Search Results (2,923)

The m⁶A RNA methylation pathway plays a critical role in host antiviral defense. Host cells employ m⁶A readers such as YTHDF2 to regulate viral RNA fate through diverse mechanisms, including degradation, translational control, and immune recognition. However, we found that YTHDF2 is essential for SARS-CoV-2 replication, suggesting that a virus may exploit this host machinery to its advantage. Through integrative RNA-proteome analysis, we identified the SARS-CoV-2 nucleocapsid (N) transcript as the most heavily m⁶A-modified viral transcript and a direct interactor of YTHDF2. The N protein forms a complex with YTHDF2 in the cytoplasm and redirects this host RNA decay machinery toward host antiviral transcripts. N suppresses ISG15, IFIT1, MX1 and pro-inflammatory cytokines in a largely YTHDF2-dependent manner, an effect that is lost in YTHDF2-knockout cells. These findings reveal a viral immune evasion strategy wherein a viral protein actively hijacks an m⁶A reader to silence antiviral gene expression, establishing the N-YTHDF2 axis as a therapeutic target against SARS-CoV-2 and other coronaviruses. Full article

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies, characterized by early metastasis, dense desmoplastic stroma and a profoundly immunosuppressive, lymphocyte-depleted tumor microenvironment that severely limits the efficacy of current systemic and immunotherapeutic approaches. Oncolytic viruses (OVs), which selectively replicate in and lyse malignant cells while activating antitumor immunity, have emerged as attractive candidates to convert this “cold” tumor into a more inflamed and therapeutically responsive disease. In this review, we summarize clinical evidence on the main OV platforms evaluated in PDAC, including adenovirus, herpes simplex virus, vaccinia virus, parvovirus and reovirus, with a focus on clinical trials. Across these classes of viruses, intratumoral administration has consistently proven feasible and generally well tolerated, with frequent evidence of viral replication, microenvironmental remodeling and immune activation, but only modest and often transient antitumor responses in small, early-phase cohorts. We then discuss key biological and translational challenges that currently limit OV impact in PDAC, such as systemic delivery in the context of pre-existing antiviral immunity and rapid clearance, penetration through the fibrotic stroma, and rational selection of encoded transgenes to reshape myeloid cell-driven, pro-tumoral inflammation and enhance T-cell recruitment. Finally, we outline future directions for the field, including carrier-cell–based systemic delivery, stroma-targeting or cytokine-armed constructs, and combinatorial strategies with chemotherapy and immune checkpoint blockade, arguing that design refinement, innovative combinations and mechanism-driven trial designs will be essential to unlock the full therapeutic potential of oncolytic virotherapy in PDAC. Full article

The single von Willebrand factor C (SVWC) domain-containing protein family represents a crucial class of immune molecules recently identified in insects and crustaceans. Initially regarded as functional analogs of vertebrate interferons (IFNs) due to their virus-induced expression and activation of the Janus kinase-signal transducer and activator of the transcription (JAK-STAT) pathway, recent studies have revealed that SVWC proteins possess far more complex functions. Many SVWC members are themselves a novel class of pattern recognition receptors (PRRs) that can directly bind to viruses and bacteria. Importantly, SVWCs are not a single entity but a highly diverse family—multiple subtypes exist in Drosophila, Bombyx mori, and shrimp—a gene expansion that implies functional differentiation. This review systematically examines the multifunctionality of SVWC proteins in insects and crustaceans, with a particular focus on the functional specialization driven by subtype diversity. We delve into the complex regulatory networks governing SVWC expression, including the differential activation by nuclear factor kappa B (NF-κB) pathways (Dorsal, Rel-2, Relish) and interferon regulatory factor (IRF) pathways. We detail the unique signaling mechanism by which SVWCs activate the JAK-STAT pathway via integrins, rather than the canonical Domeless receptor. Furthermore, we extend the discussion to the emerging roles of SVWCs as PRRs in humoral immunity (activating Toll/IMD pathways to induce antimicrobial peptides) and cellular immunity (mediating hemocyte phagocytosis). Based on current evidence, We propose that diverse SVWC subtypes may recognize distinct pathogens, bind to different integrin receptors, and activate specific STAT variants via disparate upstream induction pathways, thereby establishing a systematic and hierarchical immunoregulatory network. This understanding positions the SVWC protein family as a central hub in the insect immune network and offers a novel perspective on the complexity and evolution of invertebrate immunity. Full article

