Search Results (3,149)

Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disorder characterized by the destruction of insulin-producing pancreatic beta cells, resulting in lifelong insulin dependence. While genetic susceptibility—particularly human leukocyte antigen (HLA) class II alleles—is a major risk factor, accumulating evidence implicates viral infections as potential environmental triggers in disease onset and progression. This narrative review synthesizes current findings on the role of viral pathogens in T1DM pathogenesis. Enteroviruses, especially Coxsackie B strains, are the most extensively studied and show strong epidemiological and mechanistic associations with beta-cell autoimmunity. Large prospective studies—including Diabetes Virus Detection (DiViD), The environmental determinans of diabetes in the young (TEDDY), Miljøfaktorer i utvikling av type 1 diabetes (MIDIA), and Diabetes Autoimmunity Study in the Young (DAISY)—consistently demonstrate correlations between enteroviral presence and the initiation or acceleration of islet autoimmunity. Other viruses—such as mumps, rubella, rotavirus, influenza A (H1N1), and SARS-CoV-2—have been investigated for their potential involvement through direct cytotoxic effects, immune activation, or molecular mimicry. Interestingly, certain viruses like varicella-zoster virus (VZV) and cytomegalovirus (CMV) may exert modulatory or even protective influences on disease progression. Proposed mechanisms include direct beta-cell infection, molecular mimicry, bystander immune activation, and dysregulation of innate and adaptive immunity. Although definitive causality remains unconfirmed, the complex interplay between genetic predisposition, immune responses, and viral exposure underscores the need for further mechanistic research. Elucidating these pathways may inform future strategies for targeted prevention, early detection, and vaccine or antiviral development in at-risk populations. Full article

Several natural products have been shown to display antiviral activity against the hepatitis B virus (HBV), among a number of other viruses. In a previous study, the hydro-alcoholic extracts (n = 66) of 31 species from the Venezuelan Amazonian rain forest were tested on the hepatoma cell line HepG2.2.15, which constitutively produces HBV. One of the species that exerted inhibitory activity on HBV replication was Senna silvestris. The aim of this study was the bioassay-guided purification of the ethanol fraction of leaves of S. silvestris, which displayed the most significant inhibitory activity against HBV. After solvent extraction and two rounds of reverse-phase HPLC purification, NMR analysis identified salsolinol as the compound that may exert the desired antiviral activity. The purified compound exerted inhibition of both HBV DNA and core HBV DNA. Pure salsolinol obtained from a commercial source also displayed anti-HBV DNA inhibition, with an approximate MIC value of 12 µM. Although salsolinol is widely used in Chinese traditional medicine to treat congestive heart failure, it has also been associated with Parkinson’s disease. More studies are warranted to analyze the effect of changes in its chemical conformation, searching for potent antiviral, perhaps dual agents against HBV and HIV, with reduced toxicity. Full article

Super-resolution microscopy (SRM) has revolutionized our understanding of subcellular structures, including cell organelles and viruses. For human immunodeficiency virus (HIV), SRM has significantly advanced knowledge of viral structural biology and assembly dynamics. This review analyzes how SRM techniques (particularly PALM, STORM, STED, and SIM) have been applied over the past decade to study HIV structural components and assembly. By categorizing and comparing studies based on SRM methods, HIV components, and labeling strategies, we assess the strengths and limitations of each approach. Our analysis shows that PALM is most commonly used for live-cell imaging of HIV Gag, while STED is primarily used to study the viral envelope (Env). STORM and SIM have been applied to visualize various components, including Env, capsid, and matrix. Antibody labeling is prevalent in PALM and STORM studies, targeting Env and capsid, whereas fluorescent protein labeling is mainly associated with PALM and focused on Gag. A recent emphasis on Gag and Env points to deeper investigation into HIV assembly and viral membrane dynamics. Insights from SRM studies of HIV not only enhance virological understanding but also inform future research in therapeutic strategies and delivery systems, including extracellular vesicles. Full article

