adjuvant and toll-like receptor (TLR)5-ligand flagellin (FlaA) and the major birch pollen allergen Bet v 1 into a single molecule, significantly suppressed allergic sensitization in vivo while also changing the metabolism of myeloid dendritic cells (mDCs). Within this study, the immune-metabolic effects of rFlaA:Betv1 during mDC activation were elucidated. In line with results for other well-characterized TLR-ligands, rFlaA:Betv1 increased glycolysis while suppressing oxidative phosphorylation to different extents, making rFlaA:Betv1 a suitable model to study the immune-metabolic effects of TLR-adjuvanted vaccines. In vitro pretreatment of mDCs with cerulenin (inhibitor of fatty acid biosynthesis) led to a decrease in both rFlaA:Betv1-induced anti-inflammatory cytokine Interleukin (IL) 10 and T helper cell type (TH) 1-related cytokine IL-12p70, while the pro-inflammatory cytokine IL 1β was unaffected. Interestingly, pretreatment with the glutaminase inhibitor BPTES resulted in an increase in IL-1β, but decreased IL-12p70 secretion while leaving IL-10 unchanged. Inhibition of the glycolytic enzyme hexokinase-2 by 2-deoxyglucose led to a decrease in all investigated cytokines (IL-10, IL-12p70, and IL-1β). Inhibitors of mitochondrial respiration had no effect on rFlaA:Betv1-induced IL-10 level, but either enhanced the secretion of IL-1β (oligomycin) or decreased IL-12p70 (antimycin A). In extracellular flux measurements, mDCs showed a strongly enhanced glycolysis after rFlaA:Betv1 stimulation, which was slightly increased after respiratory shutdown using antimycin A. rFlaA:Betv1-stimulated mDCs secreted directly antimicrobial substances in a mTOR- and fatty acid metabolism-dependent manner. In co-cultures of rFlaA:Betv1-stimulated mDCs with CD4+ T cells, the suppression of Bet v 1-specific TH2 responses was shown to depend on fatty acid synthesis. The effector function of rFlaA:Betv1-activated mDCs mainly relies on glycolysis, with fatty acid synthesis also significantly contributing to rFlaA:Betv1-mediated cytokine secretion, the production of antimicrobial molecules, and the modulation of T cell responses.

Keywords:  Bet v 1; Warburg; allergy; flagellin; fusion protein; immune metabolism

DOI:  https://doi.org/10.3390/ijms232012695
JCI Insight. 2022 Oct 25. pii: e163347. [Epub ahead of print]

Consecutive BNT162b2 mRNA vaccination induces short-term epigenetic memory in innate immune cells.

Yuta Yamaguchi, Yasuhiro Kato, Ryuya Edahiro, Jonas N Søndergaard, Teruaki Murakami, Saori Amiya, Shinichiro Nameki, Yuko Yoshimine, Takayoshi Morita, Yusuke Takeshima, Shuhei Sakakibara, Yoko Naito, Daisuke Motooka, Yu-Chen Liu, Yuya Shirai, Yasutaka Okita, Jun Fujimoto, Haruhiko Hirata, Yoshito Takeda, James B Wing, Daisuke Okuzaki, Yukinori Okada, Atsushi Kumanogoh.

  Consecutive mRNA vaccinations against SARS-CoV-2 reinforced both innate and adaptive immune responses. However, it remains unclear whether the enhanced innate immune responses are mediated by epigenetic regulation and, if so, whether these effects persist. Using mass cytometry, RNA-seq, and ATAC-seq, we show that BNT162b2 mRNA vaccination upregulated antiviral and IFN-stimulated gene expression in monocytes with greater effects after the second vaccination than those after the first vaccination. Transcription factor-binding motif analysis also revealed enriched IFN regulatory factors and PU.1 motifs in accessible chromatin regions. Importantly, although consecutive BNT162b2 mRNA vaccinations boosted innate immune responses and caused epigenetic changes in isolated monocytes, we showed that these effects occur only transiently and disappear 4 weeks after the second vaccination. Furthermore, single-cell RNA sequencing analysis revealed that a similar gene signature was impaired in the monocytes of unvaccinated COVID-19 patients with acute respiratory distress syndrome. These results reinforce the importance of the innate immune response in the determination of COVID-19 severity but indicate that, unlike adaptive immunity, innate immunity is not unexpectedly sustained even after consecutive vaccination. This study, which focuses on innate immmune memory, may provide novel insights into the vaccine development against infectious diseases.

Keywords:  COVID-19; Cellular immune response; Epigenetics; Innate immunity; Vaccines

DOI:  https://doi.org/10.1172/jci.insight.163347
Viruses. 2022 Oct 08. pii: 2212. [Epub ahead of print]14(10):

Assessment of the Impact of a Toll-like Receptor 2 Agonist Synthetic Lipopeptide on Macrophage Susceptibility and Responses to African Swine Fever Virus Infection.

Giulia Franzoni, Susanna Zinellu, Elisabetta Razzuoli, Lorena Mura, Chiara G De Ciucis, Livia De Paolis, Tania Carta, Antonio G Anfossi, Simon P Graham, Bernardo Chessa, Silvia Dei Giudici, Annalisa Oggiano.

  Toll-like receptor 2 (TLR2) ligands are attracting attention as prophylactic and immunopotentiator agents against pathogens, including viruses. We previously reported that a synthetic diacylated lipopeptide (Mag-Pam2Cys_P48) polarized porcine macrophages towards a proinflammatory antimicrobial phenotype. Here, we investigated its role in modulating monocyte-derived macrophage (moMΦ) responses against African swine fever virus (ASFV), the etiological agent of one of the greatest threats to the global pig industry. Two ASFV isolates were compared: the attenuated NH/P68 and the virulent 26544/OG10. No effect on virus infection nor the modulation of surface markers' expression (MHC I, MHC II DR, CD14, CD16, and CD163) were observed when Mag-Pam2Cys_P48 treated moMΦ were infected using a multiplicity of infection (MOI) of 1. Mag-Pam2Cys_P48 treated moMΦ released higher levels of IL-1α, IL-1β, IL-1Ra, and IL-18 in response to infection with NH/P68 ASFV compared to 26544/OG10-infected and mock-infected controls. Surprisingly, when infected using a MOI of 0.01, the virulent ASFV 26544/OG10 isolate replicated even slightly more efficiently in Mag-Pam2Cys_P48 treated moMΦ. These effects also extended to the treatment of moMΦ with two other lipopeptides: Mag-Pam2Cys_P80 and Mag-Pam2Cys_Mag1000. Our data suggested limited applicability of TLR2 agonists as prophylactic or immunopotentiator agents against virulent ASFV but highlighted the ability of the virulent 26544/OG10 to impair macrophage defenses.

Keywords:  ASFV; TLR2 agonist; cytokines; pattern recognition receptor; pig macrophages; surface markers

DOI:  https://doi.org/10.3390/v14102212