Search Results (341)

Toxin–antitoxin (TA) modules represent sophisticated regulatory networks that have evolved from simple plasmid maintenance factors into multifunctional genetic modules orchestrating bacterial stress responses, pathogenesis, and ecological adaptation. This review highlights a compelling correlation between the abundance of toxin–antitoxin (TA) modules and bacterial pathogenicity, as exemplified by Mycobacterium tuberculosis (M.tb), which encodes 118 TA loci—significantly more than the fewer than 10 found in closely related saprophytic species. The clinical significance of TA modules extends beyond traditional stress response roles to encompass antimicrobial persistence, where systems like VapBC and MazEF facilitate dormant subpopulations that survive antibiotic therapy while maintaining chronic infections. Recent discoveries have revealed TA modules as sophisticated bacterial defense mechanisms against bacteriophage infection, with DarTG and ToxIN systems representing novel antiviral immunity components that complement CRISPR-Cas and restriction–modification systems. The immunomodulatory capacity of TA modules demonstrates their role in host–pathogen interactions, where systems such as VapC12 in M.tb promote macrophage polarization toward permissive M2 phenotypes while inducing anti-inflammatory cytokine production. Large-scale genomic analyses reveal that TA modules function as drivers of horizontal gene transfer networks, with their signatures enabling accurate prediction of plasmid community membership and serving as determinants of microbial community structure. The biotechnological applications of TA modules have expanded to include genetic circuit stabilization, biocontainment device construction, and multi-species microbial community engineering, while therapeutic strategies focus on developing multi-target inhibitors against conserved TA protein families as promising approaches for combating drug-resistant bacterial infections. The evolutionary conservation of TA modules across diverse bacterial lineages underscores their fundamental importance as central organizing principles in bacterial adaptation strategies, where their multifunctional nature reflects complex selective pressures operating across environmental niches and host-associated ecosystems. This review provides an integrated perspective on TA modules as dynamic regulatory elements that support bacterial persistence, immune evasion, and ecological versatility, establishing them as genetic elements with truly “many faces and functions” in prokaryotic biology. Full article

Previous studies have reported that Enterovirus A71 (EV-A71) infection could activate STING-related signaling pathways in vitro, but the role of STING in EV-A71 infection in vivo and the associated immune regulatory mechanisms remain unclear. Here, we used the STING-specific agonist diABZI to activate STING and STING-knockout mice to jointly study the role and mechanism of regulating STING on EV-A71 infection in vivo. The results showed that activating STING could inhibit the in vivo replication of EV-A71, alleviate clinical symptoms in infected mice, and increase the survival rate. Conversely, STING knockout significantly promoted viral replication in vivo and increased the lethality and severity of EV-A71 infection. Mechanistic studies further revealed that STING activation exerts its antiviral effects by stimulating interferon signaling pathways, upregulating the expression of interferon-stimulated genes (ISGs). Additionally, STING activation also modulated the serum cytokine response profile. Moreover, STING activation drove the expansion of diverse immune cell populations, including T cells, natural killer (NK) cells and myeloid cells. In contrast, STING knockout not only reduced the proportion of thymic T cells and impeded T cell developmental progression from double-positive (DP) to single-positive (SP) stages, but also impaired the effector functions of CD8+ T cells and NK cells during viral infection. In summary, this study demonstrates that STING activation effectively suppresses EV-A71 replication and mitigates infection symptoms by modulating immune and inflammatory responses. These findings provide a foundational framework for understanding how STING coordinates antiviral immunity and inform future investigations into STING-targeted therapies for viral infections. Full article

Chronic hepatitis B virus (HBV) infection is a major health problem that leads to approximately one million deaths every year worldwide. Mother-to-child transmission (MTCT) is the major cause of chronic HBV infection. HBV e antigen (HBeAg) is a secretory viral protein and modulates the immunological landscape of the newborn to promote HBV persistence. HBeAg actively reprograms innate and adaptive immunity. Mechanistically, HBeAg regulates macrophage polarization, suppresses dendritic cell and natural killer (NK) cell activities, impairs T cell and B cell functions, and promotes the expansion of myeloid-derived suppressor cells (MDSCs). These multifaceted effects contribute to immune tolerance and persistent HBV infection in the offspring of carrier mothers. Clinically, HBeAg status is a critical determinant for MTCT risk stratification and intervention, particularly in resource-limited settings. Despite advances in neonatal immunoprophylaxis and maternal antiviral therapy, residual transmission of HBV persists. Emerging approaches targeting HBeAg directly or restoring antiviral immunity offer promising avenues for breaking immune tolerance and achieving HBV elimination. This review summarizes current understanding of HBeAg-mediated immune modulation and highlights strategies that are being used to disrupt MTCT and treat HBV patients. Full article

