bims-traimu 2026-08-09 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2026–08–09
thirteen papers selected by
Yantong Wan, Southern Medical University

Epigenetic and metabolic reprogramming of innate immune cells establishes immunological memory in the Schistosomiasis vector snail Biomphalaria glabrata.
BCG HSP70 Reprograms Macrophages via Central Trained Immunity to Suppress Prostate Cancer.
Anisotropic Masked Mycobacterium Potentiates Amplified Antitumor Trained Immunity via Spleen Targeting and Myelopoiesis Conversion.
Agent-specific training directs distinctive immune response against Listeria monocytogenes infection.
Vaccination Drives Alveolar Macrophages Pool Remodeling via Training Resident Cells and Recruiting Monocyte-Derived Cells to Defend Against Multidrug-Resistant Acinetobacter baumannii.
The biological memory buffer hypothesis: can programmable nanocarriers shape cellular memory to improve the durability of mRNA vaccines and gene therapies?
Combination of trained immunity and specific inactivated vaccine against S. Choleraesuis infection in pigs.
Beyond the genetic code: orchestrating epigenetic and immune landscapes with multivalent mRNA-exosome vaccines.
Metabolic-epigenetic crosstalk in innate immune cell plasticity within the tumor microenvironment.
Emergency granulopoiesis and innate immune memory in inflammatory bowel disease.
BRD4 recruitment into HP1 condensates desilences transcription without erasure of repressive chromatin.
A bacterial fatty acid enzyme hijacks nucleic acid-sensing Toll-like receptor signaling.
Mapping enhancer-gene regulatory interactions from single-cell data.

PLoS Pathog. 2026 Aug 05. 22(8): e1014471

Epigenetic and metabolic reprogramming of innate immune cells establishes immunological memory in the Schistosomiasis vector snail Biomphalaria glabrata.

Rémi Pichon, Silvain Pinaud, Cristian Chaparro, Manon Fallet, Ricardo Lebron, Jean-François Allienne, Evgenia Turtoi, Christoph Grunau, Andrei Turtoi, David Duval, Richard Galinier, Céline Cosseau, Benjamin Gourbal.

Innate immune memory enables non-vertebrates to mount faster and more effective immune responses upon re-exposure to a previously encountered pathogen, yet its cellular and molecular bases remain poorly understood. The freshwater snail Biomphalaria glabrata, intermediate host of the human parasite Schistosoma mansoni, provides a powerful model to investigate this phenomenon. Here, we show that innate immune memory in B. glabrata is carried by hemocytes and relies on profound metabolic and epigenetic reprogramming initiated during primary infection. Using an integrative multi-omics approach combining transcriptomics, chromatin accessibility profiling, whole-genome bisulfite sequencing and targeted metabolomics, we reveal that the first parasite encounter induces a stable rewiring of hemocyte metabolism and chromatin landscape. This reprogramming primes hemocytes for a massive and rapid transcriptional response upon secondary challenge, characterized by an immune shift toward highly specific humoral effector pathways. Metabolic analyses demonstrate an early switch toward aerobic glycolysis, altered tricarboxylic acid cycle activity and amino acid metabolism, consistent with a Warburg-like metabolic state previously described in vertebrate trained immunity. Notably, metabolic and epigenetic remodeling occurs primarily during the primary infection and remains stable upon secondary exposure, suggesting that immune memory is encoded prior to pathogen re-encounter. Together, our results identify conserved metabolic and epigenetic mechanisms underlying innate immune memory in a non-vertebrate host and provide direct evidence that hemocyte-mediated innate immune memory in B. glabrata shares core features with trained immunity described in vertebrates.

DOI: https://doi.org/10.1371/journal.ppat.1014471
Adv Sci (Weinh). 2026 Aug 05. e76886

BCG HSP70 Reprograms Macrophages via Central Trained Immunity to Suppress Prostate Cancer.

Peng Liu, Kangkang Liu, Keruo Wang, Heyang Guan, Jiaming Fan, Taipeng Li, Jiaru Hao, Zeyuan Wang, Yongchao Yan, Jiatong Chen, Yuan Ma, Yang Yang, Yuanjie Niu.

