bims-traimu 2025-02-16 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2025–02–16
ten papers selected by
Yantong Wan, Southern Medical University

Bacterial translocation promotes trained immunity.
Rapid Natural Killer Cell Gene Responses, Generated by TLR Ligand-Induced Trained Immunity, Provide Protection to Bacterial Infection in rag1-/- Mutant Zebrafish (Danio rerio).
Mycobacterium spp. exposure, childhood vaccinations, and early childhood brain and CNS cancers.
Convalescent COVID-19 monocytes exhibit altered steady-state gene expression and reduced TLR2, TLR4 and RIG-I induced cytokine expression.
Macrophage memory emerges from coordinated transcription factor and chromatin dynamics.
Protection acquired upon intraperitoneal group a Streptococcus immunization is independent of concurrent adaptive immune responses but relies on macrophages and IFN-γ.
Coactivation of innate immune suppressive cells induces acquired resistance against combined TLR agonism and PD-1 blockade.
Early-age efferocytosis directs macrophage arachidonic acid metabolism for tissue regeneration.
Cellpose3: one-click image restoration for improved cellular segmentation.
Activated platelet membrane vesicles for broad-spectrum bacterial pulmonary infections management.

Immunity. 2025 Feb 11. pii: S1074-7613(25)00036-6. [Epub ahead of print]58(2): 268-270

Bacterial translocation promotes trained immunity.

Maria Francesca Viola, Elvira Mass.

Can bacteria that breach mucosal barriers drive long-lasting changes in immunity? In this issue of Immunity, Robles-Vera et al. describe how, in the context of colitis, bacteria breaching the intestinal barrier reprogram precursors in the bone marrow via Mincle-dependent signaling.

DOI: https://doi.org/10.1016/j.immuni.2025.01.011
Int J Mol Sci. 2025 Jan 23. pii: 962. [Epub ahead of print]26(3):

Rapid Natural Killer Cell Gene Responses, Generated by TLR Ligand-Induced Trained Immunity, Provide Protection to Bacterial Infection in rag1-/- Mutant Zebrafish (Danio rerio).

Preeti J Muire, Larry A Hanson, Lora Petrie-Hanson.

  T and B cell-deficient rag1-/- mutant zebrafish develop protective immunity mediated by trained immunity. In mammals, trained immune responses can be induced by Toll-like receptor (TLR) ligands. This study evaluated protective trained immunity in rag1-/- zebrafish through exposure to TLR ligands (beta glucan, R848, poly I:C), RE33® (a live-attenuated Edwardsiella ictaluri vaccine), or combinations thereof, followed by wild-type E. ictaluri challenge one month later. Survival analyses revealed that all TLR ligands and vaccine treatments provided significantly higher protection than the control, with beta glucan inducing significantly greater protection than RE33®, while R848 and poly I:C were equivalent to the vaccine. Survivals for the treatments were beta glucan 70%, beta glucan + RE33® 60%, R848 + RE33® 54%, poly I:C + RE33® 50%, R848 49%, poly I:C 32%, RE33® 24%, and control 0%. Gene expression analysis of kidney and liver tissues post challenge revealed that beta glucan training elicited early and strong increased expressions of nklb (5536 fold @ 6 hpi), nkld (147 fold @ 12 hpi), and ifng (575 fold @ 12 hpi) in the kidney, and ifng (1369 fold @ 6 hpi), nkla (250 fold @ 6 hpi), nklb (734 fold @ 6 hpi), nklc (2135 fold @ 6 hpi) and nkld (589 fold @ 6 hpi) in the liver. Principal component analysis (PCA) revealed that early kidney gene expressions at 6-12 h post secondary infection (nkla @ 12 hpi, nklb @ 6 and 12 hpi, nklc @ 6 and 12 hpi, nkld @ 6 and 12 hpi, ifng @ 6 and 12 hpi, t-bet @ 6, 12 and 48 hpi, and nitr9 @24 hpi) in the kidney and liver (nkla, nklb, nklc, nkld, ifng, t-bet and nitr9 @ 6 hpi) were associated with the highest survival. This study highlights that TLR ligand-induced trained immunity boosts innate immunity and survival, with NK cell subpopulations in kidney and liver tissues responding differently to mediate protective responses.

Keywords:  Danio rerio; TLR ligands; beta glucan; tissue-resident NK cell subsets; trained immunity; vaccine adjuvants

DOI:  https://doi.org/10.3390/ijms26030962
Front Immunol. 2025 ;16 1497436

Mycobacterium spp. exposure, childhood vaccinations, and early childhood brain and CNS cancers.

Samer Singh, Rakesh K Singh.

