bims-traimu 2024-10-20 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2024–10–20
ten papers selected by
Yantong Wan, Southern Medical University

Bacillus Calmette-Guérin vaccination induces a trained innate immunity phenotype in adults over 50 years of age: A randomized trial in Guinea-Bissau.
A distinct metabolic and epigenetic state drives trained immunity in HSC-derived macrophages from autoimmune mice.
Evaluating the effect of BCG vaccination for non-specific protection from infection in senior citizens during the COVID-19 pandemic: a randomised clinical trial.
Ccl5+ Macrophages drive pro-inflammatory responses and neutrophil recruitment in sepsis-associated acute kidney injury.
Single-cell stimulus-response gene expression trajectories reveal the stimulus specificities of dynamic responses by single macrophages.
Itaconate drives mtRNA-mediated type I interferon production through inhibition of succinate dehydrogenase.
TLR2 and NLRP3 Orchestrate Regulatory Roles in Escherichia coli Infection-Induced Septicemia in Mouse Models.
Modulation of Metabolomic Profile in Sepsis According to the State of Immune Activation.
Mechanisms of epigenomic and functional convergence between glucocorticoid- and IL4-driven macrophage programming.
Monocyte-regulated interleukin 12 production drives clearance of Staphylococcus aureus.

Vaccine. 2024 Oct 17. pii: S0264-410X(24)01121-6. [Epub ahead of print]42(26): 126439

Bacillus Calmette-Guérin vaccination induces a trained innate immunity phenotype in adults over 50 years of age: A randomized trial in Guinea-Bissau.

Mike Leonardus Theodorus Berendsen, Pauli Bles, Louise Charlotte Johanna de Bree, Kristoffer Jarlov Jensen, Clara Clipet Jensen, Christian Wejse, Delfim Vicente Mendes, Mihai Gheorghe Netea, Christine Stabell Benn.

   BACKGROUND: The beneficial effects of Bacillus Calmette-Guérin (BCG) as an intervention against non-mycobacterial infections have been extensively studied in randomized trials. These non-specific effects have been linked to a heterologous increase of pro-inflammatory cytokine production by innate immune cells. It is unknown if BCG induces such responses in older individuals from TB-endemic countries.
METHODS: In a single-blinded trial in Guinea-Bissau, 40 adults over 50 years of age were randomized 1:1 in a block of 40 to intradermal injection of BCG-Japan (intervention) or solvent (placebo). Production of interleukin (IL)-1β, IL-6, IL-10, interferon (IFN)-γ and tumor necrosis factor (TNF)-α was measured by ELISA in supernatant of peripheral blood mononuclear cells stimulated with Mycobacterium tuberculosis and heterologous pathogens. The trial was registered at clinicaltrials.gov (NCT02953327).
FINDINGS: Between January 25 and March 7, 2017, 40 individuals were randomized. Two months after vaccination, BCG-Japan recipients (n = 11) had higher production of IFN-γ to M. tuberculosis stimulation (Geometric mean ratio (GMR): 3·91 [95 % Confidence Interval (CI), 1·53-9·96]) and increased release of the pro-inflammatory innate cytokines IL-1β, IL-6 and TNF-α to non-specific stimuli (GMR TNF-α: 1·47 [95 % CI, 0·98-2·19]) than their controls (n = 13). Both the specific and non-specific responses were more pronounced among those with a positive QuantiFERON at baseline.
INTERPRETATION: BCG-Japan can induce a trained immunity phenotype in older adults. These effects were particularly strong in previously M. tuberculosis exposed individuals. Future randomized trials are needed to determine BCG's potential to protect the older populations from infections-driven morbidity and mortality.

Keywords:  Bacillus Calmette-Guérin; Boosting; Immunosenescence; Non-specific effects; Older adults; Trained immunity

DOI:  https://doi.org/10.1016/j.vaccine.2024.126439
Cell Stem Cell. 2024 Oct 14. pii: S1934-5909(24)00324-2. [Epub ahead of print]

A distinct metabolic and epigenetic state drives trained immunity in HSC-derived macrophages from autoimmune mice.