Alphavirus chikungunya (CHIKV) is an arthropod-borne alphavirus of the Togaviridae family, transmitted primarily by Aedes aegypti and Ae. albopictus mosquitoes. CHIKV infection often results in debilitating manifestations that compromise quality of life and generate significant socioeconomic impacts. Recurrent epidemics in tropical and subtropical regions underscore the urgent need to better understand the host immune responses and their contribution to disease outcome. CHIKV establishes infection by overcoming the host’s initial immunological barriers. Innate immune cells, including fibroblasts, dendritic cells, macrophages, monocytes, neutrophils and natural killer (NK) cells, are among the first to respond to infection, ensuring a rapid antiviral defense and supporting the development of adaptive immune responses. However, excessive release of inflammatory mediators and prolonged infiltration of innate cells into joint tissues contribute to disease chronicity and the persistence of arthralgia. In this review, we provide a comprehensive synthesis of current evidence on innate cells that serve as targets for CHIKV infection, highlighting mechanisms that promote effective antiviral defense as well as those responsible for pathological inflammation and chronic disease and identifying key gaps that remain to be addressed. Full article

Porcine reproductive and respiratory syndrome (PRRS) is a highly contagious epidemic caused by the porcine reproductive and respiratory syndrome virus (PRRSV). Characterized by reproductive disorders in pregnant sows and respiratory symptoms in pigs of all ages, it poses a severe threat to the global swine industry. In recent years, the high mutation rate of PRRSV has increasingly limited the effectiveness of vaccines against it, prompting the search for new anti-PRRSV drugs. scutellarin (SCU), a natural flavonoid compound extracted from the medicinal plant Scutellaria baicalensis, possesses multiple biological activities. Its antiviral effects have been demonstrated in numerous studies; however, its inhibitory activity against PRRSV and the underlying mechanism remain unknown. In this study, through in vitro cell experiments, we found that scutellarin significantly inhibits PRRSV infection in PAMs. Furthermore, it directly acts on PRRSV to exert antiviral effects. Transcriptomic analysis suggests that scutellarin may exert its anti-PRRSV effects by regulating host immunity and anti-inflammation through immune-related signaling pathways, including the complement and coagulation cascades, ECM-receptor interaction, Rap1 signaling pathway, and PI3K-Akt signaling pathway. Full article

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a global health challenge, partly due to the prolonged duration and toxicity of standard antibiotic regimens. Adjunctive therapies that enhance antimicrobial efficacy and modulate host immunity are urgently needed. Curcumin, a natural bioactive compound derived from Curcuma longa, possesses broad therapeutic properties, including anti-inflammatory, antioxidant, antibacterial, and antiviral effects. This study evaluated the effects of curcumin in combination with first- and second-line antibiotics against Mtb in both in vitro and in vivo models. Our results demonstrated that curcumin exerts direct antibacterial activity against both the drug-sensitive H37Rv strain and a multidrug-resistant (MDR) clinical isolate. Furthermore, curcumin synergized with conventional antibiotics, enhancing bacterial clearance in infected macrophages while promoting the production of IL-12, a key cytokine in protective immune responses. In a murine model of progressive pulmonary TB, combination therapy with curcumin and first-line antibiotics significantly reduced the lung bacterial burden and improved behavioral outcomes compared to antibiotic treatment alone. These findings suggest that curcumin acts through both direct antimicrobial mechanisms and immune modulation, supporting its potential as an adjunctive therapy agent for TB. Future studies should focus on optimizing curcumin formulation, dosing, and bioavailability to facilitate the clinical translation of this compound. Full article

