eLife: latest articles by subject

Male-biased Cyp17a2 orchestrates antiviral sexual dimorphism in fish via STING stabilization and viral protein degradation

zhaigang@ihb.ac.cn (Bao-jie Cui) — Wed, 18 Feb 2026 00:00:00 +0000

Differences in immunity between males and females in living organisms are generally thought to be due to sex hormones and sex chromosomes, and it is often assumed that males have a weaker immune response. Here, we report that in fish, males exhibit stronger antiviral immune responses, the male-biased gene cyp17a2 as a critical mediator of this enhanced response. First, we observed that male zebrafish exhibit enhanced antiviral resistance compared to females, and notably, zebrafish lack sex chromosomes. Through transcriptomic screening, we found that cyp17a2 was specifically highly expressed in male fish. Cyp17a2 knockout males were equivalent to wild-type males in terms of sex organs and androgen secretion, but the ability to upregulate IFN as well as antiviral resistance was greatly reduced. Then, Cyp17a2 is identified as a positive IFN regulator which is located at the endoplasmic reticulum and specifically interacts with and enhances STING-mediated antiviral responses. Mechanistically, Cyp17a2 stabilizes STING expression by recruiting the E3 ubiquitin ligase bloodthirsty-related gene family member 32 (btr32), which facilitates K33-linked polyubiquitination. The capacity of IFN induction of Cyp17a2 was abolished when STING was knocked down. Meanwhile, Cyp17a2 also attenuates viral infection directly to strengthen the antiviral capacity. As an antiviral protein, Cyp17a2 degrades the spring viremia of carp virus (SVCV) P protein by utilizing USP8 to reduce its K33-linked polyubiquitination. These findings reveal a sex-based regulatory mechanism in teleost antiviral immunity, broadening our understanding of sexual dimorphism in immune responses beyond the conventional roles of sex chromosomes and hormones.

A single microRNA miR-195 rescues the arrested B cell development induced by EBF1 deficiency

aikotani@k-lab.jp (Ai Kotani) — Fri, 06 Feb 2026 00:00:00 +0000

Accumulated studies have reported that hematopoietic differentiation was primarily regulated by transcription factors. Early B cell factor 1 (EBF1) is an essential transcription factor for B lymphopoiesis. Contrary to the canonical notion, we found that a single miRNA, miRNA-195 (Mir195) transduction let Ebf1-deficient hematopoietic progenitor cells (HPCs) express CD19, carry out V(D)J recombination and class switch recombination, which implied that B cell matured without EBF1. A part of the mechanism was caused by FOXO1 accumulation via inhibition of FOXO1 phosphorylation pathways in which targets of Mir195 are enriched. These results suggested that some miRNA transductions could function as alternatives to transcription factors.

Ly6G⁺ granulocytes-derived IL-17 limits protective host responses and promotes tuberculosis pathogenesis

dhiraj@icgeb.res.in (Aditya Rathee) — Thu, 05 Feb 2026 00:00:00 +0000

The protective correlates of Mycobacterium tuberculosis (Mtb) infection-elicited host immune responses are incompletely understood. Here, we report pro-pathogenic crosstalk involving Ly6G⁺ granulocytes (Ly6G⁺Gra), IL-17, and COX2. We show that in the lungs of Mtb-infected wild-type mice, either BCG-vaccinated or not, most intracellular bacilli are Ly6G⁺Gra-resident 4 weeks post-infection onwards. In the genetically susceptible ifng^-/- mice, excessive Ly6G⁺Gra infiltration correlates with severe bacteremia. Neutralizing IL-17 (anti-IL17mAb) and COX2 inhibition by celecoxib reverse Ly6G⁺Gra infiltration, associated pathology, and death in ifng^-/- mice. Surprisingly, Ly6G⁺Gra also serves as the major source of IL-17 in the lungs of Mtb-infected WT or ifng^-/- mice. The IL-17-COX2-Ly6G⁺Gra interplay also operates in WT mice. Inhibiting RORγt, the key transcription factor for IL-17 production or COX2, reduces the bacterial burden in Ly6G⁺Gra, leading to reduced bacterial burden and pathology in the lungs of WT mice. In the Mtb-infected WT mice, COX2 inhibition abrogates IL-17 levels in the lung homogenates and significantly enhances BCG’s protective efficacy, mainly by targeting the Ly6G⁺Gra-resident Mtb pool, a phenotype also observed when IL-17 is blocked by RORγt inhibitor. Furthermore, in pulmonary TB patients, high neutrophil count and IL-17 correlated with adverse treatment outcomes. Together, our results suggest that IL-17 and PGE2 are the negative correlates of protection, and we propose targeting the pro-pathogenic IL-17-COX2-Ly6G⁺Gra axis for TB prevention and therapy.

