Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can have a serious course with many complications, especially in immunocompromised individuals. In such persons, other latent virus infections may contribute to disease pathology, in particular viruses which infect immune cells such as Epstein-Barr virus (EBV) and cytomegalovirus (CMV).

In this study, serology-based assays were conducted to analyse antibody responses to SARS-CoV-2 spike protein (SP), EBV Epstein-Barr nuclear antigen (EBNA)-1 and CMV phosphoprotein (pp)52 in naturally SARS-CoV-2-infected individuals, non-infected healthy controls (HCs) and vaccinated healthy controls (VHCs) to identify an association between SARS-CoV-2 antibodies and EBV and CMV antibodies in order to determine whether latent EBV and CMV infected individuals are more prone to become infected with SARS-CoV-2. Moreover, SARS-CoV-2, EBV, and CMV antibody responses were characterized in serum from patients with relapsing-remitting multiple sclerosis (RRMS), a chronic inflammatory disease strongly associated with EBV infections, to determine whether the serologic virus antibody profile varies in immunocompromised RRMS individuals upon SARS-CoV-2 vaccinations compared to VHCs.

Significantly elevated SP IgG, IgM and IgA levels were identified in SARS-CoV-2-infected immunocompetent individuals when compared to non-infected HCs. However, no correlation was found to serum antibodies between SARS-CoV-2, EBV, and CMV in individuals infected with SARS-CoV-2 and in VHCs, suggesting that latent infections with neither EBV nor CMV associates to SARS-CoV-2 infection. Moreover, no significant difference in SP IgG, IgA and IgM levels was observed between vaccinated RRMS patients and VHCs, indicating that the immune system of immune deficient RRMS patients and VHCs respond identical to SARS-CoV-2 vaccinations.

Collectively, SARS-CoV-2 SP antibody levels reflect the vaccination and infection history and do not associate with EBV and CMV serostatus.

Grass carp reovirus (GCRV) is the most virulent pathogen within the genus Aquareovirus, belonging to the family Spinareoviridae. GCRV is categorized into three genotypes, with type II (GCRV-II) being the predominant strain circulating in China. Reoviruses are known to replicate and assemble in cytoplasmic inclusion bodies termed viroplasms; however, information regarding the formation of GCRV-II viroplasms and their specific roles in virus infection remains largely unknown. In this study, we investigated the formation and characteristics of viroplasms during GCRV-II infection. Immunofluorescence and confocal microscopy indicate that GCRV-II infection induces the formation of viroplasms, with the nonstructural protein NS79 being the key protein responsible for this process. Live-cell imaging and fluorescence recovery after photobleaching assays reveal that GCRV-II viroplasms lack liquid-like properties. Transmission electron microscopy confirms that GCRV-II viroplasms are membranous structures. Notably, we demonstrate that GCRV-II infection induces autophagy and the formation of autophagosomes and that GCRV-II utilizes these autophagosomes for viroplasm formation and virion assembly. Furthermore, we found that GCRV-II uses autophagosomes to evade the host immune system, establishing subclinical persistent infection. GCRV-II also employs autophagosomes for nonlytic release and viral spread. Collectively, these findings highlight distinctive characteristics of GCRV-II viroplasms compared to those of other animal reoviruses, offering valuable insights for the prevention and control of this virus.IMPORTANCEGrass carp reovirus (GCRV) is categorized into three genotypes, with GCRV-II being the most prevalent in China. Despite reoviruses being known for their replication and assembly in viroplasms, the specifics of GCRV-II viroplasm formation and its role in infection were unclear. Our study demonstrates that GCRV-II infection triggers the formation of viroplasms, primarily mediated by the nonstructural protein NS79. GCRV-II viroplasms are membranous structures that lack liquid-like properties, which are significantly different from the viroplasms of other reoviruses. Notably, our research unveils that GCRV-II infection induces autophagy and utilizes autophagosomes for viroplasm formation and virion assembly. Furthermore, we also confirm that GCRV-II utilizes autophagosomes for subclinical persistent infection, nonlytic release, and viral spread. Our results indicate that GCRV-II hijacks autophagosomes to form viroplasms and complete its life cycle. The characteristics of GCRV-II are significantly different from those of other animal reoviruses, providing important information for prevention and control of this virus.

Conventional magnetic resonance diffusion-weighted imaging (DWI) and morphological features have limitations in distinguishing benign from metastatic retropharyngeal lymph nodes (RLNs). We aimed to compare the value of continuous-time random walk (CTRW), fractional-order calculus (FROC), stretched-exponential model (SEM), and conventional DWI, in combination with morphological features, for differentiating between the two groups.

Fifty-nine patients with 68 RLNs (23 benign and 45 metastatic) were enrolled. All patients underwent DWI with 12 b-values. Diffusion data were reconstructed using conventional DWI, SEM, FROC, and CTRW models, yielding nine parameters: apparent diffusion coefficient (ADC), distributed diffusion coefficient (DDC)SEM, αSEM, DFROC, βFROC, μFROC, DCTRW, αCTRW, and βCTRW. Diffusion parameters and morphological features were compared using Mann-Whitney U, independent sample t, or χ2 tests. Logistic regression analysis was performed to identify the best diffusion indicator for classification and to develop a multiparameter model combining morphological features. Area under the receiver operating curve (AUC) and DeLong tests were used.