  Globally, with improvements in general hygiene, the incidence of early childhood (0-4Y-olds/<5Y-olds) brain and central nervous system (BCNS) cancers is increasing. Although immunological underpinning is suspected, the identification of protective variables for the majority of BCNS cancer cases remains elusive. Extant hypotheses suggest a role for progressively diminishing exposure to common microbes/pathogens in the rise of childhood cancers in industrialized countries with improved hygiene. Natural exposure to common microbes/pathogens and childhood vaccinations help train the developing immune system of children to respond appropriately to future infections and maintain a healthy immune system. Considering the established role of childhood vaccinations in augmenting immunity, including "trained immunity," their protective role in pediatric cancers may be surmised. However, a lack of definitive theoretical and practical frameworks to explain conflicting observations has impaired progress. When we analyze the epidemiological data of European region countries with different childhood vaccination policies but more similar socioeconomic conditions, access to medical services, and genetic makeup as compared to other parts of the world, the coverage of seven major childhood (0-1Y-olds) vaccines does not significantly associate with BCNS cancer incidences in the same cohort of 0-4Y-olds (2020). However, interestingly, prevailing tuberculin immunoreactivity, a surrogate for the existence of heterologous cell-mediated immunity resulting from exposure to Mycobacterium spp., including Bacille Calmette-Guérin (BCG) vaccination, for these populations, is found consistently negatively correlated with the BCNS cancer incidence in 0-4Y-olds for countries mandating neonatal BCG vaccination [r(24): -0.7226, p-value:<0.0001]. Seemingly, neonatal immune-system priming by BCG and boosting by exposure to environmental Mycobacterium spp. appear protective in 0-4Y-olds. Exploration of BCNS cancer incidence and prevailing immune correlates in matched cohorts, along with prospective randomized controlled trials, may be warranted to conclusively ascertain the impact of childhood vaccinations and boosters (including natural exposure) on early childhood BCNS cancer incidence.

Keywords:  BCG vaccine; brain and CNS cancer; cancer discovery; cancer prevention; childhood vaccinations; pediatric cancer; protective variable; trained immunity

DOI:  https://doi.org/10.3389/fimmu.2025.1497436
Hum Immunol. 2025 Feb 07. pii: S0198-8859(25)00020-5. [Epub ahead of print]86(2): 111249

Convalescent COVID-19 monocytes exhibit altered steady-state gene expression and reduced TLR2, TLR4 and RIG-I induced cytokine expression.

Sarah Unterberger, Nadia Terrazzini, Sandra Sacre.

  Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes COVID-19, can induce trained immunity in monocytes. Trained immunity is the result of metabolic and epigenetic reprogramming of progenitor cells leading to an altered inflammatory response to subsequent activation. To investigate the monocyte response 3-6 months post SARS-CoV-2 infection, steady-state gene expression and innate immune receptor stimulation were investigated in monocytes from unvaccinated SARS-CoV-2 naïve individuals and convalescent COVID-19 participants. The differentially expressed genes (DEGs) identified were involved in the regulation of innate immune signalling pathways associated with anti-viral defence. COVID-19 participants who had experienced severe symptoms exhibited a larger number of DEGs than participants that had mild symptoms. Interestingly, genes encoding receptors that recognise SARS-CoV-2 RNA were downregulated. DDX58, encoding retinoic-acid inducible gene I (RIG-I), was downregulated which corresponded with a reduced response to RIG-I activation. Furthermore, toll-like receptor (TLR)1/2 and TLR4 activation also exhibited reduced cytokine secretion from convalescent COVID-19 monocytes. These data suggest that following SARS-CoV-2 infection, monocytes exhibit altered steady-state gene expression and reduced responsiveness to innate immune receptor activation. As both RIG-I and TLRs recognise components of SARS-CoV-2, this may lead to a moderated inflammatory response to SARS-CoV-2 reinfection in the months following the initial infection.

Keywords:  COVID-19; Gene expression; Monocytes; RIG-I; SARS-CoV-2; Toll-like receptor

DOI:  https://doi.org/10.1016/j.humimm.2025.111249
Cell Syst. 2025 Feb 06. pii: S2405-4712(25)00004-3. [Epub ahead of print] 101171

Macrophage memory emerges from coordinated transcription factor and chromatin dynamics.

Andrew G Wang, Minjun Son, Aleksandr Gorin, Emma Kenna, Abinash Padhi, Bijentimala Keisham, Adam Schauer, Alexander Hoffmann, Savaş Tay.