Natural bioactive polysaccharides have been investigated for their ability to modulate antiviral immune responses. Polysaccharide peptide (PSP) from Coriolus versicolor previously restricted human immunodeficiency virus type 1 (HIV-1) entry into monocytic cells through a protein kinase R (PKR)-dependent cytoskeletal mechanism. However, its impact on antiviral signaling in adaptive cluster of differentiation 4 (CD4)+ T-cell models remains incompletely defined. Here, we evaluated concentration- and time-dependent effects of PSP (50–1000 µg/mL) in Jurkat T cells over 3 and 6 days. Cell viability was assessed by MTT, trypan blue exclusion, and viable cell density analysis. Immunoblotting and reverse transcription quantitative polymerase chain reaction (RT-qPCR) were performed to examine Toll-like receptor 4 (TLR4), nuclear factor kappa B (NF-κB), signal transducer and activator of transcription 1 and 2 (STAT1/STAT2), PKR, interferon gamma (IFN-γ), and cofilin-1 signaling. PSP did not induce cytotoxicity at any concentration. Instead, PSP promoted dose- and time-dependent upregulation of intracellular TLR4, PKR, phospho-PKR (Thr446), Cofilin-1, phospho-Cofilin-1 (Ser3), phospho-STAT1 (Tyr701), phospho-STAT2 (Tyr690), phospho-NF-κB (Ser536), and IFN-γ, with amplified responses at Day 6. These changes were paralleled by transcriptional induction of antiviral-associated genes. Collectively, PSP induces coordinated interferon (IFN)-associated and cytoskeletal regulatory signaling in Jurkat T cells without cytotoxicity, providing a mechanistic framework for future evaluation of viral permissiveness and antiviral responses in adaptive immune models. Full article

Nipah virus (NiV) is a highly pathogenic zoonotic paramyxovirus responsible for sporadic outbreaks of severe disease with high case fatality rates in South and Southeast Asia. Human infection occurs through spillover from natural reservoirs, primarily fruit bats, or via human-to-human transmission, and is characterized by a broad clinical spectrum ranging from asymptomatic infection to acute respiratory disease and fatal encephalitis. Following entry via ephrin-B2 and ephrin-B3 receptors, NiV exhibits marked endothelial and neuronal tropism, leading to systemic vasculitis, disruption of the blood–brain barrier, and direct infection of the central nervous system. Disease progression is driven by a complex interplay between viral replication strategies and host immune responses. NiV effectively counteracts innate immunity through multiple viral proteins that inhibit interferon signaling, while simultaneously inducing dysregulated inflammatory responses that contribute to tissue damage and multi-organ failure. Neurological involvement represents the most severe manifestation, often resulting in acute or relapsing encephalitis with long-term sequelae among survivors. Despite the severity of the disease, no licensed antiviral therapies or human vaccines are currently available. Therapeutic development has focused on neutralizing monoclonal antibodies targeting viral glycoproteins and small-molecule antivirals that inhibit viral RNA synthesis, both of which show promising results in preclinical models, but remain limited by timing and translational challenges. In parallel, several vaccine platforms—including viral vectors, mRNA-based constructs, and recombinant protein subunits—have advanced to early-phase clinical trials, demonstrating encouraging immunogenicity. Beyond biomedical interventions, effective outbreak containment relies on integrated public health strategies. The “Kerala model” highlights the importance of rapid case identification, isolation, contact tracing, and community engagement within a One Health framework to mitigate transmission and reduce mortality. This review synthesizes the current knowledge on NiV pathogenesis, immune evasion, clinical manifestations, and emerging therapeutic and vaccine strategies, while highlighting critical gaps and future directions for improving the preparedness and response to this high-consequence emerging pathogen. Full article