Significant differences in diffusion parameters were found between benign and metastatic RLNs, except for αCTRW (p ≤ 0.022). Benign RLNs exhibited higher ADC, DDCSEM, DFROC, and DCTRW, while metastatic RLNs had higher αSEM, βFROC, μFROC, and βCTRW. Multivariate logistic regression analysis identified βCTRW as the optimal single diffusion indicator (AUC = 0.913). The combined model of βCTRW with morphological features further improved diagnostic performance and yielded an AUC of 0.948.

βCTRW is an effective noninvasive biomarker for distinguishing between benign and metastatic RLNs. Thus, combining βCTRW with morphological features enhances diagnostic efficiency.

This study demonstrates that βCTRW, derived from the continuous-time random walk diffusion model, when integrated with morphological features, offers a reliable, noninvasive diagnostic approach for differentiating between benign and metastatic retropharyngeal lymph nodes.

Non-Gaussian diffusion metrics outperformed conventional DWI. βCTRW was the best indicator for distinguishing benign from metastatic lymph nodes. Combining βCTRW with minimal axial diameter further improved diagnostic efficiency.

Epstein-Barr virus (EBV) is a carcinogenic γ-herpesvirus that remains latent in more than 95% of adults. The virus can undergo lytic activation when immune function is suppressed or when stimulated by drugs or pathogens. EBV reactivation poses a significant threat to human health and is closely associated with various cancers, such as Burkitt's lymphoma and nasopharyngeal carcinoma. Inhibiting EBV reactivation is a current clinical challenge. Tumour necrosis factor-α (TNF-α), an important cytokine, has different effects on various viruses. It also exerts varying effects on the same virus depending on the type of infected cell. This study aimed to investigate the impact of TNF-α on EBV reactivation and its underlying mechanisms. Our experimental research revealed that TNF-α significantly inhibits EBV reactivation and that this inhibitory effect is mediated primarily through its receptor TNFR1. Furthermore, TNF-α affects the expression of the GPX4 protein and regulates the potential ferroptosis state of cells. Using transmission electron microscopy and other methods, we observed typical characteristics of ferroptosis, such as changes in mitochondrial morphology and Fe2 + accumulation. Additionally, we established stable GPX4-knockdown cell lines, which demonstrated the crucial role of GPX4 in the process of TNF-α-mediated inhibition of EBV reactivation. Overall, TNF-α acts on the TNFR1 receptor, thereby affecting the GPX4 protein and the ferroptosis pathway to achieve its inhibitory effect on EBV reactivation. These findings provide new insights into the mechanisms of EBV reactivation and may offer new perspectives for the early treatment of EBV-related diseases.

The coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2 virus infection, has been associated with a substantial risk of autoimmune disease development or exacerbation. The postulated pathophysiological mechanisms linking COVID-19 with autoimmunity include reactivation of latent Epstein-Barr virus (EBV), whose dysregulated infection in the host can trigger or promote an autoimmune response. This review summarizes recent studies highlighting a potential immunopathogenetic link between SARS-CoV-2 infection and EBV reactivation, which could underlie autoimmunity onset or worsening, as well as immune-related long COVID manifestations in COVID-19 patients. We offer our perspective on the direction that research should take to disentangle the nature (whether causal or casual) of the "COVID-19-EBV-autoimmunity" liaisons. Further advances in this research area may be crucial for designing strategies to prevent or treat EBV reactivation-related autoimmune conditions in COVID-19 patients, or patients with inflammatory co-infectious diseases, at the same time promising to improve our knowledge on the viral contribution to autoimmune phenomena.

The Epstein-Barr virus (EBV), a member of the human gamma-herpesviruses, is intricately linked to various human malignancies. Current treatment options for EBV infection involve the use of acyclovir and its derivatives, which exhibit limited efficacy and are associated with drug resistance issues. Therefore, there is a critical need for new medications with more effective therapeutic actions and less susceptibility to resistance. This review explores the therapeutic promise of flavones and flavonols, naturally occurring molecules, against EBV and its correlated cancers. It thoroughly delves into the molecular mechanisms underlying the therapeutic efficacy of these compounds and scrutinizes their complex interplay in EBV-linked processes and cancer transformation by targeting key genes and proteins pivotal to both the viral life cycle and tumor development. Additionally, the review covers current research, highlights key findings, and discusses promising avenues for future investigations in the pursuit of targeted therapies against EBV and its related tumors.

Epstein-Barr virus (EBV) infection is closely associated with the development of various tumors such as lymphomas and epithelial cancers. EBV has a discrete life cycle with latency and lytic phases. In recent years, significant progress has been made in the understanding of the mechanism underlying the transition of EBV from latency to lytic replication. Multiple new lytic activation factors have been emerged and promoted our understanding of this field. In addition, we have comprehensively presented the existing therapeutic strategies and their relationship to the mechanism underlying the transition of EBV from latency to lytic replication in this review, such as lytic induction therapy and drugs to prevent EBV from entering the lytic phase fully utilize the EBV reactivation mechanisms. This year marks the 60th anniversary of the discovery of EBV, and building a bridge between the mechanism of EBV reactivation and the treatment may help us to design new approaches for treating EBV-associated diseases.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease affecting all organ systems. The disease preferentially affects females of childbearing age. It runs a variable course. It may run a mild course that may never lead to severe disease and manifestations from critical organ systems. However, it may also run an undulating course with periods of mild and severe disease. It may run as a mild disease, quickly deteriorating to severe disease and affecting multiple organ systems. Various immune pathways related both to the innate and adaptive immune response are involved in the pathogenesis of SLE. Various drugs have been developed targeting cellular and molecular targets in these pathways. Interferons are involved in the pathogenesis of SLE, and various drugs have been developed to target this pathway. T and B lymphocytes are involved in the pathophysiology of SLE. Various treatment modalities targeting cellular targets are available for the treatment of SLE. These include biologic agents targeting B lymphocytes. However, some patients have disease refractory to these treatment modalities. For these patients, cell-based therapies may be used. Hematopoietic stem cell transplantation involving autologous cells is an option in the treatment of refractory SLE. Mesenchymal stem cells are also applied in the treatment of SLE. Chimeric antigen receptor (CAR)-T cell therapy is a novel treatment also used in SLE management. This novel treatment method holds major promise for the management of autoimmune diseases and, in particular, SLE. Major hurdles to be overcome are the logistics involved, as well as the need for specialized facilities. This review focuses on novel treatment modalities in SLE targeting cellular and molecular targets in the immune system.

