Search Results (155)

Background and Significances: In patients with Epstein–Barr virus-driven hemophagocytic lymphohistiocytosis (EBV-HLH), identifying the underlying cause poses a significant diagnostic challenge. HLH may precede overt disease, and early directed treatment for HLH can obscure histopathological findings. A liquid biopsy enables the detection of tumor-derived DNA from various sources, including cell-free DNA, circulating tumor cells, extracellular vesicles, and tumor-educated platelets, and might aid in this setting. Case Presentation: This case presents a young patient with EBV-HLH, in which genomic analysis of tumor-derived DNA from circulating tumor cells led to the diagnosis of an EBV-positive NK/T-cell lymphoma—where conventional tissue biopsies had failed. Conclusions: This report underscores the potential of the liquid biopsy as a valuable diagnostic tool in complex cases of EBV-HLH. Full article

Herpesviruses are DNA viruses that evade the immune response and persist as lifelong infections. Human gamma-herpesviruses Epstein–Barr virus (EBV) and Kaposi’s sarcoma herpesvirus (KSHV) are oncogenic; they can lead to cancer. Oncogenic viruses are responsible for 10–15% of human cancer development, which can have poor prognoses. Non-coding RNAs (ncRNAs) are RNAs that regulate gene expression without encoding proteins, and are being studied for their roles in viral immune evasion, infection, and oncogenesis. ncRNAs are classified by their size, and include long non-coding RNAs, microRNAs, and circular RNAs. EBV and KSHV manipulate host ncRNAs, and encode their own ncRNAs, regulating host processes and immune responses. Viral ncRNAs regulate host functions by post-transcriptionally modifying host RNAs, and by serving as mimics of other host RNAs, promoting immune evasion. ncRNAs in gamma-herpesvirus infection are also important for tumorigenesis, as dampening immune responses via ncRNAs can upregulate pro-tumorigenic pathways. Emerging topics such as RNA modifications, target-directed miRNA degradation, competing endogenous RNA networks, and lncRNA/circRNA–miRNA interactions provide new insights into ncRNA functions. This review compares ncRNAs and the mechanisms of viral immune evasion in EBV and KSHV, while also expanding on recent developments in the roles of ncRNAs in immune evasion, viral infection, and oncogenesis. Full article

Epstein–Barr virus (EBV) is the first oncogenic DNA virus known to encode microRNAs (miRNAs) and has been implicated in the pathogenesis of multiple malignancies, including a distinct subset of gastric cancers (EBV-associated gastric cancer, EBVaGC). However, the functional roles of individual EBV-encoded miRNAs in EBVaGC remain poorly defined. In this study, we integrate bioinformatic and experimental analyses to uncover a novel oncogenic axis driven by EBV-encoded miR-BART20-3p. Analysis of public transcriptomic datasets revealed that peroxisome proliferator-activated receptor α (PPARα) is significantly downregulated in EBVaGC compared with EBV-negative gastric tumors. We confirmed that both PPARα mRNA and protein are reduced in EBVaGC cell lines and primary tumor specimens, and that this reduction inversely correlates with miR-BART20-3p levels. A dual-luciferase reporter assay demonstrated that miR-BART20-3p directly binds the PPARα 3′-UTR. Functionally, miR-BART20-3p overexpression in AGS cells enhanced proliferation and migration, whereas inhibition of miR-BART20-3p in EBV-infected AGS cells attenuated these phenotypes. Mechanistic studies employing PPARα-specific siRNA together with qRT-PCR and ELISA reveal that suppression of PPARα or overexpression of miR-BART20-3p leads to upregulation of interleukin 6 (IL-6), indicating disruption of the PPARα–IL-6 regulatory axis. Collectively, EBV-encoded miR-BART20-3p promotes EBVaGC progression by directly targeting PPARα, and thereby derepressing IL-6 expression. This miRNA–PPARα–IL-6 pathway may serve as both a mechanistic biomarker and a novel therapeutic target in EBVaGC. Full article

