bims-traimu 2025-08-10 papers

Issue of 2025–08–10
eleven papers selected by
Yantong Wan, Southern Medical University

Front Immunol. 2025 ;16 1606626

Probiotic peptidoglycan skeleton enhances vaccine efficacy against MRSA by inducing trained immunity via the TLR2/JAK-STAT3 pathway.

Lingdi Niu, Haoyuan Duan, Jiaqing Wang, Zheng Jia, Hai Li, Junjie Guo, Shuhe Zhang, Ning Liu, Yaxin Miao, Junwei Ge, Fang Wang.

Trained immunity refers to the ability of trained innate immune cells to generate an immune memory that produces rapid, broad-spectrum, and long-lasting protection against heterologous stimuli. Based on the rapid and broad-spectrum protection that the peptidoglycan backbone from lactic acid bacteria, bacterium-like particles (BLPs), offers, we hypothesized that BLPs enhance protection through trained immunity. Here, we found that combining BLP with a vaccine significantly improves protective efficacy against methicillin-resistant Staphylococcus aureus (MRSA) infection, accompanied by changes in trained immunity markers. We demonstrate that BLP-induced trained immunity macrophages exhibit increased cytokine secretion and phagocytic activity in vitro. In an in vivo model, BLP confers protection against S. aureus 26003 even without specific antigens. In an ex vivo model, BLP induces increased markers of trained immunity. Transcriptome analysis suggests that BLP may induce trained immunity by activating the IL-6-JAK-STAT3 pathway through TLR2 receptor activation, thereby modulating macrophage metabolic reprogramming and function. In summary, our study establishes that BLP induction of trained immunity, along with regulated metabolic reprogramming and macrophage function, may contribute to enhancing vaccine efficacy. Our findings elucidate a novel mechanism for BLP-mediated immune enhancement, critical for the application of BLP as a vaccine vector to construct a vaccine that combines specific immune response with innate immune response.

Keywords: MRSA; bacterium-like particles; innate immunity; peptidoglycan backbone; trained immunity

DOI: https://doi.org/10.3389/fimmu.2025.1606626

Vet Res. 2025 Aug 08. 56(1): 166

Trained immunity in farm animals.

Marisol Báez-Magaña, Nayeli Alva-Murillo, Alejandra Ochoa-Zarzosa, Joel Edmundo López-Meza.

The mechanisms that enable the innate defence system to "remember its enemies" have opened a new field in immunology, and the evolutionary links among the various defence mechanisms are now being uncovered. In humans, advances in trained immunity have improved our understanding of host-pathogen interactions and broadened the search for new vaccines and treatments as alternatives to antimicrobial drugs. Similarly, veterinary medicine continues to seek strategies to safeguard animal safety, health, and welfare. Animal protein is obtained from meat, milk, or its derivatives, and eggs. Farms play a crucial economic and ecological role, and are a priority for ensuring global food security. The main farm animals used to obtain protein are cattle, sheep, goats, pigs, poultry, fish, and shrimp. Understanding the mechanisms underlying trained immunity in these intensive production systems will deepen our knowledge of host-pathogen interactions and support the development of more effective disease control strategies. It is therefore essential to ensure animal productivity, health, and well-being, as well as to minimise the environmental impact of these intensive production systems through more sustainable practices. This review examines advances in trained and primed immunity in farm animals and discusses the future of trained immunity in the farming sector.

Keywords: Cattle; Vaccine; aquaculture; farms; goats; infections; pigs; poultry

DOI: https://doi.org/10.1186/s13567-025-01594-w

Nat Commun. 2025 Aug 04. 16(1): 7134

Unveiling genetic signatures of immune response in immune-related diseases through single-cell eQTL analysis across diverse conditions.

Zhenhua Zhang, Wenchao Li, Qiuyao Zhan, Michelle Aillaud, Javier Botey-Bataller, Martijn Zoodsma, Rob Ter Horst, Leo A B Joosten, Christoph Bock, Leon N Schulte, Cheng-Jian Xu, Mihai G Netea, Marc Jan Bonder, Yang Li.