Viral nanoparticles (VNPs) have emerged as crucial tools in the field of biomedicine. Leveraging their biological and physicochemical properties, VNPs exhibit significant advantages in the prevention, diagnosis, and treatment of human diseases. Through techniques such as chemical bioconjugation, infusion, genetic engineering, and encapsulation, these VNPs have been endowed with multifunctional capabilities, including the display of functional peptides or proteins, encapsulation of therapeutic drugs or inorganic particles, integration with imaging agents, and conjugation with bioactive molecules. This review provides an in-depth analysis of VNPs in biomedicine, elucidating their diverse types, distinctive features, production methods, and complex design principles behind multifunctional VNPs. It highlights recent innovative research and various applications, covering their roles in imaging, drug delivery, therapeutics, gene delivery, vaccines, immunotherapy, and tissue regeneration. Additionally, the review provides an assessment of their safety and biocompatibility and discusses challenges and future opportunities in the field, underscoring the vast potential and evolving nature of VNP research.

This study aimed to analyze the relationship between the risk of common opportunistic pathogens Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infection in intestinal mucosal tissues of Ulcerative Colitis (UC) patients and the number of peripheral blood NK cells.

UC patients admitted to a third-grade class-A hospital from January 2018 to December 2023 were selected as research population. Clinical data of the patients were collected from the electronic medical record system. Additionally, samples of intestinal mucosal tissues were obtained for real-time fluorescence quantitative PCR to detect and analyze the viral load of CMV and EBV. Blood samples were collected for lymphocyte subsets analysis. Multivariable logistic regression models analyses was used to determine the odds ratio (OR) and 95% confidence interval (95% CI) for the independent association between NK cells and EBV/CMV infections in UC. We further applied the restricted cubic spline analysis and smooth curve fitting to examine the non-linear relationship between them.

378 UC patients were enrolled. Of these patients, there were 194 patients (51.32%) with EBV /CMV infection. In multivariable logistic regression analyses NK cells was independently associated with EBV and/or CMV infection after adjusted potential confounders (OR 8.24, 95% CI 3.75-18.13, p < 0.001). A nonlinear relationship was found between NK cells and EBV/CMV infections, which had a threshold around 10.169. The effect sizes and CIs below and above the threshold were 0.535 (0.413-0.692), p < 0.001 and 1.034 (0.904-1.183), p > 0.05, respectively.

There was a non-linear relationship between NK cells and EBV/CMV infections. The risk for EBV/CMV infections was not increased with increasing NK cells in individuals with NK cells ≥ 10.169%, whereas the risk for EBV and/or CMV infection was increased with an decreasing NK cells in those with NK cells < 10.169%. The risk of EBV/CMV infections increases when NK cells were below a certain level.

In this research, a recombinant Bacillus Calmette Guerin (rBCG) vector vaccine carrying a human IL-2 and EBV BZLF1 fusion gene (IL-2-BZLF1-rBCG) was constructed. The IL-2-BZLF1-rBCG construct was successfully generated and stably expressed the IL-2 and BZLF1 proteins. IL-2-BZLF1-rBCG activated the immune system and promoted the secretion of IFN-γ and TNF-α by CD4+ and CD8+ T cells. IL-2-BZLF1-rBCG activated lymphocytes to effectively kill EBV-positive NPC cells in vitro. Additionally, IL-2-BZLF1-rBCG stimulated the proliferation of NK cells and lymphocytes in vivo, activated related immune responses, and effectively treated EBV-positive NPC. The immune response to and pharmacological effect of IL-2-BZLF1-rBCG were explored in vitro and in vivo to provide a theoretical and experimental basis for the prevention and treatment of EBV-positive tumors with an rBCG vector vaccine. KEY POINTS: • rBCG with human IL-2 and BZLF1 of EB virus was constructed • The IL-2-BZLF1 fusion gene was stably expressed with rBCG • rBCG with IL-2-BZLF1 has an obvious immune response in vitro and in vivo.

