Search Results (1,327)

Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) represent fundamental cellular adaptive mechanisms that maintain protein homeostasis and metabolic balance. Many RNA viruses, particularly flaviviruses such as dengue virus (DENV), Zika virus (ZIKV), West Nile virus (WNV), yellow fever virus (YFV), and Japanese encephalitis virus (JEV), extensively remodel the ER to establish replication compartments and assemble progeny virions. This massive reorganization disrupts ER homeostasis, leading to UPR activation. Emerging evidence reveals that flaviviruses not only trigger but also manipulate the three UPR branches—PERK, IRE1, and ATF6—to optimize viral translation, replication, and egress. In parallel, flavivirus infection profoundly alters host lipid metabolism and promotes dynamic changes in lipid droplets (LDs), key organelles that mediate lipid storage and serve as scaffolds for viral replication and assembly. The UPR intimately connects to LD biogenesis through transcriptional and translational programs mediated by XBP1, ATF4, and ATF6, thereby coupling ER stress responses to lipid remodeling and energy homeostasis. This intricate crosstalk between UPR and LDs creates a metabolic and structural niche favorable for viral replication but detrimental to host cell integrity. This review provides a comprehensive analysis of the molecular mechanisms by which flaviviruses exploit ER stress and the UPR to reprogram lipid metabolism and LD dynamics. We highlight the dual role of UPR signaling in promoting adaptive lipid synthesis and initiating cell death under prolonged stress, discuss recent insights into ER–LD interactions during flavivirus infection, and explore therapeutic opportunities targeting UPR–lipid metabolic pathways as broad-spectrum antiviral strategies. Understanding this interconnected network will advance our knowledge of viral pathogenesis and identify new avenues for host-directed antiviral intervention. Full article

Background/Objectives: The efficacy of inactivated foot-and-mouth disease virus (FMDV) vaccines depends on the structural integrity of the 146S virions. However, instability of 146S antigens during vaccine manufacturing and storage can compromise vaccine quality. Despite its high immunogenicity, the Korean serotype O strain O Jincheon (O JC) exhibits poor physical stability. Methods: To enhance antigenic stability while preserving strain-specific antigenicity, we engineered a VP1-substituted recombinant virus, (R) O1 M–O JC_VP1, by integrating the VP1 coding region of O JC into the O1 Manisa (O1 M) backbone. Results: The resulting chimeric virus exhibited significantly improved capsid stability, as demonstrated by an increased melting temperature and enhanced resistance to thermal stress, chloroform exposure, and long-term storage. Importantly, the recombinant antigen maintained its immunogenicity and induced antibody responses comparable to those induced by the parental O JC strain in vaccinated pigs. Conclusions: These findings demonstrate that VP1-direct chimeric engineering can improve capsid stability without compromising antigenicity and provide a practical approach for developing a stable FMDV vaccine. 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

Polyamines are small, positively charged molecules essential for fundamental cellular processes, including transcription, translation, and membrane fluidity. In the central nervous system (CNS), these molecules serve as homeostatic gatekeepers by modulating neuroreceptors like NMDA and supporting autophagic clearance. While basal polyamine levels are necessary for proper neuronal differentiation and memory formation, their dysregulation is a hallmark of neurodegenerative pathologies such as Alzheimer’s and Parkinson’s diseases. Neurotropic viruses, including poliovirus, Zika virus, and human cytomegalovirus are significant human pathogens that rely on cellular metabolites for their replication, including polyamines. These pathogens exploit polyamines at multiple stages of their life cycles, relying on them for virion stability, cellular attachment, and the stimulation of viral enzyme activity. Notably, diverse viral families share this dependence, making polyamine biosynthesis a prime target for broad-spectrum antiviral therapies. This review covers the current understanding of polyamine metabolism in virus infection and CNS health and disease, as well as considering antiviral therapies targeting host polyamines to limit neurotropic virus infection. Full article