Deciphering the intricate regulatory mechanisms underlying biological processes holds promise for elucidating how genetic variants contribute to immune-related disorders. We map genetic effects on gene expression (expression quantitative trait locus, eQTL) using single-cell transcriptomes of 152 samples from 38 healthy individuals, covering baseline state and lipopolysaccharide challenge either before or after Bacillus Calmette-Guerin vaccination. Interestingly, we uncover a monocyte eQTL linked to the LCP1, shedding light on inter-individual variations in trained immunity. Furthermore, we elucidate genetic and epigenetic regulatory networks of CD55 and SLFN5. Of note, our results support the pivotal roles of SLFN5 in COVID-19 pathogenesis by incorporating disease-associated loci, chromatin accessibility, and transcription factor binding affinities, aligning with the established functions of SLFN5 in restricting virus replication during viral infection. Our study provides a paradigm to decipher genetic underpinnings of complex traits by integrating single-cell eQTLs with multi-omics data from patients and public databases.

DOI: https://doi.org/10.1038/s41467-025-61192-4

Nat Commun. 2025 Aug 02. 16(1): 7108

TLR4+group 2 innate lymphoid cells contribute to persistent type 2 immunity in airway diseases.

Yan Li, Zaichuan Wang, Su Duan, Xue Wang, Yuling Zhang, Claus Bachert, Nan Zhang, Wei Wang, Sun Ying, Feng Lan, Chengshuo Wang, Luo Zhang.

Group 2 innate lymphoid cells (ILC2s) directly contribute to local inflammation in type 2 inflammatory airway diseases. Here, we identify ILC2 subsets by single cell RNA sequencing in chronic rhinosinusitis with nasal polyps (CRSwNP) and in a memory inflammatory mouse model. We find that toll-like receptor 4 (TLR4)+ILC2s, with similar markers to their human counterparts, expresse memory cell markers, persist over time, and respond more vigorously to a secondary unrelated antigen challenge in the mouse model. Genetic ablation of TLR4 or blockade by anti-TLR4 antibodies leads to the reduction of IL-13 expression from ILC2s and mucus production in mice. The assay for transposase-accessible chromatin sequencing further confirms the importance of accessible TLR4 gene loci and its down-stream signaling pathway in maintaining trained immunity of TLR4+ILC2s after repeated stimulation by HDM. Taken together, TLR4 has a function in trained immunity maintenance within ILC2s, which may contribute to disease chronicity through a non-specific immunological memory.

DOI: https://doi.org/10.1038/s41467-025-62532-0

J Virol. 2025 Aug 04. e0053225

Trained ILCs confer adaptive immunity-independent protection against influenza.