Epstein-Barr virus (EBV) is a herpesvirus capable of establishing lifelong latent infections, leading to a wide spectrum of diseases. It can affect multiple organs, including the gastrointestinal tract, typically through lymphoproliferative syndromes or gastric cancer, while acute gastrointestinal disease is rare and poorly understood. Two cases of EBV-induced acute colitis in kidney transplant recipients were described. Additionally, a scoping review of the literature was conducted to identify all reported cases of EBV infection presenting with acute gastrointestinal involvement. A total of 11 174 articles from PubMed and Embase were analyzed, from which 30 articles were ultimately selected, encompassing 33 cases. Two distinct patient profiles emerged. Patients with gastric-limited disease were typically healthy women and exhibited a benign course, characterized by a more acute presentation and complete recovery in all cases. In contrast, patients with intestinal disease were often immunocompromised, presenting with deep colonic ulcers frequently associated with rectal bleeding, high rates of perforation, frequent need for surgical intervention, and significant mortality. Antiviral therapy and reduction of immunosuppression were commonly employed, although no specific treatment approach demonstrated a clear benefit in reducing mortality or complications. In conclusion, EBV-related gastrointestinal disease varies by patient immunocompetence and the site of involvement. Gastric-limited disease usually has a favorable prognosis, while intestinal involvement in immunocompromised patients is linked to severe complications and higher mortality. Individualized treatment strategies and vigilant long-term follow-up are needed due to the lack of standardized treatment protocols and the risk of relapse or development of EBV-associated lymphoproliferative disorders.

Viral infection leads to heterogeneous cellular outcomes ranging from refractory to abortive and fully productive states. Single cell transcriptomics enables a high resolution view of these distinct post-infection states. Here, we have interrogated the host-pathogen dynamics following reactivation of Epstein-Barr virus (EBV). While benign in most people, EBV is responsible for infectious mononucleosis, up to 2% of human cancers, and is a trigger for the development of multiple sclerosis. Following latency establishment in B cells, EBV reactivates and is shed in saliva to enable infection of new hosts. Beyond its importance for transmission, the lytic cycle is also implicated in EBV-associated oncogenesis. Conversely, induction of lytic reactivation in latent EBV-positive tumors presents a novel therapeutic opportunity. Therefore, defining the dynamics and heterogeneity of EBV lytic reactivation is a high priority to better understand pathogenesis and therapeutic potential. In this study, we applied single-cell techniques to analyze diverse fate trajectories during lytic reactivation in three B cell models. Consistent with prior work, we find that cell cycle and MYC expression correlate with cells refractory to lytic reactivation. We further found that lytic induction yields a continuum from abortive to complete reactivation. Abortive lytic cells upregulate NFκB and IRF3 pathway target genes, while cells that proceed through the full lytic cycle exhibit unexpected expression of genes associated with cellular reprogramming. Distinct subpopulations of lytic cells further displayed variable profiles for transcripts known to escape virus-mediated host shutoff. These data reveal previously unknown and promiscuous outcomes of lytic reactivation with broad implications for viral replication and EBV-associated oncogenesis.

This review focuses on three major aspects of oncoviruses' role in cancer development. To begin, we discuss their geographic distribution, revealing that seven oncoviruses cause 20% of all human cancers worldwide. Second, we investigate the primary carcinogenic mechanisms, looking at how these oncogenic viruses can induce cellular transformation, angiogenesis, and local and systemic inflammation. Finally, we investigate the possibility of SARS-CoV-2 infection reactivating latent oncoviruses, which could increase the risk of further disease. The development of oncovirus vaccines holds great promise for reducing cancer burden. Many unanswered questions about the host and environmental cofactors that contribute to cancer development and prevention remain, which ongoing research is attempting to address.

This study aimed to assess the long-term risks associated with a history of infectious mononucleosis (IM), primarily caused by the Epstein-Barr virus (EBV). Specifically analyzing the potential increase in developing nasopharyngeal cancer (NPC) and lymphoma in patients with a history of IM and exploring the prevalence of other EBV-associated conditions.

The Korean National Health Insurance Service (NHIS) database was utilized for a retrospective analysis, covering data from 2002 to 2021. A total of 25,582 IM patients and controls were included, with 1:1 propensity score matching. The study monitored outcomes, including lymphoma, NPC, gastric cancer, multiple sclerosis, and all-cause mortality.

Patients with a history of IM demonstrated a significantly higher incidence of lymphoma (hazard ratio [HR], 5.320; 95% confidence interval [CI], 3.208 to 8.820; p < 0.001) and NPC (HR, 7.116; 95% CI, 1.617 to 31.314; p=0.009) during the follow-up period compared with the control group. Additionally, the IM group showed an increased rate of all-cause mortality (HR, 2.225; 95% CI, 1.858 to 2.663; p < 0.001).

This study suggests that individuals with a history of IM have an elevated risk of developing lymphoma and NPC in South Korea, emphasizing the importance of vigilant follow-up and monitoring. The results advocate for heightened awareness and potential national monitoring policies to address the long-term health implications of EBV infection and to implement preventive measures.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease with a complex clinical presentation and an unknown etiology. Various viral infections have been proposed as potential triggers of ME/CFS onset, but no specific pathogen has been identified in all cases of postinfectious ME/CFS. The symptomatology of the postacute sequelae of SARS-CoV-2, or long COVID, mirrors that of ME/CFS, with nearly half of long COVID patients meeting ME/CFS diagnostic criteria. The influx of newly diagnosed patients has reinvigorated interest in ME/CFS pathogenesis research, with an emphasis on viral triggers. This review summarizes the current understanding of ME/CFS research on viral triggers, including blood virome screening studies. To further elucidate the molecular basis of ME/CFS, there is a need to develop innovative bioinformatics tools capable of analyzing complex virome data and integrating multiomics information.