Polymorphisms in intron 1 of HLA-DRA differentially associate with type 1 diabetes and celiac disease and implicate involvement of complement system genes C4A and C4B

ozkanaydemir@gmail.com (Agnes Andersson Svärd) — Mon, 02 Feb 2026 00:00:00 +0000

Polymorphisms in genes in the human leukocyte antigen (HLA) class II region comprise the most important inherited risk factors for many autoimmune diseases, including type 1 diabetes (T1D) and celiac disease (CD): both diseases are positively associated with the HLA-DR3 haplotype (DRB1*03:01-DQA1*05:01-DQB1*02:01). Studies of two different populations have recently documented that T1D susceptibility in HLA-DR3 homozygous individuals is stratified by a haplotype consisting of three single nucleotide polymorphisms (‘tri-SNP’) in intron 1 of the HLA-DRA gene. In this study, we use a large cohort from the longitudinal ‘The Environmental Determinants of Diabetes in the Young’ (TEDDY) study to further refine the tri-SNP association with T1D and with autoantibody-defined T1D endotypes. We found that the tri-SNP association is primarily in subjects whose first-appearing T1D autoantibody is to insulin. In addition, we discovered that the tri-SNP is also associated with CD, and that the particular tri-SNP haplotype (‘101’) that is negatively associated with T1D risk is positively associated with risk for CD. The opposite effect of the tri-SNP haplotype on two DR3-associated diseases can enhance and refine current models of disease prediction based on genetic risk. Finally, we investigated possible functional differences between the individuals carrying high and low-risk tri-SNP haplotypes and found that differences in complement system genes C4A and C4B may underlie the observed divergence in disease risk.

Single-cell transcriptomics identifies altered neutrophil dynamics and accentuated T-cell cytotoxicity in tobacco-flavored e-cigarette-exposed mouse lungs

Irfan_Rahman@urmc.rochester.edu (Ariel Tjitropranoto) — Thu, 29 Jan 2026 00:00:00 +0000

Despite the growing public health threat of electronic cigarettes (e-cigs), the cell-specific immune responses to differently flavored e-cig exposure remain poorly understood. To bridge this gap, we characterized the lung immune landscape following acute nose-only exposure to flavored e-cig aerosols in vivo using single-cell RNA sequencing (scRNA seq) in mice. Metal analysis of daily generated aerosols revealed flavor-dependent, day-to-day variation in metal (Ni, Cu, K, and Zn) leaching. scRNA seq profiling of 71,725 lung cells from control and exposed mice revealed pronounced dysregulation of myeloid cell function in menthol (324 differentially expressed genes, DEGs) and tobacco (553 DEGs) flavors, and lymphoid cell dysregulation in fruit-flavor (112 DEGs) e-cig aerosol exposed mouse lung, compared to air controls. Flow cytometry corroborated these findings, showing increased neutrophil frequencies and reduced eosinophil counts in menthol- and tobacco-exposed lungs. Flavored e-cig exposure also increased CD8⁺ T-cell proportions, upregulated inflammatory gene expression (Stat4, Il1b, Il1bos, Il1ra, and Cxcl3), and enriched terms like ‘Th1 cytokine signaling’ and ‘NK cell degranulation’. Notably, tobacco-flavored e-cig aerosol exposure increased immature (Ly6G⁻) neutrophils and reduced S100A8 expression, suggesting altered neutrophil activation in vivo. Overall, this study identifies flavor-dependent immune alterations in the lung following acute e-cig aerosol exposure and provides a foundation for future mechanistic studies.

Correction: Down-regulated GAS6 impairs synovial macrophage efferocytosis and promotes obesity-associated osteoarthritis

Thu, 29 Jan 2026 00:00:00 +0000

Microglia replacement by ER-Hoxb8 conditionally immortalized macrophages provides insight into Aicardi–Goutières syndrome neuropathology