Taylor S Mills, Bailee Kain, Matt A Burchill, Etienne Danis, Erin D Lucas, Rachel Culp-Hill, Courtney M Cowan, Wolfgang E Schleicher, Sweta B Patel, Brandon T Tran, Ruoqiong Cao, Andrew Goodspeed, Sarah Ferrara, Shaun Bevers, Beth A Jirón Tamburini, James R Roede, Angelo D'Alessandro, Katherine Y King, Eric M Pietras.

  Here, we investigate the contribution of long-term hematopoietic stem cells (HSCsLT) to trained immunity (TI) in the setting of chronic autoimmune disease. Using a mouse model of systemic lupus erythematosus (SLE), we show that bone marrow-derived macrophages (BMDMs) from autoimmune mice exhibit hallmark features of TI, including increased Mycobacterium avium killing and inflammatory cytokine production, which are mechanistically linked to increased glycolytic metabolism. We show that HSCs from autoimmune mice constitute a transplantable, long-term reservoir for macrophages that exhibit the functional properties of TI. However, these BMDMs exhibit reduced glycolytic activity and chromatin accessibility at metabolic genes while retaining elevated expression of TI-associated transcriptional regulators. Hence, HSC exposed to autoimmune inflammation can give rise to macrophages in which the functional and metabolic properties of TI are decoupled. Our data support a model in which TI is characterized by a spectrum of molecular and metabolic states driving augmented immune function.

Keywords:  autoimmune disease; bone marrow-derived macrophage; hematopoietic stem cell; inflammation; metabolism; trained immunity

DOI:  https://doi.org/10.1016/j.stem.2024.09.010
J Infect. 2024 Oct 16. pii: S0163-4453(24)00253-6. [Epub ahead of print] 106319

Evaluating the effect of BCG vaccination for non-specific protection from infection in senior citizens during the COVID-19 pandemic: a randomised clinical trial.

Anne Marie Rosendahl Madsen, Lise Gehrt, Frederik Schaltz-Buchholzer, Sören Möller, Rikke Christiansen, Lars Schellerup, Lene Annette Norberg, Tyra Grove Krause, Sebastian Nielsen, Mette Bliddal, Peter Aaby, Christine Stabell Benn.

   OBJECTIVES: The Bacillus Calmette-Guérin (BCG) vaccine may induce non-specific protection against unrelated infections. We tested the effect of BCG on the risk of infections among Danish senior citizens.
METHODS: Single-blinded randomised controlled trial including 1,676 volunteers >65 years. Participants were randomised 1:1 to BCG or placebo and followed for 12 months. The primary outcome was acute infection leading to medical contact. Secondary outcomes were verified SARS-CoV-2 infection, self-reported respiratory symptoms, and all-cause hospitalisation. Data was analysed using Cox regression models, estimating hazard ratios (HR) with 95% confidence intervals (CI).
RESULTS: The incidence of acute infection was 52.1 and 58.2 per 100 person-years for BCG and placebo respectively (HR=0.89, 95% CI=0.78-1.02). There was no effect of BCG on SARS-CoV-2 infections (0.97, 0.75-1.26) or all-cause hospitalisations (1.10, 0.80-1.50), but BCG was associated with more respiratory symptoms (1.21, 1.10-1.33). BCG reduced the incidence of acute infections among participants <75 years (0.82, 0.70-0.95) but not among those >75 years (1.14, 0.88-1.47). In participants, who were COVID-19 vaccinated before enrolment, BCG was associated with lower incidence of acute infections (0.65, 0.50-0.85).
CONCLUSION: BCG did not reduce risk of acute infections among Danish seniors overall, but the effect was modified by age group and COVID-19 vaccination.
TRIAL REGISTRATION: ClinicalTrials.gov (NCT04542330) and EU Clinical Trials Register (EudraCT number 2020-003904-15).
SUMMARY: In a randomised clinical trial among Danish senior citizens, BCG vaccination did not reduce the overall risk of acute infection, but BCG was associated with reduced risk in participants <75 years and participants who received COVID-19 vaccines prior to enrolment.