  Cells of the immune system operate in dynamic microenvironments where the timing, concentration, and order of signaling molecules constantly change. Despite this complexity, immune cells manage to communicate accurately and control inflammation and infection. It is unclear how these dynamic signals are encoded and decoded and if individual cells retain the memory of past exposure to inflammatory molecules. Here, we use live-cell analysis, ATAC sequencing, and an in vivo model of sepsis to show that sequential inflammatory signals induce memory in individual macrophages through reprogramming the nuclear factor κB (NF-κB) network and the chromatin accessibility landscape. We use transcriptomic profiling and deep learning to show that transcription factor and chromatin dynamics coordinate fine-tuned macrophage responses to new inflammatory signals. This work demonstrates how macrophages retain the memory of previous signals despite single-cell variability and elucidates the mechanisms of signal-induced memory in dynamic inflammatory conditions like sepsis.

Keywords:  NF-κB; Toll-like receptors; dynamics; inflammatory signaling; innate immune memory; modeling; sepsis; signaling dynamics; systems biology

DOI:  https://doi.org/10.1016/j.cels.2025.101171
Virulence. 2025 Dec;16(1): 2457957

Protection acquired upon intraperitoneal group a Streptococcus immunization is independent of concurrent adaptive immune responses but relies on macrophages and IFN-γ.

Shiva Emami, Elsa Westerlund, Thiago Rojas Converso, Bengt Johansson-Lindbom, Jenny J Persson.

  Group A Streptococcus (GAS; Streptococcus pyogenes) is an important bacterial pathogen causing over 700 million superficial infections and around 500.000 deaths due to invasive disease or severe post-infection sequelae yearly. In spite of this major impact on society, there is currently no vaccine available against this bacterium. GAS strains can be separated into >250 distinct emm (M)-types, and protective immunity against GAS is believed to in part be dependent on type-specific antibodies. Here, we analyse the nature of protective immunity generated against GAS in a model of intraperitoneal immunization in mice. We demonstrate that multiple immunizations are required for the ability to survive a subsequent lethal challenge, and although significant levels of GAS-specific antibodies are produced, these are redundant for protection. Instead, our data show that the immunization-dependent protection in this model is induced in the absence of B and T cells and is accompanied by the induction of an altered acute cytokine profile upon subsequent infection, noticeable e.g. by the absence of classical pro-inflammatory cytokines and increased IFN-γ production. Further, the ability of immunized mice to survive a lethal infection is dependent on macrophages and the macrophage-activating cytokine IFN-γ. To our knowledge these findings are the first to suggest that GAS may have the ability to induce forms of trained innate immunity. Taken together, the current study proposes a novel role for the innate immune system in response to GAS infections that potentially could be leveraged for future development of effective vaccines.

Keywords:  Group A Streptococcus; adaptive immune memory; immunization; innate immune memory; protective immunity

DOI:  https://doi.org/10.1080/21505594.2025.2457957
Sci Transl Med. 2025 Feb 12. 17(785): eadk3160

Coactivation of innate immune suppressive cells induces acquired resistance against combined TLR agonism and PD-1 blockade.

Hitomi Nishinakamura, Sayoko Shinya, Takuma Irie, Shugo Sakihama, Takeo Naito, Keisuke Watanabe, Daisuke Sugiyama, Motohiro Tamiya, Tatsuya Yoshida, Tetsunari Hase, Takao Yoshida, Kennosuke Karube, Shohei Koyama, Hiroyoshi Nishikawa.

Immune checkpoint blockade therapy has been successfully applied in clinical settings as a standard therapy for many cancer types, but its clinical efficacy is restricted to patients with immunologically hot tumors. Various strategies to modify the tumor microenvironment (TME), such as Toll-like receptor (TLR) agonists that can stimulate innate immunity, have been explored but have not been successful. Here, we show a mechanism of acquired resistance to combination treatment consisting of an agonist for multiple TLRs, OK-432 (Picibanil), and programmed cell death protein 1 (PD-1) blockade. Adding the TLR agonist failed to convert the TME from immunogenically cold to hot and did not augment antitumor immunity, particularly CD8+ T cell responses, in multiple animal models. The failure was attributed to the coactivation of innate suppressive cells, such as polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) expressing CXCR2, through high CXCL1 production by macrophages in the TME upon OK-432 treatment. A triple combination treatment with OK-432, PD-1 blockade, and a CXCR2 neutralizing antibody overcame the resistance induced by PMN-MDSCs, resulting in a stronger antitumor effect than that of any dual combinations or single treatments. The accumulation of PMN-MDSCs was similarly observed in the pleural effusions of patients with lung cancer after OK-432 administration. We propose that successful combination cancer immunotherapy intended to stimulate innate antitumor immunity requires modulation of unwanted activation of innate immune suppressive cells, including PMN-MDSCs.

DOI: https://doi.org/10.1126/scitranslmed.adk3160
Immunity. 2025 Feb 11. pii: S1074-7613(24)00533-8. [Epub ahead of print]58(2): 344-361.e7

Early-age efferocytosis directs macrophage arachidonic acid metabolism for tissue regeneration.