Natural killer (NK) cells are the main cytotoxic lymphocytes of the natural immune system, which play an important role in tumor immune surveillance and anti-viral response. The surface receptor NKG2D can recognize NKG2D ligands on the surface of tumor or metabolism-stressed cells, thereby activating immune responses and mediating cytotoxicity and anti-tumor activity of NK cells. However, NKG2D-positive NK cells are regulated by metabolites, and play a negative role in metabolic diseases. Various metabolites, including lipids, reactive oxygen species (ROS), glucose and amino acids, regulate NKG2D expression and NK cell activity and decide the immune microenvironment of pathological tissue. Thus, targeted therapies based on NKG2D-positive NK cell have entirely different strategies in the treatment of tumor or metabolic diseases. This article focuses on the metabolic regulation of NKG2D-positive NK cells and their opposite roles in disease progression, including of cancer and metabolic disease. In the future, in-depth studies of the regulatory mechanisms of the NKG2D signaling pathway by metabolites and the optimization of the safety and efficacy of targeted therapeutic strategies will lead to new breakthroughs in the treatment of tumors and metabolic diseases, providing patients with more effective treatment options. Full article

Background/Objectives: β-Carotene oxygenase-2 (BCO2) is a mitochondrial carotenoid-cleaving enzyme expressed in multiple tissues, including the lungs. While BCO2 regulates carotenoid handling, its role in shaping pulmonary immune architecture and antiviral responses is unknown. We hypothesized that BCO2 deficiency reprograms epithelial–innate circuits and alters antiviral outcomes. Methods: BCO2-knockout (KO) and C57BL/6J wild-type (WT) mice underwent lung single-cell RNA sequencing (scRNA-seq), immunoblotting, and intranasal SARS-CoV-2 challenge to assess cell-type heterogeneity, pathway programs (by gene set variation analysis, GSVA), and antiviral responses. Results: scRNA-seq resolved 14 major lung cell populations with cell-type-specific pathway shifts. Compared with WT, BCO2 KO lungs showed increased conventional dendritic cells and natural killer (NK) cells, with reductions in macrophages, B cells, and endothelial cells. In KO alveolar type II cells, GSVA indicated a stress-adapted metabolic program. Ciliated epithelium exhibited vitamin-K-responsive and axoneme-remodeling signatures with attenuated glucocorticoid and very-low-density lipoprotein remodeling. Innate lymphoid type 2 cells favored fatty acid oxidation and chromatin dynamics with reduced mitochondrial activity. NK cells were biased toward constitutive chemokine/cytokine secretion and counter-inflammatory signaling. Immunoblotting confirmed the elevated level of interferon regulatory factor-3 protein in BCO2-KO lungs. Functionally, BCO2-KO mice had improved outcomes after intranasal SARS-CoV-2 exposure. Conclusions: Loss of BCO2 reconfigures the pulmonary immune landscape and enhances antiviral responsiveness in mice. These findings identify BCO2 as a nutrient-linked enzyme with immunomodulatory impact and highlight cell-state changes as candidate mechanisms for improved antiviral tolerance. Full article

Bats are natural reservoirs for diverse viruses, yet they rarely develop disease, suggesting unique antiviral adaptations. In this study, we performed a comprehensive genome-wide analysis in the common vampire bat (Desmodus rotundus), integrating comparative genomics, functional annotation, microRNA (miRNA) discovery, target prediction, and network-based analyses. Comparative genomic analysis revealed that Phyllostomus discolor exhibits the highest protein homology (97.4%) with D. rotundus. Alignment of interferon regulatory factors (IRFs) indicated strong conservation of IRF1, IRF5, and IRF8, while IRF4 and IRF7 showed divergence, reflecting bat-specific modulation of interferon signaling. Functional annotation of previously uncharacterized proteins identified immune-related elements, including toll-like receptor 4, syncytin-1, and endogenous retroviral sequences, highlighting the integration of viral components into host immunity. We further identified 19 novel miRNAs in D. rotundus, with high-confidence target genes such as SOD2, TRIM28, and FGFR1 involved in antiviral defense, apoptosis regulation, and oxidative stress response. Functional enrichment analyses revealed processes associated with wound healing, apoptosis suppression, infection response, and longevity. Network entropy analysis highlighted central regulatory hubs, including MYC, BCL2, and KIF1B, influencing cell cycle, survival, and immune balance. Collectively, these results demonstrate that D. rotundus employs an integrated regulatory network combining conserved immune factors, lineage-specific gene divergence, and miRNA-mediated fine-tuning to achieve viral tolerance without pathology. This study expands our understanding of bat antiviral biology and provides candidate molecular targets for future functional and translational research. Full article