Background: The 2024/25 influenza season in Hungary experienced a major surge in cases, the largest since the COVID-19 pandemic. We evaluated influenza vaccine effectiveness (VE) in primary care settings among adults and vaccination target groups, and also according to time since vaccination, prior seasonal vaccination, and influenza type. Methods: A test-negative case–control study was conducted in Hungary. Data and specimens were collected from primary care patients with an acute respiratory infection (ARI). Patients with positive PCR test results for influenza were classified as cases, while those with negative test results for influenza were classified as controls. Adjusted VEs were calculated using logistic regression as (1 − odds ratio of vaccination) × 100. Results: Between November 2024 and May 2025, 2074 patients were included in the analysis, of whom 395 cases had influenza. Of the 129 vaccinated patients, 123 (95%) received trivalent inactivated adjuvanted whole-cell vaccine (TIAV), and 6 (5%) received quadrivalent split-virion vaccine. The VE against any influenza was 53% (95% CI: 13–74) in the 18+ age group and 52% (95% CI: 7–75) in the target group for vaccination. The VE against any influenza was 63% (95% CI: 17–84) 14–89 days after vaccination, and 27% (95% CI: −67–68) 90 days or more after vaccination. The VE against any influenza was 56% (95% CI: 1–80) with both current and prior seasonal vaccination, and 5% (95% CI: −64–45) with only prior seasonal vaccination. The VE against influenza A was 39% (95% CI: −16–68), and against influenza B was 80% (95% CI: 2–96). Conclusions: We observed moderate vaccine effectiveness against any influenza, with higher protection within three months after vaccination. Our research findings provide evidence to inform the development of vaccines and the scheduling of vaccination campaigns, with the aim of maximizing the level of protection provided by vaccines throughout the entire influenza season. Full article

Background/Objectives: Seasonal waves of respiratory viruses—including SARS-CoV-2, influenza A virus (IAV), and respiratory syncytial virus (RSV)—continue to pose a global health burden and highlight the need for antiviral agents that are effective, safe, broadly active, affordable, and widely accessible. Current interventions are limited by the need for their early administration, the risk of resistance, their costs, and the restricted availability in large parts of the world. For certain natural products, such as European black elderberry (Sambucus nigra L.) fruit extract (ElderCraft^®; EC) and the seaweed-derived sulfated polymer iota-carrageenan (IC), antiviral activities against respiratory viruses, particularly IAV and SARS-CoV-2, have previously been shown. Here, we assessed the antiviral activity of IC and an anthocyanin-standardized EC extract against SARS-CoV-2, IAV, and RSV, either as monotherapy or in multiple-dose combinations. Methods: MDCKII cells were infected with IAV_PR8, human Calu-3 lung epithelial cells with the SARS-CoV-2 Omicron variant, and HEp-2 cells with RSV (A2 strain). Inhibitors were administered either by pre-incubation of cell-free virions prior to infection or, in separate time-of-addition experiments, during or post-infection. Viral replication was quantified by qRT-PCR or intracellular immunostaining. Cytotoxicity was evaluated using a neutral red uptake assay. Results: Most intriguingly, both EC and IC are able to neutralize virions derived from SARS-CoV-2, IAV, or RSV extracellularly in a dose-dependent manner. Notably, EC and IC alone exhibited strong anti-RSV activity, which was not reported previously. Most importantly, combined treatment with IC and EC caused a pronounced synergistic antiviral effect against the tested viruses, as confirmed by the Bliss independence model, without any detectable impact on cell viability. Finally, solutions prepared from matrix-standardized mono- or combi-lozenges, containing IC and/or EC in high or low doses, reproduced the antiviral and synergistic combination effects observed with the pure compounds. Conclusions: In summary, these findings support further development of EC and IC as a topically accessible, virion-neutralizing combination (e.g., lozenges) to provide additional protection against major respiratory viruses and potentially strengthen pandemic preparedness. Full article