  Trained immunity offers a promising yet clinically challenging strategy for cancer immunotherapy, as current inducers such as BCG pose safety concerns and their active components remain ill-defined. BCG-derived heat shock protein 70 (BCG HSP70, Dnak) has previously been recognized only as an immune adjuvant, while its role in trained immunity remains unexplored. This study identifies Dnak as a safe, defined inducer that establishes durable central trained immunity through epigenetic and metabolic reprogramming of bone marrow hematopoietic stem cells, conferring protection against bacterial infection. In prostate cancer models, a single Dnak pre-treatment significantly inhibits tumor growth-an effect transferable via bone marrow transplantation and dependent on tumor-associated macrophages. Mechanistically, Dnak-trained macrophages exhibit enhanced glycolysis, mTOR/HIF-1α pathway activation, and M1-like polarization. Notably, O-GlcNAcylation emerges as a previously unrecognized regulator of trained immunity. Furthermore, combining Dnak-induced trained immunity with a tumor vaccine achieves superior tumor control, reshapes the tumor microenvironment, and generates durable memory T cell responses upon rechallenge. These findings establish BCG HSP70 as a safe and effective protein-based trained immunity inducer with translational potential for cancer immunotherapy.

Keywords:  BCG HSP70; macrophage; trained immunity; tumor environment

DOI:  https://doi.org/10.1002/advs.76886
Adv Mater. 2026 Aug 05. e74513

Anisotropic Masked Mycobacterium Potentiates Amplified Antitumor Trained Immunity via Spleen Targeting and Myelopoiesis Conversion.

Jin-Ho Choi, Sang Nam Lee, Jang Hun Heo, Soyoung Park, Sei Hyun Park, Yong Taik Lim.

  Cancer progression involves systemic immune suppression and tumor recurrence facilitated by increased splenic protumoral myelopoiesis. To address this clinical challenge, we developed an engineered Trojan Mycobacterium as a trained immunity (TI)-mediated splenic myelopoiesis converter (t-SMC). This design provides an intravenously injectable anisotropic TI inducer with an aspect ratio of 3.6 for preferential spleen targeting and cellular uptake via a Mycobacterium "peeling-off and masking-up" strategy with human serum albumin incorporating an enzyme‑activatable Toll‑like receptor 7/8 agonist that boosts TI activation. t-SMC induces antitumoral myelopoiesis with metabolic and epigenetic reprogramming in splenic macrophages. This shift toward antitumoral myelopoiesis markedly enriches the tumor microenvironment with inflammatory myeloid effectors in an E.G7-OVA model, and the adoptive transfer of splenic myeloid cells confirmed the TI-driven antitumor effect. Furthermore, comparative analysis revealed that the bacterial scaffold (alb-Mycobac) initiates myeloid reprogramming, but only the integrated TLR7/8 agonist (t-SMC) crosses the therapeutic threshold for tumor regression. In the MC38 surgical recurrence model, preoperative t-SMC combined with standard adjuvant αPD-L1 plus oxaliplatin achieved complete inhibition of recurrence in 50% of treated mice (3 of 6) with 62.5% long-term survival, establishing TI priming as a translation-ready preoperative adjuvant that converts immune-checkpoint non-responders into responders.

Keywords:  TLR agonist; preoperative treatment; splenic myelopoiesis; trained immunity; tumor recurrence

DOI:  https://doi.org/10.1002/adma.74513
Front Immunol. 2026 ;17 1868138

Agent-specific training directs distinctive immune response against Listeria monocytogenes infection.

Marie Kim, Hailey G Main, Aaron P Esser-Kahn.

  The nonspecific protection provided by the innate immune system can be enhanced through training with stimuli, a phenomenon called 'trained immunity'. However, it remains unknown if distinct training programs with various functional outcomes can be induced. Here, we show that two training agents, flunisolide and myricetin, distinctively train and modulate the immune response against in vivo Listeria monocytogenes infection. Training with either agent led to significant reduction in pathogen burden but differed in the resulting immune functions. Training with myricetin led to the expansion of myeloid progenitor lineages, rapid cell recruitment, and enhanced phagocytosis. In contrast, training with flunisolide led to expansion of stem cell and multipotent progenitor populations, increase in antigen processing, and faster T cell expansion. We provide preliminary evidence that this divergent training outcomes may arise from agent-specific modulation of transcription factors. This study importantly shows that training can be directed at both the innate response and the onset of the adaptive response, highlighting the potential of modulating distinct training programs to influence protective immune responses.