bennettm2@chop.edu (Adam P Williamson) — Tue, 27 Jan 2026 00:00:00 +0000

Microglia, the brain’s resident macrophages, can be reconstituted by surrogate cells – a process termed ‘microglia replacement’. To expand the microglia replacement toolkit, we here introduce estrogen-regulated (ER) homeobox B8 (Hoxb8) conditionally immortalized macrophages, a cell model for generation of immune cells from murine bone marrow, as a versatile model for microglia replacement. We find that ER-Hoxb8 macrophages are highly comparable to primary bone marrow-derived macrophages in vitro, and, when transplanted into a microglia-free brain, engraft the parenchyma and differentiate into microglia-like cells. Furthermore, ER-Hoxb8 progenitors are readily transducible by virus and easily stored as stable, genetically manipulated cell lines. As a demonstration of this system’s power for studying the effects of disease mutations on microglia in vivo, we created stable, Adar1-mutated ER-Hoxb8 lines using CRISPR-Cas9 to study the intrinsic contribution of macrophages to Aicardi–Goutières syndrome (AGS), an inherited interferonopathy that primarily affects the brain and immune system. We find that Adar1 knockout elicited interferon secretion and impaired macrophage production in vitro, while preventing brain macrophage engraftment in vivo – phenotypes that can be rescued with concurrent mutation of Ifih1 (MDA5) in vitro, but not in vivo. Lastly, we extended these findings by generating ER-Hoxb8 progenitors from mice harboring a patient-specific Adar1 mutation (D1113H). We demonstrated the ability of microglia-specific D1113H mutation to drive interferon production in vivo, suggesting microglia drive AGS neuropathology. In sum, we introduce the ER-Hoxb8 approach to model microglia replacement and use it to clarify macrophage contributions to AGS.

HIV-specific CD8+ T-cell proliferative response 24 weeks after early antiretroviral therapy initiation is associated with the subsequent reduction in the viral reservoir

p.vanpaassen@amsterdamumc.nl (Ad C van Nuenen) — Fri, 23 Jan 2026 00:00:00 +0000

Antiretroviral therapy (ART) initiated in the acute phase of HIV infection (AHI) results in a smaller viral reservoir. However, the impact of early HIV-specific T-cell responses on long-term reservoir dynamics is less well characterized. Therefore, we measured the size of the viral reservoir and functionality of HIV-specific CD8+ T-cell responses after the acute phase at 24 and 156 weeks after ART initiation in people with HIV who started treatment during AHI. A significant reduction in total and defective HIV DNA and a trend toward a reduction in intact HIV DNA were observed between 24 and 156 weeks. Functional CD8+ T-cell responses against HIV peptides Env, Gag, Nef, and Pol were maintained over 3 years after treatment initiation. The proliferative capacity of HIV-specific CD8+ T-cells at 24 weeks of ART was predictive of the degree of reduction in total and defective HIV DNA between 24 and 156 weeks, suggesting HIV-specific CD8+ T-cells may at least partially drive the decline of the viral reservoir. Therefore, enforcing HIV-specific immune responses as early as possible after diagnosis of AHI should be a central focus of HIV cure strategies.

Doubling dolutegravir dosage reduces the viral reservoir in ART-treated people with HIV

a.o.pasternak@amsterdamumc.nl (Alexander O Pasternak) — Fri, 23 Jan 2026 00:00:00 +0000

Whether antiretroviral therapy (ART) is always completely suppressive, or HIV might continue to replicate at low levels despite ART in some people with HIV (PWH), is still debated. Here, we intensified the ART regimen by doubling dolutegravir (DTG) dosage and investigated the impact of this strategy on HIV blood and tissue reservoirs, immune activation, and inflammation. Twenty HIV-infected adults, who had received a triple ART consisting of 50 mg DTG/600 mg abacavir/300 mg lamivudine pre-intensification and had been suppressed on ART for at least 2 years, were enrolled in a phase 2 randomized clinical trial (https://clinicaltrials.gov/ identifier: NCT05351684). Half of them received an additional 50 mg of DTG for a period of 84 days. As expected, plasma and tissue DTG concentrations significantly increased during the study period in the intensified group but not in the control group. Accordingly, significant decreases in total HIV DNA, intact HIV DNA, and cell-associated unspliced (US) HIV RNA in peripheral blood mononuclear cells, as well as in the US RNA/total DNA ratio, were observed in the intensified group but not in the control group. Intensification also modestly reduced markers of immune activation and exhaustion but had no measurable impact on systemic or tissue inflammation. Together with this, intensification resulted in a temporary decrease in the CD4/CD8 ratio that returned to baseline by day 84. Our results strongly suggest that the pre-intensification ART regimen was not completely suppressive. If confirmed in larger clinical trials, these results could have an impact on the clinical management of PWH and HIV curative strategies.

Western lifestyle linked to maladaptive trained immunity

Dennis.degraaf@uni-bonn.de (Aurelia Josephine Merbecks) — Wed, 21 Jan 2026 00:00:00 +0000

Trained immunity (TI) refers to a state of innate immune cells that, after encountering an initial stimulus and undergoing epigenetic reprogramming and metabolic changes, allows them to respond more effectively to a subsequent challenge. TI yields a survival advantage, particularly in a pathogen-rich context. However, maladaptive TI may damage the host by exacerbating inflammatory diseases. Here we review which aspects of Western lifestyle may contribute to maladaptive TI, including a Western diet, periodontitis, chronic psychological stress, and environmental triggers such as air pollution and microplastics. Finally, we consider lifestyle intervention as a way to prevent or reduce the impact of maladaptive TI.

