bims-traimu 2025-01-12 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2025–01–12
nine papers selected by
Yantong Wan, Southern Medical University

Trained immunity: from kidney failure to organ transplantation.
The Cellular and Transcriptomic Early Innate Immune Response to BCG Vaccination in Mice.
PBMC transcriptomic signatures reflect Trypanosoma cruzi strain diversity and trained immunity in chronically infected macaques.
Orally Administered Lactobacilli Strains Modulate Alveolar Macrophages and Improve Protection Against Respiratory Superinfection.
IRF1 cooperates with ISGF3 or GAF to form innate immune de novo enhancers in macrophages.
β-Glucan reprograms neutrophils to promote disease tolerance against influenza A virus.
Metabolic reprogramming of macrophages by PKM2 promotes IL-10 production via adenosine.
Enterobactin inhibits microbiota-dependent activation of AhR to promote bacterial sepsis in mice.
Transcription factor networks in cellular quiescence.

Nat Rev Nephrol. 2025 Jan 06.

Trained immunity: from kidney failure to organ transplantation.

Jordi Ochando, Alberto Ortiz.

DOI: https://doi.org/10.1038/s41581-024-00927-w
Cells. 2024 Dec 11. pii: 2043. [Epub ahead of print]13(24):

The Cellular and Transcriptomic Early Innate Immune Response to BCG Vaccination in Mice.

Liya G Kondratyeva, Olga A Rakitina, Victor V Pleshkan, Alexey I Kuzmich, Irina A Linge, Sofia A Kondratieva, Eugene V Snezhkov, Irina V Alekseenko, Eugene D Sverdlov.

  It is established that BCG vaccination results in the development of both a specific immune response to mycobacterial infections and a nonspecific (heterologous) immune response, designated as trained immunity (TRIM), to other pathogens. We hypothesized that local BCG immunization may induce an early immune response in bone marrow and spleen innate immunity cells. The early transcriptomic response of various populations of innate immune cells, including monocytes, neutrophils, and natural killer (NK) cells, to BCG vaccination was examined. To this end, C57Bl/6J mice were subcutaneously immunized with 106 CFU of BCG. Three days following BCG administration, the three cell populations were collected from the control and BCG-vaccinated groups using FACS. All cell populations obtained were utilized for the preparation and sequencing of RNA-seq libraries. The analysis of FACS data revealed an increase in the proportion of splenic NK cells and monocytes 3 days post-vaccination. Transcriptomic analysis revealed the deregulation of genes associated with the regulation of immune response (according to Gene Ontology terms) in NK cells, monocytes, and unsorted bone marrow cells. Two NK cell-specific immune ligands (Tnfsf14 and S100a8) and two bone marrow-specific immune receptors (C5ar1 and Csf2rb) were identified among differentially expressed genes. No alterations were identified in neutrophils in either their percentage or at the transcriptomic level. Thus, in this study, we demonstrated that BCG vaccination provides an early increase in the proportion of murine bone marrow and spleen immune cell populations, as well as transcriptomic alterations in monocytes, NK cells, and non-sorted bone marrow cells. This early innate immune response may be beneficial for enhancing TRIM.

Keywords:  BCG; RNA-seq; innate immunity; trained immunity; transcriptome; vaccination

DOI:  https://doi.org/10.3390/cells13242043
JCI Insight. 2025 Jan 07. pii: e186003. [Epub ahead of print]

PBMC transcriptomic signatures reflect Trypanosoma cruzi strain diversity and trained immunity in chronically infected macaques.

Hans Desale, Weihong Tu, Kelly Goff, Preston A Marx, Claudia Herrera, Eric Dumonteil.

  Chagas disease is a neglected tropical disease caused by Trypanosoma cruzi with clinical presentations ranging from asymptomatic to cardiac and/or gastrointestinal complications. The mechanisms of pathogenesis are still poorly understood, but T. cruzi strain diversity may be associated with disease progression. Therefore, we evaluated the transcriptomic response of PBMCs from macaques with natural chronic infections and tested for heterogeneity in their gene signatures. Remarkably, transcriptomic response to T. cruzi infection matched parasite strain profiles, indicating that parasite diversity is a key determinant of host response. While differences in adaptive immune responses were identified, more striking alterations of innate immune processes were detected. Thus, initial innate response to T. cruzi infection may be conditioned by parasite strain diversity, resulting in different profiles of trained immunity modulating subsequent adaptive responses, allowing parasite control or its persistence during the chronic phase. These results call for further characterization of the cross-talk between innate and adaptive immunity according to parasite diversity, and how altered trained immunity contributes to pathogenesis, as this may lead to better treatments and vaccines.

Keywords:  Infectious disease; Microbiology; Parasitology

DOI:  https://doi.org/10.1172/jci.insight.186003
Biomolecules. 2024 Dec 14. pii: 1600. [Epub ahead of print]14(12):

Orally Administered Lactobacilli Strains Modulate Alveolar Macrophages and Improve Protection Against Respiratory Superinfection.