Keywords:  flunisolide; infection; innate immune memory; myricetin; trained immunity

DOI:  https://doi.org/10.3389/fimmu.2026.1868138
MedComm (2020). 2026 Aug;7(8): e70887

Vaccination Drives Alveolar Macrophages Pool Remodeling via Training Resident Cells and Recruiting Monocyte-Derived Cells to Defend Against Multidrug-Resistant Acinetobacter baumannii.

Xiaomin Zhang, Yangyang Zhou, Chuanying Xiang, Ning Wang, Yan Li, Kai Chen, Yu Xie, Hong Yang, Xiangcheng Sun, Yun Shi.

  Alveolar macrophages (AMs) serves as a frontline innate barrier against pulmonary bacterial invasion. The AM pool comprises tissue-resident AMs (TR-AMs) and monocyte-derived AMs (Mo-AMs); yet how vaccination remodels the mixed AM pool for long-term antimicrobial defense against multidrug-resistant bacteria remains poorly understood. In this work, we applied intranasal inactivated whole-cell (IWC) vaccination against Acinetobacter baumannii and systematically dissected AM population dynamics at cellular and molecular levels. Vaccination reshaped the AM pool by recruiting CD11B+CD13+ Mo-AMs that gradually acquire a TR-AMs-like phenotype and training TR-AMs via sustained transcriptional adaptations. Functionally, the IWC-remodeled AM pool exhibited enhanced antigen presentation, TNF-α secretion, and phagocytosis, accompanied by metabolic rewiring, thereby conferring durable protection against A. baumannii infection. ATAC-seq revealed immune-related chromatin remodeling and enrichment of transcription factors, including ETS, IRF, and bZIP family members. Similar AM pool remodeling was observed following immunization with IWC vaccines against Pseudomonas aeruginosa and Klebsiella pneumoniae, suggesting parallel innate responses across multiple common respiratory bacterial vaccines. Collectively, our study delineates the single-cell transcriptional and epigenetic landscapes of vaccine-remodeled AM subsets, providing mechanistic insights to guide the development of AM-targeted prophylactic vaccines against multidrug-resistant A. baumannii.

Keywords:  Acinetobacter baumannii (A. baumannii); alveolar macrophages; intranasal vaccination; multidrug‐resistant (MDR) bacteria; trained immunity

DOI:  https://doi.org/10.1002/mco2.70887
Front Drug Deliv. 2026 ;6 1902184

The biological memory buffer hypothesis: can programmable nanocarriers shape cellular memory to improve the durability of mRNA vaccines and gene therapies?

Okechukwu Paul-Chima Ugwu, Chinyere Nneoma Ugwu, Godson Emeka Anyanwu, Mariam Basajja, Maryann Chiamaka Ebuoh.

   Introduction: Messenger RNA vaccines and gene therapies enable rapid and programmable biological intervention, but their therapeutic durability remains variable. Existing nanomedicine research primarily evaluates delivery efficiency, targeting, RNA protection and early protein expression, which do not fully explain why some biological effects persist while others rapidly decline.
Methods: This Hypothesis and Theory article presents a narrative conceptual synthesis of peer-reviewed literature on lipid nanoparticle delivery, mRNA vaccinology, RNA therapeutics, genome editing, trained innate immunity, epigenetic regulation and regenerative medicine. Evidence was integrated to develop an operational and falsifiable framework for evaluating the contribution of nanocarriers to therapeutic durability.
Results: We propose the Biological Memory Buffer Hypothesis, according to which programmable nanocarriers may influence biological systems that encode, maintain or recall therapeutic information after RNA delivery. The framework distinguishes payload persistence from biological-outcome persistence and introduces three measurable constructs: therapeutic memory engineering, nanocarrier memory capacity and the therapeutic persistence window. It further proposes matched-cargo and matched-early-exposure experiments, candidate monophasic and biphasic decay models, a minimum durability reporting set and safety monitoring for maladaptive innate immune imprinting.
Discussion: The framework does not assume that adaptive immune memory, trained immunity, epigenetic regulation and regenerative repair share a single molecular mechanism. Rather, it treats them as distinct biological substrates with a common functional relevance to durability. The hypothesis is falsifiable: failure to detect reproducible carrier-attributable differences under matched conditions would argue against nanocarrier memory capacity as an independent determinant. Incorporating longitudinal, tissue-specific and host-stratified durability measurements may support the rational development of longer-lasting RNA vaccines and gene therapies.