Background: Oncolytic virus (OV) therapy couples direct tumor lysis with systemic immune priming, yet clinical benefit remains heterogeneous and the predictive biomarker landscape is poorly defined. We undertook a systematic review and meta-analysis to quantify the efficacy and safety of OV therapy in solid tumors and to synthesize current evidence on response-modulating biomarkers. Methods: Following PRISMA 2020 guidelines, MEDLINE, Embase, Cochrane CENTRAL, ProQuest and Scopus were searched from inception to May 2025. Phase II–III randomized trials of genetically engineered or naturally occurring OV reporting objective response rate (ORR), progression-free survival (PFS), overall survival (OS) or biomarker data were eligible. Hazard ratios (HRs) or odds ratios (OR) were pooled with random-effects models; heterogeneity was assessed with I² statistics. Qualitative synthesis integrated genomic, immunologic and microbiome biomarkers. Results: Thirty-six trials encompassing around 4190 patients across different tumor types met inclusion criteria. Compared with standard therapy, OV-based regimens significantly improved ORR nearly three-fold (pooled OR = 2.77, 95% CI 1.85–4.16), prolonged PFS by 11% (HR = 0.89, 95% CI 0.80–0.99) and reduced mortality by 16% (OS HR = 0.84, 95% CI 0.72–0.97; I² = 59%). Benefits were most pronounced in melanoma (ORR 26–49%; OS HR 0.57–0.79) and in high-dose vaccinia virus for hepatocellular carcinoma (HR = 0.39). Grade ≥ 3 adverse events were not increased versus control (risk ratio 1.05, 95% CI 0.89–1.24); common toxicities were transient flu-like symptoms and injection-site reactions. Biomarker synthesis revealed that high tumor mutational burden, interferon-pathway loss-of-function mutations, baseline CD8⁺ T-cell infiltration, post-OV upregulation of IFN-γ/PD-L1, and favorable gut microbial signatures correlated with response, whereas intact antiviral signaling, immune-excluded microenvironments and myeloid dominance predicted resistance. Conclusions: OV therapy confers clinically meaningful improvements in tumor response, PFS and OS with a favorable safety profile. Integrating composite genomic–immune–microbiome biomarkers into trial design is critical to refine patient selection and realize precision viro-immunotherapy. Future research should prioritize biomarker-enriched, rational combination strategies to overcome resistance and extend benefit beyond melanoma. Full article

Cancer is a prevalent disease worldwide. Photodynamic therapy (PDT) is a non-invasive and highly targeted treatment for certain types of cancer. Recently, it has been combined with nanotechnology, e.g., nanogel, for enhancing its therapeutic efficacy. “Curcumin” is a more typical naturally occurring photosensitizer (PS) in PDT, due to its wide range of pharmacological activities, including anticancer, anti-inflammatory, antibacterial, and antiviral effects. However, curcumin has low bioavailability, limiting its therapeutic potential, which can be improved with the help of nanotechnology. Growing evidence has shown that curcumin-loaded nanogels have their specific functions, such as drug delivery and cancer targeting. Curcumin-loaded nanogel has overcome the limitations of free curcumin, such as solubility and controlled release, with the help of these, as they provide a multifunctional platform to enhance the therapeutic effects of PDT. However, it is still required to further investigate the combinations of curcumin, nanogel, and PDT. Much more work needs to be done, including safety assessments of curcumin-loaded nanogel with PDT delivery systems, long-term toxicity on the human body, and optimization of dosage for curcumin, nanogels, PS, light parameters, and delivery mechanisms for the PDT process, as well as the exploration of tumor-specific targeting and immune response for humans, for example, adverse drug reactions or drug to herbal interaction. Full article