Epstein–Barr virus (EBV), a double-stranded DNA virus, is implicated in nasopharyngeal carcinoma (NPC), with particularly high incidence in regions such as southern China and Hong Kong. Although NPC is typically treated with radio- and chemotherapy, outcomes remain poor for advanced-stage diagnoses, highlighting the need for targeted therapies. This study explores the potential of CRISPR/CRISPR-associated protein 13 (Cas13) technology to target essential EBV RNA in NPC cells. Previous research demonstrated that CRISPR/Cas9 could partially reduce EBV load, but suppression was incomplete. Here, the combination of CRISPR/Cas13 with CRISPR/Cas9 shows enhanced viral clearance. Long-term EBNA1 suppression via CRISPR/Cas13 reduced the EBV genome, improved CRISPR/Cas9 effectiveness, and identified suitable AAV serotypes for delivery. Furthermore, cotreatment increased NPC cell sensitivity to 5-fluorouracil and cisplatin. These findings underscore the potential of CRISPR/Cas13 as an anti-EBV therapeutic approach, effectively targeting latent EBV transcripts and complementing existing treatments. The study suggests a promising new direction for developing anti-EBV strategies, potentially benefiting therapies for NPC and other EBV-associated malignancies. Full article

Background and Objectives: The Epstein-Barr virus (EBV) belongs to the gamma herpesviruses family. Evidence from the literature suggests that EBV initiates immune responses and the production of antibodies. Chronic or recurrent EBV infections may be associated with autoimmune diseases such as systemic lupus erythematosus, Sjögren’s syndrome, rheumatoid arthritis, multiple sclerosis, or inflammatory bowel diseases. This review aims to establish the role of EBV in the development and progression of autoimmune diseases. Materials and Methods: A literature search was conducted using PubMed, PMC, Google Scholar, and SCOPUS. Relevant studies, including meta-analyses, case-control studies, literature reviews, cross-sectional studies, and longitudinal studies, were identified through titles and abstracts screening for a comprehensive analysis. Results: Our study revealed a strong association between EBV infection and several autoimmune diseases, including multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, and inflammatory bowel disease. Epstein-Barr virus seropositivity was significantly higher in affected individuals. Elevated EBV-specific antibodies correlated with disease onset and severity. EBV DNA and latency proteins were detected in diseased tissues, alongside immune dysregulation and molecular mimicry mechanisms. Conclusions: Our findings highlight that EBV may be an important factor in autoimmune disease pathogenesis, contributing to immune activation and tissue damage. Further research is needed to explore EBV-targeted therapies and their potential in preventing or managing autoimmune diseases. Full article

Background/Objectives: Inflammatory bowel disease (IBD) is a chronic inflammatory condition encompassing ulcerative colitis (UC) and Crohn’s disease (CD). The role of environmental factors in the pathogenesis of IBD remains elusive. Nevertheless, evidence suggests a pivotal role of viruses, specifically Epstein–Barr virus (EBV), in the progression of IBD through mechanisms such as molecular mimicry and bystander activation. Our previous findings demonstrate EBV DNA’s significant role in exacerbating colitis symptoms and elevating the levels of the pro-autoimmune cytokine interleukin-17A (IL-17A) in an IBD mouse model via toll-like receptor 9 (TLR9). Therefore, we aimed to examine the role of EBV particles in the pathogenesis of IBD, and the potential role of TLR9 inhibition in ameliorating disease outcomes. Methods: Three days post colitis induction, EBV particles were intra-rectally injected into female C57BL/6J mice, followed by the intra-peritoneal administration of TLR9 inhibitor. Thereupon, mice were monitored daily and the disease activity index (DAI), colon lengths, and damage scores, as well as the number of cells, double-positive for IL-17A+ and IFN-γ+, and triple-positive for IL-17A+, IFN-γ+, and FOXP3+, were evaluated. Results: Our findings revealed a significant role of TLR9 inhibition in mitigating colitis features in an EBV-injected IBD mouse model compared to the control group. Conclusions: These results indicate an essential role of TLR9 in initiating immune responses against recurrent EBV reactivation events, which ultimately contributes to inflammation aggravation in IBD patients. Consequently, TLR9 could serve as a potential therapeutic target to alleviate the severe symptoms of IBD in EBV-infected individuals. Full article

