bims-traimu 2026-03-01 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2026–03–01
eleven papers selected by
Yantong Wan, Southern Medical University

An Rv1471-Expressing Chimpanzee Adenovirus Vaccine Confers Protection Against Tuberculosis by Inducing Alveolar Macrophage Trained Immunity and Polyfunctional T-Cell Responses.
Trained immunity: new paradigm in the immunological memory of cardiovascular disease.
Maladaptive Trained Immunity Drives Persistent IL-6 Production and Enhanced TLR Responsiveness in Monocyte-Derived Macrophages from People Living with HIV.
Macrophages From Latently Infected Mice Have Trained Immunity to HSV-1.
Innate Immunity Trained in the Protective Response of Vaccine Candidates Against Intracellular Pathogens.
Role of trained immunity in DCs and macrophages in the induction of Th2 responses and allergy treatment. What do we know?
Type-2-immune history imprints local training in nerve-airway associated interstitial macrophages (NAMs) for disease tolerance during respiratory viral infection.
Sustained monocyte activation by persistent challenges with either oxLDL or free cholesterol and underlying mechanisms.
Differential disease tolerance mediates sex-biased illness severity in sepsis.
Activated Platelet-Released Heat Shock Protein 90α Triggers Autophagy-Dependent Neutrophil Extracellular Trap Formation and Amplifies Sepsis.
PAF Triggered Pyroptotic NETosis Aggravates Myocardial Ischemia/Reperfusion Injury.

Emerg Microbes Infect. 2026 Feb 24. 2637292

An Rv1471-Expressing Chimpanzee Adenovirus Vaccine Confers Protection Against Tuberculosis by Inducing Alveolar Macrophage Trained Immunity and Polyfunctional T-Cell Responses.

Huiling Wang, Ying Zhang, Jianhui Li, Juan Wu, Shaoqiong Huang, Shiqi Xie, Xuejiao Huang, Jing Wang, Xiao-Yong Fan, Zhidong Hu.

  The limited protection afforded by Bacille Calmette-Guérin (BCG) against pulmonary tuberculosis (TB) underscores the critical need for novel vaccine strategies. Alveolar macrophages (AMs), as the primary sentinel cells encountering inhaled Mycobacterium tuberculosis (Mtb), play a decisive role in early infection outcomes, yet their potential as a direct vaccine target remains largely untapped. Here, we developed a chimpanzee adenovirus vaccine expressing the Mtb antigen Rv1471 (rAd-Rv1471), which we previously identified for its unique capacity to induce innate immune memory. In murine models, intranasal rAd-Rv1471 administration reprogrammed AMs into a trained state, characterized by enhanced production of pro-inflammatory cytokines, elevated surface expression of MHC II and CD86, and improved cell-intrinsic control of intracellular mycobacterial growth. Transcriptomic analysis revealed upregulation of key immunometabolic pathways, including Akt/mTOR/HIF-1α signaling and glycolysis. Concurrently, intranasal rAd-Rv1471 administration induced potent antigen-specific, polyfunctional T cells in the lung. This dual engagement of innate and adaptive immunity conferred significant protection against aerosol Mtb challenge. Furthermore, rAd-Rv1471 acted as an effective heterologous booster, enhancing protection in BCG-primed mice. Our findings establish rAd-Rv1471 as a synergistic mucosal vaccine candidate that concurrently induces trained immunity in AMs and polyfunctional T-cell responses, highlighting a promising dual-targeting strategy for next-generation TB vaccines.

Keywords:  Mycobacterium tuberculosis; Rv1471; alveolar macrophage; trained immunity; vaccine

DOI:  https://doi.org/10.1080/22221751.2026.2637292
Immunohorizons. 2026 Feb 17. pii: vlag008. [Epub ahead of print]10(SI):

Trained immunity: new paradigm in the immunological memory of cardiovascular disease.

Emma Hope, Azuah L Gonzalez, Lola S Norman, Hunter C Smith, Jean W Wassenaar, Kasey C Vickers, Jonathan D Brown, Amanda C Doran.

