bims-traimu 2025-09-21 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2025–09–21
nine papers selected by
Yantong Wan, Southern Medical University

Gut commensal Lactobacillus strain induces a balanced trained immunity phenotype to enhance vaccine efficacy through JAK-STAT-SOCS pathway.
Recent Advances of Trained immunity in Macrophages.
The impact of mycobacteria-induced trained immunity on SARS-CoV-2 vaccine responses.
Long-term effects of influenza and Bacille Calmette-Guérin vaccination on systemic inflammation.
Deciphering immunoregulatory mechanisms and structure-guided biosynthesis of β-glucans.
Innate immune molecular landscape following controlled human influenza virus infection.
Platelet factor 4 modulates endothelial cell antimicrobial activity to enhance bacterial clearance and improve sepsis outcomes.
Delaying pyroptosis with an AI-screened gasdermin D pore blocker mitigates inflammatory response.
Endothelial STING and STAT1 mediate interferon-independent effects of IL-6 in an endotoxemia-induced model of shock.

Probiotics Antimicrob Proteins. 2025 Sep 18.

Gut commensal Lactobacillus strain induces a balanced trained immunity phenotype to enhance vaccine efficacy through JAK-STAT-SOCS pathway.

Lingdi Niu, Hai Li, Junjie Guo, Zheng Jia, Qingru Chang, Ning Liu, Shuhe Zhang, Junwei Ge.

  The gut microbiota plays a complex role in immune system maturation and function. The induction of memory in innate immune cells appears to be part of a co-adaptation between the host and microbiome. As important gut commensals, certain Lactobacillus have been shown to induce innate immune memory. However, the universality, phenotypic characteristics, mechanisms of Lactobacillus-induced innate immune memory, and its potential applications in vaccine immunology remain poorly understood. Here, we discovered that specific strains of the gut commensal Lactobacillus can induce innate immune memory, resulting in a more balanced trained immunity phenotype through SOCS activation. Upon secondary stimulation, macrophages exhibited increased expression of IL-6, IL-1β, IL-10, IL-12, IFN-β, and TGF-β. Peptidoglycan and components in the secretome sensitive to pancreatic enzymes were identified as key elements in inducing trained immunity. Furthermore, mice that underwent training demonstrated rapid resistance to S. aureus infection. Additionally, Lactobacillus-induced trained immunity significantly enhanced the protective efficacy of vaccines against MRSA. Our findings demonstrate that certain Lactobacillus strains can activate non-classical trained immunity, offering potential for enhancing vaccine efficacy. Our study provides new insights into the role of some gut commensals in immune modulation and suggests a novel approach to vaccine enhancement through trained immunity induced by specific gut commensals.

Keywords:   Levilactobacillus brevis 23,017 ; S. aureus ; Macrophages; Trained immunity

DOI:  https://doi.org/10.1007/s12602-025-10769-y
Int J Biol Sci. 2025 ;21(12): 5258-5283

Recent Advances of Trained immunity in Macrophages.

Peizhi Li, Manman Liu, Yakun Liu, Jing Guo, Jingfeng Jiang, Guidan Wang, Chenlong Cao, Xinru Wang, Junxing Qu, Zhiheng Sun.

  Trained immunity (TI), also known as innate immune memory, is the long-term change in the functional program of innate immune cells after transient stimulation through epigenetic and metabolic alterations. This reprogramming augments the response to secondary challenges fueled by various stimulus and contributes to the resistance of cancer, infectious diseases, auto-inflammatory disorders, and other diseases. Macrophages, which are versatile innate immune cells with remarkable plasticity, can adapt to different microenvironments and perform diverse functions. TI of macrophages has been deeply involved in pathogen infection. However, current understandings in the effect of TI are still incomplete and require further investigation and summarization. In this review, we summarized the existing knowledge in this field including the hallmark and mechanism of TI, its impact on health and disease, as well as the potential as a therapeutic tool. This study provides new perspectives for a comprehensive insight of TI.

Keywords:  Autoimmune diseases.; Cancer; Infectious disease; Macrophage; TI

DOI:  https://doi.org/10.7150/ijbs.115515
Front Immunol. 2025 ;16 1633977

The impact of mycobacteria-induced trained immunity on SARS-CoV-2 vaccine responses.

Lidia Sánchez-Morales, Néstor Porras, Andrea Pérez-Domingo, Marta Pérez-Sancho, Teresa García-Seco, Marta Diaz-Frutos, Aranzazu Buendia, Inmaculada Moreno, Leydis Zamora, Ana Balseiro, M A Risalde, Antonio Rodriguez-Bertos, Christian Gortázar, Mercedes Domínguez, Lucas Domínguez.