Fatigue is a common complication of stroke that has a significant impact on quality of life. The biological mechanisms that underly post-stroke fatigue are currently unclear, however, reactivation of latent viruses and their impact on systemic immune function have been increasingly reported in other conditions where fatigue is a predominant symptom. Epstein-Barr virus (EBV) in particular has been associated with fatigue, including in long-COVID and myalgic encephalomyelitis/chronic fatigue syndrome, but has not yet been explored within the context of stroke.

We performed an exploratory analysis to determine if there is evidence of a relationship between EBV reactivation and post-stroke fatigue.

In a chronic ischemic stroke cohort (> 5 months post-stroke), we assayed circulating EBV by qPCR and measured the titres of anti-EBV antibodies by ELISA in patients with high fatigue (FACIT-F < 40) and low fatigue (FACIT-F > 41). Statistical analysis between two-groups were performed by t-test when normally distributed according to the Shapiro-Wilk test, by Mann-Whitney test when the data was not normally distributed, and by Fisher's exact test for categorical data.

We observed a similar incidence of viral reactivation between people with low versus high levels of post-stroke fatigue (5 of 22 participants (24%) versus 6 of 22 participants (27%)). Although the amount of circulating EBV was similar, we observed an altered circulating anti-EBV antibody profile in participants with high fatigue, with reduced IgM against the Viral Capsid Antigen (2.244 ± 0.926 vs. 3.334 ± 2.68; P = 0.031). Total IgM levels were not different between groups indicating this effect was specific to anti-EBV antibodies (3.23 × 105 ± 4.44 × 104 high fatigue versus 4.60 × 105 ± 9.28 × 104 low fatigue; P = 0.288).

These data indicate that EBV is not more prone to reactivation during chronic stroke recovery in those with post-stroke fatigue. However, the dysregulated antibody response to EBV may be suggestive of viral reactivation at an earlier stage after stroke.

As a common chronic recurrent inflammatory skin disease, psoriasis is characterized by erythema and scaly skin lesions, with infection as an integral part of the pathogenesis of many diseases. Many previous cases reported the impact of psoriasis on infection. However, the existing research fails to completely clarify the infection factors associated with the potential of these diseases and causality.

Thirteen kinds of pathogens and their immune responses and psoriasis in the phenotype of 46 species of SNPs data were respectively obtained from the GWAS catalog database and the UK biobank database. With the help of R software, three methods of inverse variance weighted (IVW), weighted median (WME), and MR-Egger regression were used to analyze the causality of the dataset.

According to the results of IVW analysis, there is a causal relationship between anti-Epstein Barr virus antibody and psoriasis (OR: 1.003, 95% CI: 1.001∼1.006, P = 0.046) with a positive correlation.

Based on the results of MR analysis, there is a causal relationship between psoriasis and EBV infection, which indicates that EBV infection can increase the risk or severity of psoriasis. Therefore, in clinical scenarios, patients afflicted with psoriasis should be prevented from contracting the infection and recurrence of EBV as well as symptoms of psoriasis. The underlying immunological mechanism also provides a new perspective for experimental research.

Our objective was to correlate parvovirus-B19 and Epstein-Barr virus (EBV) infections with apoptotic biomarker levels in tissues from placentas from spontaneous abortions and cases of elective termination of pregnancy. We also explored if viral presence could cause spontaneous abortions by trying to associate the levels of pro-apoptotic markers with adverse pregnancy outcomes.

We used 194 placental samples, of which 152 came from spontaneous abortions and were the study group and 42 controls came from cases of elective pregnancy termination. Hematoxylin and eosin (H&E) staining was performed to investigate morphological changes in the tissues, and then indirect immunohistochemistry to evaluate the expression of B19, EBV, M30, terminal deoxynucleotidyl transferase assay (TUNEL), and nuclear factor kappa B (NF-kB). Statistical analysis was performed using SPSS v. 19.0 (IBM).

Higher levels of apoptosis were observed in the spontaneous abortion group (p<0.001) with statistical significance and their presence was also correlated with statistical significance with viral infection (p<0.001). Also, viral infections were observed only in cases of spontaneous abortion. When simple and multivariate logistic regression was performed we confirmed that viral presence remained an independent prognostic factor for high expression of all apoptotic biomarkers with statistical significance (p<0.001).

Our results indicate that viral presence can lead to deregulation of apoptotic pathways within the maternal-fetal environment and thus work as a trigger event for spontaneous abortions.

Virus, particularly respiratory tract virus infection is likely to co-occur in children with community-acquired pneumonia (CAP). Study focusing on the association between common viruses coinfection and children with CAP is rare. We aimed to study the association between seven common viruses coinfection and clinical/laboratory indexes in children with CAP.

Six hundred and eighty-four CAP cases from our hospital were enrolled retrospectively. Seven common viruses, including influenza A (FluA), influenza B (FluB), human parainfluenza virus (HPIV), Esptein-Barr virus (EBV), coxsackie virus (CoxsV), cytomegalovirus (CMV), and herpes simplex virus (HSV) were investigated for their associations with CAP. We analyzed the differences of hospitalization days, white blood cell (WBC), c-reactive protein (CRP), platelet (PLT), erythrocyte sedimentation rate (ESR), procalcitonin (PCT), urine red blood cell (uRBC), blood urea nitrogen (BUN), serum creatinine (Scr), alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), creatine kinase (CK) and creatine kinase isoenzyme (CKMB) among different viruses coinfection groups by using one-way ANOVA analysis. The differences of clinical/laboratory indexes between ordinary and severe pneumonia groups, as well as non-virus vs multi co-infection viruses groups, and single vs multi co-infection viruses groups by using independent samples T test. Receiver operating characteristic (ROC) curve analyses were applied to test the the predictive value of the clinical/laboratory parameters for the risk of viruses coinfections among CAP. Binary logistic analysis was performed to test the association between various indexes and viruses co-infection.