  Cardiovascular disease (CVD) remains the leading cause of death worldwide, despite significant progress in identifying and managing traditional risk factors such as hyperlipidemia, hypertension, and diabetes. While targeted therapies addressing these factors reduce the risk of primary and secondary cardiac events, a substantial "residual risk" persists even after successful clinical intervention. This residual risk has prompted renewed interest in understanding the long-term biological effects of cardiovascular risk factors, particularly through the lens of chronic inflammation. Recent advances highlight a pivotal role for trained immunity-a form of innate immune memory driven by epigenetic and metabolic reprogramming-in driving this inflammation. Unlike adaptive immune memory, trained immunity occurs in innate immune cells and enhances their responsiveness to subsequent, unrelated stimuli. Emerging evidence suggests that various cardiovascular risk states, including hypercholesterolemia, obesity, and diabetes, can induce trained immunity, leading to heightened inflammatory tone that persists over time. Cardiac macrophages, as central mediators of tissue homeostasis and inflammation in the heart, are increasingly recognized as critical targets of this phenomenon. In this review, we explore how established cardiovascular risk factors can induce trained immunity on cardiac macrophages and examine the implications for disease progression, myocardial remodeling, and post-injury repair. Finally, we discuss emerging therapeutic strategies aimed at modulating trained immunity to reduce residual cardiovascular risk, offering a new frontier in the prevention and treatment of CVD.

Keywords:  inflammation; memory; monocyte/macrophages

DOI:  https://doi.org/10.1093/immhor/vlag008
Microorganisms. 2026 Feb 03. pii: 355. [Epub ahead of print]14(2):

Maladaptive Trained Immunity Drives Persistent IL-6 Production and Enhanced TLR Responsiveness in Monocyte-Derived Macrophages from People Living with HIV.

Larisa Dubrovsky, Tatiana Pushkarsky, Beda Brichacek, Ashley Bastin, Afsoon Roberts, Jose Lucar, Maria Elena Ruiz, Oleksandr Semeniuk, Marc Siegel, Dmitri Sviridov, Michael I Bukrinsky.

  Trained immunity (TRIM) enhances innate immune responses through epigenetic and metabolic reprogramming but may become maladaptive, contributing to chronic inflammation. In people living with HIV (PLWH), maladaptive TRIM has been proposed but remains insufficiently characterized. We examined inflammatory cytokine production in monocyte-derived macrophages (MDMs) obtained from PLWH and age-matched individuals without HIV infection. Baseline cytokine output and responses to stimulation of Toll-like receptors (TLR) were measured. We further examined whether TRIM influenced susceptibility to HIV infection in MDMs derived from monocytes exposed to extracellular vesicles carrying the HIV-1 Nef protein (Nef EVs). Baseline IL-6 production did not differ between unstimulated MDMs from PLWH and uninfected controls. Although sex-associated differences were initially observed, these effects were no longer significant after adjustment for infection duration. IL-6 responses following TLR2 and TLR7 stimulation, but not TLR4 stimulation, were significantly amplified in PLWH-derived MDMs, consistent with a trained phenotype. Similar trends were observed in sex-stratified analyses but did not reach statistical significance. The magnitude of unstimulated IL-6 production positively correlated with duration of HIV infection, suggesting cumulative TRIM imprinting over time. Despite heightened inflammatory responsiveness, TRIM did not reduce susceptibility to HIV infection in Nef EV-exposed MDMs, indicating functional maladaptation rather than protective priming. These findings provide evidence of maladaptive TRIM in PLWH, characterized by preserved basal cytokine output but exaggerated inflammatory responses to innate immune stimulation without antiviral benefit. The association with infection duration supports progressive innate immune reprogramming as a contributor to HIV-associated inflammation. No statistically significant differences in trained immune responses were observed between male and female PLWH after accounting for duration of infection. Further studies are needed to define the mechanisms underlying this maladaptation and its clinical consequences.

