Search Results (499)

Influenza A virus (IAV) remains a major cause of respiratory morbidity and mortality worldwide. However, the precise role of the RNA sensor Toll-like receptor 7 (TLR7) and its downstream signaling mediator, interferon regulatory factor 7 (IRF7), during IAV infection remains elusive. To address this gap, we utilized single-cell RNA sequencing (scRNA-seq) alongside Tlr7-deficient and Irf7-deficient mouse models infected with the mouse-adapted IAV strain PR8. Pulmonary scRNA-seq of PR8-infected wild-type mice revealed robust upregulation of Tlr7 and interferon (IFN) pathway-associated genes specifically in dendritic cells (DCs) and B cells, whereas Irf7 induction occurred globally across all major lung compartments. Following PR8 infection, Irf7-deficient but not Tlr7-deficient mice exhibited significantly greater daily weight loss, increased mortality, and more severe bronchial epithelial hyperplasia compared to wild-type controls. Furthermore, infected Irf7-deficient mice displayed diminished early IFN-α and IFN-γ levels. Interestingly, both Irf7- and Tlr7-deficient strains demonstrated impaired anti-hemagglutinin (HA) antibody production. Notably, Tlr7 deficiency did not alter Irf7 protein expression or the production of IFNs and NF-κB in response to IAV, indicating that Tlr7 does not modulate Irf7 activation during infection. Collectively, these findings demonstrate that Irf7 protects against severe IAV pathogenesis independently of Tlr7 recognition in mice, whereas both Irf7 and Tlr7 are required for optimal anti-HA antibody production. Importance: Influenza A virus is a respiratory pathogen that remains a major threat to global health as a seasonal disease and a source of periodic pandemics. The outcomes of the infection can range from mild illness to severe pneumonia and death, particularly in vulnerable populations, yet the reasons why some individuals develop more severe disease are not fully understood. Early immune defenses in the lungs are critical for controlling the virus, but they can also contribute to harmful inflammation if not properly regulated. Key sensors that detect viral genetic material, such as TLR7, and the signaling pathways that activate antiviral responses, such as IRF7, play an essential role in shaping these outcomes. However, whether TLR7 is essential or redundant in IAV remains debated, and the independent role of IRF7 in IAV has not been directly demonstrated in mouse models. The significance of our study lies in defining how these early immune mechanisms influence the course of influenza A infection, providing insight that may guide the development of improved therapies for influenza and related respiratory viruses. Full article

The lymphocytic choriomeningitis virus (LCMV) represents a strong T cell activating virus with anti-tumoral properties. In recent work, we developed an attenuated cancer cell-adapted reassortant LCMV strain carrying tumor-tropic mutations. The immunological mechanisms underlying these mutations remained unknown. Here, we passaged wild-type LCMV-WE in human lung cancer H1975 cells for 52 passages. After 29 passages, the virus acquired the GP1 mutations I181M and R185W, involved in viral receptor interactions, which remained stable throughout the subsequent 33 passages. Compared with wild-type LCMV-WE, LCMV-P52 showed increased infectivity, partly concomitant with enhanced propagation in human tumor cells. In vivo, LCMV-P52 induced reduced type I interferon (IFN-I) responses and showed accelerated expansion in CD169⁺ macrophages. Propagation within the splenic marginal zone correlated with accelerated priming of virus-specific CD8⁺ T cells and limited liver tissue damage. Mechanistic in vitro experiments showed that the I181M and R185W mutations were associated with substantially reduced infection of plasmacytoid dendritic cells (pDCs). Collectively, the I181M and R185W mutations limit systemic IFN-I induction and accelerate LCMV propagation in CD169⁺ macrophages, correlating with improved CD8⁺ T cell function and reduced liver damage. These findings provide mechanistic insight into how defined GP mutations can modulate viral tropism and antiviral immune responses. Full article