Eighty-four multiple viruses coinfections yielded different prognosis compared with that in 220 single virus coinfection. CMV coinfection was associated with longest hospitalization days, highest ALT, AST and CKMB level. HSV coinfection was associated with highest WBC count, CRP, ESR, and BUN. EBV coinfection was associated with highest PLT and PCT level. FluB coinfection was associated with highest Scr level. CoxsV coinfection was associated with highest uRBC, LDH and CK level. ROC curve analyses showed that CK had the largest area under the curve (AUC: 0.672, p < 10-4) for the risk of viruses coinfections risk in CAP. Significant association between PLT, uRBC, BUN, CK, and CKMB and virus coinfection risk in CAP was observed.

Multiple viruses coinfections indicated different prognosis. Different viruses coinfection yielded varying degrees of effects on the cardiac, liver, kidney and inflamatory injury in CAP. The alterations of clinical/laboratory parameters, particularly CK may be associated with the risk of viruses coinfections in CAP.

Epstein-Barr Virus (EBV), is a ubiquitous γ-Herpesvirus that infects over 95% of the human population and can establish a life-long infection without causing any clinical symptoms in healthy individuals by residing in memory B-cells. Primary infection occurs in childhood and is mostly asymptomatic, however in some young adults it can result in infectious mononucleosis (IM). In immunocompromised individuals however, EBV infection has been associated with many different malignancies. Since EBV can infect both epithelial and B-cells and very rarely NK cells and T-cells, it is associated with both epithelial cancers like nasopharyngeal carcinoma (NPC) and gastric carcinoma (GC), with lymphomas including Burkitt Lymphoma (BL) or Post-transplant Lymphoproliferative Disorder (PTLD) and rarely with NK/T-cell lymphomas. Currently there are no approved antivirals active in PTLD nor in any other malignancy. Moreover, lytic phase disease almost never requires antiviral treatment. Although many novel therapies against EBV have been described, the management and/or prevention of EBV primary infections or reactivations remains difficult. In this review, we discuss EBV infection, therapies targeting EBV in both lytic and latent state with novel therapeutics developed that show anti-EBV activity as well as EBV-associated malignancies both, epithelial and lymphoproliferative malignancies and emerging therapies targeting the EBV-infected cells.

Viral infection leads to heterogeneous cellular outcomes ranging from refractory to abortive and fully productive states. Single cell transcriptomics enables a high resolution view of these distinct post-infection states. Here, we have interrogated the host-pathogen dynamics following reactivation of Epstein-Barr virus (EBV). While benign in most people, EBV is responsible for infectious mononucleosis, up to 2% of human cancers, and is a trigger for the development of multiple sclerosis. Following latency establishment in B cells, EBV reactivates and is shed in saliva to enable infection of new hosts. Beyond its importance for transmission, the lytic cycle is also implicated in EBV-associated oncogenesis. Conversely, induction of lytic reactivation in latent EBV-positive tumors presents a novel therapeutic opportunity. Therefore, defining the dynamics and heterogeneity of EBV lytic reactivation is a high priority to better understand pathogenesis and therapeutic potential. In this study, we applied single-cell techniques to analyze diverse fate trajectories during lytic reactivation in two B cell models. Consistent with prior work, we find that cell cycle and MYC expression correlate with cells refractory to lytic reactivation. We further found that lytic induction yields a continuum from abortive to complete reactivation. Abortive lytic cells upregulate NFκB and IRF3 pathway target genes, while cells that proceed through the full lytic cycle exhibit unexpected expression of genes associated with cellular reprogramming. Distinct subpopulations of lytic cells further displayed variable profiles for transcripts known to escape virus-mediated host shutoff. These data reveal previously unknown and promiscuous outcomes of lytic reactivation with broad implications for viral replication and EBV-associated oncogenesis.

Epstein-Barr virus (EBV) infection involves distinct clinical and serological profiles. We evaluated the frequency of alleles of locus DRB1 of HLA class II in different serological profiles of EBV infection among HIV-1 infected patients.

We recruited 19 patients with primary infection, 90 with serological transition and 467 with past infection by EBV, HIV-1 co-infection was 100% in primary infection and approximately 70% in other serological profiles. EBV viral load was quantified by real-time PCR, T lymphocyte quantification and cytokine level analysis were performed by flow cytometry, and HLA locus genotyping was performed by PCR-SSO.