Trained immunity in acute and chronic neurological diseases

Arthur.Liesz@med.uni-muenchen.de (Arthur Liesz) — Thu, 15 Jan 2026 00:00:00 +0000

Trained immunity, the long-term reprogramming of innate immune cells to elicit an enhanced response upon subsequent challenges, has become a key concept in understanding a wide range of pathologies, including both acute and chronic inflammatory disorders. Recent evidence suggests that trained immunity also plays a significant role in the development and progression of various neurological disorders and related comorbidities, in which brain pathology can lead to trained immunity. This review summarizes the current understanding of trained immunity within both brain-resident immune cells and myeloid-derived innate immune cells, focusing on their roles in neurological disorders, such as ischemic brain injury, Parkinson’s disease, and Alzheimer’s disease. Additionally, we explore the heterogeneity of trained immunity across different conditions and its potential applications in clinical neurology.

Fish CDK2 recruits Dtx4 to degrade TBK1 through ubiquitination in the antiviral response

bob@ihb.ac.cn (Bao-Jie Cui) — Wed, 14 Jan 2026 00:00:00 +0000

Although the classical biological protein cell cycle protein kinase CDK2 has been extensively studied in higher vertebrates, its function in lower vertebrates beyond the regulation of mitosis remains unknown. In this study, we report a distinct mechanism whereby IFN expression is negatively regulated in fish by CDK2. After infection with the spring viremia of carp virus (SVCV), fish CDK2 expression significantly increased in tissues and cells. Moreover, antiviral resistance was improved in cdk2^-/- homozygotes, and the antiviral cytokine interferon (IFN) expression was significantly higher. At the cellular level, CDK2 overexpression reduced IFN expression, while cdk2 knockdown increased the ability of cells to produce IFN. Subsequently, it was discovered that fish CDK2 binds and degrades TBK1, resulting in reduced IFN. CDK2 increases the K48-linked ubiquitination of TBK1, causing its degradation, while E3 ubiquitin ligase Dtx4 was found to be involved in this process following the significant enhancement of TBK1 K48-linked ubiquitination. Protein mass spectrometry and immunoblot analysis confirmed that the K567 site on TBK1 is essential for CDK2 to engage with Dtx4 and degrade TBK1; thus, after mutating the K567 site, K48-linked ubiquitination of TBK1 was not enhanced by Dtx4, and TBK1 was not degraded by CDK2. Our data demonstrate that fish CDK2 recruits the E3 ubiquitin ligase Dtx4 to target the K567 site of TBK1 and promote its degradation. These results suggest that CDK2 in lower vertebrates is implicated in a specialized role for antiviral innate immunity.

A co-evolutionary perspective on humans and Mycobacterium tuberculosis in the era of systems biology

p.elkington@soton.ac.uk (Alasdair Leslie) — Wed, 07 Jan 2026 00:00:00 +0000

Tuberculosis is once again the most fatal global infectious disease and has killed many more humans than any other pathogen. Despite the identification of Mycobacterium tuberculosis (Mtb) over 140 years ago, we have yet to control the epidemic. A central issue is the complexity of the host–pathogen interaction, with multiple underlying pathways leading to tuberculosis disease. This intricate relationship stems from the prolonged co-evolution of the pathogen with humans, resulting in diverse immunological processes leading to tuberculosis disease. Conversely, Mtb exposure may give a survival advantage through innate immune training, thereby providing selective pressure over millennia. Emerging methodologies, such as single-cell and spatial transcriptomics, offer a golden opportunity to understand the immunology unpinning this host–pathogen interaction at unprecedented resolution. However, these analyses will be fundamentally flawed if they do not consider the intricacies of human Mtb infection. Here, we propose that attempts to find single immunological mechanisms leading to tuberculosis are hindering progress, and we must embrace the complexity of multiple paths to disease to allow the systems biology era to deliver transformative solutions.