   Introduction: Beyond the role of Bacillus Calmette-Guérin (BCG) for tuberculosis prevention, BCG has demonstrated heterologous protective effects. The global health crisis caused by the SARS-CoV-2 virus led to research on whether BCG-induced trained immunity could strengthen antiviral defenses. However, studies reported quite different results on its effect against COVID-19.
Methods and results: In this study, we evaluated the impact of pre-existing trained immunity induced by a BCG-derived Mycobacterium bovis strain (dpB), in both live and inactivated forms, in combination with SARS-CoV-2 vaccination prior to challenge in a mouse model. While the SARS-CoV-2 vaccine was enough for protection in morbidity and mortality terms, its combination with live dpB significantly enhanced immune responses reflected in higher levels of pro-inflammatory cytokines, reduced pulmonary viral loads, and improved histopathological outcomes. Additionally, the formation of inducible bronchus-associated lymphoid tissue (iBALT) in lungs in vaccinated animals pre-exposed to live dpB points to a potential mechanism for long-term immune surveillance in the respiratory tract.
Conclusions: These immunological findings highlight the potential benefits of integrating trained immunity inducers with pathogen-specific vaccines to enhance immune responses and protection. Further research is needed to optimize immunomodulation strategies, dosing regimens and administration routes to maximize these synergistic effects and prevent potential negative effects.

Keywords:  SARS-CoV-2 vaccine; adaptative immunity; innate memory; mycobacteria; trained immunity

DOI:  https://doi.org/10.3389/fimmu.2025.1633977
Clin Transl Immunology. 2025 ;14(9): e70047

Long-term effects of influenza and Bacille Calmette-Guérin vaccination on systemic inflammation.

Priya A Debisarun, Rutger J Röring, Özlem Bulut, Thijs Ten Doesschate, Thomas W van der Vaart, Vinod Kumar, Helga Lemmers, Heidi Dijkstra, Axel B Janssen, Karin Veerman, Rob Ter Heine, Reinout van Crevel, Jaap Ten Oever, Leo Ab Joosten, Marc J Bonten, Cornelis H van Werkhoven, Janneke Hhm van de Wijgert, Mihai G Netea.

   Objective: Chronic systemic inflammation can lead to metabolic, cardiovascular and neurodegenerative complications, but the factors influencing it are incompletely understood. In this study, we evaluated several factors, including Bacille Calmette-Guérin (BCG) and influenza vaccination, SARS-CoV-2 infection and sex, that may impact systemic inflammation as assessed by targeted inflammatory plasma proteome analysis in healthy individuals.
Methods: Participants were randomised to BCG or placebo vaccination at the start of the Dutch SARS-CoV-2 epidemic in March/April 2020. They reported their influenza vaccination status for the most recent influenza season. Twelve weeks after BCG or placebo vaccination, we assessed relative concentrations of 69 proteins in plasma of 357 individuals.
Results: Both BCG and quadrivalent influenza vaccination were associated with overall trends towards reduced systemic inflammation in both sexes, but with a more pronounced effect in men. However, the impact on specific immunological proteins varied between BCG and influenza vaccinations. SARS-CoV-2 infection in the 12 weeks between randomisation and plasma sampling was also associated with overall trends towards reduced systemic inflammation, reaching significance for CXCL10 and TNF concentrations. Notably, individuals who had received BCG vaccination prior to SARS-CoV-2 infection did not exhibit this protein profile. Furthermore, elevated CXCL11 and OPG concentrations at 12 weeks were associated with subsequent respiratory symptoms during the additional 9 months of follow-up.
Conclusions: Our study revealed distinctive alterations in the plasma inflammation proteome associated with BCG vaccination, influenza vaccination, SARS-CoV-2 infection and sex. These findings are exploratory and hypothesis-generating and warrant further investigation in well-controlled longitudinal cohort studies.

Keywords:  Bacille Calmette–Guérin; SARS‐CoV‐2; inflammatory biomarkers; influenza vaccine; low‐grade inflammation; trained immunity

DOI:  https://doi.org/10.1002/cti2.70047
Carbohydr Polym. 2025 Nov 15. pii: S0144-8617(25)01039-2. [Epub ahead of print]368(Pt 2): 124254

Deciphering immunoregulatory mechanisms and structure-guided biosynthesis of β-glucans.

Weiwei He, Zhipeng Li.

