Search Results (117)

VISA/MAVS is a central signaling hub that links viral RNA sensing to type I interferon production and inflammatory responses. Because of its potent signal-amplifying capacity, VISA activity must be precisely controlled: insufficient activation compromises antiviral defense, whereas excessive or spontaneous activation can drive chronic inflammation and autoimmune disease. Recent studies have revealed a complex regulatory network governing VISA signaling, involving post-translational modifications, dynamic protein interactions, selective degradation pathways, metabolic cues, and intrinsic inhibitory mechanisms that collectively determine its activation threshold, signaling duration, and downstream output. In this review, we discuss the molecular mechanisms that regulate VISA activation, signal propagation, signal termination, and quiescence maintenance under resting conditions. We propose that immune homeostasis is achieved not through a simple on–off switch, but through continuous regulation of the VISA signalosome life cycle. This framework provides an integrated view of VISA and offers new insights into the molecular mechanisms underlying immune homeostasis. 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

Background: Measles, mumps, rubella (MMR) and varicella vaccines are often co-administered to optimize coverage, yet safety concerns regarding febrile convulsions persist. In South Korea, MMR and varicella vaccines are administered as separate injections during a single visit (MMR + V). This study evaluated the real-world safety of concurrent MMR + V vaccination, focusing on the domestically implemented MAV/06 and Oka-derived strains. Methods: We conducted a multicenter self-controlled case series (SCCS) study of children aged 12–23 months who received MMR + V and hepatitis A vaccine (HAV) between 2015 and 2024. Using electronic health records, we identified predefined adverse events (AEs), including fever and healthcare visits. Adjusted relative risks (aRRs) were estimated using conditional Poisson regression. Results: Among 3035 children (52.3% male; median age, 12 months), 71.7% received the MAV/06 varicella strain. A distinct peak in AEs occurred 7–13 days after MMR + V administration, with fever showing the greatest increase (aRR, 4.27; 95% CI, 2.76–6.60). The risks of total sick visits (aRR, 2.15; 95% CI, 1.70–2.71) and acute care visits (aRR, 2.13; 95% CI, 1.46–3.10) were similarly confined to this interval and returned to baseline thereafter. Febrile convulsions were uncommon (aRR, 5.37; 95% CI, 1.20–24.01). No excess risks were observed during the HAV or overlap periods, and no synergistic effects of intensive multi-vaccine administration were detected. Conclusions: Concurrent administration of MMR and varicella vaccines in Korean infants—predominantly using the MAV/06 strain—was associated only with expected, transient increases in fever during days 7–13 postvaccination. No serious or sustained safety signals were identified, supporting the continued use of Korea’s separate-injection MMR + V strategy. Full article

Persistence of human papillomavirus (HPV) infection leading to cervical carcinogenesis can be attributed to the action of high-risk HPVs, but there are still some unclear factors involved in the mechanisms of either viral clearance or persistence. Although many infections may be self-limiting and cleared successfully by the immune response of the infected individuals, other infections result in persistent HPV infection. Recent studies indicate that microbiota in the gut and cervicovaginal tract modulate host immune status, mucosal inflammation, and epithelial barrier integrity. All these factors determine susceptibility to persistent infection. Inflammation, overproduction of reactive oxygen species (ROS), genomic instability, and impaired antiviral transcription pathways are associated with dysbiosis. In parallel, redox imbalance contributes to mitochondrial dysfunction, impairing mitochondrial antiviral signaling (MAVS)-dependent interferon responses and attenuating induction of interferon-stimulated genes. Additionally, extracellular vesicles (EVs) further promote immune evasion, metabolic programming, and epigenetic regulation by facilitating the intercellular exchange of viral constituents, microRNAs, and signaling molecules. Through this interconnected network of mechanisms, microbial dysbiosis, mitochondrial disruption, and EV signaling collectively shape a niche conducive to persistence. Unlike previous reviews that primarily examine microbiome alterations, oxidative stress (OS), mitochondrial dysfunction, extracellular vesicles, or immune responses as separate processes, this review integrates clinical and omics findings into a systems-based conceptual framework of HPV persistence. By emphasizing the potential interactions among these interconnected biological systems, we aim to identify points of biological convergence, generate mechanistic hypotheses, and highlight opportunities for future biomarker development and therapeutic intervention. Full article