The precipitation of cryoglobulins, serum immunoglobulins, below 37 °C defines the clinical cryoglobulinemic syndrome, a systemic vasculitis usually characterized by purpura, weakness, and arthralgia. In most cases, this condition is associated with chronic infection by the hepatitis C virus (HCV) and can evolve into B-cell dysregulation and malignancies. The current literature on non-HCV-associated cryoglobulinemia is very limited, and little is known about the immunological and serological profile of affected patients. The cryoglobulinemic syndrome not associated with HCV infection is often found concomitantly with other infections, autoimmune diseases, and B-cell lymphoproliferative disorders. The cryoprecipitation of fibrinogen has been described as a rare disorder, perhaps underestimated and not fully understood, causing thrombotic occlusion and ischemia in different rheumatic disorders. Cold temperature plays a pathogenetic role in autoimmune hemolytic anemias, in which the presence of cold agglutinins produced by B cells at the lymphoplasmacytic cell stage may promote agglutination of red blood cells in the coldest parts of the circulation, even at mild room temperatures, undergoing hemolysis. Laboratory methods for the detection and quantification of cryoproteins are downright critical, and their concurrent detection is pivotal for the diagnosis. In this review, we summarize the clinical involvement of cryoglobulins, cryofibrinogen, and cold agglutinins in non-HCV autoimmune diseases, underlining the crucial steps of the most employed analytic methods. Full article

Porcine lymphotropic herpesviruses -1, -2, and -3 (PLHV-1, PLHV-2, and PLHV-3) are gammaherpesviruses that are widespread in pigs. These viruses are closely related to the human pathogens Epstein–Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus (KSHV), both of which are known to cause severe diseases in humans. To date, however, no definitive association has been established between PLHVs and any disease in pigs. With the growing interest in xenotransplantation as a means to address the shortage of human organs for transplantation, the safety of using pig-derived cells, tissues, and organs is under intense investigation. In preclinical trials involving pig-to-nonhuman primate xenotransplantation, another porcine herpesvirus—porcine cytomegalovirus, a porcine roseolovirus (PCMV/PRV)—was shown to be transmissible and significantly reduced the survival time of the xenotransplants. In the present study, we examined donor pigs and their respective baboon recipients, all of which were part of preclinical pig heart xenotransplantation studies, for the presence of PLHV. PLHV-1, PLHV-2, and PLHV-3 were detected in nearly all donor pigs; however, no evidence of PLHV transmission to the baboon recipients was observed. Full article

Barley leaf stripe, caused by Pyrenophora graminea (Pg), significantly reduces yields across various regions globally. Understanding the resistance mechanisms of barley to Pg is crucial for advancing disease resistance breeding efforts. In this study, two barley genotypes—highly susceptible Alexis and immune Ganpi2—were inoculated with the highly pathogenic Pg isolate QWC for 7, 14, and 18 days. The number of differentially expressed genes (DEGs) in Alexis was 1350, 1898, and 2055 at 7, 14, and 18 days, respectively, while Ganpi2 exhibited 1195, 1682, and 2225 DEGs at the same time points. Gene expression pattern analysis revealed that Alexis responded more slowly to Pg infection compared to Ganpi2. A comparative analysis identified 457 DEGs associated with Ganpi2’s immunity to Pg. Functional enrichment of these DEGs highlighted the involvement of genes related to plant-pathogen interactions and kinase activity in Pg immunity. Additionally, 20 resistance genes and 24 transcription factor genes were predicted from the 457 DEGs. Twelve candidate genes were selected for qRT-PCR verification, and the results showed that the transcriptomic data was reliable. We conducted cloning of the candidate Pg resistance gene HvLRR_8-1 by the barley cultivar Ganpi2, and the sequence analysis confirmed that the HvLRR_8-1 gene contains seven leucine-rich repeat (LRR) domains and an S_TKc domain. Subcellular localization in tobacco indicates that the HvLRR_8-1 is localized on the cell membrane. Through the functional analysis using virus-induced gene silencing, it was demonstrated that HvLRR_8-1 plays a critical role in regulating barley resistance to Pg. This study represents the first comparative transcriptome analysis of barley varieties with differing responses to Pg infection, providing that HvLRR_8-1 represents a promising candidate gene for improving durable resistance against Pg in cultivated barley. Full article