Keywords:  RNA therapeutics; biological memory; gene therapy; immune memory; lipid nanoparticles; mRNA vaccines; nanomedicine; therapeutic durability

DOI:  https://doi.org/10.3389/fddev.2026.1902184
Front Vet Sci. 2026 ;13 1879508

Combination of trained immunity and specific inactivated vaccine against S. Choleraesuis infection in pigs.

Lidia Sánchez-Morales, Marta Pérez-Sancho, Teresa García-Seco, Ana Balseiro, Andrea Pérez-Domingo, Aránzazu Buendía, Alberto Díez-Guerrier, Álvaro Fernández-Manzano, David Relimpio, María Ugarte-Ruiz, María de Los Ángeles Risalde, Christian Gortázar, Lucas Domínguez.

   Introduction: Salmonella enterica subsp. enterica serovar Choleraesuis is a pathogen that can cause severe systemic disease and remains a challenge in swine production due to its impact on animal health, economic losses, and zoonotic risk. While vaccination is a key control tool, current vaccines often provide limited protection to the targeted (and untargeted) serovar. Trained immunity has gained attention as a possible way to enhance non-specific protection.
Methods: This study explored whether a porcine-derived BCG strain (dpB), administered live or inactivated, could improve the protective effect of a conventional S. Choleraesuis vaccine in pigs, not only against homologous challenge but also against heterologous serovars.
Results: Pigs immunized with inactivated dpB in conjunction with the S. Choleraesuis vaccine showed a trend toward better bacterial control, with the lowest levels of S. Choleraesuis recovered from feces and ileocecal lymph nodes. Additionally, this group demonstrated a slight improved immune reactivity to heterologous serovars and a balanced cytokine response, without indications of excessive inflammation. In contrast, animals that received live dpB in addition to the vaccine showed the most severe pulmonary lesions, lowest phagocytic activity and a dysregulated cytokine profile.
Discussion: These results suggest that inactivated dpB may modulate immune responses when administered together with a conventional S. Choleraesuis vaccine and could contribute to improved bacterial control. However, the observed effects were generally modest and require confirmation in larger studies. These preliminary results support further investigation of trained immunity-based approaches as potential strategies added to conventional vaccination against Salmonella in swine.

Keywords:  S. Choleraesuis; Salmonella; cross-protection; mycobacteria; trained immunity; vaccine

DOI:  https://doi.org/10.3389/fvets.2026.1879508
Precis Clin Med. 2026 Sep;9(3): pbag019

Beyond the genetic code: orchestrating epigenetic and immune landscapes with multivalent mRNA-exosome vaccines.

Huiqin Bian, William Tse, Gang Huang, Shujun Liu.

  mRNA therapeutics are transitioning from transient anti-viral vaccines into precise cancer immunotherapies capable of orchestrating potent antigen-specific T-cell and humoral responses. However, therapeutic resistance within immunologically "cold" tumors remains a formidable barrier, necessitating multiaxial optimization across transcript architecture, neoantigen selection, delivery vector engineering, and tumor microenvironment (TME) reprogramming. This review synthesizes critical breakthroughs in mRNA biochemistry-including chemical nucleotide modifications, optimized untranslated regions, structural codon adjustments, and stringent purification methodologies-that extend transcript longevity while limiting off-target reactogenicity to maximize functional antigen expression. We evaluate multiomic neoantigen discovery workflows leveraging genomics, transcriptomics, immunoproteomics, and computational HLA-binding algorithms to refine patient-specific target selection. Next, we dissect advanced lipid nanoparticles, surface-functionalized biomaterials, and engineered extracellular vesicles optimized to enhance antigen-presenting cell tropism and lymphoid homing. We further detail how vaccine-induced cytokine fluxes actively remodel the TME, successfully reversing local immune tolerance and driving robust effector leukocyte infiltration into the tumor stroma. Specifically, we highlight the convergence of mRNA-mediated cytokine signaling and epigenetic imprinting, which cooperatively induce trained immunity for durable preventive surveillance. Finally, we delineate rational combinations with immune checkpoint blockades while addressing translational challenges: identifying predictive biomarkers, mapping presentation kinetics, and structuring adaptive clinical trial frameworks.