Mpox is a zoonotic disease caused by the Mpox virus (MPXV). The rapid and accurate diagnosis of MPXV is essential for the timely and effective prevention, control, and treatment of the disease. In this study, we combined Multienzyme Isothermal Rapid Amplification (MIRA) (at 42 °C) and Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated protein 12b(CRISPR/Cas12b) (at 60 °C) to develop a single-tube two-step assay for rapid MPXV detection, leveraging the distinct physical states of tricosane at these temperatures. MIRA amplification primers and CRISPR/cas12b SgRNA were designed based on the MPXV F3L gene. After screening the primers and sgRNAs, the reaction conditions were optimized, and the performances of the assay were evaluated. The detection limit (LOD) of this single-tube two-step MIRA-CRISPR/Cas12b assay for MPXV is four copies of DNA molecules. No cross-reactivity with other pathogens (herpes simplex virus (HSV), Epstein–Barr virus (EBV), Coxsackievirus A16 (CVA16), Enterovirus A71 (EV-A71), and measles virus (MeV)) was found. The assay also showed good consistency with quantitative real-time PCR (qPCR) (Kappa = 0.9547, p < 0.05, n = 100) in the detection of clinical samples, with a sensitivity of 98.5% and a specificity of 97.0%. The single-tube two-step MIRA-CRISPR/Cas12b assay permits the rapid (within 45 min), sensitive, and specific detection of MPXV. The lack of need for opening the reaction tube eliminates the risk of product contamination. Full article

Background: Helicobacter pylori (HP) and Epstein–Barr virus (EBV) coinfection lead to chronic inflammation and contribute to the development of gastric cancer. However, studies examining the association between HP virulence factors and EBV infection in gastric cancer are limited. This study investigated the polymorphisms of HP virulence factors associated with EBV infection and their effects on clinical outcomes in EBV-associated gastric cancer (EBVaGC). Methods: A total of 96 HP isolates from 54 patients with gastric cancer were divided and analyzed based on EBV coinfection status. Polymerase chain reaction amplifications of virulence factors were conducted using DNA extracts from HP isolates cultured from gastric mucosal specimens. Results: EBV infection was significantly associated with gastric carcinoma with lymphoid stroma morphology and a proximal location in the stomach. Most HP strains from patients with gastric cancer were positive for cagA (100.0%), vacA (100.0%), and iceA1 (87.5%). Among HP isolates with EBV coinfection, the prevalence of iceA2 (21.7% vs. 0.0%, p < 0.001) and ureA (21.7% vs. 4.0%, p = 0.009) was significantly more frequent, and that of iceA1 (78.3% vs. 96.0%, p = 0.009) and vacA s1a (4.3% vs. 22.0%, p = 0.012) was less frequent than those of EBV– colonies. Multivariate analysis indicated that ureA (odds ratio, 6.148; 95% confidence interval [CI], 1.221 to 30.958; p = 0.028) was associated with EBVaGC. No significant difference in clinical outcomes was observed based on the presence of ureA expression in EBVaGC. Conclusions: In gastric cancer, regardless of EBV infection, most HP strains were highly virulent, testing positive for cagA, vacA, and iceA1. Although ureA was significantly associated with EBV infection, it did not influence the clinical outcomes of EBVaGC. Full article

Epstein–Barr virus (EBV) is strongly associated with the development of post-transplant lymphoproliferative disorder (PTLD) in pediatric liver transplant recipients. PTLD is one of the most common malignancies following liver transplantation and is associated with significant morbidity and mortality. Factors such as EBV–serostatus mismatch and prolonged or high levels of immunosuppression impact a patient’s risk of developing PTLD. While pre-transplant EBV serological screening and post-transplant monitoring of EBV-DNA levels are strongly recommended, universal guidelines for its prevention and management are lacking. Due to a lack of robust prospective studies, current clinical practices vary widely. The treatment of PTLD typically involves reducing immunosuppression and using targeted therapies such as rituximab, or chemotherapy for refractory cases. This review aims to address our current understanding of EBV’s relationship with PTLD, evaluate the available treatment modalities, and highlight evolving strategies for using EBV as a biomarker for PTLD screening and prevention. Full article