Epstein–Barr virus (EBV) establishes lifelong infection in most humans, yet its biology in immunocompetent hosts is commonly framed as a binary alternation between latency and productive lytic replication. Accumulating molecular and single-cell evidence challenges this view, indicating that EBV frequently enters abortive forms of lytic reactivation that do not culminate in virion production. Here, we propose a conceptual framework in which EBV persistence is governed by feedback-regulated interactions and permissive conditions for reactivation rather than a strictly sequential life cycle. Immediate-early and early gene expression can be repeatedly induced by inflammatory signaling, cellular stress, and epigenetic changes. However, progression to viral DNA replication represents a highly functional barrier that likely requires the coordinated convergence of multiple viral and host conditions. Failure to reach this threshold arrests reactivation before late gene expression, generating a stable partial lytic state characterized by sustained immunomodulatory viral protein expression without the production of infectious particles. Immune surveillance reinforces this bottleneck by eliminating cells undergoing full lytic replication while sparing those stalled in early phases. We argue that EBV persistence reflects a dynamic equilibrium shaped by regulatory interactions between viral gene expression and host immunity, with implications for biomarker interpretation and therapeutic strategies in chronic inflammatory and autoimmune disease. Full article

Foodborne pathogens of Enterobacteriaceae are becoming an increasing global concern, with multidrug-resistant strains posing significant risks to food safety and public health, especially in high-risk products like dairy. This research focused on isolating, biologically characterizing, and genomically profiling new bacteriophages that target key Enterobacteriaceae members as potential biocontrol agents. Eight phages were isolated from wastewater using four bacterial hosts and analyzed through transmission electron microscopy, one-step growth analysis, adsorption kinetics, host range evaluation, whole-genome sequencing, comparative genomics, phylogenetic analysis, proteomic profiling, and virion assembly pathway characterization. All eight isolates exhibited icosahedral heads with contractile tails typical of Myoviridae morphology, demonstrated broad-spectrum lytic activity against 21 bacterial strains (infectivity: 47.6–95.2%), showed high adsorption efficiencies (84.75–99.98%), and had burst sizes ranging from 11 to 166 particles per cell. Genome sizes varied from 103 to 170 kb with coding densities between 92–96%. Importantly, none contained antimicrobial resistance genes, virulence factors, or lysogeny-associated elements, confirming their strictly lytic lifestyles and favorable biosafety profiles. Phylogenetic and comparative analyses indicated mosaic genomic structures influenced by horizontal gene transfer rather than host phylogeny. These findings provide a robust biological and genomic basis for evaluating these phages as potentially safe and effective alternatives to antibiotics in controlling foodborne Enterobacteriaceae, pending further in situ validation. Full article

Infectious pancreatic necrosis virus (IPNV), a member of the family Birnaviridae, is a major pathogen of farmed salmonids and an important model in fish virology. Despite its small genome, which encodes only five viral proteins, IPNV exhibits complex molecular processes that govern genome expression, replication, and particle assembly. Comprehensive descriptions of the molecular biology and replication cycle of IPNV were largely established in reviews published in the mid-1990s, whereas more recent reviews have primarily focused on virulence determinants, epidemiology, or host–virus interactions. This review provides an updated synthesis of available experimental knowledge on the molecular biology of IPNV by integrating classical and recent studies addressing virion architecture, genome organization, and the functions of viral proteins. Particular attention is given to the molecular events involved in the viral replication cycle, including virus entry, genome transcription, translation and replication in the cytoplasm, polyprotein processing by the viral protease, and the coordination between genome replication and virion assembly. When appropriate, experimental observations from the related Avibirnavirus infectious bursal disease virus are considered to provide additional context for molecular mechanisms conserved within the family Birnaviridae. Together, these studies outline the current understanding of the molecular processes governing IPNV replication and morphogenesis. Full article