Epidermal resident memory T cell fitness requires antigen encounter in the skin

dankaplan@pitt.edu (Andrew Liu) — Tue, 30 Dec 2025 00:00:00 +0000

CD8⁺ tissue-resident memory T cells (T_RM) develop from effectors that seed peripheral tissues where they persist providing defense against subsequent challenges. T_RM persistence requires autocrine TGFβ transactivated by integrins expressed on keratinocytes. T_RM precursors that encounter antigen in the epidermis during development outcompete bystander T_RM for TGFβ resulting in enhanced persistence. ScRNA-seq analysis of epidermal T_RM revealed that local antigen experience in the skin resulted in an enhanced differentiation signature in comparison with bystanders. Upon recall, T_RM displayed greater proliferation dictated by affinity of antigen experienced during epidermal development. Finally, local antigen experienced T_RM differentially expressed TGFβRIII, which increases avidity of the TGFβRI/II receptor complex for TGFβ. Selective ablation of Tgfbr3 reduced local antigen experienced T_RM capacity to persist, rendering them phenotypically like bystander T_RM. Thus, antigen-driven TCR signaling in the epidermis during T_RM differentiation results in a lower TGFβ requirement for persistence and increased proliferative capacity that together enhance epidermal T_RM fitness.

Glycosylated IgG antibodies contribute to the recovery of haemorrhagic fever with renal syndrome patients

shiwf@ioz.ac.cn (Chuansong Quan) — Mon, 29 Dec 2025 00:00:00 +0000

Haemorrhagic fever with renal syndrome (HFRS) is a fatal disease caused by Hantaan virus (HTNV) infection. Humoral immunity is essential for effective viral clearance; however, the glycosylation characteristics of immunoglobulin G (IgG) in HFRS patients are not well known. Peripheral blood mononuclear cells from HFRS patients were obtained for B subset analysis using scRNA-seq and flow cytometry. HTNV-specific IgG antibody titers were detected by enzyme-linked immunosorbent assay, and IgG glycosylation was analyzed by ultra-performance liquid chromatography. The proportions of the antibody-secreting memory (ASM) B cells and plasmablasts (PB) were significantly expanded among acute HFRS patients. We discovered significantly increased fucosylated IgG and decreased bisecting N-acetylglucosamine during the convalescent phase of HTNV infection. Meanwhile, positive correlations were observed between ASM subsets and galactosylation/sialylation in the IgG Fc region, and between PB subsets and sialylation. Notably, the glycosylation-related genes, such as RPN1 and RPN2, were primarily expressed differentially in the ASM and PB subclusters, which were enriched in the N-glycosylation modifications of proteins through asparagine. Our findings indicated that IgG N-glycosylation may play a crucial role in combating HTNV infection and contributing to clinical recovery, which provided new insights for optimizing glycoengineered therapeutic antibodies.

Phospholipid scramblase 1 (PLSCR1) regulates interferon-lambda receptor 1 (IFN-λR1) and IFN-λ signaling in influenza A virus (IAV) infection

yang_zhou@brown.edu (Alina Xiaoyu Yang) — Wed, 24 Dec 2025 00:00:00 +0000

Phospholipid scramblase 1 (PLSCR1) is an interferon-stimulated gene (ISG) that has several known anti-influenza functions. However, the mechanisms in relation to its expression compartment and enzymatic activity have not been completely explored. Moreover, only limited animal models have been studied to delineate its role at the tissue level in influenza infections. Our results showed that influenza A virus (IAV)-infected Plscr1^-/- mice exhibited exacerbated body weight loss, decreased survival rates, heightened viral replication, and increased lung damage. Interestingly, transcriptomic analyses demonstrated that Plscr1 was required for the expression of type 3 interferon receptor (Ifn-λr1) upon IAV infection by binding to its promoter. In addition, PLSCR1 interacted with IFN-λR1 on the cell surface of pulmonary epithelial cells following IAV infection, suggesting it also modulated IFN-λ signaling via protein-protein interactions. The lipid scramblase activity of PLSCR1 was found to be dispensable for its anti-flu activity. Finally, single-cell RNA sequencing data indicated that Plscr1 expression was significantly upregulated in ciliated airway epithelial cells in mice following IAV infection. Consistently, Plscr1^floxStop;Foxj1-Cre⁺mice with ciliated epithelial cell-specific Plscr1 overexpression showed reduced susceptibility to IAV infection, less inflammation, and enhanced Ifn-λr1 expression, suggesting that Plscr1 primarily regulates type 3 IFN signaling as a cell-intrinsic defense factor against IAV in ciliated airway epithelial cells. Our research will elucidate virus-host interactions and pave the way for the development of novel anti-influenza drugs that target human elements like PLSCR1, thereby mitigating the emergence of drug-resistant IAV strains.

Class A scavenger receptor MARCO negatively regulates Ace expression and aldosterone production

ana.domingos@dpag.ox.ac.uk (Ana I Domingos) — Wed, 24 Dec 2025 00:00:00 +0000

Aldosterone is a potent cholesterol-derived steroid hormone that plays a major role in controlling blood pressure via regulation of blood volume. The release of aldosterone is typically controlled by the renin–angiotensin–aldosterone system, situated in the adrenal glands, kidneys, and lungs. Here, we reveal that the class A scavenger receptor MARCO, expressed on alveolar macrophages, negatively regulates aldosterone production and suppresses angiotensin-converting enzyme (Ace) expression in the lungs of male mice. Collectively, our findings suggest alveolar macrophages as additional players in the renin–angiotensin–aldosterone system and introduce a novel example of interplay between the immune and endocrine systems.