Connor Lantz, Amanda Becker, Matthew DeBerge, Mallory Filipp, Kristofor Glinton, Aparnaa Ananthakrishnan, Jessica Urbanczyk, Madeline Cetlin, Afnan Alzamroon, Ahmed Abdel-Latif, Matthew Spite, Zhi-Dong Ge, Edward B Thorp.

  In response to organ injury in adults, macrophages often promote scarring, yet during early life, they are required for tissue regeneration. To elucidate the mechanisms underlying age-associated regeneration, we compared the macrophage injury response in newborn versus adult hearts. Single-cell analysis revealed an accumulation of tissue-resident macrophages in neonates that were selectively polarized for apoptotic cell recognition and uptake (efferocytosis). Ablation of the apoptotic cell recognition receptor Mertk in newborns prevented cardiac regeneration. These findings could be attributed to reprogramming of macrophage gene expression that was required for biosynthesis of the eicosanoid thromboxane A2, which unexpectedly activated parenchymal cell proliferation. Markers of thromboxane A2 production were suppressed in adult macrophages after efferocytosis. Moreover, macrophage-neighboring neonatal cardiomyocytes expressed the thromboxane A2 receptor, whose activation induced a metabolic shift that supported cellular proliferation. Our data reveal a fundamental age-defined macrophage response in which lipid mitogens produced during efferocytosis support receptor-mediated tissue regeneration.

Keywords:  aging; arachidonic acid; efferocytosis; heart; immunometabolism; macrophage; proliferation; regeneration; thromboxane

DOI:  https://doi.org/10.1016/j.immuni.2024.11.018
Nat Methods. 2025 Feb 12.

Cellpose3: one-click image restoration for improved cellular segmentation.

Carsen Stringer, Marius Pachitariu.

Generalist methods for cellular segmentation have good out-of-the-box performance on a variety of image types; however, existing methods struggle for images that are degraded by noise, blurring or undersampling, all of which are common in microscopy. We focused the development of Cellpose3 on addressing these cases and here we demonstrate substantial out-of-the-box gains in segmentation and image quality for noisy, blurry and undersampled images. Unlike previous approaches that train models to restore pixel values, we trained Cellpose3 to output images that are well segmented by a generalist segmentation model, while maintaining perceptual similarity to the target images. Furthermore, we trained the restoration models on a large, varied collection of datasets, thus ensuring good generalization to user images. We provide these tools as 'one-click' buttons inside the graphical interface of Cellpose as well as in the Cellpose API.

DOI: https://doi.org/10.1038/s41592-025-02595-5
J Control Release. 2025 Feb 11. pii: S0168-3659(25)00137-3. [Epub ahead of print]

Activated platelet membrane vesicles for broad-spectrum bacterial pulmonary infections management.

Anqi Wei, Tianhao Ding, Guanghui Li, Feng Pan, Kaisong Tian, Ziwei Sun, Mengyuan Liu, Yinyu Ma, Zhiwei Guo, Yifei Yu, Changyou Zhan, Zui Zhang, Ye Zhu, Xiaoli Wei.

  The development of new antibiotics has lagged behind the rapid evolution of bacterial resistance, prompting the exploration of alternative antimicrobial strategies. Host-directed therapy (HDT) has emerged as a promising approach by harnessing innate immune system's natural defense mechanisms, which reduces reliance on antibiotics, and mitigates the development of resistance. Building on the important role of platelets in host immunity, activated platelet membrane vesicles (PLTv) are developed here as a host-directed therapy for broad-spectrum antibacterial infection management, leveraging several key mechanisms of action. PLTv neutralizes bacterial toxins, thereby reducing cytotoxicity. The presence of platelet receptors on PLTv enables them to act as decoys, binding bacteria through receptor interactions and facilitating their phagocytosis by neutrophils and macrophages. Additionally, PLTv bound to bacteria promote the formation of neutrophil extracellular traps (NETs), enhancing the immune system's ability to trap and kill bacteria. In mouse models of pulmonary infections caused by the Methicillin-resistant Staphylococcus aureus, P. aeruginosa, and A. baumannii, administration of PLTv significantly reduces bacterial counts in the lungs and protects against mortality. Taken together, the present work highlights PLTv as a promising host-directed therapy for combating broad-spectrum pulmonary drug-resistant bacterial infections, leveraging their ability to neutralize toxins, act as decoys, promote phagocytosis, and facilitate NETs formation.

Keywords:  Activated platelet membrane vesicle; Bacteria; Decoy; Host-directed therapy; Neutrophil

DOI:  https://doi.org/10.1016/j.jconrel.2025.02.024