Members of Marseilleviridae, a family of icosahedral giant viruses, have been identified worldwide in all types of environments. The virion shows a characteristic internal membrane extrusion at the five-fold vertices of the capsid, but its structural details need to be elucidated. We now report the 4.4 Å cryo-electron microscopy structure of the melbournevirus capsid by using a block-based reconstruction approach. Results: An atomic model of the major capsid protein (MCP) shows a unique cup structure on the trimer that accommodates additional proteins. A polyalanine model of the Penton base protein shows internally extended N- and C-terminals, which indirectly connect to the internal membrane extrusion. The Marseilleviruses share the same orientational organization of the MCPs as previously reported for other giant viruses, but the unique minor capsid protein components named Scaffold may be alternatively utilized to control the dimensions of the capsid during assembly as the tape measure protein. Full article

The rate at which bacteria are gaining resistance to antibiotics is outpacing the discovery of new drugs. The rise of superbugs such as Carbapenem-resistant and Extended-Spectrum Beta-Lactamase Producing Enterobacteriaceae are leading to infections that are resistant to our last lines of defense. One of the most prolific genera of these bacteria is Klebsiella, which causes one third of Gram-negative infections. The need for alternative and companion treatments has never been greater. Bacteriophages are bacteria-infecting viruses with high specificity to their host. They show great promise as a potential treatment for antibiotic-resistant infections. Here, we describe the characterization of five closely related bacteriophages (ValerieMcCarty01–05) isolated against an antibiotic-resistant clinical strain of Klebsiella oxytoca, which is an emerging antimicrobial-resistant threat within the Klebsiella genus. These phages demonstrate high similarity at both the genomic and proteomic levels and share homology with other T4-like Enterobacterales phage. Two phages were further characterized through a mass spectrometry analysis of purified virions, identifying peptide spectrum matches for 40 proteins which appear to be virion proteins. In addition, the peptide spectrum matches for 39 hypothetical proteins suggest they are indeed proteins. Amino acid alignment revealed that the tail fibers display more variability than most of their genome, suggesting possible adaptive tail fiber gene shuffling. Despite this variability, these phages maintained broad but high specificity for Klebsiella species in this paper, including K. oxytoca, K. pneumoniae and K. aerogenes and several clinical Klebsiella isolates, with infectivity differences seen only in efficiency. This specificity for Klebsiella is consistent with the genus to which they belong (the Jiaodavirus, which contains only Klebsiella phages) and suggests they may be involved in the evolution of Klebsiella and be useful therapeutics. Full article

Porcine epidemic diarrhea virus (PEDV) causes acute diarrhea, dehydration and death in piglets, resulting in significant economic losses in the pig industry. It is crucial to identify the pathogenesis and mechanism between host–PEDV interactions. In our study, we performed transcriptomic and metabolomic analyses in PEDV-infected Large White (LW) pigs. PEDV infection caused blunted and fused intestinal villi, necrosis of the intestinal mucosal epithelial cells and atrophy of intestinal glands. Transcriptomic and metabolomic analyses revealed 692 differentially expressed genes and 1485 differential metabolites, respectively. Among them, differentially expressed genes were enriched in virion assembly, lipoprotein metabolic process and PPAR signaling pathway. Differential metabolites were enriched in primary bile acid biosynthesis and lipoic acid metabolism. An integrated analysis of the transcriptome and metabolome revealed that differentially expressed genes and metabolites were co-enriched in steroid hormone biosynthesis and bile secretion. In addition, key metabolites Dehydroepiandrosterone (DHEA) and Estriol in steroid hormone biosynthesis both inhibited PEDV infection and alleviated the excessive inflammatory response in vitro. Collectively, our study constructed a multi-omics landscape of PEDV infection in LW pigs, providing potential targets for developing metabolic-targeted antiviral interventions. Full article