Leonardo Albarracin, Stefania Dentice Maidana, Kohtaro Fukuyama, Mariano Elean, Julio Nicolás Argañaraz Aybar, Yoshihito Suda, Keita Nishiyama, Haruki Kitazawa, Julio Villena.

  Orally administered immunomodulatory lactobacilli can stimulate respiratory immunity and enhance the resistance to primary infections with bacterial and viral pathogens. However, the potential beneficial effects of immunomodulatory lactobacilli against respiratory superinfection have not been evaluated. In this work, we showed that the feeding of infant mice with Lacticaseibacillus rhamnosus CRL1505 or Lactiplantibacillus plantarum MPL16 strains can reduce susceptibility to the secondary pneumococcal infection produced after the activation of TLR3 in the respiratory tract or after infection with RVS. The treatment of mice with CRL1505 or MPL16 strains by the oral route improved the production of interferons in the respiratory tract, differentially modulated the balance of pro- and anti-inflammatory cytokines, reduced bacterial replication, and diminished lung damage. Additionally, we demonstrated that orally administered lactobacilli confer longstanding protection against secondary Streptococcus pneumoniae infection and that this effect would be mediated by the stimulation of trained alveolar macrophages. This work contributes to revealing the mechanisms involved in the modulation of the gut-lung axis by beneficial microbes by demonstrating that specific lactobacilli strains, through the stimulation of the common mucosal immune system, would be able to support the development of trained alveolar macrophages that would confer longstanding protection against secondary bacterial challenges produced after a primary inflammatory event in the respiratory mucosa.

Keywords:  Lacticaseibacillus rhamnosus CRL1505; alveolar macrophages; probiotic lactobacilli; respiratory immunity; superinfection

DOI:  https://doi.org/10.3390/biom14121600
Sci Signal. 2025 Jan 07. 18(868): eado8860

IRF1 cooperates with ISGF3 or GAF to form innate immune de novo enhancers in macrophages.

Carolina Chavez, Kelly Lin, Alexis Malveaux, Aleksandr Gorin, Stefanie Brizuela, Quen J Cheng, Alexander Hoffmann.

Macrophages exposed to immune stimuli reprogram their epigenomes to alter their subsequent functions. Exposure to bacterial lipopolysaccharide (LPS) causes widespread nucleosome remodeling and the formation of thousands of de novo enhancers. We dissected the regulatory logic by which the network of interferon regulatory factors (IRFs) induces the opening of chromatin and the formation of de novo enhancers. We found that LPS-activated IRF3 mediated de novo enhancer formation indirectly by activating the type I interferon (IFN)-induced ISGF3. However, ISGF3 was generally needed to collaborate with IRF1, particularly where chromatin was less accessible. At these locations, IRF1 was required for the initial opening of chromatin, with ISGF3 extending accessibility and promoting the deposition of H3K4me1, marking poised enhancers. Because IRF1 expression depends on the transcription factor NF-κB, which is activated in infected but not bystander cells, IRF-regulated enhancers required activation of both the IRF3 and NF-κB branches of the innate immune signaling network. However, type II IFN (IFN-γ), which is typically produced by T cells, may also induce IRF1 expression through the STAT1 homodimer GAF. We showed that, upon IFN-γ stimulation, IRF1 was also responsible for opening inaccessible chromatin sites that could then be exploited by GAF to form de novo enhancers. Together, our results reveal how combinatorial logic gates of IRF1-ISGF3 or IRF1-GAF restrict immune epigenomic memory formation to macrophages exposed to pathogens or IFN-γ-secreting T cells but not bystander macrophages exposed transiently to type I IFN.

DOI: https://doi.org/10.1126/scisignal.ado8860
Nat Immunol. 2025 Jan 08.

β-Glucan reprograms neutrophils to promote disease tolerance against influenza A virus.

Nargis Khan, Kim A Tran, Raphael Chevre, Veronica Locher, Mathis Richter, Sarah Sun, Mina Sadeghi, Erwan Pernet, Andrea Herrero-Cervera, Alexandre Grant, Ahmed Saif, Jeffrey Downey, Eva Kaufmann, Shabaana Abdul Khader, Philippe Joubert, Luis B Barreiro, Bryan G Yipp, Oliver Soehnlein, Maziar Divangahi.

Disease tolerance is an evolutionarily conserved host defense strategy that preserves tissue integrity and physiology without affecting pathogen load. Unlike host resistance, the mechanisms underlying disease tolerance remain poorly understood. In the present study, we investigated whether an adjuvant (β-glucan) can reprogram innate immunity to provide protection against influenza A virus (IAV) infection. β-Glucan treatment reduces the morbidity and mortality against IAV infection, independent of host resistance. The enhanced survival is the result of increased recruitment of neutrophils via RoRγt+ T cells in the lung tissue. β-Glucan treatment promotes granulopoiesis in a type 1 interferon-dependent manner that leads to the generation of a unique subset of immature neutrophils utilizing a mitochondrial oxidative metabolism and producing interleukin-10. Collectively, our data indicate that β-glucan reprograms hematopoietic stem cells to generate neutrophils with a new 'regulatory' function, which is required for promoting disease tolerance and maintaining lung tissue integrity against viral infection.