Viral infections such as human papillomavirus (HPV) and Epstein–Barr virus (EBV) play a critical role in the onset of oropharyngeal (OPC) and nasopharyngeal cancer (NPC), respectively. Despite advancements in targeted therapies and immunotherapies, in the recurrent/metastatic setting, these tumors remain incurable diseases with poor prognosis. The development of therapeutic tumor vaccines, utilizing either neoantigens or oncoviral antigens, represents a promising addition to the cancer immunotherapy arsenal. Research on vaccine-based immunotherapy for OPC and NPC focuses on targeting viral antigens, particularly HPV E6/E7 and EBV EBNA1/LMP2. The potential for vaccine platforms, including peptide-based, DNA, RNA, and viral vector-based vaccines, to induce durable immune responses against viral antigens is reported. The early-phase clinical trials evaluating vaccine-based therapies for HPV-related OPC and EBV-related NPC revealed safety and preliminary signs of efficacy; however, further clinical trials are crucial for validation. This review provides an overview of the current landscape of vaccine-based strategies for HPV-related OPC and EBV-related NPC, discussing their biological mechanisms and immune processes involved in anti-HPV and anti-EBV vaccine treatments, with a particular focus on the immune factors that influence these therapies. Full article

Repressor element-1 silencing transcription factor or neuron-restrictive silencer factor (REST/NRSF) is an extensively studied neuronal gene regulator both in neuronal cells and non-neuronal cells. Even though the role of REST in host cellular gene regulation is well established, its role in the establishment of viral infections and its capability to stabilize and destabilize such viral infections are scarcely studied. Co-repressor and DNA modifiers are involved in REST-mediated repressive action of its target genes. The role of REST and co-repressors together or individually in the regulation of viral as well as host genes has been unraveled in a few viruses such as HIV and influenza as well as two of the herpesvirus family members, namely herpes simplex virus type 1 (HSV-1) and Kaposi’s sarcoma-associated herpesvirus (KSHV). Here, we summarize all such virus studies involved with REST to gain a better insight into REST biology in virus infections. We also focus on unraveling the possible RE-1 binding sites in the Epstein–Barr virus (EBV) genome, a well-known human oncogenic herpesvirus that is associated with infectious mononucleosis and neoplasms such as B-cell lymphomas, nasopharyngeal carcinoma, gastric carcinoma, etc. An in silico-based approach was employed towards the prediction of such possible RE-1 binding elements in the EBV genome. This review advances the present knowledge of REST in virus infection which will aid in future efforts towards a better understanding of how REST acts in herpesviruses and other viruses for their infections and pathogenesis. Full article

Rheumatoid arthritis (RA), an autoimmune disease with complex pathogenesis, is characterized by an immune imbalance reflected, e.g., in the disturbed cytokines’ profile. Various viruses and bacteria can cause the upregulation of pro-inflammatory cytokines influencing RA development. In particular, oral cavity dysbiosis, observed in multiple chronic diseases including periodontitis, may be linked to RA. The cytokine profile (IL-1β, IP-10, IL-29, GM-CSF, IFN-α2, IFN-β, TGF-β1, MPC-1, TNF-α, IFN-γ, IL-6, IL-10, IL-17A, IL-12p70, IL-2, and IL-4) of RA patients’ saliva was evaluated using flow cytometry and benchmarked with their levels in saliva of healthy controls and patients with other rheumatic diseases. The levels of IL-1β, IP-10, IL-2, and IL-4 were significantly elevated in RA patients’ saliva compared to other studied groups. To define the potential role of the most suspicious microbial agents (Epstein–Barr Virus (EBV), Cytomegalovirus, Parvovirus B19, Porphyromonas gingivalis, and Segatella copri) for RA pathogenesis, the amounts of their DNA in the saliva of patients with RA were assessed in all the groups mentioned above. The EBV and P. gingivalis DNA levels measured by qRT-PCR were significantly higher in RA patients’ saliva than in other groups, indicating either the important role of these agents in RA pathogenesis or the higher susceptibility of RA patients for those infectious factors. The comprehension of the association of specific cytokine profiles in RA and the occurrence of specific viral and/or bacterial infections can be a key to a better understanding of RA pathogenesis. These results illustrate the complexity of the immunological profile of RA, show the high diagnostic potential of saliva, and provide insight into how various infections can contribute to RA development. Full article