Keywords:  HIV infection; Nef; PLWH; extracellular vesicles (EVs); inflammation; monocytes; trained immunity

DOI:  https://doi.org/10.3390/microorganisms14020355
Invest Ophthalmol Vis Sci. 2026 Feb 02. 67(2): 49

Macrophages From Latently Infected Mice Have Trained Immunity to HSV-1.

Ujjaldeep Jaggi, Shaohui Wang, Satoshi Hirose, Deepak Arya, Homayon Ghiasi.

Purpose: Our previous studies demonstrated that macrophages play a crucial role in both primary and latent herpes simplex virus 1 (HSV-1) infections. Here, we sought to determine whether HSV-1 exposure induces long-lasting functional and epigenetic changes in macrophages consistent with trained immunity, leading to enhanced responses upon secondary stimulation.
Methods: To explore this, we performed Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq) analysis on isolated spleen- and bone marrow (BM)-derived macrophages from latently infected mice before and after stimulation with UV-inactivated virus to identify open chromatin regions indicative of changes in gene regulation. Additionally, we performed flow cytometric analysis of infected spleen macrophages, BM-derived macrophages, corneas, and the trigeminal ganglia (TG). Moreover, to assess the durability of training response to infection, we evaluated responses after secondary infection.
Results: The study revealed that immunity-related GTPase family M protein (IRGM1) expression in isolated macrophages from latently infected mice was significantly elevated after stimulation, compared with that of more than 900 genes with open or closed chromatin accessibility. Flow cytometry further confirmed a higher proportion of IRGM1+ macrophages in the spleen, BM, cornea, and the TG of latently infected mice compared with mock-infected controls. The qRT-PCR determined that macrophages isolated from the spleen, trigeminal ganglia, and BM of latently infected mice continued to exhibit elevated IRGM1 expression levels relative to controls.
Conclusions: Collectively, our findings indicate that macrophages develop a durable trained immunity to HSV-1 infection, with IRGM1 emerging as a key component in the long-term maintenance of macrophage immunological memory.

DOI: https://doi.org/10.1167/iovs.67.2.49
Vaccines (Basel). 2026 Feb 23. pii: 197. [Epub ahead of print]14(2):

Innate Immunity Trained in the Protective Response of Vaccine Candidates Against Intracellular Pathogens.

Jefferson B S Oliveira, Laice A Silva, Monique F S Sousa, Aldcejam M F Junior, Camila G Almeida, Robson S Barducci, Marcella P Milazzotto, Humberto M Brandão, Renato L Santos, Tatiane A Paixão.

   BACKGROUND/OBJECTIVES: Trained innate immunity refers to the enhanced responsiveness of innate immune cells, particularly macrophages, following exposure to stimuli such as β-glucan or zymosan, enabling improved defense against unrelated pathogens. This phenomenon has been widely investigated to better understand host-pathogen interactions and to support the development of improved infection control strategies. This study evaluated whether these training stimuli could enhance the protective efficacy of attenuated or inactivated vaccine models against Brucella ovis and Listeria monocytogenes infection.
METHODS: Trained innate immunity was induced in vivo using β-glucan or zymosan, and seven days later mice were vaccinated with attenuated or gamma-irradiated formulations and subsequently challenged with B. ovis or L. monocytogenes. Vaccine-induced protection and immune responses were assessed through multiple experimental approaches.
RESULTS: β-glucan significantly reduced bacterial infection in vitro in bone-marrow-derived macrophages and in vivo in target organs compared with zymosan. Although β-glucan did not enhance the efficacy of the attenuated B. ovis ΔabcBA vaccine, it markedly reduced bacterial colonization in mice vaccinated with gamma-irradiated B. ovis. β-glucan also did not improve the efficacy of the gamma-irradiated L. monocytogenes vaccine; however, 50% of the trained and vaccinated mice showed no detectable bacterial recovery. Increasing the number of β-glucan doses negatively affected infection control, suggesting that overstimulation may impair trained immunity.
CONCLUSION: Trained innate immunity enhances the protective effect of inactivated experimental vaccines against B. ovis and L. monocytogenes, while exerting a detrimental influence on the efficacy of a live attenuated B. ovis vaccine model.