Trained Immunity: RoadMap for drug discovery and development

jvanpuffelen@kupando.com (Callum Campbell) — Tue, 23 Dec 2025 00:00:00 +0000

Trained Immunity is the nonspecific (pathogen agnostic) memory of innate immune cells, characterized by altered responses upon secondary stimulation. This review provides a RoadMap for the discovery and development of therapeutics targeting Trained Immunity, aimed at researchers with strong scientific backgrounds but limited drug development experience. The article outlines five drug development domains – epigenetic, metabolic, differentiation, inflammatory, and memory changes – that guide the identification of molecular targets, model selection, and biomarker development for the discovery and development of Trained Immunity-based therapeutics. It emphasizes the application of preclinical models and artificial intelligence in target discovery and compound screening. Additionally, the review addresses challenges in translating preclinical Trained Immunity findings to clinical trials and highlights relevant disease indications and ongoing clinical trials. This review integrates scientific findings with development strategy and thereby aims to bridge the gap between discovery and clinical application, advancing the field of Trained Immunity-based therapeutics.

Immunoglobulin M regulates airway hyperresponsiveness independent of T helper 2 allergic inflammation

sabelo.hadebe@uct.ac.za (Amkele Ngomti) — Tue, 16 Dec 2025 00:00:00 +0000

Allergic asthma is a disease driven by T helper 2 (Th2) cells, eosinophilia, airway hyperresponsiveness (AHR), and IgE-secreting B cells. Asthma is largely controlled by corticosteroids and β₂ adrenergic receptor agonists that target and relax airway smooth muscle (ASM). Immunoglobulin M (IgM) isotype secreted by naïve B cells is important for class switching but may have other undefined functions. We investigated the role of IgM in a house dust mite (HDM)-induced Th2 allergic asthma model. We sensitised wild-type (WT) and IgM-deficient (IgM KO) mice with HDM and measured AHR, and Th2 responses. We performed RNA sequencing on the whole lung of WT and IgM KO mice sensitised to saline or HDM. We validated our AHR data on human ASM by deleting genes using CRISPR and measuring contraction by single-cell force cytometry. We found IgM to be essential in AHR but not Th2 airway inflammation or eosinophilia. RNA sequencing of lung tissue suggested that IgM regulated AHR through modulating brain-specific angiogenesis inhibitor 1-associated protein 2-like protein 1 (Baiap2l1) and other genes. Deletion of BAIAP2L1 led to a differential reduction in human ASM contraction when stimulated with TNF-α and Acetylcholine, but not IL-13. These findings have implications for future treatment of asthma beyond current therapies.

IL-27 limits HSPC differentiation during infection and protects from stem cell exhaustion

chunter@vet.upenn.edu (Anthony T Phan) — Mon, 15 Dec 2025 00:00:00 +0000

Many inflammatory stimuli can induce progenitor cells in the bone marrow to produce increased numbers of myeloid cells as part of the process of emergency myelopoiesis. These events are associated with trained immunity and have long-term impacts on hematopoietic stem and progenitor cell (HSPC) development but can also compromise their function. While many cytokines support emergency myelopoiesis, less is known about the mechanisms that temper these events. When mice that lack the cytokine IL-27 were infected with Toxoplasma gondii, there was enhanced generation of monocyte progenitors and increased numbers of inflammatory monocytes. In the bone marrow of infected mice, there was increased production of IL-27 that localized with HSPCs, and a survey of cytokine receptor expression highlighted that HSPCs were uniquely poised to respond to IL-27. Furthermore, the use of in vitro differentiation assays and mixed bone marrow chimeras revealed that HSPCs from IL-27-deficient mice are predisposed toward the monocyte lineage. Additional studies highlighted that after infection, loss of the IL-27R resulted in reduced HSPC fitness that manifested as reduced proliferative responses and a decreased ability to reconstitute the hematopoietic system. Thus, the ability of IL-27 to act on HSPC provides a regulatory brake on differentiation to limit monocyte induction and preserve HSPC stemness.