Epstein–Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV), which are the only members of the gamma(γ) herpesviruses, are oncogenic viruses that significantly contribute to the development of various human cancers, such as Burkitt’s lymphoma, nasopharyngeal carcinoma, Hodgkin’s lymphoma, Kaposi’s sarcoma, and primary effusion lymphoma. Oncogenesis triggered by γ-herpesviruses involves complex interactions between viral genetics, host cellular mechanisms, and immune evasion strategies. At the genetic level, crucial viral oncogenes participate in the disruption of cell signaling, leading to uncontrolled proliferation and inhibition of apoptosis. These viral proteins can modulate several cellular pathways, including the NF-κB and JAK/STAT pathways, which play essential roles in cell survival and inflammation. Epigenetic modifications further contribute to EBV- and KSHV-mediated cancerogenesis. Both EBV and KSHV manipulate host cell DNA methylation, histone modification, and chromatin remodeling, the interplay of which contribute to the elevation of oncogene expression and the silencing of the tumor suppressor genes. Immune factors also play a pivotal role in the development of cancer. The γ-herpesviruses have evolved intricate immune evasion strategies, including the manipulation of the major histocompatibility complex (MHC) and the release of cytokines, allowing infected cells to evade immune detection and destruction. In addition, a compromised immune system, such as in HIV/AIDS patients, significantly increases the risk of cancers associated with EBV and KSHV. This review aims to provide a comprehensive overview of the genetic, epigenetic, and immune mechanisms by which γ-herpesviruses drive cancerogenesis, highlighting key molecular pathways and potential therapeutic targets. Full article

Epstein–Barr virus (EBV) is a rare cause of acute retinal necrosis (ARN) and is known for its poor prognosis and limited response to conventional antiviral treatment. Herein, we report a case of EBV ARN successfully treated with conventional systemic acyclovir and intravitreal ganciclovir injection. An 85-year-old man presented with visual disturbance of the right eye from 10 days prior. His visual acuity was 20/200 in the right eye and slit lamp examination showed keratic precipitates, 4+ anterior chamber cells, and 1+ anterior vitreous cells. Fundus examination revealed multiple retinal hemorrhages and yellow-whitish necrotic lesion. The patient was clinically diagnosed with ARN. A few days later, EBV DNA was identified in the aqueous humor and in the serum PCR assay. The patient received 350 mg of intravenous acyclovir three times a day with oral prednisolone, and an intravitreal ganciclovir injection (2 mg per dose) was given five times. Over the course of seven weeks, systemic acyclovir was switched to 1g of per-oral valaciclovir three times a day, and oral steroids were successfully tapered. His visual acuity improved to 20/100, and the previous necrotic lesion was markedly decreased in size. Intravenous acyclovir combined with intravitreal ganciclovir may yield successful treatment outcomes in acute retinal necrosis caused by EBV. Full article

R-loops are triple-stranded nucleic acid structures that occur when newly synthesized single-stranded RNA anneals to duplex DNA upon the collision of replication forks with transcription complexes. These RNA–DNA hybrids facilitate several transcriptional processes in the cell and have been described extensively in the literature. Recently, evidence has emerged that R-loops are key regulators of DNA tumor virus transcription and the replication of their lifecycle. Studies have demonstrated that R-loops on the Human Papillomavirus (HPV) genome must be resolved to maintain genome maintenance and avoid viral integration, a hallmark of HPV cancers. For Epstein–Barr virus (EBV), R-loops are formed at the oriLyt to establish lytic replication. Structural maintenance of chromosome proteins 5/6 (SMC5/6) bind to these viral R-loops to repress EBV lytic replication. Most viruses in the herpesvirales order, such as KSHV, contain R-loop-forming sequences. In this perspective, we will describe the current, although limited, literature demonstrating the importance of RNA–DNA hybrids to regulate DNA virus transcription. We will also detail potential new areas of R-loop research and how these viruses can be used as tools to study the growing field of R-loops. Full article