Chikungunya virus (CHIKV) is an alphavirus that infects dermal fibroblasts as a primary target cell during natural mosquito-borne transmission. While primary human dermal fibroblasts (hDFs) have been implicated as a key source of type I interferon (IFN-I) during CHIKV infection, the dynamics of this response and its sufficiency for antiviral protection remain incompletely understood. Here, we systematically characterize in vitro CHIKV infection of primary hDFs, evaluating the effects of single-passage viral stock origin (mammalian- vs. mosquito-propagated), donor variability, and multiplicity of infection (MOI) on infection kinetics and innate immune induction. We demonstrate that hDFs support high-titered CHIKV replication at both MOI 1 and 0.01, resulting in universal cell death by 72 hpi despite robust IFNβ transcript induction—reaching up to ~2800-fold over mock—and secretion of pro-inflammatory cytokines, including IFNα2, TNFα, IL-1β, and IL-8. Notably, IFNβ protein levels remained below 10 pg/mL under all infection conditions, revealing a disconnect between transcriptional and translational responses, suggesting CHIKV-mediated translational suppression. Pharmacological inhibition of TBK1/IKKε via amlexanox did not suppress IFNβ transcript induction at any tested concentration, suggesting that canonical PRR signaling through this node—including both RIG-I/MAVS and TLR3/TRIF pathways—is not the major driver of the observed transcriptional response. In contrast, co-inoculation with exogenous IFNβ as low as 20 pg/mL activated IFNAR signaling, robustly upregulated interferon-stimulated genes (ISGs), and fully rescued hDFs from otherwise lethal infection. Together, these findings demonstrate that CHIKV-infected hDFs mount a transcriptionally robust but translationally insufficient innate immune response and that the transcriptional response appears to operate independently of TBK1/IKKε. These results have direct implications for understanding how the skin microenvironment may modulate early CHIKV pathogenesis and suggest that paracrine IFNβ signaling from neighboring cell types may be critical for fibroblast survival during natural infection. Full article

Surface electromyography (sEMG) signals are important for assessing muscle activity, neuromuscular behavior, and movement stability. sEMG signals are widely used in athlete performance monitoring and human–machine interface applications. However, existing methods have limitations in classification, accuracy and generalization across users. In this study, a real-world dataset was generated from 30 professional wrestlers using an 8-channel system based on 10 physical movements and technical elements. Nine time-domain and energy features, mean absolute value (MAV), integrated EMG (IEMG), root mean square (RMS), simple square integral (SSI), fourth power (4POW), wavelength (WL), difference absolute standard deviation (DASDV), variance (VAR), and average amplitude change (AAC), were systematically evaluated separately and in combination. Five classifiers were compared: Logistic Regression (LR), Support Vector Machine (SVM), Random Forest (RF), k-Nearest Neighbor (KNN), and Neural Networks (NNs). The models were evaluated for accuracy, sensitivity, specificity, positive predictive value, and F1-score. The generalization ability was analyzed through cross-subject (24/6) and cross-session validation protocols. The nine feature combinations achieved the highest classification accuracy of 97.8% with the RF algorithm. The proposed approach can serve as a practical basis for real-time muscle activity monitoring, movement classification, and rehabilitation systems. Full article