Keywords:  BCG revaccination; BCG vaccine; COVID-19 pandemic; heterologous effects; infectious diseases; non-specific effects of vaccines; randomised controlled trial; senior citizens

DOI:  https://doi.org/10.1016/j.jinf.2024.106319
Int Immunopharmacol. 2024 Oct 16. pii: S1567-5769(24)01861-7. [Epub ahead of print]143(Pt 2): 113339

Ccl5+ Macrophages drive pro-inflammatory responses and neutrophil recruitment in sepsis-associated acute kidney injury.

Wenlin Fan, Chunli Wang, Kang Xu, Huaping Liang, Qingjia Chi.

  Sepsis leads to dysfunctional immune responses with multi-organ damage, and acute kidney injury (AKI) is a common complication of sepsis. To gain a deeper understanding of the specific underlying mechanisms of sepsis, we investigated the effects of specific macrophages on sepsis. To gain a deeper understanding of the specific underlying mechanisms of sepsis, we investigated the effects of specific macrophages on sepsis. Single-cell sequencing of a mouse model of endotoxemia revealed that sepsis is a common complication of sepsis. Single-cell sequencing of a mouse model of endotoxemia revealed that the emerging macrophage subpopulation Ccl5+ Mac was significantly pro-inflammatory, activating a large number of pathways activating a large number of pathways associated with immune response and inflammatory response, including IL6-JAK-STAT3 signaling, TGF-β signaling, and inflammatory response. Interestingly, we found that Ccl5+ Mac recruits neutrophil through CCL5-CCR1 ligand receptor pairs by cellular communication analysis thereby further affecting sepsis. We therefore hypothesize that this macrophage subpopulation is actively involved in the underlying molecular mechanisms of AKI. We therefore hypothesize that this macrophage subpopulation is actively involved in the underlying molecular mechanisms of AKI in sepsis and provide valuable insights.

Keywords:  CCL5; Cell communication; Macrophage; Sepsis-induced AKI; scRNA-seq

DOI:  https://doi.org/10.1016/j.intimp.2024.113339
Mol Cell. 2024 Oct 10. pii: S1097-2765(24)00779-2. [Epub ahead of print]

Single-cell stimulus-response gene expression trajectories reveal the stimulus specificities of dynamic responses by single macrophages.

Katherine M Sheu, Aditya Pimplaskar, Alexander Hoffmann.

  Macrophages induce the expression of hundreds of genes in response to immune threats. However, current technology limits our ability to capture single-cell inducible gene expression dynamics. Here, we generated high-resolution time series single-cell RNA sequencing (scRNA-seq) data from mouse macrophages responding to six stimuli, and imputed ensembles of real-time single-cell gene expression trajectories (scGETs). We found that dynamic information contained in scGETs substantially contributes to macrophage stimulus-response specificity (SRS). Dynamic information also identified correlations between immune response genes, indicating biological coordination. Furthermore, we showed that the microenvironmental context of polarizing cytokines profoundly affects scGETs, such that measuring response dynamics offered clearer discrimination of the polarization state of individual macrophage cells than single time-point measurements. Our findings highlight the important contribution of dynamic information contained in the single-cell expression responses of immune genes in characterizing the SRS and functional states of macrophages.

Keywords:  context dependence; dynamics; gene expression trajectories; inducible gene expression; information theory; machine learning; macrophage; single cell; stimulus-response specificity; trajectory ensembles

DOI:  https://doi.org/10.1016/j.molcel.2024.09.023
Nat Metab. 2024 Oct 15.

Itaconate drives mtRNA-mediated type I interferon production through inhibition of succinate dehydrogenase.

Shane M O'Carroll, Christian G Peace, Juliana E Toller-Kawahisa, Yukun Min, Alexander Hooftman, Sara Charki, Louise Kehoe, Maureen J O'Sullivan, Aline Zoller, Anne F Mcgettrick, Emily A Day, Maria Simarro, Neali Armstrong, Justin P Annes, Luke A J O'Neill.