Keywords:  attenuated; brucellosis; inactivated vaccine; listeriosis; trained innate immunity; zymosan; β-glucan

DOI:  https://doi.org/10.3390/vaccines14020197
Front Immunol. 2026 ;17 1748337

Role of trained immunity in DCs and macrophages in the induction of Th2 responses and allergy treatment. What do we know?

Hannah Ruth Schiller, Carola Zeigermann, Stefan Schülke.

  In a process termed trained immunity activated dendritic cells (DCs) and macrophages undergo distinct metabolic changes that contribute to their effector function: While certain activated DC subsets and M1 macrophages undergo a switch towards higher rates of glycolysis and a "disrupted Krebs cycle" to produce important immune effector molecules, alternatively activated (M2) macrophages, plasmacytoid DCs (pDCs), and conventional DCs type 1 (cDC1s) can rely on oxidative phosphorylation for their effector function. DCs and macrophages are also important cells in allergic reactions. While the induction of trained immune responses by microbial stimuli and vaccines is meanwhile well characterized, the contribution of trained immunity to either the establishment, elicitation, or treatment of allergic responses is largely unknown. In this context, recent results suggest distinct trained immunity responses to be established in allergic children. Here it seems that infections early in life predispose to the latter development of allergies, and trained immunity to also contribute to the immune modulation occurring in allergic patients during allergen-specific immunotherapy. Therefore, better understanding of trained immunity in these antigen-presenting cell (APC) subsets may allow to establish new biomarkers and enable a more targeted and efficient treatment of allergic diseases. This article summarizes the specific immune metabolic alterations observed in activated DCs and macrophages explaining their connection to DC and macrophage effector function. It then discusses our current knowledge on the contribution of trained immune responses in the establishment and treatment of allergic diseases.

Keywords:  APC; Th2 response; allergen-specific immunotherapy; allergy; dendritic cell; epigenetics; macrophage; metabolism

DOI:  https://doi.org/10.3389/fimmu.2026.1748337
Res Sq. 2026 Feb 12. pii: rs.3.rs-8780633. [Epub ahead of print]

Type-2-immune history imprints local training in nerve-airway associated interstitial macrophages (NAMs) for disease tolerance during respiratory viral infection.

Payal Damani-Yokota, Yavor Yordanov, Eduardo D Bernier, Chaitra Sreenivasaiah, Alireza Khodadadi-Jamayran, Matthias Kugler, Stephen T Yeung, Stacey Bartlett, Valeria Mezzano, Eric Bartnicki, Mingjun Liu, Fei Chen, William C Gause, Iannis Aifantis, Aristotelis Tsirigos, Mila Ortigoza, Bettina Nadorp, Musa Mhlanga, Kamal M Khanna.

Severe respiratory viral disease varies widely among individuals and often reflects immunopathology rather than inadequate pathogen control, suggesting that prior immune history can prime the lung's inflammatory-regulatory balance to promote disease tolerance. Here we show that nerve- and airway-associated macrophages (NAMs), a subset of interstitial macrophages expand following type 2 inflammation induced by Nippostrongylus brasiliensis . We hypothesized that NAMs acquire epigenetically imprinted trained immunity and tested this in a heterologous challenge model in which mice infected with Nippostrongylus brasiliensis were challenged 4-6 weeks later with lethal H1N1 influenza. Remarkably, all Nb -conditioned mice survived, whereas all unconditioned controls succumbed by days 5-6 post-infection. Protection occurred without improved viral burden or enhanced T cell responses, and instead tracked with reduced immunopathology, amplified type 2 cues, increased efferocytosis and accelerated tissue repair. Using NAM-DTR mice, we show that conditioned NAMs are necessary and sufficient for protection: depletion or replacement with unconditioned NAMs abrogated survival, whereas adoptive transfer of conditioned NAMs conferred tolerance without enhancing viral clearance. Genomic analyses implicated an IL-4-STAT6-PPARγ and Arginase-1 chromatin program that imprints a pro-resolving and reparative NAM state driving programs of tissue repair, type 2 immunity and efferocytosis during lethal respiratory viral infections. Finally, meta-analysis of human lung single-cell atlases from healthy, IPF and COPD cohorts indicated that reparative NAM-like programs aligned with fibrotic remodeling in IPF but diverged in COPD, supporting context-dependent consequences of sustained repair states. These findings establish local trained immunity in lung-resident macrophages as a mechanism of disease tolerance and a therapeutic entry point for severe inflammatory respiratory infections.