Poliovirus represents an oncolytic agent for human glioblastoma—one of the most aggressive types of cancer. Since interference of viruses with metabolic and redox pathways is often linked to their pathogenesis, drugs targeting metabolic enzymes are regarded as potential enhancers of oncolysis. Our goal was to reveal an imprint of poliovirus on the metabolism of glioblastoma cell lines and to assess the dependence of the virus on these pathways. Using GC-MS, HPLC, and Seahorse techniques, we show that poliovirus interferes with amino acid, purine and polyamine metabolism, mitochondrial respiration, and glycolysis. However, many of these changes are cell line- and culture medium-dependent. 2-Deoxyglucose, the pharmacologic inhibitor of glycolysis, was shown to enhance the cytopathic effect of poliovirus, pointing to its possible repurposing as an enhancer of oncolysis. Inhibitors of polyamine biosynthesis, pyruvate import into mitochondria, and fatty acid oxidation exhibited antiviral activity, albeit in a cell-dependent manner. We also demonstrate that poliovirus does not interfere with the production of superoxide anions or with levels of H₂O₂, showing an absence of oxidative stress during infection. Finally, we showed that a high rate of poliovirus replication is associated with fragmentation of the mitochondrial network, pointing to the significance of these organelles for the virus. Full article

Type-I Interferon (IFN) is essential for antiviral immunity in both mice and humans; thus, we investigated whether LAT affects HSV-1 infectivity in the absence of IFN by infecting IFNαβR^−/− and wild-type control mice with HSV-1 McKrae (LAT-plus) and dLAT2903 (LAT-minus) viruses. IFNαβR^−/− mice survived ocular infection with the LAT-plus virus, while no infected mice survived infection with the LAT-minus virus. Increased death in infected mice correlated with a higher expression in the neurovirulence γ34.5 gene but not with gB expression. To determine the region of LAT that contributed to higher mortality, IFNαβR^−/− mice were infected with recombinant viruses expressing the first 1.5 kb or the first 811bp region of 1.5 kb LAT. Similar to LAT-plus infected mice, IFNαβR^−/− mice infected with LAT1.5kb were protected from death, while infection with the LAT811bp virus was similar to that of LAT-minus, suggesting that increased pathogenicity in the absence of LAT depends on the second half of 1.5 kb LAT. To confirm the in vivo upregulation of γ34.5 expression in the absence of LAT, rabbit skin and Neuro2A cells were infected with LAT-plus, LAT-minus, LAT1.5kb, or LAT811bp viruses. γ34.5 expression was significantly higher in LAT-minus- and LAT811bp-infected rabbit skin cells and Neuro2A cells than in LAT-plus- and LAT1.5kb-infected cells, suggesting that sequences after the 811bp of LAT contribute to γ34.5 upregulation. However, except for γ34.5 expression, ICP0, ICP4, and gB expression were not affected by the absence of LAT or truncated forms of LAT. To confirm that higher γ34.5 expression contributes to higher mortality in the absence of LAT, we infected IFNαβR^−/− mice with a recombinant virus lacking LAT and γ34.5 expression, and, in contrast to LAT-minus, all infected mice survived. Our results suggest that LAT controls γ34.5 expression and that higher γ34.5 expression and mortality in infected mice are associated with the second half of 1.5 kb LAT. Full article

Myxoma virus (MYXV), a rabbit-specific poxvirus and non-pathogenic in humans and mice, is an excellent candidate oncolytic virus for cancer therapy. MYXV also has immunotherapeutic benefits. In ovarian cancer (OC), immunosuppressive tumor-associated macrophages (TAMs) are key to inhibiting antitumor immunity while hindering therapeutic benefit by chemotherapy and dendritic cell (DC) vaccine. Because MYXV favors binding/entry of macrophages/monocytes, we examined the therapeutic potential of MYXV against TAMs. We found previously that a replication-defective MYXV with targeted deletion of an essential gene, M062R, designated ΔM062R MYXV, activated both the host DNA sensing pathway and the SAMD9 pathway. Treatment with ΔM062R confers therapeutic benefit comparable to that of wild-type replicating MYXV in preclinical models. Here we found that ΔM062R MYXV, when integrated with cisplatin and DC immunotherapy, further improved treatment benefit, likely through promoting tumor antigen-specific T cell function. Moreover, we also tested ΔM062R MYXV in targeting human immunosuppressive TAMs from OC patient ascites in a co-culture system. We found that ΔM062R treatment subverted the immunosuppressive properties of TAMs and elevated the avidity of cytokine production in tumor antigen-specific CD4⁺ T cells. Overall, ΔM062R presents a promising immunotherapeutic platform as a beneficial adjuvant to chemotherapy and DC vaccine. Full article