Both oncolytic virotherapy and immune checkpoint blockade are being actively explored as immunotherapy treatments for glioblastoma, one of the most lethal malignancies. Nevertheless, the antitumor molecular mechanisms of these therapies remain poorly understood, particularly whether they induce overlapping or distinct transcriptional programs. No comprehensive transcriptome-wide characterization and direct comparison of the responses induced by VV-GMCSF-Lact and anti-PD-1 therapy in glioma have been reported. To address this question, we performed whole-transcriptome profiling of GL261 tumors from immunocompetent C57BL/6 mice treated with VV-GMCSF-Lact, anti-PD-1 antibodies, or their combination. We analyzed therapy-associated changes in gene expression, signaling pathways, and tumor composition. Our findings indicate that anti-PD-1 and combination treatment led to distinctive activation of interferon-gamma response, JAK/STAT signaling, and TNF-alpha/NF-kB pathways. In contrast, VV-GMCSF-Lact preferentially activated T, B, and natural killer T cell-associated programs and reduced the relative abundance of malignant cells. Notably, combination therapy was associated with unique molecular patterns, including induction of monocyte and granulocyte chemotaxis-associated genes, downregulation of PP2A-regulated signaling, and suppression of Rap1-related pathways. This suggests that VV-GMCSF-Lact and anti-PD-1 therapy induce transcriptionally distinct, yet complementary, immune reprogramming and support further evaluation of their combination for glioma immunotherapy. Full article

Neurotropic viruses have evolved sophisticated mechanisms to evade host immune responses within the central nervous system (CNS), enabling viral replication, persistence, latency, and neuropathogenesis while minimizing irreversible neuronal damage. Unlike peripheral tissues, the CNS requires tightly regulated antiviral immunity to balance effective pathogen control with the preservation of neural function. This review examines the diverse yet convergent immune evasion strategies employed by major neurotropic RNA and DNA viruses, including herpes simplex virus (HSV), varicella-zoster virus (VZV), cytomegalovirus (CMV), rabies virus (RABV), flaviviruses, alphaviruses, enteroviruses, and JC virus (JCV). We discuss viral interference with innate immune sensing pathways, including RIG-I-like receptors (RLRs) and cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING) signaling, inhibition of type I interferon induction and Janus kinase–signal transducer and activator of transcription (JAK–STAT) signaling, modulation of interferon-stimulated effector mechanisms, and disruption of antigen presentation and adaptive immune surveillance. The review further highlights the distinct roles of viral latency, long-term persistence, neuronal–glial interactions, and metabolic reprogramming in facilitating prolonged infection within the CNS. Emerging evidence indicates that successful neurotropic viruses rarely achieve immune evasion through complete suppression of host defenses; instead, they fine-tune antiviral responses to preserve host cell viability while preventing viral clearance. Finally, we discuss current knowledge gaps and emphasize the need for advanced human-relevant models, single-cell and spatial multi-omics, and systems-level approaches to better define virus–host interactions within the CNS. A deeper understanding of these integrated immune evasion networks may reveal novel therapeutic strategies that enhance antiviral immunity while limiting neuroinflammation and preserving neurological function. Full article

Bacterial diseases caused by Flavobacterium covae (Fc), Vibrio harveyi (Vh), Vibrio vulnificus (Vv) and Photobacterium damselae (Pd) seriously constrain Asian seabass aquaculture. Here we dissect the mucosal immune mechanisms engaged by a five-month sequential vaccination strategy that combines nanoemulsion immersion priming with multivalent oral hydrogel boosting. Juvenile seabass were vaccinated, then challenged with F. covae by freshwater immersion and with a Vibrio–Photobacterium (Vh/Vv/Pd) mix by immersion or intraperitoneal injection. Gills were sampled after immersion challenges and intestine after injection, and profiled by RNA sequencing and label-free quantitative proteomics, with selected genes validated by RT-qPCR. Principal component analysis showed clear separation of vaccinated and control fish in all tissues and challenges, indicating a strong and coherent transcriptional reprogramming. Vaccination markedly increased the number of upregulated genes, with Gene Ontology enrichment revealing dominant signatures of ribosome biogenesis, RNA processing, lysosomal organization and immune response. KEGG analysis highlighted cytokine receptor interaction; NOD and Toll-like receptor signaling; oxidative phosphorylation; and phagosome, lysosome and cell adhesion molecule pathways, consistent with heightened antimicrobial readiness. Volcano plots and focused heatmaps showed strong induction of interferon-stimulated genes, cytokines and chemokine receptors, complement components, macrophage mannose receptor, epithelial barrier mediators and numerous immunoglobulin transcripts, with tissue- and challenge-specific patterns. Proteomics corroborated these trends, demonstrating a higher abundance of immunoglobulin heavy chains, complement proteins, cathepsins, heat shock and redox chaperones, ribosomal proteins and cytoskeletal and adhesion regulators in vaccinated mucosae. Integrated pathway mapping linked endothelial adhesion molecules and leukocyte integrins with T cell costimulation networks and an intestinal immune network for immunoglobulin production, including enhanced pIgR-mediated transcytosis. Overall, the sequential vaccination regimen was associated with coordinated transcriptomic and proteomic signatures related to epithelial responses, innate immunity, and humoral immune functions across gill and intestinal tissues. These molecular patterns were accompanied by improved survival following bacterial challenge; however, the present data do not directly demonstrate the functional activity of the inferred immune mechanisms in Asian seabass. Full article