Seasonal influenza causes 290,000-650,000 deaths annually, with vaccination efficacy ranging from 10 to 60%. The emergence of drug-resistant and highly pathogenic avian influenza viruses underscores the urgent need for novel protective strategies. Epidemiological observations have long suggested that certain vaccines, such as Bacillus Calmette-Guérin (BCG), can provide protection against diverse pathogens (S. Biering-Sørensen, P. Aaby, N. Lund, et al., Clin Infect Dis 65:1183-1190, 2017, https://doi.org/10.1093/cid/cix525; M.-L. Garly, C. L. Martins, C. Balé, et al., Vaccine 21:2782-2790, 2003, https://doi.org/10.1016/s0264-410x(03)00181-6; C. A. G. Timmermann, S. Biering-Sørensen, P. Aaby, et al., Trop Med Int Health 20:1733-1744, 2015, https://doi.org/10.1111/tmi.12614). While the cellular and molecular mechanisms underlying such protection remain incompletely understood, emerging research offers critical insights into innate immune system modulation (B. Cirovic, L. C. J. de Bree, L. Groh, et al., Cell Host Microbe 28:322-334, 2020, https://doi.org/10.1016/j.chom.2020.05.014; L. Kong, S. J. C. F. M. Moorlag, A. Lefkovith, et al., Cell Rep 37:110028, 2021, https://doi.org/10.1016/j.celrep.2021.110028; H. Mohammadi, N. Sharafkandi, M. Hemmatzadeh, et al., J Cell Physiol 233:4512-4529, 2018, https://doi.org/10.1002/jcp.26250; S. J. C. F. M. Moorlag, Y. A. Rodriguez-Rosales, J. Gillard, et al., Cell Rep 33:108387, 2021, https://doi.org/10.1016/j.celrep.2020.108387). We investigated whether a trained innate immune system with non-replicating adenoviruses could provide protection against diverse influenza virus strains. We demonstrated that replication-defective human adenoviruses can effectively train the innate immune system, conferring protective immunity in mice against multiple influenza virus strains, including H1N1, H3N2, H5N2, H7N9, and H9N2. In addition, bovine and chimpanzee adenoviruses can also activate human innate lymphoid cells (ILCs) and confer protection against challenge with influenza H3N2 virus in mice. Remarkably, this protection occurs in the complete absence of influenza-specific adaptive immune responses (influenza virus-specific hemagglutination-inhibiting antibodies, neutralizing antibodies, and influenza nucleoprotein-specific CD8 T cells). Key protective mechanisms include increased activation of ILC1, ILC2, and ILC3 populations, enhanced expression of interferon-stimulated genes (ISGs), upregulation of antiviral signaling pathways, and metabolic reprogramming of ILC subsets. Adoptive transfer experiments demonstrated that trained ILCs were sufficient to protect against influenza H1N1 infection in ILC-deficient mice. This research establishes a novel strategy for enhancing innate antiviral immunity, offering broad-spectrum protection against diverse influenza strains, a promising approach for not only pandemic preparedness but also against emerging infectious diseases. Training innate lymphoid cells through non-replicating adenoviral vectors represents a promising approach to enhancing broad-spectrum antiviral immunity, complementing traditional vaccination strategies.IMPORTANCEThe findings represent a potential game-changer for fighting influenza, which kills hundreds of thousands of people worldwide each year despite our best vaccination efforts. Current flu vaccines often provide limited protection because they must be reformulated annually to match circulating strains, and their effectiveness varies dramatically from year to year. The scientists discovered something remarkable: common adenoviruses (which typically cause mild cold-like symptoms) can essentially "train" our immune system's first line of defense to recognize and fight off multiple types of flu viruses simultaneously. This protection works through a completely different mechanism than traditional vaccines-it does not rely on creating specific antibodies against flu proteins. Instead, the treatment activates special immune cells called innate lymphoid cells (ILCs), which act like the body's rapid response team. These trained cells provide broad protection against various flu strains, including dangerous bird flu variants that could cause future pandemics. The significance lies in potentially creating a universal flu protection strategy that could work against unknown future flu strains, offering hope for better pandemic preparedness and reducing seasonal flu's devastating global impact.

Keywords: RNA-seq; adenoviral vectors; influenza; innate lymphoid cells; trained immunity

DOI: https://doi.org/10.1128/jvi.00532-25

JCI Insight. 2025 Aug 08. pii: e194633. [Epub ahead of print]10(15):

BCG immunization mitigates SARS-CoV-2 replication in macaques via monocyte efferocytosis and neutrophil recruitment in lungs.

Mohammad Arif Rahman, Katherine C Goldfarbmuren, Sarkis Sarkis, Massimiliano Bissa, Anna Gutowska, Luca Schifanella, Ramona Moles, Melvin N Doster, Hanne Andersen, Yogita Jethmalani, Leonid Serebryannyy, Timothy Cardozo, Mark G Lewis, Genoveffa Franchini.

Exposure to Bacillus Calmette-Guérin (BCG) or Canarypox ALVAC/Alum vaccine elicits pro- or antiinflammatory innate responses, respectively. We tested whether prior exposure of macaques to these immunogens protected against SARS-CoV-2 replication in lungs and found more efficient replication control after the pro-inflammatory immunity elicited by BCG. The decreased virus level in lungs was linked to early infiltrates of classical monocytes producing IL-8 with systemic neutrophils, Th2 cells, and Ki67+CD95+CD4+ T cells producing CCR7. At the time of SARS-CoV-2 exposure, BCG-treated animals had higher frequencies of lung infiltrating neutrophils and higher CD14+ cells expressing efferocytosis marker MERTK, responses correlating with decreased SARS-CoV-2 replication in lung. At the same time point, plasma IL-18, TNF-α, TNFSF-10, and VEGFA levels were also higher in the BCG group and correlated with decreased virus replication. Finally, after SARS-CoV-2 exposure, decreased virus replication correlated with neutrophils producing IL-10 and CCR7 preferentially recruited to the lungs of BCG-vaccinated animals. These data point to the importance of the spatiotemporal distribution of functional monocytes and neutrophils in controlling SARS-CoV-2 levels and suggest a central role of monocyte efferocytosis in curbing replication.