Alphaviruses are mosquito-borne viruses that can infect the central nervous system (CNS) and cause encephalomyelitis, which is a rare but dangerous complication from infection. In mice, this can be studied in a model of infection with Sindbis virus (SINV), which infects neurons and causes neurological disease. Due to the non-renewable nature of neurons, the immune response in the CNS is specialized to prevent neuronal damage or death, even if they are infected. Therefore, insights into the nuances of antiviral immunity in the CNS provide a better understanding of disease pathogenesis and mechanisms of recovery. Type I interferons (IFNs) are critically important for survival; they are an innate antiviral defense mechanism that consists mainly of IFNα and IFNβ. Although both use the same receptor, type-specific differences between IFNα and IFNβ have been described in other contexts. To this end, Ifnb^−/− mice were used to elucidate the role of IFNβ in recovery from alphavirus encephalomyelitis. IFNβ-deficient mice have intact IFNα expression and downstream signaling, but symptomatic disease occurs earlier and is more severe. This is accompanied by increased virus replication in the early stages of infection. Microgliosis is reduced in Ifnb^−/− mice compared to wildtype, but inflammatory cytokine/chemokine levels are higher and associated with alterations in monocyte and NK cell recruitment into the CNS. Ifnb^−/− mice have no deficiencies in the expression of factors known to be required for viral clearance. Therefore, IFNβ modulates the early stages of the immune response and facilitates restriction of virus replication, contributing to delayed disease onset. Full article

The efficacy of the host antiviral response against Influenza A virus (IAV), a leading cause of global pandemics, hinges upon the rapid recognition of the pathogen and the prompt activation of immune mechanisms. Nevertheless, the epigenetic landscape that orchestrates this antiviral response remains largely elusive. Here, we identify histone demethylase JMJD2D as a critical regulator in defense against IAV infection. A significant upregulation of JMJD2D expression was observed clinically in response to IAV infection, indicating that JMJD2D may play a role in regulating IAV infection. Indeed, JMJD2D-deficient mice exhibit increased susceptibility to IAV, characterized by elevated viral loads, severe lung tissue damage, and reduced survival rates, suggesting that JMJD2D plays an essential role in defense against IAV infection. Consistently, knockdown or pharmacological inhibition of JMJD2D in lung cells suppressed IAV replication and the IAV-triggered innate immune response. Mechanistically, JMJD2D suppressed IAV infection by removing H3K9me3 at the promoter region of retinoic acid inducible gene-I (RIG-I) and cooperating with NF-κB to enhance the expression of RIG-I, a critical sensor for IAV RNA. This study identifies JMJD2D as an epigenetic rheostat that governs RIG-I-mediated antiviral signaling, highlighting its potential as a therapeutic target for mitigating severe IAV infection. Full article

Manganese ions (Mn²⁺) are an essential trace element within organisms spanning the entire tree of life. It has reported that Mn²⁺ exerts strong immunocompetence effects and exhibits antiviral effects against various human and animal viruses, including DNA and RNA viruses. Recently, Mn²⁺ has been found to be involved in the activation of the innate immune DNA-sensing cyclic GMP-AMP synthase (cGAS) stimulator of interferon genes (STING) pathway and subsequent antiviral function. However, the antiviral mechanism of Mn²⁺ remains unclear. In the current study, the results suggest that the cGAS-STING pathway is essential for Mn²⁺ to promote interferon (IFN) signaling, but it is not essential for triggering antiviral functions. After knocking out the STING or interferon regulatory factor 3 (IRF3) gene, Mn²⁺ still retains its antiviral activity against herpes simplex virus type 1 (HSV-1) and vesicular stomatitis virus (VSV). Furthermore, the results from transcriptomic analysis indicate that Mn²⁺ can induce a significant change in the apoptotic process in STING⁻/⁻ 3D4/21 cells. Mn²⁺ can induce cell apoptosis through the oxidative stress pathway, and inhibiting the apoptotic signal could suppress Mn²⁺-mediated antiviral activity in STING⁻/⁻ 3D4/21 cells. Additionally, dual knockout of IRF3 and caspase3, resulting in concurrent loss of IFN and apoptotic signals, eliminates the antiviral effects of Mn²⁺. In summary, the current study suggests that Mn²⁺ could exert antiviral effects not only through the cGAS-STING-IFN pathway but also via the reactive oxygen species (ROS)-apoptosis pathway. Full article