DOI: https://doi.org/10.21203/rs.3.rs-8780633/v1
Immunohorizons. 2026 Feb 12. pii: vlag005. [Epub ahead of print]10(2):

Sustained monocyte activation by persistent challenges with either oxLDL or free cholesterol and underlying mechanisms.

Yajun Wu, Shuo Geng, Grace Atkinson, Blake Caldwell, Jing Wang, Liwu Li.

  Chronic low-grade inflammation is a hallmark of atherosclerosis and cardiovascular diseases, with monocytes playing a central role in sustaining this pathological state. In this study, we demonstrate that prolonged exposure to oxidized low-density lipoprotein (oxLDL) or cholesterol reprograms murine bone marrow-derived monocytes into a persistent pro-inflammatory phenotype. This is characterized by elevated surface markers (CD49d, CD74, CD38, CD86), enhanced endothelial and T cell interactions, and sustained activation of the Src-SYK-mTORC1-STAT3/5 signaling axis. Notably, the inflammatory state persisted even after stimulus withdrawal, suggesting the establishment of an immune memory-like phenotype. Mechanistically, we defined the membrane clustering of Src is responsible for the generation of intra-cellular stress signaling and sustained monocyte activation, which can be alleviated by the administration of fumagillin, a selective inhibitor of protein myristoylation and Src membrane clustering. Our findings uncover mechanistic insights into the generation of sustained monocyte low-grade inflammatory memory and pinpoint potential therapeutic strategies in erasing low-grade inflammation related to chronic diseases.

Keywords:  low-grade inflammation; memory; monocyte; resolution

DOI:  https://doi.org/10.1093/immhor/vlag005
Proc Natl Acad Sci U S A. 2026 Mar 03. 123(9): e2522764123

Differential disease tolerance mediates sex-biased illness severity in sepsis.

Breenna Dobson, Kathryn Strayer, Ayesha Wijesinghe, Jared Schlechte, Oscar Tejada, Alexandria Bartlett, Matthew Stephens, Diana Changirwa, Nicole A Cho, Ian-Ling Yu, Nargis Khan, Braedon McDonald.

  Sepsis in humans, as well as mouse models of infection, demonstrates sex-biased outcomes in which males tend to have a higher incidence, higher severity, and higher mortality compared to females. Despite this important sex-bias in sepsis outcomes, little is known about its mechanistic drivers nor therapeutic implications. Much of the foundational data on sepsis pathogenesis is derived from animal studies that included only male subjects, potentially contributing to the notable paucity of successful mouse-to-human translation of sepsis therapeutics. In this study, we demonstrate that male-biased illness severity and organ dysfunction in mouse models of bacterial sepsis are mediated by impaired disease tolerance in males, involving impaired tolerogenic shifts in mitochondrial oxidative metabolism compared to females. Microbiological and immunological analyses of sepsis between males and females revealed that sex-biased disease tolerance was independent of infection resistance mechanisms, as well as canonical immune/inflammatory dysregulation. Therapeutic potentiation of mitochondrial tolerance with doxycycline neutralized sexual dimorphism of illness severity and organ dysfunction through a male-predominant treatment effect. These data reveal that biological sex is a fundamental determinant of illness severity and treatment responsiveness in sepsis through modulation of disease tolerance, which may be harnessed therapeutically to address sex-biased outcomes in sepsis.

Keywords:  biological sex; disease tolerance; mitochondrial tolerance; sepsis

DOI:  https://doi.org/10.1073/pnas.2522764123
Adv Sci (Weinh). 2026 Feb 24. e15933

Activated Platelet-Released Heat Shock Protein 90α Triggers Autophagy-Dependent Neutrophil Extracellular Trap Formation and Amplifies Sepsis.