Keywords: COVID-19; Immunology; Infectious disease; Innate immunity; Vaccines

DOI: https://doi.org/10.1172/jci.insight.194633

bioRxiv. 2025 Jul 26. pii: 2025.07.23.664455. [Epub ahead of print]

Human iPSC derived alveolar macrophages reveal macrophage subtype specific functions of itaconate in M. tuberculosis host defense.

Mycobacterium tuberculosis (Mtb) must survive within multiple macrophage populations during infection, including alveolar macrophages (AM) and recruited inflammatory macrophages. In mice, itaconate, produced in macrophages by ACOD1 mediated decarboxylation of aconitate, has direct antimicrobial activity, modulates inflammatory cytokines, and is required for resistance to M. tuberculosis (Mtb) infection. The role of itaconate in human macrophages is less clear and whether itaconate mediates distinct effects in macrophage subtypes is unknown. Here, we investigated the role of itaconate in human iPSC-derived macrophages, either induced by GM-CSF to resemble alveolar macrophages (AM-Like cells), or treated with M-CSF to generate control macrophages (MCDM cells). Both types of human macrophages produce substantially less itaconate than mouse macrophages and AM-Ls produced 4-fold less itaconate than MCDMs. Surprisingly, ACOD1 deficient AM-L macrophages, but not MCDM macrophages, were permissive for Mtb growth. Moreover, itaconate functioned to dampen the Mtb induced inflammatory response in MCDMs, but not AM-L macrophages, affecting both the Type I IFN and TNF pathways. These results indicate that itaconate is involved in human macrophage responses to TB, with distinct roles in different macrophage subsets. These results also show that genetically tractable hiPSC-derived macrophages are a robust and versatile model to dissect cellular host pathogen interactions.

DOI: https://doi.org/10.1101/2025.07.23.664455

Adv Sci (Weinh). 2025 Aug 04. e06209

Endothelial-Derived CCL7 Promotes Macrophage Polarization and Aggravates Septic Acute Lung Injury via CCR1-Mediated STAT1 Succinylation.

Xue Li, Yuqin Long, Yunxi Zhu, Jiahui Gu, Ping Zhou, Changhong Miao.

Acute lung injury (ALI) is a significant complication of sepsis, wherein the interaction between pulmonary vascular endothelial cells and immune cells plays a pivotal role in the pathogenesis. In this study, it is demonstrated that secretion of chemokine C-C motif ligand 7 (CCL7) by endothelial cells (ECs) induces metabolic reprogramming and M1 polarization of C-C motif chemokine receptor 1-positive (CCR1⁺) macrophages. It is noteworthy that mice with specific inhibition of endothelial-derived CCL7 exhibit reduced severity of septic ALI, underscoring the critical role of CCL7 in the progression of sepsis. Mechanistically, activation of the CCL7-CCR1 axis enhances STAT1 succinylation through upregulation of KAT2A expression, leading to increased STAT1 binding to the promoter of glycolytic genes in macrophages. This epigenetic regulation modulates metabolic reprogramming and M1 polarization of macrophages, thereby driving inflammatory cascades in septic ALI. Furthermore, in sepsis models, Ccr1-knockout (Ccr1-KO) mice demonstrate attenuated lung inflammation and decreased mortality, highlighting the therapeutic potential of targeting the CCL7-CCR1 axis for the treatment of septic ALI. Collectively, findings provide novel insights into the metabolic reprogramming of macrophages and identify the CCL7-CCR1 axis as a promising therapeutic target for septic ALI.

Keywords: CCL7; glycolysis; macrophage; sepsis; succinylation

DOI: https://doi.org/10.1002/advs.202506209

Nature. 2025 Aug 06.

RNA N-glycosylation enables immune evasion and homeostatic efferocytosis.