Keywords:  epigenetic reprogramming; exosome-mediated delivery; multivalent mRNA vaccines; precision immunotherapy; trained immunity; tumor microenvironment plasticity

DOI:  https://doi.org/10.1093/pcmedi/pbag019
Exp Mol Med. 2026 Aug 06.

Metabolic-epigenetic crosstalk in innate immune cell plasticity within the tumor microenvironment.

Junho Noh, Jaehyun Lee, Chaelin You, Kyuho Kang.

The tumor microenvironment exerts profound metabolic and epigenetic pressures that shape the plasticity of innate immune cells, influencing their capacity to promote or suppress tumor progression. Emerging evidence highlights the intricate interplay between metabolic reprogramming and epigenetic modifications in macrophages, neutrophils, and other innate immune populations within the tumor microenvironment. Tumor-derived metabolites, hypoxia, and nutrient availability dynamically regulate chromatin accessibility, histone modifications, and DNA methylation patterns, thereby driving context-dependent immune phenotypes. Notably, metabolic rewiring can imprint long-lasting epigenetic changes, a phenomenon known as innate immune memory, which alters subsequent immune responses. Here, we discuss how key metabolic pathways, including glycolysis, fatty acid oxidation, and amino acid metabolism, govern innate immune cell fate and function via epigenetic mechanisms. We also highlight recent advances in epigenomic profiling that have unveiled distinct chromatin landscapes associated with innate immune dysfunction across cancer types. Finally, we explore emerging therapeutic strategies that target the metabolic-epigenetic axis to restore innate immune surveillance and enhance immunotherapy efficacy. A deeper understanding of this metabolic-epigenetic crosstalk could reveal novel avenues for modulating innate immunity in cancer therapy.

DOI: https://doi.org/10.1038/s12276-026-01802-3
Trends Immunol. 2026 Aug 05. pii: S1471-4906(26)00183-3. [Epub ahead of print]

Emergency granulopoiesis and innate immune memory in inflammatory bowel disease.

Sílvia Pires, Randy S Longman.

Emerging evidence now points to innate tissue immunity as a critical orchestrator of both local tissue adaptation and long-range hematopoietic reprogramming, including the amplification of emergency granulopoiesis through bone marrow progenitor remodeling. These findings position the intestine as an instructive niche capable of imprinting long-lived changes both locally and systemically. This review synthesizes current findings at the intersection of gut and bone marrow biology, examining how intestinal inflammation shapes granulopoietic output and how bone marrow-derived effectors, in turn, reinforce maladaptive tissue responses that underlie chronic intestinal manifestations, including colitis-associated cancer and extraintestinal inflammatory complications frequently seen in IBD. We delineate the physiological framework governing these regulatory nodes and highlight the translational implications for next-generation therapeutic intervention.

DOI: https://doi.org/10.1016/j.it.2026.07.004
Nat Cell Biol. 2026 Aug 05.

BRD4 recruitment into HP1 condensates desilences transcription without erasure of repressive chromatin.

Christopher J Brandon, Sarah Robinson-Thiewes, Mangesh Kaulage, Wojciech Rosikiewicz, Matthew J Cuneo, Joseph Brett, Jindpreet Kandola, Walter H Lang, Jonathan Low, Ashraf Mohammed, Adithi Danda, Sam Rider, Marcus Valentine, Jason Ochoada, Brandon Young, Theresa Nguyen, Sandra J Kietlinska, Aaron B Taylor, Burkhard Hoeckendorf, Patrick Rodrigues, Wenwei Lin, Khaled Khairy, Beisi Xu, Anang A Shelat, Taosheng Chen, Tanja Mittag, Aseem Z Ansari.