Herpes simplex virus type 1 (HSV-1) is associated with eye infections. Specifically, the acute consequences of eye infections have been extensively studied. This review gathers information on possible collateral damage caused by HSV-1 in the retina, such as age-related macular degeneration (AMD), a neurodegenerative disease. The synthesis and accumulation of Amyloid-β peptide (Aβ) is a key hallmark in these types of pathologies. AMD is a disease of multifactorial origin, and viral infections play an important role in its development. It is known that once this virus has entered the eye, it can infect adjacent cells, thus having the ability to infect almost any cell type with great tropism. In the retina, retinal pigment epithelial (RPE) cells are primarily involved in AMD. This work reviews publications that show that RPE can produce Aβ, and once they are infected by HSV-1, the release is promoted. Also, all the information available in the literature that explains how these events may be interconnected has been compiled. This information is valuable when planning new treatments for multifactorial neurodegenerative diseases. Full article

Various SARS-CoV-2 remdesivir resistance-associated substitutions (RAS) have been reported, but a comprehensive comparison of their resistance levels is lacking. We identified novel RAS and performed head-to-head comparisons with known RAS in Vero E6 cells. A remdesivir escape polyclonal virus exhibited a 3.6-fold increase in remdesivir EC₅₀ and mutations throughout the genome, including substitutions in nsp12 (E796D) and nsp14 (A255S). However, in reverse-genetics infectious assays, viruses harboring both these substitutions exhibited only a slight decrease in remdesivir susceptibility (1.3-fold increase in EC₅₀). The nsp12-E796D substitution did not impair viral fitness (Vero E6 cells or Syrian hamsters) and was reported in a remdesivir-treated COVID-19 patient. In replication assays, a subgenomic replicon containing nsp12-E796D+nsp14-A255S led to a 16.1-fold increase in replication under remdesivir treatment. A comparison with known RAS showed that S759A, located in the active site of nsp12, conferred the highest remdesivir resistance (106.1-fold increase in replication). Nsp12-RAS V166A/L, V792I, E796D or C799F, all adjacent to the active site, caused intermediate resistance (2.0- to 11.5-fold), whereas N198S, D484Y, or E802D, located farther from the active site, showed no resistance (≤2.0-fold). In conclusion, our classification system, correlating replication under remdesivir treatment with RAS location in nsp12, shows that most nsp12-RAS cause moderate resistance. Full article

Human T-cell lymphotropic virus (HTLV), a retrovirus associated with severe conditions such as leukemia/lymphoma and myelopathy, exhibits variable global prevalence, with higher rates observed in regions such as northeastern Brazil and sub-Saharan Africa. While intrauterine transmission can occur via viral expression in placental tissue and contact with umbilical cord blood, the predominant route is vertical transmission through breastfeeding. Diagnostic testing, particularly serological screening with ELISA and confirmatory methods such as Western blot and PCR, is essential for early detection during pregnancy. The implementation of prenatal screening programs, as seen in Japan and Brazil, has proven effective in reducing vertical transmission by guiding interventions such as breastfeeding cessation in infected mothers. Beyond clinical implications, the psychosocial impact on affected pregnant women highlights the need for an interdisciplinary approach. Although the association between HTLV infection and adverse obstetric outcomes remains controversial, studies suggest increased risks of preterm birth, low birth weight, and other neonatal complications. Given the importance of early diagnosis and prevention, universal prenatal screening protocols represent a critical strategy to reduce viral transmission and its long-term consequences. Full article