Dendritic cells (DCs) integrate innate immune sensing with adaptive immune priming through coordinated transcriptional programs that regulate antiviral defense, inflammatory signaling, and antigen presentation. However, the hierarchical organization and interdependence of these pathways following stimulation remain incompletely defined. Here, we performed an in silico re-analysis with full reproducibility of publicly available RNA-sequencing data (GSE108526) to characterize the temporal architecture and associations of immune transcriptional modules in human dendritic cells at 6 h and 16 h following innate immune activation. Principal component analysis revealed stimulation status as the dominant source of transcriptomic variance. Differential expression analysis confirmed robust induction of interferon-stimulated genes (ISGs) alongside modulation of inflammatory mediators and antigen presentation-associated genes. Module-level quantification showed that interferon signaling constituted the primary early transcriptional axis, whereas inflammatory cytokine programs displayed moderate induction and antigen presentation-associated genes exhibited distinct temporal dynamics. Association analysis demonstrated strong relationships between CIITA and downstream MHC class II genes, supporting coordinated antigen presentation regulation, while relationships between interferon and inflammatory modules were positive but non-proportional, indicating partial modular independence. Collectively, these findings reveal a structured yet non-uniform transcriptional organization in stimulated human dendritic cells, characterized by dominant interferon responses accompanied by context-dependent inflammatory activation and differentially associated antigen presentation programs. This integrative framework provides a reproducible systems-level approach for dissecting immune transcriptional architecture in human dendritic cell activation. Full article

Background: Hepatitis B virus (HBV) infection continues to be a major public health concern, especially in sub-Saharan Africa, where widespread epidemics and restricted availability of long-term antiviral therapies result in higher mortality and morbidity rates. Drug repurposing represents a strategic approach to accelerate the discovery of effective therapies by leveraging agents with demonstrated antiviral and immunomodulatory activity. Product Nkabinde (PN) is a patented African polyherbal formulation initially developed for the treatment of HIV. Recent experimental studies demonstrate PN’s potent anti-HIV activity and significant immunomodulatory effects in human immune cells, implicating host-directed mechanisms relevant to chronic viral infections. This study combines an integrative application of network pharmacology and molecular docking to evaluate the repurposing potential of PN as a multi-target agent in HBV. Method: Bioactive components of PN were screened, and compound-associated targets were intersected with HBV-associated genes (proteins) to construct a protein–protein interaction (PPI) network. Topological analysis identified 10 hub targets (STAT1, STAT3, SRC, HCK, EGFR, SYK, PIK3CA, PIK3CB, PIK3R1, and PTPN11). Gene Ontology and KEGG pathway enrichment were performed with an FDR cut-off < 0.05. Significantly enriched pathways included JAK–STAT signaling, chemokine signaling, EGFR-TKI resistance, PI3K complex signaling, and viral infection pathways, particularly those related to Kaposi sarcoma virus and HSV-1, indicating immunoregulatory and antiviral roles. Molecular docking was performed using AutoDock Vina 1.1.2 to evaluate binding affinity and interaction mode of key PN phytochemicals against the hub proteins, and results were compared to their respective co-crystallized ligands. Results: Molecular docking indicated that major phytochemicals from PN exhibited significant binding affinities across all 10 hub host targets, typically outperforming or closely matching their respective co-crystallized ligands. The strongest contacts were observed for β-sitosterol–PIK3CB (−14.2 kcal/mol) and oleanolic acid–SYK (−14.0 kcal/mol), which were significantly stronger than the co-crystallized ligands (−7.9 and −8.3 kcal/mol, respectively), indicating robust stabilization within catalytic and regulatory pockets. Procyanidin B2 toward HCK (−10.5 vs. −7.9 kcal/mol) and PIK3CA (−9.5 vs. −7.3 kcal/mol), quercetin toward PIK3R1 (−10.6 vs. −8.2 kcal/mol) and PTPN11 (−9.2 vs. −7.5 kcal/mol), rutin toward SRC (−10.5 vs. 7.8 kcal/mol), and diosgenin toward EGFR (−9.4 vs. 8.4 kcal/mol). Procyanidin B2 maintained robust multi-hydrogen bonding networks, demonstrating significant binding, despite STAT1 and STAT3 docking showing identical affinities to co-crystals. Conserved hydrogen bonds, π–cation interactions, and significant hydrophobic packing at ATP-binding clefts and regulatory domains supported these interaction patterns, indicating competitive suppression of host signaling nodes taken over by HBV. Conclusions: Together, these results demonstrate that the components of PN possess strong multitarget binding capabilities across the PI3K/AKT, JAK–STAT, SRC-family kinase, EGFR, and SYK pathways, supporting their potential repurposing as host-directed HBV therapeutics with the ability to impede immune evasion, viral persistence, and HBV-associated oncogenic progression. Full article