Apolipoprotein B mRNA editing enzyme catalytic polypeptide 3s (APOBEC3s, A3s) are single-stranded DNA cytidine deaminases with antiviral activity against diverse DNA and RNA viruses. The human APOBEC3 locus encodes seven members: A3A, A3B, A3C, A3D, A3F, A3G, and A3H. Of these, A3C, A3D, A3F, A3G, and A3H are packaged into HIV-1, lacking the viral infectivity factor (VIF, HIV-1Δvif), while A3D, A3F, A3G, and A3H hap II exhibit strong antiviral activity. Packaging of A3s into virions is critical for viral restriction, yet the underlying mechanisms remain incompletely understood. A3 incorporation requires interactions with the GAG polyprotein, especially the matrix (MA) and nucleocapsid (NC) domains, and binding to cellular or viral RNAs. Specific amino acid residues within A3 proteins mediate these contacts, and A3G localization to lipid rafts facilitates packaging. While A3F and A3G incorporation have been extensively characterized, mechanisms for other A3s remain poorly defined. This review synthesizes current knowledge on A3 packaging, emphasizing the interplay of protein, RNA, and membrane determinants in efficient virion incorporation. Full article

Interferon-induced transmembrane proteins (IFITMs) are broad-spectrum antiviral factors that restrict the entry of many enveloped viruses, including HIV-1, by modifying host membrane properties and trapping fusion at the hemifusion stage. Beyond blocking entry in target cells, IFITMs also reduce the infectivity of virions produced from IFITM-expressing cells, a phenomenon termed “negative imprinting”. Conserved motifs, such as the amphipathic helix and oligomerization motifs, have been reported to be essential for IFITM-mediated protection of target cells from viral infection. Yet, the impact of IFITM incorporation on progeny virion infectivity remains poorly defined. Here, we show that IFITM3 mutants defective in target cell protection activity still markedly impair HIV-1 fusion/infection upon incorporating into virions, without affecting viral maturation or Env incorporation. Immunofluorescence studies suggest mislocalization of the IFITM3 mutants as the reason for the lack of antiviral activity in target cells. Testing the antiviral activity of chimeras between antiviral and non-antiviral IFITM orthologs failed to clearly identify a domain responsible for reduction of HIV-1 infectivity, suggesting that multiple domains may be required for negative imprinting. Interestingly, co-incorporation of non-antiviral dog IFITM1 with human IFITM3 did not interfere with IFITM3’s negative imprinting activity, despite forming mixed hetero-oligomers. This finding implies a dominant, oligomerization-independent antiviral phenotype of IFITM3 in virions. Our findings suggest that IFITMs may protect target cells and negatively imprint progeny virions through distinct mechanisms, underscoring the need to further characterize the molecular basis for the reduced fusion competence of IFITM-containing HIV-1 particles. Full article

Background/Objectives: Bovine ephemeral fever (BEF) is a significant disease affecting the cattle industry. The current control strategy for BEF in the field primarily relies on inactivated vaccines. However, some individuals have experienced hypersensitive reactions to these vaccines, prompting the exploration of subunit vaccines as a potential alternative for BEF prevention. Glycoprotein (G protein)-based subunit vaccines derived from virions have successfully induced neutralizing antibodies in cattle for over a decade. Nevertheless, the lack of recent studies evaluating their efficacy using recombinant proteins has raised concerns regarding the development of BEF subunit vaccines for practical field application. Therefore, the objective of this study was to evaluate the antigenicity of a novel truncated G protein produced in mammalian cells as a candidate subunit vaccine for BEF in cattle. Methods: In this study, the G protein with full ectodomain and a version truncated at the C-terminal domain were successfully generated using the ExpiCHO™ expression system. Vaccine efficacy was evaluated weekly by measuring neutralizing antibody titers and cytokine mRNA expression levels following vaccination. Results: Results show that the recombinant protein s510, derived from the G protein of BEF, can stimulate cattle to produce an average 35-fold increase in neutralizing antibodies after three doses of vaccination. The significant upregulation of IFN-γ mRNA supports the effectiveness of the s510-based subunit vaccine and indicates the activation of a cytotoxic immune response in cattle following vaccination. Conclusions: In conclusion, the results indicate that the recombinant protein s510 is a promising antigen for future BEF subunit vaccine development in this study. Full article