The DRB1*09 allele was associated with primary infection (p: 0.0477), and carriers of the allele showed changes in EBV viral load (p: 0.0485), CD8(+) T lymphocyte counts (p: 0.0206), double-positive T lymphocyte counts (p: 0.0093), IL-4 levels (p: 0.0464) and TNF levels (p: 0.0161). This allele was also frequent in HIV-coinfected individuals (p: 0.0023) and was related to the log10 HIV viral load (p: 0.0176) and CD8(+) T lymphocyte count (p: 0.0285). In primary infection, the log10 HIV viral load was high (p: 0.0060) and directly proportional to the EBV viral load (p: 0.0412). The DRB1*03 allele correlated with serological transition (p: 0.0477), EBV viral load (p: 0.0015), CD4(+) T lymphocyte count (p: 0.0112), CD8(+) T lymphocyte count (p: 0.0260), double-negative T lymphocyte count (p: 0.0540), IL-4 levels (p: 0.0478) and IL-6 levels (p: 0.0175). In the serological transition group, the log10 HIV viral load was high (p: 0.0060), but it was not associated with the EBV viral load (p: 0.1214). Past infection was related to the DRB1*16 allele (p: 0.0477), with carriers displaying IgG levels (p: 0.0020), CD4(+) T lymphocyte counts (p: 0.0116) and suggestive CD8(+) T count alterations (p: 0.0602). The DRB01*16 allele was also common in HIV-1 patients with past EBV infection (p: 0.0192); however, the allele was not associated with clinical markers of HIV-1 infection.

Our results suggest that HLA class II alleles may be associated with the modulation of the serological profiles of the immune response to Epstein-Barr virus infection in patients coinfected with HIV-1.

Opportunistic viral infections in individuals with severe immunodeficiency can lead to fatal conditions such as progressive multifocal leukoencephalopathy (PML), for which treatment options are limited. These infections pose significant risks, especially when co-infections with other viruses occur. We describe a combined therapy approach using directly isolated allogeneic Human Polyomavirus 1 (also known as BKV) and Epstein-Barr virus (EBV) specific cytotoxic T-cells for the treatment of PML in conjunction with identified EBV in the cerebrospinal fluid (CSF) of a male patient infected with human immunodeficiency virus (HIV). A 53-year-old HIV-positive male, recently diagnosed with PML, presented with rapidly worsening symptoms, including ataxia, tetraparesis, dysarthria, and dysphagia, leading to respiratory failure. The patient developed PML even after commencing highly active antiretroviral therapy (HAART) 3 months prior. Brain magnetic resonance imaging (MRI) revealed multifocal demyelination lesions involving the posterior fossa and right thalamus suggestive of PML. In addition to the detection of human polyomavirus 2 (also known as JCV), analysis of CSF showed positive results for EBV deoxyribonucleic acid (DNA). His neurological condition markedly deteriorated over the following 2 months. Based on MRI, there was no evidence of Immune Reconstitution Inflammatory Syndrome contributing to this decline. The patient did not have endogenous virus-specific T-cells. We initiated an allogeneic, partially human leukocyte antigen-matched transfer of EBV and utilizing the cross-reactivity between BKV and JCV-BKV specific T-cells. This intervention led to notable neurological improvement and partial resolution of the MRI lesions within 6 weeks. Our case of a patient with acquired immune deficiency syndrome demonstrates that PML and concurrent EBV co-infection can still occur despite undergoing HAART treatment. This innovative experimental therapy, involving a combination of virus-specific T-cells, was demonstrated to be an effective treatment option in this patient.

The Epstein-Barr virus (EBV) is frequently found in endomyocardial biopsies (EMBs) from patients with heart failure, but the detection of EBV-specific DNA has not been associated with progressive hemodynamic deterioration. In this paper, we investigate the use of targeted next-generation sequencing (NGS) to detect EBV transcripts and their correlation with myocardial inflammation in EBV-positive patients with heart failure with reduced ejection fraction (HFrEF). Forty-four HFrEF patients with positive EBV DNA detection and varying degrees of myocardial inflammation were selected. EBV-specific transcripts from EMBs were enriched using a custom hybridization capture-based workflow and, subsequently, sequenced by NGS. The short-read sequencing revealed the presence of EBV-specific transcripts in 17 patients, of which 11 had only latent EBV genes and 6 presented with lytic transcription. The immunohistochemical staining for CD3+ T lymphocytes showed a significant increase in the degree of myocardial inflammation in the presence of EBV lytic transcripts, suggesting a possible influence on the clinical course. These results imply the important role of EBV lytic transcripts in the pathogenesis of inflammatory heart disease and emphasize the applicability of targeted NGS in EMB diagnostics as a basis for specific treatment.

The vast spectrum of aggressive B-cell non-Hodgkin neoplasms (B-NHL) encompasses several infrequent entities occurring in association with viral infections, posing diagnostic challenges for practitioners. In the emerging era of precision oncology, the molecular characterization of malignancies has acquired paramount significance. The pathophysiological comprehension of specific entities and the identification of targeted therapeutic options have seen rapid development. However, owing to their rarity, not all entities have undergone exhaustive molecular characterization. Considerable heterogeneity exists in the extant body of work, both in terms of employed methodologies and the scale of cases studied. Presently, therapeutic strategies are predominantly derived from observations in diffuse large B-cell lymphoma (DLBCL), the most prevalent subset of aggressive B-NHL. Ongoing investigations into the molecular profiles of these uncommon virus-associated entities are progressively facilitating a clearer distinction from DLBCL, ultimately paving the way towards individualized therapeutic approaches. This review consolidates the current molecular insights into aggressive and virus-associated B-NHL, taking into consideration the recently updated 5th edition of the WHO classification of hematolymphoid tumors (WHO-5HAEM) and the International Consensus Classification (ICC). Additionally, potential therapeutically targetable susceptibilities are highlighted, offering a comprehensive overview of the present scientific landscape in the field.