Parainfluenza virus 5 (PIV5) can establish persistent infections in host cells despite encountering innate immune defenses, including the complement (C′) system. The host determinants that enable persistently infected cells (PI) to evade C’-mediated clearance remain largely undefined. Here, we identify the mitochondrial antiviral signaling (MAVS) protein, a central adaptor in double-stranded RNA-triggered antiviral and pro-survival signaling pathways, as a critical mediator of both PIV5 persistence and acquired resistance to C’ lysis. Wild-type (WT) PIV5-infected A549 cells were initially sensitive to C’-directed killing, but these cells rapidly establish a PI in culture with ~25% of the cell population becoming resistant to C’ lysis by day 2 and ~75% by day 4. In contrast, PIV5-infected A549 MAVS-deficient (MAVS KO) cells exhibited elevated viral gene expression, increased deposition of C3 and the membrane attack complex, and were more susceptible than WT cells to C′ killing. PIV5-infected MAVS KO cells showed rapid cytopathic effects and never established a stable PI. While pharmacological suppression of viral gene expression with ribavirin (RBV) restored the survival of PIV5-infected MAVS KO cells into a long-term PI-like state, these RBV-induced PI cells remained sensitive to C’ lysis. Collectively, these findings demonstrate a role of MAVS in modulating a PIV5 infection in culture, to facilitate both the conversion of a PIV5 acute infection to a PI and development of resistance to C’ killing. Full article

The mitochondrial anti-viral signaling protein, MAVS, is a central regulator of innate anti-viral immunity. Recently, we demonstrated that MAVS is overexpressed in cancer, where its downregulation resulted in reduced cell proliferation and the expression and nuclear translocation of proteins associated with transcriptional regulation and inflammation. In this study, we demonstrate that CRISPR/Cas9-mediated MAVS depletion in PC-3 prostate cancer cells suppresses proliferation, disrupts immune evasion, and alters the tumor microenvironment. Proteomic profiling of the MAVS-KO cells by LC-MS/MS revealed changes in the expression of proteins associated with immunity, cell signaling, mitochondrial function, metabolism, protein synthesis and degradation, and epigenetic regulation. In contrast to MAVS-expressing cells, MAVS-KO cells implanted subcutaneously in mice formed very small tumors. This inhibited tumor growth was linked to reduced proliferation, and enhanced apoptosis, as indicated by strong TUNEL staining and elevated activated caspase-3. Importantly, the small “tumors” derived from MAVS-KO cells displayed a distinct morphology: diminished cancer stem-cell populations, an altered tumor microenvironment and inflammatory response, increased immune cell infiltration, and reduced PD-L1 expression. Together, these findings establish MAVS as a key mediator of cancer-cell survival, inflammation, and immune regulation, and, thus, its upregulation in tumors makes it a potential anti-cancer target. Full article

Human papillomavirus type 16 (HPV16) persistence relies on early viral mechanisms that synchronize oncogenic signaling with immune evasion, with the E5 oncoprotein serving as a central regulator of the viral cycle and the initiation of cell transformation. This review integrates current evidence on how E5 reconfigures host cell dynamics: first, by hijacking signaling pathways such as EGFR, MAPK/ERK, and PI3K/AKT to drive keratinocyte proliferation and survival; and second, by organizing a multi-step immune evasion strategy. We detail how E5 suppresses innate antiviral responses, specifically by repressing IFN-κ and IFN-β via interference with IRF1, TGF-β/SMAD, STING, and MAVS signaling. Simultaneously, E5 interferes with the adaptive immunity by disrupting MHC-I trafficking and impairing MHC-II maturation. Furthermore, preclinical studies utilizing various vaccine platforms targeting HPV16 E5 have demonstrated the capacity to reduce tumor burden and significantly increase survival rates. By integrating these molecular and immunological checkpoints, we highlight the role of E5 in sustaining viral persistence and underscore its potential as a high-value target for next-generation immunotherapeutic and vaccine-based strategies. Full article