A modular platform to display multiple hemagglutinin subtypes on a single immunogen

aschmidt@crystal.harvard.edu (Aaron G Schmidt) — Mon, 08 Dec 2025 00:00:00 +0000

Next-generation influenza vaccines aim to elicit cross-reactive humoral responses to multiple influenza subtypes. Such increased breadth would not only improve seasonal vaccines but may afford ‘universal’ protection against influenza subtypes, including those with pandemic potential. Here, we describe a ‘beads-on-a-string (BOAS)’ immunogen that tandemly links up to eight distinct hemagglutinin (HA) head domains from circulating and non-circulating influenzas. These BOAS are immunogenic in the murine model and elicit comparable serum responses to each individual component. Notably, we also find that BOAS elicit cross-reactive responses to influenza subtypes not included in the immunizing immunogen. Furthermore, BOAS conjugation to protein-based ferritin nanoparticles does not significantly augment serum responses suggesting that our BOAS platform is sufficient for eliciting cross-reactive responses without off-target effects induced by the nanoparticle scaffold. Finally, vaccination with a mixture of the same HA head domains is not sufficient to elicit the same neutralization profile as the BOAS immunogens or nanoparticles. This mix-and-match immunogen design strategy is a robust platform for eliciting responses to multiple influenza subtypes via a single immunogen, and a potential platform for other viral glycoproteins.

Extracellular matrices regulate extravasation journey of leukocytes and inflammatory tissue fate

tomli_yt@sts.med.osaka-u.ac.jp (Yu-Tung Li) — Thu, 04 Dec 2025 00:00:00 +0000

Leukocyte extravasation across the blood endothelium to inflamed tissues is a crucial defence mechanism against invading pathogens. After the elimination of the pathogen in the tissue, inflammation needs to be resolved back to steady state. This cascade comprises at least three stages: transmigration through the endothelium and the underlying basement membrane, intra-tissue leukocyte activity, and tissue resolution. In each stage, extracellular matrix proteins in the vascular basement membrane and in tissues regulate a multitude of endothelial and leukocyte functions essential to completion of the cascade, either as a collective force-permissive structure or through signaling by individual matrix proteins. Proper orchestration of these diverse processes during the extravasation journey ensures effective defence and avoids development of chronic inflammatory diseases. This review will focus on how these extracellular matrices regulate the extravasation journey of leukocytes to illustrate their tight functional interdependence with profound impacts on the ultimate post-inflammation tissue fate.

The Shigella flexneri effector IpaH1.4 facilitates RNF213 degradation and protects cytosolic bacteria against interferon-induced ubiquitylation

jorn.coers@duke.edu (Jorn Coers) — Fri, 28 Nov 2025 00:00:00 +0000

A central signal that marshals host defense against many infections is the lymphocyte-derived cytokine interferon-gamma (IFNγ). The IFNγ receptor is expressed on most human cells, and its activation leads to the expression of antimicrobial proteins that execute diverse cell-autonomous immune programs. One such immune program consists of the sequential detection, ubiquitylation, and destruction of intracellular pathogens. Recently, the IFNγ-inducible ubiquitin E3 ligase RNF213 was identified as a pivotal mediator of such a defense axis. RNF213 provides host protection against viral, bacterial, and protozoan pathogens. To establish infections, potentially susceptible intracellular pathogens must have evolved mechanisms that subdue RNF213-controlled cell-autonomous immunity. In support of this hypothesis, we demonstrate here that a causative agent of bacillary dysentery, Shigella flexneri, uses the type III secretion system (T3SS) effector IpaH1.4 to induce the degradation of RNF213. S. flexneri mutants lacking IpaH1.4 expression are bound and ubiquitylated by RNF213 in the cytosol of IFNγ-primed host cells. Linear (M1-) and lysine-linked ubiquitylation of S. flexneri requires RNF213 but is independent of the linear ubiquitin chain assembly complex (LUBAC). We find that ubiquitylation of S. flexneri is insufficient to kill intracellular bacteria, suggesting that S. flexneri employs additional virulence factors to escape from host defenses that operate downstream from RNF213-driven ubiquitylation. In brief, this study identified the bacterial IpaH1.4 protein as an inhibitor of mammalian RNF213 and highlights evasion of RNF213-driven immunity as a characteristic of the human-tropic pathogen Shigella.

The role of co-infection in the pathogenesis of acute SARS-CoV-2 infection and development of post-acute sequelae: A perspective

adolfo.garcia-sastre@mssm.edu (Aayush Pagaria) — Mon, 17 Nov 2025 00:00:00 +0000

A major health challenge resulting from the COVID-19 pandemic is the manifestation of post-acute sequelae of SARS-CoV-2 (PASC). PASC (or long COVID) is a collective term used for clinical symptoms, various pathologies, and life-quality-changing functional impairment that persist for months to years after the initial SARS-CoV-2 infection. The mechanisms underlying PASC are not understood, although advances have been made in identifying factors that may contribute to long-term pathology. Recent data have emerged, showing an association between SARS-CoV-2 viral persistence and non-SARS-CoV-2 infections (pre-existing, viral reactivation, or new infections) in facilitating or mediating PASC. However, the heterogeneous nature and timing of co-infections have made it challenging to understand, interpret, and contextualize their contribution to PASC. Here, we summarize the impact of potential viral, bacterial, and fungal infections on SARS-CoV-2 pathogenesis, with a focus on their possible roles in the development of PASC. We also provide a framework to understand the mechanisms of PASC and inform basic, translational, and clinical research initiatives, including RECOVER, a large and ongoing research initiative to understand, treat, and prevent long COVID.