DOI: https://doi.org/10.1038/s41590-024-02041-2
Cell Rep. 2025 Jan 07. pii: S2211-1247(24)01523-7. [Epub ahead of print]44(1): 115172

Metabolic reprogramming of macrophages by PKM2 promotes IL-10 production via adenosine.

Juliana Escher Toller-Kawahisa, Paula Ramos Viacava, Eva Margareta Palsson-McDermott, Daniele Carvalho Nascimento, Mariana Patricia Cervantes-Silva, Shane Myles O'Carroll, Alessia Zotta, Luis Eduardo Alves Damasceno, Gabriel Azevedo Públio, Pedro Forti, João Paulo Mesquita Luiz, Bruno Marcel Silva de Melo, Timna Varela Martins, Vitor Marcel Faça, Annie Curtis, Thiago Mattar Cunha, Fernando de Queiroz Cunha, Luke Anthony John O'Neill, José Carlos Alves-Filho.

  Macrophages play a crucial role in immune responses and undergo metabolic reprogramming to fulfill their functions. The tetramerization of the glycolytic enzyme pyruvate kinase M2 (PKM2) induces the production of the anti-inflammatory cytokine interleukin (IL)-10 in vivo, but the underlying mechanism remains elusive. Here, we report that PKM2 activation with the pharmacological agent TEPP-46 increases IL-10 production in LPS-activated macrophages by metabolic reprogramming, leading to the production and release of ATP from glycolysis. The effect of TEPP-46 is abolished in PKM2-deficient macrophages. Extracellular ATP is converted into adenosine by ectonucleotidases that activate adenosine receptor A2a (A2aR) to enhance IL-10 production. Interestingly, IL-10 production induced by PKM2 activation is associated with improved mitochondrial health. Our results identify adenosine derived from glycolytic ATP as a driver of IL-10 production, highlighting the role of tetrameric PKM2 in regulating glycolysis to promote IL-10 production.

Keywords:  CP: Immunology; CP: Metabolism; IL-10; PKM2; adenosine; macrophage; mitochondria dynamics

DOI:  https://doi.org/10.1016/j.celrep.2024.115172
Nat Microbiol. 2025 Jan 08.

Enterobactin inhibits microbiota-dependent activation of AhR to promote bacterial sepsis in mice.

Robert C Keskey, Jason Xiao, Sanjiv Hyoju, Adam Lam, Daniel Kim, Ashley M Sidebottom, Alexander Zaborin, Anne Dijkstra, Rebecca Meltzer, Abhimanyu Thakur, Kui Zhang, Huanhuan Joyce Chen, Natalia V Beloborodova, Alisa K Pautova, Krysta Wolfe, Bhakti Patel, Renee Thewissen, Olga Zaborina, John C Alverdy.

Sepsis is a major cause of morbidity and mortality, but our understanding of the mechanisms underlying survival or susceptibility is limited. Here, as pathogens often subvert host defence mechanisms, we hypothesized that this might influence the outcome of sepsis. We used microbiota analysis, faecal microbiota transplantation, antibiotic treatment and caecal metabolite analysis to show that gut-microbiota-derived tryptophan metabolites including indoles increased host survival in a mouse model of Serratia marcescens sepsis. Infection in macrophage-specific aryl hydrocarbon receptor (AhR) knockout mice revealed that AhR activation induced transcriptional reprogramming in macrophages and increased bacterial clearance and host survival. However, culture supernatants from multiple bacterial pathogens inhibited AhR activation in vitro. We showed that the secreted siderophore, enterobactin, inhibited AhR activation in vitro and increased sepsis mortality in vivo. By contrast, oral or systemic tryptophan supplementation increased survival. These findings show that sepsis survival depends upon the interplay between pathogen inhibition and the activation of AhR by a microbiota-derived metabolite.

DOI: https://doi.org/10.1038/s41564-024-01882-9
Nat Cell Biol. 2025 Jan 09.

Transcription factor networks in cellular quiescence.

Mithun Mitra, Sandra L Batista, Hilary A Coller.

Many of the cells in mammalian tissues are in a reversible quiescent state; they are not dividing, but retain the ability to proliferate in response to extracellular signals. Quiescence relies on the activities of transcription factors (TFs) that orchestrate the repression of genes that promote proliferation and establish a quiescence-specific gene expression program. Here we discuss how the coordinated activities of TFs in different quiescent stem cells and differentiated cells maintain reversible cell cycle arrest and establish cell-protective signalling pathways. We further cover the emerging mechanisms governing the dysregulation of quiescence TF networks with age. We explore how recent developments in single-cell technologies have enhanced our understanding of quiescence heterogeneity and gene regulatory networks. We further discuss how TFs and their activities are themselves regulated at the RNA, protein and chromatin levels. Finally, we summarize the challenges associated with defining TF networks in quiescent cells.

DOI: https://doi.org/10.1038/s41556-024-01582-w