Clinically robust molecular biomarkers for depression have remained elusive, despite extensive transcriptomic research. This gap is consequential: depression is prevalent and heterogeneous, yet objective measures to quantify burden, stratify patients, and track recovery remain limited. Here, we review evidence that intron retention (IR) can serve as a homeostatic state variable—and therefore a sensitive biomarker—reporting stress adaptation and recovery at an upstream regulatory layer, often preceding or outperforming differential gene expression (DEG) readouts. Mechanistically, IR enables bidirectional fine-tuning of effective gene output: increased IR (IncIR) can throttle output under overload, whereas decreased IR (DecIR) releases this brake to restore gene output. Because these shifts are reversible and treatment-responsive, IR signatures can function not only as disease markers but also as pharmacodynamic metrics for blood-based monitoring of drug response and recovery. To evaluate the clinical utility of IR, we use depression as a proof of concept and focus on two interventions: (i) the Kampo formula hangekobokuto (HKT), which is associated with IR normalization consistent with reduced peripheral inflammatory load; and (ii) ketamine, where IR patterns measured before ketamine treatment in non-responders are linked to stronger innate-immune/antiviral activity, suggesting a higher inflammatory load that may limit treatment benefit. Finally, we discuss transdiagnostic extensions beyond depression, using early cognitive decline (mild cognitive impairment, MCI) as a stringent, biologically distal test case for blood-based IR/DI readouts and motivating independent cohort replication and longitudinal validation. Full article

In this paper, we present a mathematical analysis of within-host CHIKV dynamics by developing and studying a novel delay differential equation model that incorporates persistent infected monocytes, discrete time delays, and an antibody-mediated humoral immune response. The model includes five compartments: susceptible monocytes, persistent infected monocytes, actively infected monocytes, CHIKV pathogens, and neutralizing antibodies. To reflect key biological latencies, we introduce four distinct discrete delays accounting for the periods between viral entry and the emergence of infected cell populations, intracellular virion production, and antibody activation. We analyze the model, establishing the positivity, boundedness, and invariance of solutions, and derive the basic reproduction number ${\mathcal{R}}_0$ via the next-generation matrix method. Using Lyapunov functions and LaSalle’s Invariance Principle, we prove a threshold dynamic: the infection-free equilibrium is globally asymptotically stable (GAS) when ${\mathcal{R}}_0\le 1$, while a unique endemic equilibrium is GAS when ${\mathcal{R}}_0>1$. Numerical simulations validate the analytical results and illustrate threshold behavior. A detailed local sensitivity analysis of ${\mathcal{R}}_0$ identifies the most influential parameters, offering theoretical insights into potential intervention strategies. We further investigate the effects of antiviral therapy as a theoretical intervention, deriving a treatment-dependent reproduction number and the critical drug efficacy required for eradication, and explore how the intracellular production delay can itself serve as a critical threshold for infection clearance. The study provides a rigorous theoretical framework that highlights the roles of latency, immune response, and biological delays in CHIKV pathogenesis and offers qualitative insights that may inform future experimental and treatment design studies. Full article