Human metapneumovirus (hMPV) is an important respiratory pathogen and a major cause of respiratory tract infections, particularly among vulnerable populations. Although hMPV was identified in 2001, it remains less extensively studied than other major respiratory viruses, such as influenza virus and respiratory syncytial virus (RSV), hindering the development of effective preventive and therapeutic strategies. This review examines the primary mechanisms by which hMPV evades host immune responses. The virus disrupts early innate immune signaling pathways, particularly those involved in the induction and signaling of antiviral interferons (IFNs) and modulates inflammatory responses. At the level of adaptive immunity, hMPV impairs T-cell activation and the development of long-lasting immunological memory, which may contribute to susceptibility to reinfection. The virus also alters the functions of several immune and structural cell types, including macrophages, dendritic cells, and respiratory epithelial cells. In addition, hMPV may modulate host microRNA expression to promote immune evasion and prolong infection. The recurrent nature of hMPV infections highlights the need to further investigate the immune-evasion mechanisms. Such research is essential for developing safer and more effective vaccines, antiviral agents, and immunomodulatory therapies. Full article

Interferons (IFNs) are a family of cytokines which serve as the first line of defense against pathogen infections while also exerting critical immunomodulatory roles. IFNs can induce hundreds of IFN-stimulated genes (ISGs) with cell-specificity, yet a high-resolution comparison of time-serial ISG induction across cell types is lacking. By using RNA sequencing, we conducted a comparative transcriptomic profiling during time-serial IFN-γ stimulation for up to 24 h in HeLa and HEK293T cells, the two most widely used immortalized human cell lines. We uncovered remarkably stronger IFN responses in HeLa cells, regarding the global transcriptomic dynamics, the number of induced ISGs, and the level of ISG expression. Both cell lines share a core set of ISGs associated with canonical JAK-STAT signaling, yet HeLa uniquely activates additional inflammatory and adaptive immunity-related pathways. Despite the much weaker IFN response in HEK293T cells, we also identified a few HEK293T-specific ISGs, including several with crucial immune-related functions. Notably, transposable elements—including many adjacent to ISGs—are also highly up-regulated in HeLa cells, implying their potential links to ISG induction. Collectively, this study provides a high-resolution temporal atlas of IFN-γ-stimulated transcriptomic dynamics in HeLa and HEK293T cells, revealing the shared core module and cell-specific patterns of their interferon responses. Full article

Sjögren’s disease (SjD) is a systemic autoimmune disease characterized by exocrine dysfunction, lymphocytic infiltration of the exocrine glands, and prominent activation of the interferon (IFN) pathway. Although IFN signatures are recognized as a central feature of SjD, endogenous triggers that sustain chronic IFN-driven inflammation remain incompletely understood. Mitochondrial RNAs (mtRNAs), particularly double-stranded species, have recently emerged as immunostimulatory molecules capable of linking mitochondrial stress to innate immune activation. In this review, we discuss the biological basis of mtRNA biogenesis and processing, the formation and mislocalization of mitochondrial double-stranded RNAs, and their recognition by innate immune sensors relevant to induction of type I IFN. We also describe how epithelial stress, mitochondrial dysfunction, and mtRNA accumulation amplify IFN-rich inflammatory circuits and glandular injury in SjD. Experimental studies in salivary gland epithelial models and SjD-relevant tissues support a mechanistic role for the mtRNA–type I IFN axis, while emerging clinical data suggest that extracellular mtRNA levels in saliva and plasma may have potential as biomarkers of disease activity and patient stratification. Although current evidence remains limited, the mtRNA–type I IFN axis provides a biologically plausible link between epithelial stress and immune dysregulation, and may have translational implications in SjD. Full article