Hepatitis C virus (HCV) chronically infects over 50 million people worldwide and poses a significant risk to global health. The HCV NS3/4A complex, a bifunctional enzyme comprising a protease and a helicase domain, is indispensable for viral replication and immune evasion, making it a pivotal target for direct-acting antiviral agents (DAAs). Here, we summarize its structural features, functional mechanisms, and implications in drug design and protein engineering (e.g., nanopore sequencing applications). The NS3 protease domain is activated by the NS4A cofactor, which mediates viral polyprotein processing and relies on a zinc-binding site for structural stability. The C-terminal helicase domain catalyzes ATP-dependent 3′→5′ unwinding, and allosteric crosstalk between the protease and helicase domains dynamically modulates the enzymatic activity, balancing unwinding velocity and processivity. Beyond supporting viral replication, NS3/4A cleaves MAVS to abolish RIG-I/MDA5 signaling but spares TRIF, leaving TLR3-mediated immunity intact; it also modulates host lipid and iron metabolism, contributing to HCV pathogenesis. Notably, structural and functional studies of NS3/4A lay a solid theoretical foundation for developing novel therapeutic strategies. Currently, DAAs targeting NS3/4A have achieved high sustained virologic response rates; however, resistance-associated substitutions remain a major clinical challenge, particularly in genotype 3 infections. Emerging therapeutic strategies targeting NS3/4A include allosteric inhibition and proteolysis-targeting chimeras (PROTACs)-mediated degradation. Full article

Estimating the relative position and velocity of micro aerial vehicles (MAVs) using visual signals is a critical issue in numerous tasks. However, traditional relative motion estimation algorithms suffer severely from non-Gaussian noise interference and have limited observability, making it difficult to meet the practical requirements of complex dynamic scenarios. To address this dilemma, this paper proposes a Multimodal Decoupled Spatiotemporal Adaptive Network (MDSAN). Designed for air-to-air scenarios, MDSAN achieves high-precision relative pose and velocity estimation of dynamic MAVs while overcoming the observability limitations of traditional algorithms. In detail, MDSAN is collaboratively composed of two core sub-modules: Modality-Specific Convolutional Normalization (MSCN) blocks and Spatiotemporal Adaptive State (STAS) blocks. Specifically, MSCN uses custom convolution kernels tailored to three modalities—visual, physical, and geometric—to separate their features. This prevents interference between modalities and reduces non-Gaussian noise. STAS, built on a state-space model, combines two key functions: it tracks long-term MAV motion trends over time and strengthens the synergy between different modal features across space. Adaptive weights balance these two functions, enabling stable estimation, even when traditional methods struggle with low observability. Furthermore, MDSAN adopts a full-vision multimodal fusion scheme, completely eliminating the dependence on wireless communication and reducing hardware costs. Extensive experimental results demonstrate that MDSAN achieves the best performance in all scenarios, significantly outperforming existing motion estimation algorithms. It provides a new technical path that balances high precision, high robustness, and cost-effectiveness for technologies such as MAV swarm perception. Full article

Surface electromyography (sEMG) is widely used for decoding motion intent in prosthetic control and rehabilitation, yet the impact of external load on sEMG-to-kinematics mapping remains insufficiently characterized, particularly for wrist flexion-extension This pilot study investigates wrist angle estimation (0–90°) under four discrete counter-torque levels (0, 25, 50, and 75 N·cm) using a multilayer perceptron neural network (MLPNN) regressor with mean absolute value (MAV) features. Multi-channel sEMG was acquired from three healthy participants while performing isotonic wrist extension (clockwise) and flexion (counterclockwise) in a constrained single-degree-of-freedom setup with potentiometer-based ground truth. Signals were filtered and normalized, and MAV features were extracted using a 200 ms sliding window with a 20 ms step. Across all load levels, the within-subject models achieved very high accuracy (R² = 0.9946–0.9982) with test MSE of 1.23–3.75 deg²; extension yielded lower error than flexion, and the largest error was observed in flexion at 25 N·cm. Because the cohort is small (n = 3), the movement is highly constrained, and subject-independent validation and embedded implementation were not evaluated, these results should be interpreted as a best-case baseline rather than evidence of deployable rehabilitation performance. Future work should test multi-DoF wrist motion, freer movement conditions, richer feature sets, and subject-independent validation. Full article