Monkeypox virus (MPXV) has caused 148,892 confirmed cases and 341 deaths from 137 countries worldwide, as reported by the World Health Organization (WHO), highlighting the urgent need for effective vaccines to prevent the spread of MPXV. Traditional vaccine development is low-throughput, expensive, time consuming, and susceptible to reversion to virulence. Alternatively, a reverse vaccinology approach offers a rapid, efficient, and safer alternative for MPXV vaccine design. Here, MPXV proteins associated with viral infection were analyzed for immunogenic epitopes to design multi-epitope vaccines based on B-cell, CD4+, and CD8+ epitopes. Epitopes were selected based on allergenicity, antigenicity, and toxicity parameters. The prioritized epitopes were then combined via peptide linkers and N-terminally fused to various protein adjuvants, including PADRE, beta-defensin 3, 50S ribosomal protein L7/12, RS-09, and the cholera toxin B subunit (CTB). All vaccine constructs were computationally validated for physicochemical properties, antigenicity, allergenicity, safety, solubility, and structural stability. The three-dimensional structure of the selected construct was also predicted. Moreover, molecular docking and molecular dynamics (MD) simulations between the vaccine and the TLR-4 immune receptor demonstrated a strong and stable interaction. The vaccine construct was codon-optimized for high expression in the E. coli and was finally cloned in silico into the pET21a (+) vector. Collectively, these results could represent innovative tools for vaccine formulation against MPXV and be transformative for other infectious diseases. Full article

Marek’s disease (MD), induced by the highly contagious Marek’s disease virus (MDV), remains a significant challenge to global poultry health despite extensive vaccination efforts. This study employed integrated transcriptomic and metabolomic analyses to investigate liver responses in naturally MDV-infected Wenchang chickens during late infection stages. RNA sequencing identified 959 differentially expressed genes (DEGs) between the infected and uninfected groups. Functional enrichment analysis demonstrated that these DEGs were primarily associated with canonical pathways related to metabolism and cellular processes, including lipid, carbohydrate, and amino acid metabolism, as well as the p53 signaling pathway, cell cycle, and apoptosis. Ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) detected 561 differentially expressed metabolites (DEMs), showing near-significant enrichment (p = 0.069) in phenylalanine metabolism. Integrated analysis of transcriptomics and metabolomics data highlighted that critical gene–metabolite pairs such as SGPL1-palmitaldehyde–sphinganine-1-phosphate and ME1-NADP+–malic acid potentially mediate functional crosstalk between sphingolipid metabolism and cellular redox homeostasis during viral oncogenesis. This comprehensive mapping of regulatory networks provides insights into host–virus interactions during MDV pathogenesis, offering potential applications in immunomodulation approaches, targeted therapeutic strategies, and vaccine adjuvant development. Full article

Co-infections of Orthopoxviruses (OPVs), such as vaccinia virus (VACV) and monkeypox virus (MPXV), and the human immunodeficiency virus (HIV) can be associated with severe outcomes. Serro’s dairy region, located in Minas Gerais, southeastern Brazil, is an endemic area for VACV, where zoonotic outbreaks affect rural communities. This epidemiological context is especially relevant for at-risk populations, such as people living with HIV (PLHIV). This study aimed to assess the presence of neutralizing antibodies (NAbs) against OPV in PLHIV in this endemic setting. Serum samples were collected from 177 PLHIV in treatment at the specialized service between December 2021 and August 2022. VACV and MPXV NAbs were measured using the plaque reduction neutralization test (PRNT) and VACV-infected cells. The overall occurrence of OPV NAbs was 27.7%. NAbs were higher in individuals born before 1980 (53.3%) than those born after 1980 (1.1%). Among anti-VACV-seropositive individuals, 40.8% also had MPXV NAbs, suggesting cross-immunity. These findings indicate the circulation of VACV in PLHIV and highlight the increased susceptibility to OPV infections among individuals born after the cessation of smallpox vaccination. The results reinforce the importance of continued surveillance of OPV, especially in endemic regions and vulnerable populations. Full article