Itaconate is one of the most highly upregulated metabolites in inflammatory macrophages and has been shown to have immunomodulatory properties. Here, we show that itaconate promotes type I interferon production through inhibition of succinate dehydrogenase (SDH). Using pharmacological and genetic approaches, we show that SDH inhibition by endogenous or exogenous itaconate leads to double-stranded mitochondrial RNA (mtRNA) release, which is dependent on the mitochondrial pore formed by VDAC1. In addition, the double-stranded RNA sensors MDA5 and RIG-I are required for IFNβ production in response to SDH inhibition by itaconate. Collectively, our data indicate that inhibition of SDH by itaconate links TCA cycle modulation to type I interferon production through mtRNA release.

DOI: https://doi.org/10.1038/s42255-024-01145-1
J Innate Immun. 2024 Oct 15. 1-23

TLR2 and NLRP3 Orchestrate Regulatory Roles in Escherichia coli Infection-Induced Septicemia in Mouse Models.

Zhiguo Gong, Wei Mao, Jiamin Zhao, Peipei Ren, Zhuoya Yu, Yunjie Bai, Chao Wang, Yuze Liu, Shuang Feng, Surong Hasi.

Introduction Escherichia coli (E. coli) is a significant commensal gram-negative bacterium that can give rise to various diseases. The roles of Toll-like receptor 2 (TLR2) and the NLR pyrin domain-containing 3 (NLRP3) inflammasome in sepsis induced by E. coli infection remain unclear. Methods In vivo, we investigated differences in mortality, production of inflammatory mediators, organ damage, neutrophil count, and bacterial load during E. coli infection in C57BL/6J mice, as well as in mice deficient in TLR2 or NLRP3. In vitro, we investigated the impact of E. coli on the activation of TLR2 and NLRP3 in macrophages and the influence of TLR2 and NLRP3 on the activation of inflammatory signaling pathways and the secretion of inflammatory mediators in macrophages induced by E. coli infection. Results TLR2-deficient (TLR2-/-) and NLRP3-deficient (NLRP3-/-) mice exhibit significantly increased mortality and organ damage after E. coli infection. These mice also show elevated levels of TNF-α and IL-10 in serum and peritoneal lavage fluid (PLF). Additionally, TLR2-/- and NLRP3-/- mice display heightened neutrophil recruitment, increased bacterial load in the blood. Furthermore, macrophages from these mice demonstrate a significant reduction in the activation of the MAPK signaling pathway. Conclusion TLR2 and NLRP3 play crucial roles in modulating inflammatory mediator expression, immune cell recruitment, and bactericidal activity, thereby preventing excessive tissue damage and reducing mortality in E. coli-induced sepsis.

DOI: https://doi.org/10.1159/000541819
Crit Care Med. 2024 Nov 01. 52(11): e536-e544

Modulation of Metabolomic Profile in Sepsis According to the State of Immune Activation.

Eleftheria Kranidioti, Isis Ricaño-Ponce, Nikolaos Antonakos, Evdoxia Kyriazopoulou, Antigone Kotsaki, Iraklis Tsangaris, Dimitra Markopoulou, Nikoleta Rovina, Eleni Antoniadou, Ioannis Koutsodimitropoulos, George N Dalekos, Glykeria Vlachogianni, Karolina Akinosoglou, Vasilios Koulouras, Apostolos Komnos, Theano Kontopoulou, George Dimopoulos, Mihai G Netea, Vinod Kumar, Evangelos J Giamarellos-Bourboulis.

OBJECTIVE: To investigate the metabolomic profiles associated with different immune activation states in sepsis patients.
DESIGN: Subgroup analysis of the PROVIDE (a Personalized Randomized trial of Validation and restoration of Immune Dysfunction in severe infections and Sepsis) prospective clinical study.
SETTING: Results of the PROVIDE study showed that patients with sepsis may be classified into three states of immune activation: 1) macrophage-activation-like syndrome (MALS) characterized by hyperinflammation, sepsis-induced immunoparalysis, and 3) unclassified or intermediate patients without severe immune dysregulation.
PATIENTS OR SUBJECTS: Two hundred ten patients from 14 clinical sites in Greece meeting the Sepsis-3 definitions with lung infection, acute cholangitis, or primary bacteremia.
INTERVENTIONS: During our comparison, we did not perform any intervention.
MEASUREMENTS AND MAIN RESULTS: Untargeted metabolomics analysis was performed on plasma samples from 210 patients (a total of 1394 products). Differential abundance analysis identified 221 significantly different metabolites across the immune states. Metabolites were enriched in pathways related to ubiquinone biosynthesis, tyrosine metabolism, and tryptophan metabolism when comparing MALS to immunoparalysis and unclassified patients. When comparing MALS to unclassified, 312 significantly different metabolites were found, and pathway analysis indicated enrichment in multiple pathways. Comparing immunoparalysis to unclassified patients revealed only two differentially regulated metabolites.
CONCLUSIONS: Findings suggest distinct metabolic dysregulation patterns associated with different immune dysfunctions in sepsis: the strongest metabolic dysregulation is associated with MALS.