Upon RNA virus infection, viral RNA is sensed by the RIG-I-like receptors (RLRs), which signal through the adaptor protein VISA/MAVS to induce an innate antiviral response. How the VISA-mediated innate antiviral response is regulated and whether it can be targeted for drug development against diseases caused by RNA virus infection needs to be further investigated. Here we report that physalin F, a natural secosteroid isolated from Physalis angulata L., inhibits innate immune response to RNA virus. Mechanistically, physalin F binds to and promotes the activation of the mitochondrial m-AAA protease AFG3L2, which subsequently mediates the degradation of VISA. Knockdown of AFG3L2 promotes RLR-mediated innate antiviral signaling, whereas physalin F inhibits innate immune response to RNA virus both in cells and mice. Our study discovers physalin F as an inhibitor of VISA-mediated innate antiviral response as well as a candidate compound for the treatment of related diseases. More importantly, our findings suggest that AFG3L2 constitutively mediates degradation of VISA under physiological conditions, which represents a novel negative regulatory mechanism of RLR-mediated innate antiviral response. Full article

Background: Infectious bronchitis virus (IBV) poses a significant threat to poultry health, and exploring effective antiviral agents is of considerable importance. This study aimed to investigate the antiviral activity of baicalin against IBV and its underlying immunomodulatory mechanisms. Methods: The antiviral effect of baicalin was evaluated in chicken embryo kidney cells using various treatment schedules. Viral replication was assessed through nucleocapsid protein expression and viral titers. Mechanistic studies involved analysis of key signaling pathways, IRF3 knockdown experiments, and proteasomal degradation assays. Results: Baicalin (20 µg/mL) significantly inhibited IBV replication, with optimal efficacy observed when administered at 2 h post-infection. The compound demonstrated time-dependent regulation of antiviral and inflammatory pathways, enhancing the MDA5-MAVS-STAT1 axis and IFN-β signaling at late infection stage while showing biphasic modulation of NF-κB pathway. IRF3 was identified as essential for both anti-inflammatory and antiviral effects. Baicalin enhanced IκBα stability by inhibiting its proteasomal degradation. Conclusions: Baicalin suppresses IBV replication through coordinated enhancement of type I interferon response and temporal regulation of NF-κB pathway, with IRF3 serving as a key regulatory molecule. These findings provide mechanistic support for baicalin’s potential as an anti-IBV therapeutic agent. Full article

Enterovirus A71 (EV-A71) is a critical global pathogen, primarily causing Hand-Foot-and-Mouth Disease (HFMD) but frequently leading to severe neurological complications, including fatal neurogenic pulmonary edema (PE). This review elucidates the complex interplay between viral pathogenesis and the host immune response. EV-A71 utilizes receptors like SCARB2 and PSGL-1 for entry, while its proteases (2A^pro, 3C^pro) efficiently evade innate immunity by cleaving key signaling adaptors (MAVS, TRIF), suppressing Type I IFN response. Critical to disease progression is the age-dependent vulnerability in infants and the subsequent shift toward immunopathology. Severe disease is driven by a systemic cytokine storm and T cell dysregulation, characterized by a loss of control from Treg cells and a profound Th17/Treg imbalance, resulting in high levels of pathogenic cytokines (e.g., IL-17A, IFN-γ). Clinical progression is predicted by specific biomarkers, including Treg depletion, monocyte exhaustion (PD-1/PD-L1), and suppressed regulatory signaling (low cAMP). These findings highlight that effective therapeutic strategies must target host-mediated damage through immunomodulation (e.g., by exploring interventions against key pathogenic axes like IL-6 and IL-1β) and call for the development of next-generation vaccines capable of eliciting balanced cellular immunity to prevent immunopathology. Full article