Innate immune memory: The evolving role of macrophages in therapy

payal.damani-yokota@nyulangone.org (Kamal Mohan Khanna) — Fri, 14 Nov 2025 00:00:00 +0000

Trained immunity is reshaping our understanding of host defense by demonstrating that innate immune cells once thought to lack memory can be reprogrammed to mount heightened responses to subsequent challenges. Unlike tolerance, differentiation, or priming, trained immunity relies on epigenetic and metabolic rewiring of resident myeloid cells, particularly in mucosal barriers such as the skin, gut, and lungs, where these cells provide continuous protection against toxins and pathogens. Here, we review recent advances showing how an initial stimulus endows monocytes and macrophages with long-lasting functional changes that can be either protective or maladaptive upon re-exposure. We highlight therapeutic opportunities that harness trained immunity to boost vaccine efficacy and discuss strategies to modulate this program in cancer and hyper-inflammatory disorders. Finally, we propose new directions for enhancing or dampening trained immunity to promote human health.

Engineered migrasomes provide a robust and thermally stable vaccination platform

liyulab@mail.tsinghua.edu.cn (Dongju Wang) — Thu, 13 Nov 2025 00:00:00 +0000

The growing ability of pathogens and tumor cells to evade immune surveillance underscores the urgent need for new vaccine platforms that harness diverse biological mechanisms. Logistical constraints associated with cold-chain transport further limit vaccine accessibility, particularly in resource-limited settings. Migrasomes—specialized organelles produced during cell migration—are inherently stable and enriched with immune-modulating molecules. To overcome the low yield of natural migrasomes, we engineered migrasome-like vesicles (eMigrasomes) using hypotonic shock combined with cytoskeletal disruption to promote vesicle formation. eMigrasome biogenesis depends on core migrasome machinery and recapitulates the biophysical and molecular features of native migrasomes while achieving higher production efficiency. In murine models, eMigrasomes loaded with a model antigen elicited potent antibody responses and retained structural integrity and immunogenicity at room temperature. Moreover, eMigrasomes displaying the SARS-CoV-2 Spike protein induced strong humoral responses and conferred protection against viral challenge in mice. These results establish eMigrasomes as an innovative, thermally stable, and broadly applicable vaccine platform derived from migrasome biology.

Layers of immunity: Deconstructing the Drosophila effector response

m.hanson@exeter.ac.uk (Bruno Lemaitre) — Wed, 05 Nov 2025 00:00:00 +0000

The host innate immune response relies on the cooperation of multiple defense modules. In insects and other arthropods, which have only innate immune mechanisms, four main immune-specific modules have been described in the defense against microbial invaders: the Toll pathway, the Imd pathway, the melanization response, and phagocytosis by plasmatocytes. Our present understanding of their relative importance remains fragmented as their contribution to host defense has never been simultaneously assessed across a large panel of pathogens. Here, we use newly described immune mutants in a controlled genetic background to systematically delete these four immune modules individually, in pairs, or even all four simultaneously. Surprisingly, flies simultaneously deficient in all four immune modules are viable (poor viability), homozygous fertile, and display no overt morphological defects, suggesting these immune mechanisms are not strictly required for organismal development. We assessed the contribution of each module individually and collectively against a diverse panel of viruses, fungi, and bacteria. We find these four modules largely function independently and additively in host defense. We could confirm previous findings on the importance of Imd and Toll, and their antimicrobial peptide and Bomanin (Bom) effectors, against relevant microbes. We also reveal a highly important role of melanization against viruses. Examining microbial load kinetics confirms how these modules contribute to resistance or tolerance against specific microbes. The set of immune-deficient lines provided here offers tools to better assess the role of these immune modules in host defense.

Evolving our understanding of trained immunity

eva.kaufmann@mcgill.ca (Boris Novakovic) — Wed, 05 Nov 2025 00:00:00 +0000

The articles in this focus issue discuss progress towards a more complete understanding of memory in the innate immune system, and efforts to exploit “trained immunity” for the development of new vaccines and therapeutics.