The geographic range and outbreak intensity of vector-borne viral infections are increasing as climate, land use, urbanization, and human mobility reshape vector ecology and human exposure. Despite their growing importance to public health, effective antiviral and preventive options remain limited for many emerging and reemerging vector-borne viruses due to viral genetic diversity, rapid evolutionary capacity, sporadic outbreak patterns, and economic constraints. While these viruses differ in taxonomy, genome organization, vector specificity, tissue tropism, and clinical manifestations, they exploit a shared vulnerability in host antiviral defense, particularly the timing of innate antiviral immunity to support viral replication, immune evasion, inflammatory dysregulation, and disease progression. Rather than simply suppressing antiviral defense, vector-borne viruses can delay early viral nucleic acid sensing, attenuate interferon induction or responsiveness, and extend the initial phase for viral replication. As viral burden increases and infected tissues undergo stress or damage, delayed immune activation can shift toward excessive inflammatory amplification, contributing to disease-specific pathology. In this study, we examine this temporal rewiring of innate antiviral immunity in representative vector-borne viruses such as dengue virus, chikungunya virus, and severe fever with thrombocytopenia syndrome virus and propose that understanding these conserved host dependencies may lead to broader, stage-specific, adaptable antiviral strategies that complement conventional virus-directed approaches. Full article

Background/Objectives: Glioblastoma (GBM) is the most lethal primary brain malignancy in adults, with a median overall survival of approximately 15 months. Temozolomide (TMZ) resistance develops in virtually all patients, and no second-line regimen has improved outcomes over the past two decades. The DNA methyltransferase inhibitor decitabine (DAC) has attracted interest as a chemosensitizer, but whether it directly reverses the TMZ-resistance transcriptome or operates through distinct, complementary mechanisms has not been tested at multi-omics resolution. Methods: We performed an integrative six-layer multi-omics analysis across five public GEO datasets (bulk RNA-seq, EPIC 850K methylation, and 21,676 single cells) re-purposed from studies conducted for unrelated aims, formally tested DAC-mediated reversal of the TMZ-resistance transcriptome across 11,707 genes, mapped pharmacogenomic targets with DGIdb v5, and built an exploratory, hypothesis-generating 11-gene prognostic model internally validated in TCGA-GBM (n = 166) and externally tested in the independent CPTAC-GBM cohort (n = 96). Results: DAC reprogrammed transcription across 1114–1882 differentially expressed genes per cohort and reactivated 146 direct epigenetic targets, identifying INPP5D/SHIP1 as the top-ranked direct epigenetic-reactivation target. Genome-wide reversal analysis across 11,707 co-detected genes showed a negligible effect (Spearman ρ = 0.073), but single-cell analysis revealed significant per-cell attenuation of MES-like and stem-like programs (Δ = −0.071 and −0.135, respectively; both p < 0.001). The 11-gene risk model achieved a Harrell’s C-index of 0.706 (apparent); after correcting for the two-stage gene selection with a full-pipeline bootstrap, the optimism-corrected C-index was 0.63, and external validation in an independent cohort (CPTAC-GBM, n = 96) showed only near-chance discrimination (C-index 0.55), indicating that the signature does not generalize and is exploratory. Pharmacogenomic mapping yielded 734 unique therapeutic agents (230 FDA-approved) across 69 druggable targets after excluding AR. Most of these agents are not GBM-directed, so this catalog-level mapping is hypothesis-generating rather than a set of therapeutic recommendations. Conclusions: DAC does not broadly reverse the TMZ-resistant transcriptome but acts through three complementary mechanisms: epigenetic reactivation of INPP5D/SHIP1, cancer-testis-antigen and type I interferon induction, and per-cell attenuation of mesenchymal–stem-like transcriptional intensity, supporting hypotheses for rationally designed DAC-based combination therapy in TMZ-resistant GBM. Full article