Chengbo Wang, Maodong Leng, Chenchen Sun, Jingyu Cao, Linfei Li, Yangyang Jia, Yongshuai Han, Yuchun Liu, Yaodong Zhang, Chenglong Zhang, Yingli Men, Ningyuan Liu, Yibing Cheng, Yixia Zhang, Ya Li, Zhenlong Li, Lidan Cui, Xiangzhan Zhu.

  Platelets are crucial to the development of thrombosis and coagulation abnormalities in sepsis, but the mechanisms by which they contribute to these pathological processes are not fully understood. Here, we identify a key role for platelet-released heat shock protein 90α (HSP90α) in driving neutrophil extracellular trap (NET) formation and supporting thromboinflammation during sepsis. Proteomic analysis of platelets from patients with sepsis showed a significant increase in HSP90α, which we traced back to trafficking pathways originating from megakaryocytes. When activated, platelets translocate HSP90α to their plasma membrane and release it into the extracellular space in both free and exosome-associated forms. Extracellular HSP90α acts as a damage-associated molecular pattern that binds to toll-like receptor 4 (TLR4) on neutrophils. This binding activates a downstream MyD88-Beclin 1 signaling pathway, triggering autophagy and leading to NET formation. Blocking extracellular HSP90α with a neutralizing monoclonal antibody significantly reduced NET formation both in vitro and in vivo, resulting in decreased sepsis-related thrombosis and inflammation. This platelet-HSP90α-TLR4-autophagy-NET pathway not only deepens our understanding of platelet-induced immunothrombosis but also suggests potential targets for therapies aimed at reducing coagulation problems and organ failure in septic patients.

Keywords:  HSP90α; NET; autophagy; platelet; sepsis

DOI:  https://doi.org/10.1002/advs.202515933
Adv Sci (Weinh). 2026 Feb 25. e19140

PAF Triggered Pyroptotic NETosis Aggravates Myocardial Ischemia/Reperfusion Injury.

Jiawei Wu, Shule Zhang, Ruofan Du, Lina Kang, Guodong Zhao, Xue Bao, Haochi Yang, Ziqing Xie, Tianyu He, Huiyong Sun, Haiping Hao, Lijuan Cao.

  Myocardial ischemia-reperfusion (MI/R) injury remains a critical challenge in cardiovascular therapeutics, with metabolic-inflammatory signaling axis emerging as a critical mediator of pathological outcomes. Yet, the specific metabolic pathways interplay with inflammation to exacerbate MI/R injury remain poorly defined. Here we verify that NETosis of neutrophils is an initiative and causal factor in driving MI/R injury, specifically, platelet activating factor (PAF) secreted by cardiomyocytes during MI/R, drives neutrophil extracellular traps (NETs) formation and subsequent NETosis. Increased expression of PAF synthesis enzyme PLA2G6 explains excessive production of PAF. PAF-induced NETosis requires gasdermin D (GSDMD) mediated pore-forming to facilitate NETs extrusion. Both inhibiting NETs and PAF synthesis significantly alleviate MI/R injury. We further identify dapagliflozin as a potent NETosis inhibitor that protects mice from MI/R injury in a sodium-glucose co-transporter 2 (SGLT2)-independent manner, which targets neutrophil gelatinase-associated lipocalin-2 (LCN2). Notably, increased serum PAF concentration in acute myocardial infarction patients with percutaneous coronary intervention was positively correlated with NETosis and myocardial injury indexes. Of interest, patients receiving dapagliflozin exhibited attenuated myocardial injury in comparison to those without dapagliflozin. Collectively, our study demonstrates PAF serves as a danger signal in triggering NETosis in early MI/R injury, and manipulating PAF-NETosis signal by dapagliflozin or LCN2 inhibitor might be effective in combating MI/R injury.

Keywords:  NETosis; dapagliflozin; myocardial ischemia‐reperfusion injury; platelet activating factor

DOI:  https://doi.org/10.1002/advs.202519140