Encephalomyocarditis virus (EMCV) belongs to the genus Cardiovirus of the family Picornaviridae. It is a non-enveloped, positive-sense, single-stranded RNA virus and an important pathogen causing encephalomyocarditis (EMC). Tripartite motif 13 (TRIM13) is a member of the tripartite motif (TRIM) family and serves as an important effector molecule in antiviral innate immunity. However, its antiviral activity and underlying molecular mechanisms during EMCV infection remain unknown. In this study, we identified TRIM13 as a regulator of NF-κB activation. TRIM13, dependent on its E3 ubiquitin ligase activity, directly binds to IκBα and dose-dependently increases its phosphorylation level. To determine the chain type of IκBα polyubiquitination, antibodies specific for K48-linked and K63-linked ubiquitin were used. Our data indicated that IκBα was subjected to polyubiquitination independent of K48 and K63 linkages. This interaction promotes non-K48/K63-linked polyubiquitination of IκBα, thereby inducing NF-κB nuclear translocation. Subsequently, nuclear NF-κB activates the secretion of pro-inflammatory cytokines, exacerbating inflammatory responses and ultimately facilitating EMCV infection. Full article

Orf virus (ORFV) is a globally distributed zoonotic parapoxvirus that causes a highly contagious mucocutaneous disease in small ruminants. Despite the urgent demand for vaccination-based control, no licensed vaccines are currently available universally. In this study, we generated two recombinant Sendai virus (SeV) vectors expressing ORFV 011 (rSeV-GFP-B2L) and ORFV 059 (rSeV-GFP-059) genes and evaluated their ability to stimulate antiviral responses in vitro. Following the transduction, we assessed transgene expression, innate immune activation, induction of interferon-stimulated genes (A3Z1, OBST2, SAMHD1), and antiviral activity. Both vectors significantly upregulated pattern recognition receptors (TLRs, RIG-I) and type I interferon (IFN-β) genes, with rSeV-GFP-059 inducing the strongest response. Remarkably, OBST2 was robustly upregulated, suggesting a potential role in restricting ORFV replication. Antiviral activity assays revealed a marked reduction in ORFV DNA copies and a mild decrease in ORFV RNA transcription in rSeV-GFP-059-transduced cells, particularly at later time points, accompanied by complete abrogation of the typical cytopathic effect. Collectively, these results demonstrate that SeV-based vectors, particularly rSeV-GFP-059, efficiently prime antiviral immunity and suppress ORFV replication, establishing a promising platform for further in vivo vaccine evaluation in sheep. Full article

Context/Objectives: In patients with COPD (chronic obstructive pulmonary disease), SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection represents an overlap of viral injury on a lung already affected by pathological mucus, altered mucociliary clearance, chronic inflammation, and impaired antiviral immunity. Methods: A focused narrative review (2020–2025) was conducted using clinical, experimental, and consensus evidence. The evidence was synthesized qualitatively, with priority given to cohort studies, meta-analyses, and mechanism-focused studies with clinical relevance. Results: Mucus obstruction (“mucus plugs”) is frequent in COPD (41–67%) and is associated with unfavorable outcomes. COPD also increases the risk of post-COVID respiratory sequelae. Bacterial coinfection at presentation is uncommon (3–5%), whereas secondary bacterial infections are more frequent (14–18%), especially in severe disease requiring intensive care, where VA-LRTI/VAP (ventilator-associated lower respiratory tract infection/ventilator-associated pneumonia) become predominant. Sepsis, whether viral or mixed, reflects disease severity and may contribute to functional decline and susceptibility to reinfections; however, the concept of a post-acute “sepsis legacy” in COPD after COVID-19 should currently be regarded as a clinically plausible but still emerging hypothesis rather than an established COPD-specific outcome. During recovery, acute exacerbation risk rises to 5.6% versus 3.9%, peaking in the first 30 days after severe disease (aHR ≈ 8.14). Persistent dyspnea and reduced DLCO (diffusing capacity for carbon monoxide) suggest ARDS-related injury, tissue remodeling, and microvascular dysfunction. Conclusions: In COPD, post-COVID respiratory sequelae result from the interaction of mucus, immunity, and infectious/sepsis-related complications. The first post-discharge month is a critical period requiring careful risk stratification and targeted follow-up. Full article