Senotherapeutic agents targeting senescent cell (SnC) accumulation represent a promising frontier in aging research. These agents encompass senolytics that selectively eliminate accumulated SnCs and senomorphics that suppress the pathological persistence of the senescence-associated secretory phenotype (SASP). Concerns regarding off-target effects of synthetic senolytics have intensified interest in plant-derived alternatives that offer multitargeted mechanisms and favorable safety profiles. This scoping review was conducted following Joanna Briggs Institute guidelines and PRISMA-ScR, mapped preclinical evidence on plant-derived senotherapeutics published between 2015 and 2025 across PubMed, Scopus, Web of Science, Wiley Library and Google Scholar. Of 1355 identified articles, 111 studies met inclusion criteria. Most characterized compound classes included flavonoids, non-flavonoid polyphenols and stilbenes, terpenoids and alkaloids, and combination and complex plant extracts. Mechanistically, BCL-2/BCL-XL apoptosis, PI3K/AKT/mTOR and p53/p21/p16^INK4a modulation emerged as senolytic mechanisms, while NF-κB-mediated SASP suppression predominated among senomorphic agents. Ginkgetin-mediated cyclic GMP-AMP-synthase–stimulator of interferon genes (cGAS-STING) inhibition was identified as a mechanistically novel target within natural senotherapy. Metabolomics demonstrated dual utility in guiding compound discovery from complex plant matrices (e.g., phenolamides from Allium hookeri) and mechanistic validation by characterizing senescence-associated metabolic remodeling, including retinoic acid metabolism restoration, lipotoxic metabolites attenuation, tricarboxylic acid (TCA) cycle, and choline-betaine-TCA cascade regulation. However, challenges in pharmacokinetic optimization, methodological heterogeneity in senescence induction and biomarker panels persist. Plant-derived senotherapy characterized through metabolomics-guided pipelines provides a compelling foundation for their progression toward clinical validation and functional food applications as accessible interventions for healthy aging and age-related disease management. Full article

Ferroptosis has emerged as a promising strategy to overcome resistance to conventional cancer therapies. Pancreatic ductal adenocarcinoma (PDAC) is characterized by hypoxia, therapy resistance, and an immunosuppressive microenvironment. Although hypoxia is likely to influence ferroptosis susceptibility and the associated inflammatory pathways that regulate antitumor immunity, their impact on ferroptosis sensitivity and innate immune responses remains poorly understood. In this study, we investigated the effects of hypoxia on the induction of ferroptosis and immune-related signaling in PDAC cell lines. We examined how hypoxia affects the responses of Panc-1, BxPC3, and Capan-1 cells to the ferroptosis inducers RAS-selective lethal 3 (RSL3)/Imidazole ketone erastin (IKE) under normoxic and hypoxic (0.1% O₂) conditions. Cell viability assays were used to assess ferroptosis sensitivity, and rescue experiments were performed using liproxstatin-1 (LIP). Gene expression analysis was conducted to evaluate changes in immune, interferon, inflammatory, and hypoxia-related genes following ferroptosis induction. Panc-1 cells were the most sensitive, whereas Capan-1 cells were resistant, particularly under hypoxia. Ferroptosis triggered cell line-specific responses involving interferon signaling, inflammation, and stress pathways. Panc-1 cells showed over-expression of RIG-I, MAVS, IRF3/7/9, STAT1/2, and CXCL10, particularly under hypoxia, indicating activation of Type I interferon (IFN)-associated transcriptional program. BxPC3 cells demonstrated broader cytokine induction, including IL-8, CCL2, CXCL2, GM-CSF, and IL-11, whereas Capan-1 cells were minimally responsive. Hypoxia also increased ANGPTL4 and GDF15 expression following ferroptosis induction. These findings show that hypoxia differentially affects ferroptosis sensitivity and immune responses in PDAC, revealing complex interactions among ferroptosis, innate immunity, and the tumor microenvironment. Full article