Poly-γ-glutamic acid (γ-PGA), also known as polyglutamate, is a naturally derived polymer produced by Bacillus species that has demonstrated antiviral properties. Growing evidence from preclinical and clinical studies supports its therapeutic potential against various viral infections, highlighting both effective antiviral activity and a favorable safety profile. This review emphasizes current findings on the antiviral mechanisms of γ-PGA, including its ability to interfere with viral entry and to activate serial immune signaling pathways, with additional insights from structural biology. Collectively, γ-PGA represents a promising biomaterial for the development of future broad-spectrum antiviral strategies and applications. Full article

African swine fever virus (ASFV) is an important transboundary animal pathogen with significant impacts on the global swine industry. Overwhelming proinflammatory responses are a major virulence mechanism for ASFV, but the dynamics of these changes during clinical disease are not completely understood. We constructed a detailed portrait of the innate immune responses during acute African swine fever (ASF) at the cellular, transcriptomic, and cytokine levels. Samples serially obtained from infected piglets show that progression of acute ASF is characterized by rapid increases in plasma type I interferons, TNF-α, IL-12p40, and IL-10, which coincide with the manifestation of clinical disease and viral DNAemia. Lymphocytes and natural killer (NK) cells progressively declined, with fluctuations in B cell, CD8+ T cell, and CD4+/CD8+ T cell populations. Blood monocytes and macrophages were highly variable throughout infection, with an abrupt spike in CD203+ mature macrophages immediately prior to death. Transcriptomic analysis of blood showed downregulation of cellular translation as early as 1 day post-challenge (DPC) and significant upregulation of antiviral immune processes at 5 DPC and 7 DPC, which overlapped with the onset of clinical disease. Together, these results present a detailed delineation of fatal ASF which involves an initial infection and damage of susceptible myeloid cells prior to symptomatic disease characterized by pro-inflammatory immune responses, lymphoid depletion, and clinical deterioration. Full article

Viral hepatitis remains a global health concern, with growing recognition of the impact of hepatitis A virus (HAV), hepatitis E virus (HEV), and herpesvirus-associated hepatitis, particularly in vulnerable groups. This narrative review from the ESCMID Study Group for Viral Hepatitis (ESGVH) summarizes recent advances and expert perspectives. For HAV, insights into viral evolution, epidemiology, and risk groups underline the preventable nature of severe disease. HEV is increasingly recognized as both a hepatotropic and a systemic pathogen, with expanding knowledge on natural and vaccine-induced immunity. Herpesvirus-associated hepatitis, while rare, poses significant challenges, especially in patients with immunosuppression or during pregnancy, where early suspicion and empirical antiviral therapy can be lifesaving. Collectively, these evolving insights highlight the importance of strengthened diagnostics, targeted prevention, and tailored management strategies to mitigate the burden of these underappreciated but clinically significant causes of viral hepatitis. Full article

This review explores the pharmacological potential of chondroitin sulfate and fucoidan as immunomodulatory agents targeting N-acetylgalactosaminidase (nagalase) to normalize immune responses. Nagalase, an enzyme produced by tumor and virus-infected cells, contributes to immune suppression by deactivating macrophage-activating factor. Both chondroitin sulfate and fucoidan, as representatives of glycosaminoglycans and heteropolysaccharides, exhibit significant potential in inhibiting nagalase activity, thereby restoring immune functionality. Chondroitin sulfate, a key component of the extracellular matrix, demonstrates anti-inflammatory and tissue-regenerative properties by modulating nuclear factor (NF)-κB pathways and cytokine expression. Fucoidan, a sulfated polysaccharide derived from brown seaweed, enhances immune responses through macrophage and natural killer cell activation, while also exhibiting antiviral and anticancer activities. This dual action positions these compounds as promising agents for therapeutic interventions in chronic inflammatory conditions, cancer, and infectious diseases. The synergistic effects of chondroitin sulfate and fucoidan highlight their potential to address the root causes of immune dysregulation. This review aims to elucidate the underlying mechanisms of action and explore the clinical applications of these compounds within the framework of innovative immunotherapeutic strategies. However, current evidence is limited by the predominance of preclinical studies and variability in experimental models. Well-designed clinical trials are needed to validate their efficacy for therapeutic use. Full article