Glycosylation is central to the localization and function of biomolecules1. We recently discovered that small RNAs undergo N-glycosylation2 at the modified RNA base 3-(3-amino-3-carboxypropyl) uridine (acp3U)3. However, the functional significance of N-glycosylation of RNAs is unknown. Here we show that the N-glycans on glycoRNAs prevent innate immune sensing of endogenous small RNAs. We found that de-N-glycosylation of cell-culture-derived and circulating human and mouse glycoRNA elicited potent inflammatory responses including the production of type I interferons in a Toll-like receptor 3- and Toll-like receptor 7-dependent manner. Furthermore, we show that N-glycans on cell surface RNAs prevent apoptotic cells from triggering endosomal RNA sensors in efferocytes, thus facilitating the non-inflammatory clearance of dead cells. Mechanistically, N-glycans conceal the hypermodified uracil base acp3U, which we identified as immunostimulatory when exposed in RNA. Consistent with this, genetic deletion of an enzyme (DTWD2) that synthesizes acp3U abrogated innate immune activation by de-N-glycosylated small RNAs and apoptotic cells. Furthermore, synthetic acp3U-containing RNAs are sufficient to trigger innate immune responses. Thus, our study has uncovered a natural mechanism by which N-glycans block RNAs from inducing acp3U-dependent innate immune activation, demonstrating how glycoRNAs exist on the cell surface and in the endosomal network without inducing autoinflammatory responses.

DOI: https://doi.org/10.1038/s41586-025-09310-6

Curr Opin Immunol. 2025 Aug 01. pii: S0952-7915(25)00106-2. [Epub ahead of print]96 102630

The role of epigenetics in inflammatory memory.

Yaqin Yu, Yueqi Qiu, Ming Zhao.

Inflammatory memory refers to the ability of an organism to mount a stronger or faster response upon re-exposure to similar inflammatory stimuli. This heightened sensitivity was once thought to be a unique characteristic of immune cells. However, recent studies have challenged this traditional view, revealing that inflammatory memory is a widely prevalent phenomenon that extends beyond immune cells to include nonimmune cells. These studies indicate that the formation and maintenance of inflammatory memory largely depend on the regulation of epigenetics. Epigenetics involves heritable changes in gene expression without altering the DNA sequence, including mechanisms such as DNA methylation and histone modifications. These modifications regulate gene transcription and influence the cellular response to inflammatory stimuli. In this review, we will discuss the epigenetic mechanisms of inflammatory memory in both immune and nonimmune cells, focusing on new mechanistic insights from the past few years, and briefly discuss the unknowns and future strategies.

DOI: https://doi.org/10.1016/j.coi.2025.102630

Nat Commun. 2025 Aug 08. 16(1): 7329

Time-varying stimuli that prolong IKK activation promote nuclear remodeling and mechanistic switching of NF-κB dynamics.

Steven W Smeal, Chaitanya S Mokashi, A Hyun Kim, P Murdo Chiknas, Robin E C Lee.

Temporal properties of molecules within signaling networks, such as sub-cellular changes in protein abundance, encode information that mediate cellular responses to stimuli. How dynamic signals relay and process information is a critical gap in understanding cellular behaviors. In this work, we investigate transmission of information about changing extracellular cytokine concentrations from receptor-level supramolecular assemblies of IKK kinases downstream to the NF-κB transcription factor. In a custom robot-controlled microfluidic cell culture, we simultaneously measure input-output encoding of IKK-NF-κB in dual fluorescent-reporter cells. When compared with single cytokine pulses, dose-conserving pulse trains prolong IKK assemblies and lead to disproportionately enhanced retention of nuclear NF-κB. Using particle swarm optimization, we demonstrate that a mechanistic model does not recapitulate this emergent property. By contrast, invoking mechanisms for NF-κB-dependent chromatin remodeling to the model recapitulates experiments, showing how temporal dosing that prolongs IKK assemblies facilitates switching to permissive chromatin that sequesters nuclear NF-κB. Remarkably, using simulations to resolve single-cell receptor data accurately predicts same-cell NF-κB time courses for more than 80% of our single cell trajectories. Our data and simulations therefore suggest that cell-to-cell heterogeneity in cytokine responses are predominantly due to mechanisms at the level receptor-associated protein complexes.

DOI: https://doi.org/10.1038/s41467-025-62837-0