  As one of the most well-studied natural bioactive polysaccharides, β-glucans are widely applied in health foods, pharmaceuticals, skincare products, and animal feed. According to Future Market Insights, the β-glucan industry is growing rapidly, with its market size projected to reach $2.3 billion by 2033. Immunomodulation is one of the primary bioactivities of β-glucans, and their applications in tumor adjuvant therapy, infection prevention, and vaccine adjuvants are gaining increasing attention. This review provides a comprehensive synthesis of the current understanding of β-glucans, covering their sources, structural diversity, intestinal absorption, pharmacokinetics, multifaceted immunoregulatory mechanisms, and strategies of efficient biosynthesis. Moreover, we dissected their bidirectional immunomodulatory properties and significant role in inducing trained immunity, alongside the gut microbiota-dependent and -independent mechanisms underlying their actions. Furthermore, we examined the current advances in the structure-activity relationships of β-glucans and the cutting-edge strategies for structure-guided biosynthesis through genetic engineering and culture optimization. Finally, we identified key knowledge gaps in molecular mechanism research and efficient biosynthesis technologies, offering strategic insights and perspectives to advance the fundamental research of β-glucans and their industrial-scale production and applications.

Keywords:  Biosynthesis; Gut-microbiota; Immunoregulation; Structure-activity relationship; Trained immunity; Β-glucan

DOI:  https://doi.org/10.1016/j.carbpol.2025.124254
Cell Rep. 2025 Sep 16. pii: S2211-1247(25)01083-6. [Epub ahead of print]44(10): 116312

Innate immune molecular landscape following controlled human influenza virus infection.

William Thistlethwaite, Sindhu Vangeti, Wan-Sze Cheng, Pankaj Agarwal, Antonio Cappuccio, Wenliang Wang, Bei Wei, Rachel Myers, Aliza B Rubenstein, Daniel Chawla, Manoj Hariharan, Micah T McClain, Thomas W Burke, Steven H Kleinstein, Joseph R Ecker, Christopher W Woods, William J Greenleaf, Xi Chen, Irene Ramos, Elena Zaslavsky, Thomas G Evans, Olga G Troyanskaya, Stuart C Sealfon.

  Viral infections can induce prolonged changes in innate immunity. Here, we use blood samples from a human influenza H3N2 challenge study (NCT03883113) to perform comprehensive multi-omics analyses. We detect remodeling of immune programs in circulating innate immune cells that persist after resolution of the infection. We find changes associated with suppressed inflammation, including decreased cytokine and AP-1 gene expression as well as decreased accessibility at AP-1 targets and interleukin-related gene promoter regions. We also find decreased histone deacetylase gene expression, increased MAP kinase gene expression, and increased accessibility at interferon-related gene promoter regions. Genes involved in inflammation and methylation remodeling show modulation of gene-chromatin site regulatory circuit activity. These results reveal a coordinated rewiring of the molecular landscape in innate immune cells induced by mild influenza virus infection.

Keywords:  CP: Immunology; CP: Molecular biology; human challenge; influenza; innate immunity; multi-omics; scATAC-seq; scRNA-seq; transcriptomics

DOI:  https://doi.org/10.1016/j.celrep.2025.116312
bioRxiv. 2025 Sep 03. pii: 2025.09.02.673783. [Epub ahead of print]

Platelet factor 4 modulates endothelial cell antimicrobial activity to enhance bacterial clearance and improve sepsis outcomes.

Anh T P Ngo, Weronika Ortmann, Abigail Skidmore, Hyunjun Kim, Jenna Oberg, Amrita Sarkar, Veronica Bochenek, Nate Levine, Lubica Rauova, Irina Chernysh, Zachary Martinez, Caroline Diorio, Mark Goulian, Victor Nizet, Mortimer Poncz, Kandace Gollomp.

  Sepsis is a life-threatening condition characterized by dysregulated host responses to infection. Here, we identify platelet factor 4 (PF4) as a key mediator of vascular antimicrobial defense. In vitro, PF4 enhanced endothelial cell internalization of Escherichia coli via interactions with the PF4 receptor CXCR3 and the endothelial glycocalyx, directing bacteria to clathrin-mediated endocytosis and lysosomal degradation. In vivo, PF4 administration improved survival and reduced sepsis severity, bacterial burden, inflammation, and thrombosis in wild-type (WT) and PF4 knockout (PF4italic-/-) mice challenged with systemic polymicrobial infection. Using intravital microscopy, we observed that infused bacteria were rapidly sequestered in the pulmonary microvasculature. However, PF4 -/- mice exhibited impaired bacterial clearance and increased microvascular platelet adhesion and aggregation. In the liver, following Kupffer cell depletion, PF4 -/- mice had increased sinusoidal platelet accumulation, larger bacterial aggregates, and elevated hepatic bacterial burden compared to WT controls. Collectively, these findings reveal that PF4 promotes bacterial clearance and restrains immunothrombosis during sepsis in part via endothelial cell uptake and destruction of microbes. By enhancing endothelial antimicrobial function, PF4 represents a significant yet previously underrecognized host defense mechanism that limits bacterial spread and alleviates vascular injury during infection.