The MUCIN 1 (MUC1) gene evolved in eutherian mammals in association with the marked expansion of endogenous retroviruses (ERVs). MUC1 encodes the MUC1-C/M1C protein that protects barrier epithelia from exogenous viruses. Activation of M1C in response to loss of homeostasis induces STAT1 and the type I interferon (IFN-I) pathway. Studies in cancer cells have found that M1C regulates human ERV (HERV) expression by a STAT1-mediated mechanism. These discoveries have uncovered new insights into M1C-induced regulation of HERVs and other retrotransposons, such as LINE-1 (L1) and Alu. M1C signaling integrates retrotransposon transcription with induction of the counteracting apolipoprotein B mRNA-editing catalytic 3 (APOBEC3) genes that, like MUC1, first appeared in placental mammals. Activation of retrotransposons induces viral mimicry characterized as an IFN-I response that promotes innate anti-tumor immunity. Conversely, M1C protects cancer cells by sustained induction of the IFN-I pathway and immune evasion. This review posits that M1C-dependent regulation of retrotransposon and APOBEC3 expression represents an adaptive response exploited by cancer cells that promotes malignant progression. Full article

Viral infections are the main cause of asthma exacerbation, particularly in children. Impaired interferon induction by the airway epithelium has been linked to increased asthma exacerbation during viral infections. Several studies have suggested that epithelial cells in asthmatic mice induce low levels of type I and type III interferons, which leads to increased viral load. However, emerging evidence suggests that epithelial cells from asthmatic individuals induce delayed interferon responses. This study aimed to assess the ability of asthmatic and healthy epithelial cells to mount interferon-associated responses after exposure to viral stimuli. Variations in gene expression associated with interferon response were analyzed using datasets obtained from the Gene Expression Omnibus (GEO) database. Airway epithelial cells derived from healthy and asthmatic individuals were infected with RNA virus and then subjected to microarray or RNA sequencing. Lung tissues obtained from the animal models (mice and rats) were analyzed using RNA sequencing. Further data analysis was performed using integrated differential expression and pathway analysis (iDEP). Viral infection of airway epithelial cells derived from healthy and asthmatic subjects induces strong expression of interferon- and interferon-related genes. Interferon-stimulated genes (ISGs) were robustly induced in both asthmatic and healthy human epithelial cells after viral infection. However, the induction of virus-induced interferon-related responses was significantly lower in the lung tissues of animals with pre-allergic inflammation. Although previous studies have reported that the antiviral-interferon response is impaired or diminished in asthmatic individuals, our findings suggest that interferon-associated transcriptional responses are preserved in the airway epithelial cells of asthmatics during viral infection. This suggests that asthmatic epithelial cells induce an antiviral immune response, characterized by the induction of interferon-associated genes necessary for viral removal. Future studies should investigate the mechanisms underlying virus-induced asthma exacerbation. Full article

The concurrent circulation of influenza A virus (IAV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has unveiled complex host–pathogen interactions governed by temporal dynamics of innate immune activation. This narrative review synthesizes evidence from human air–liquid interface (ALI) epithelial models, animal studies (hamster, ferret), clinical cohorts, and randomized controlled trials (2015–2026) to delineate the molecular mechanisms underlying viral interference between these two major respiratory pathogens. Prior IAV infection induces a robust type I/III interferon (IFN) response and broad interferon-stimulated gene (ISG) upregulation that restricts subsequent SARS-CoV-2 replication within a critical 24–72 h temporal window. Conversely, SARS-CoV-2 employs a multi-layered immune evasion strategy that blunts IFN induction, providing minimal heterologous protection. Simultaneous co-infection tends to exacerbate disease severity. Host genetic determinants, including OAS1 and TLR7 variants, modulate interference capacity. Therapeutically, early pegylated IFN-λ shows clinical benefit, while experimental evidence from in vitro and animal models suggests oseltamivir may paradoxically reduce IAV-induced interference. These findings underscore the need for multi-pathogen diagnostics, temporally informed clinical decision-making, and IFN-based therapeutic strategies during co-circulation periods. Full article