How genes are desilenced without erasure of repressive chromatin is a poorly understood phenomenon. A dominant mode of repression occurs through methylation of lysine 9 of histone H3 (H3K9me3), a mark that engages heterochromatin protein 1 (HP1) to drive chromatin compaction and transcriptional silencing. The erasure and replacement of this repressive mark with acetyl/acyl groups recruits positive factors such as BRD4/BET to elicit gene transcription. Here we report that, in Friedreich's ataxia, a synthetic gene regulator (SynGR1/SynTEF1) licenses transcription across repressive chromatin without removal or replacement of H3K9me3 or HP1. By recruiting BRD4/BET into repressive GAA repeats in frataxin (FXN), SynGR1 creates a paradoxical state wherein gene transcription and repressive chromatin coexist. Contrary to convention, we find that BRD4 partitions into phase separated HP1 condensates in vitro and into HP1 puncta in patient-derived cells, thus offering a mechanistic explanation for desilencing transcription without the dispersal of mesoscale repressive chromatin. More broadly, our study highlights the dynamic nature of repressive chromatin and the context dependence of epigenetic marks in regulating gene expression.

DOI: https://doi.org/10.1038/s41556-026-02044-1
Proc Natl Acad Sci U S A. 2026 Aug 11. 123(32): e2620143123

A bacterial fatty acid enzyme hijacks nucleic acid-sensing Toll-like receptor signaling.

William A Lathram, Priscilla C Lages, Christopher D Radka.

  Innate immune recognition shapes infection outcomes by linking microbial detection to host defense. Although pattern recognition receptors are classified by the ligands they detect (lipids, peptidoglycans, or nucleic acids) cross-talk between these pathways is increasingly recognized. Staphylococcus aureus, a major cause of skin and soft tissue infections, can persist intracellularly, evading immunity and antibiotics. Here, we describe a lipid-based immune evasion strategy in which the S. aureus enzyme oleate hydratase (OhyA) converts host fatty acids into hydroxylated lipids that antagonize TLR3-TRIF-IRF7 signaling, a pathway activated by double-stranded RNA. Deletion of ohyA unleashed this pathway, triggering rapid bacterial clearance, whereas loss of TLR3, TRIF, or IRF7 restored bacterial persistence, establishing a noncanonical antibacterial role for an antiviral signaling pathway. These findings identify a previously unrecognized interface between bacterial lipid metabolism and antiviral immune machinery, highlighting how pathogens manipulate cross-kingdom signaling to evade intracellular immunity.

Keywords:  Staphylococcus aureus; acute-phase virulence; innate immunity; macrophages; oleate hydratase (OhyA)

DOI:  https://doi.org/10.1073/pnas.2620143123
Nat Genet. 2026 Aug;58(8): 1941-1952

Mapping enhancer-gene regulatory interactions from single-cell data.

Maya U Sheth, Wei-Lin Qiu, X Rosa Ma, Andreas R Gschwind, Evelyn Jagoda, Anthony S Tan, James Galante, Judhajeet Ray, Dulguun Amgalan, Hjörleifur Einarsson, Bram L Gorissen, Danilo Dubocanin, Christopher S McGinnis, Jacob Huang, Glen Munson, Kayla Brand, Ansuman T Satpathy, Thouis R Jones, Lars M Steinmetz, Anshul Kundaje, Berk Ustun, Jesse M Engreitz, Robin Andersson.

Mapping enhancers and their target genes in specific cell types is crucial for understanding gene regulation and human disease genetics. However, accurately predicting enhancer-gene regulatory interactions from single-cell datasets has been challenging. Here we introduce a family of classification models, scE2G, to predict enhancer-gene regulation. These models use features from single-cell assay for transposase-accessible chromatin with sequencing (ATAC-seq) or multiomic RNA and ATAC-seq data, and are trained on a CRISPR perturbation dataset including >10,000 evaluated element-gene pairs. We benchmark scE2G models against CRISPR perturbations, fine-mapped expression quantitative trait loci and genome-wide association study variant-gene associations and demonstrate state-of-the-art performance at prediction tasks across several cell types and categories of perturbations. We apply scE2G to build maps of enhancer-gene regulatory interactions in heterogeneous tissues and interpret noncoding variants associated with complex traits, nominating regulatory interactions linking INPP4B and IL15 to lymphocyte count. The scE2G models will enable accurate mapping of enhancer-gene regulatory interactions across thousands of human cell types.

DOI: https://doi.org/10.1038/s41588-026-02695-8