DOI: https://doi.org/10.1097/CCM.0000000000006391
Nat Commun. 2024 Oct 18. 15(1): 9000

Mechanisms of epigenomic and functional convergence between glucocorticoid- and IL4-driven macrophage programming.

Dinesh K Deochand, Marija Dacic, Michael J Bale, Andrew W Daman, Vidyanath Chaudhary, Steven Z Josefowicz, David Oliver, Yurii Chinenov, Inez Rogatsky.

Macrophages adopt distinct phenotypes in response to environmental cues, with type-2 cytokine interleukin-4 promoting a tissue-repair homeostatic state (M2IL4). Glucocorticoids (GC), widely used anti-inflammatory therapeutics, reportedly impart a similar phenotype (M2GC), but how such disparate pathways may functionally converge is unknown. We show using integrative functional genomics that M2IL4 and M2GC transcriptomes share a striking overlap mirrored by a shift in chromatin landscape in both common and signal-specific gene subsets. This core homeostatic program is enacted by transcriptional effectors KLF4 and the glucocorticoid receptor, whose genome-wide occupancy and actions are integrated in a stimulus-specific manner by the nuclear receptor cofactor GRIP1. Indeed, many of the M2IL4:M2GC-shared transcriptomic changes were GRIP1-dependent. Consistently, GRIP1 loss attenuated phagocytic activity of both populations in vitro and macrophage tissue-repair properties in the murine colitis model in vivo. These findings provide a mechanistic framework for homeostatic macrophage programming by distinct signals, to better inform anti-inflammatory drug design.

DOI: https://doi.org/10.1038/s41467-024-52942-x
PLoS Pathog. 2024 Oct 17. 20(10): e1012648

Monocyte-regulated interleukin 12 production drives clearance of Staphylococcus aureus.

Adeline Peignier, Jisun Kim, Alexander Lemenze, Dane Parker.

Staphylococcus aureus is a versatile bacterium responsible for conditions ranging from mild skin and soft-tissue infections to serious disorders such as pneumonia and sepsis. Monocytes play a role in protection against pathogens by migrating to inflamed tissues and differentiating into macrophages but their specific role in the context of S. aureus pulmonary infection has not been fully elucidated. Using a CCR2-DTR transgenic mouse model we demonstrate that over the course of infection monocyte depletion resulted in worse airway clearance of S. aureus. The bronchoalveolar lavage fluid (BALF) of CCR2-DTR mice after S. aureus infection displayed significant decreases in interleukin-12 (IL-12), IFN-γ, IP-10, MIG and RANTES, all IFN-γ regulated, compared to wild-type (WT) infected controls. NK cells were identified as the main producers of IFN-γ, but both NK cells and IFN-γ were dispensable for clearance. We demonstrated through cytokine production and RNA-seq analysis that IL-12 and IL-12 regulated genes are strongly induced in monocytes upon S. aureus infection. Administration of IL-12 during infection restored the bacterial burdens in the BALF and lungs of monocyte-depleted CCR2-DTR mice to the levels of WT mice, independent of IFN-γ. In the absence of monocytes, alveolar macrophages are the primary phagocytic cells, and IL-12 influences their capacity to produce reactive oxygen species and clear S. aureus. These results show that production of IL-12 contributes to the control of S. aureus via its influence on alveolar macrophage function.

DOI: https://doi.org/10.1371/journal.ppat.1012648