Keywords:  bacterial clearance; endothelial cell; platelet factor 4; sepsis

DOI:  https://doi.org/10.1101/2025.09.02.673783
Nat Immunol. 2025 Sep 15.

Delaying pyroptosis with an AI-screened gasdermin D pore blocker mitigates inflammatory response.

Jianhui Sun, Jun Yang, Jie Tao, Yifan Yang, Rui Wang, Huacai Zhang, Wenyi Liu, Shulin Zhao, Runze Shao, Yuhui He, Shaolin Tao, Yaxiong Li, Hai Qu, Di Liu, Jingwen Li, Jianxin Jiang, Bo Deng, Chu Gao, Ping Lin, Ling Zeng, Ping Meng, Gan Wang.

The formation of membrane pores by cleaved N-terminal gasdermin D (GSDMD-NT) results in the release of cytokines and inflammatory cell death, known as pyroptosis. Blocking GSDMD-NT pores is an attractive and promising strategy for mitigating inflammation. Here we demonstrate that SK56, an artificial intelligence-screened peptide, effectively obstructs GSDMD-NT pores and inhibits pyroptosis and cytokine release in macrophages and human peripheral blood leukocyte-induced pyroptosis. SK56 prevents septic death induced by lipopolysaccharide or cecal ligation and puncture surgery in mice. SK56 does not influence cleavage of interleukin-1β or GSDMD. Instead, SK56 inhibits the release of cytokines from pyroptotic macrophages, mitigates the activation of primary mouse dendritic cells triggered by incubation with pyroptotic cytomembranes and prevents widespread cell death of human alveolar organoids in an organoid-macrophage coculture model. SK56 blocks GSDMD-NT pores on lipid-bilayer nanoparticles and enters pyroptotic macrophages to inhibit mitochondrial damage. SK56 presents new therapeutic possibilities for counteracting inflammation, which is implicated in numerous diseases.

DOI: https://doi.org/10.1038/s41590-025-02280-x
J Clin Invest. 2025 Sep 16. pii: e189570. [Epub ahead of print]

Endothelial STING and STAT1 mediate interferon-independent effects of IL-6 in an endotoxemia-induced model of shock.

Nina Martino, Erin K Sanders, Ramon Bossardi Ramos, Iria Di John Portela, Fatma Awadalla, Shuhan Lu, Dareen Chuy, Neil Poddar, Mei Xing G Zuo, Uma Balasubramanian, Peter A Vincent, Pilar Alcaide, Alejandro P Adam.

  Severe systemic inflammatory reactions, including sepsis, often lead to shock, organ failure and death, in part through an acute release of cytokines that promote vascular dysfunction. However, little is known about the vascular endothelial signaling pathways regulating the transcriptional profile in failing organs. This work focuses on signaling downstream of IL-6, due to its clinical importance as a biomarker for disease severity and predictor of mortality. Here, we show that loss of endothelial expression of the IL-6 pathway inhibitor, SOCS3, promoted a type I interferon (IFNI)-like gene signature in response to endotoxemia in mouse kidneys and brains. In cultured primary human endothelial cells, IL-6 induced a transient IFNI-like gene expression in a non-canonical, interferon-independent fashion. We further show that STAT3, which we had previously shown to control IL-6-driven endothelial barrier function, was dispensable for this activity. Instead, IL-6 promoted a transient increase in cytosolic mitochondrial DNA and required STAT1, cGAS, STING, and the IRFs 1, 3, and 4. Inhibition of this pathway in endothelial-specific STING knockout mice or global STAT1 knockout mice led to reduced severity of an acute endotoxemic challenge and prevented the endotoxin-induced IFNI-like gene signature. These results suggest that permeability and DNA sensing responses are driven by parallel pathways downstream of this cytokine, provide new insights into the complex response to acute inflammatory responses, and offer the possibility of potential novel therapeutic strategies for independently controlling the intracellular responses to IL-6 in order to tailor the inflammatory response.

Keywords:  Cell stress; Endothelial cells; Inflammation; Innate immunity; Vascular biology

DOI:  https://doi.org/10.1172/JCI189570