Primary central nervous system (CNS) lymphoma is a very rare extranodal non-Hodgkin lymphoma. The bilateral pattern, as we call it "mirror type", has been identified in other CNS lesions such as gliomas, metastases, and demyelinating lesions, so the differential diagnosis includes imaging studies such as magnetic resonance imaging contrasted with spectroscopy, ruling out immunodeficiency or metastatic disease.

A 65-year-old female presented progressing headache, loss of memory and language alterations, as well as sensory alterations. Neuroimaging showed the presence of two equidistant periventricular lesions at the level of both ventricular atria, a spectroscopy study suggestive of malignancy. Serological studies showed no evidence of immunodeficiency or the presence of positive tumor markers; however, a biopsy was performed, which revealed a histopathological result of primary lymphoma of the CNS.

In neuro-oncology, primary CNS tumors with multiple lesions are rare, even more, the "mirror type" lesions. Lymphomas are lesions that can present in different ways on imaging and clinical presentation. These tumors that present a vector effect due to their size, perilesional edema, or that lead to loss of neurological function are highly discussed in diagnostic and surgical treatment. Due to their prognosis, action on diagnosis and treatment must be taken as quickly as hospital resources allow.

The etiology behind different types of chronic sialadenitis (CS), some of which exhibit IgG4 overexpression, is unknown. Further, IgG4-related disease (IgG4-RD) commonly affects the submandibular gland, but its relationship to IgG4-overexpressing CS, and the antigen triggering IgG4 overexpression, remain unknown.

By qPCR, we assessed the presence of 21 DNA-viruses causing IgG4 overexpression in submandibular gland tissue from patients with IgG4-positive and IgG4-negative CS. Healthy submandibular glands and glands with sialolithiasis without CS were used as controls. We examined the distribution of HHV-7, HHV-6B and B19V DNA, within virus PCR-positive tissues with RNAscope in-situ hybridization (RISH).

We detected DNA from seven viruses in 48/61 samples. EBV DNA was more prevalent within the IgG4-positive samples (6/29; 21%) than the IgG4-negative ones (1/19; 5.3%). B19V DNA was more prevalent within the IgG4-negative samples (5/19; 26%) than the IgG4-positive ones (4/29; 14%). The differences in virus prevalence were not statistically significant. Of the IgG4-RD samples (n = 3) one contained HHV-6B DNA. RISH only showed signals of HHV-7.

None of the studied viruses are implicated as triggering IgG4-overexpression in CS. Although our results do not confirm viral etiology in the examined conditions, they provide valuable information on the prevalence of viruses in both diseased and healthy submandibular gland tissue.

Epstein-Barr virus (EBV) is a pathogen known to cause a number of malignancies, often taking years for them to develop after primary infection. EBV-associated gastric cancer (EBVaGC) is one such malignancy, and is an immunologically, molecularly and pathologically distinct entity from EBV-negative gastric cancer (EBVnGC). In comparison with EBVnGCs, EBVaGCs overexpress a number of immune regulatory genes to help form an immunosuppressive tumor microenvironment (TME), have improved prognosis, and overall have an "immune-hot" phenotype. This review provides an overview of the histopathology, clinical features and clinical outcomes of EBVaGCs. We also summarize the differences between the TMEs of EBVaGCs and EBVnGCs, which includes significant differences in cell composition and immune infiltration. A list of available EBVaGC and EBVnGC gene expression datasets and computational tools are also provided within this review. Finally, an overview is provided of the various chemo- and immuno-therapeutics available in treating gastric cancers (GCs), with a focus on EBVaGCs.

Epstein-Barr virus (EBV) is widely infected in humans and causes various diseases. Among them, microRNAs of EBV play a key role in the progression of EBV-associated febrile diseases. There're few specific indicators for rapid differential diagnosis of various febrile diseases associated with EBV, and the lack of more reliable screening methods with high diagnostic utility has led to spaces for improvement in the accurate diagnosis and efficient treatment of relevant patients, making EBV infection a complicated clinical problem. With recent advances in plasma microRNA testing, the apparent presence of EBV microRNAs in plasma can help screen for EBV infection. The gene networks targeted by these microRNAs can also indicate potential biomarkers of EBV-associated febrile diseases. This study aimed to identify some novel miRNAs as potential biomarkers for early diagnosis of respectively EBV-associated febrile diseases.

A total of 110 participants were recruited for this task. First, we performed high-throughput sequencing and preliminary PCR validation of differentially expressed miRNAs in 15 participants with EBV-associated fever (divided into common EBV carriers), infectious mononucleosis (IM) and chronic active EBV infection (CAEBV), EBV-associated Hemophagocytic Lymphohistiocytosis group (EBV-HLH), and 3 healthy individuals. After a comprehensive analysis, 10 miRNAs with abnormal expression were screened, and then qRT-PCR was performed in the rest of 95 participants to detect the validation of miRNAs expression in plasma samples. Thereafter, we further investigated their potential for clinical application in EBV-related febrile diseases by using a combination of Gene Ontology analysis, Kyoto Encyclopedia of Genes and Genomes pathway analysis, and Protein-protein interaction network analysis.

Through identification and detailed analysis of the obtained data, we found significant differences in the expression of Hsa-miR-320d, EBV-miR-BART22, and EBV-miR-BART2-3p in blood samples from patients with different EBV-related febrile diseases. We found that the expression levels of Hsa-miR-320d, EBV-miR-BART22, and EBV-miR-BART2-3p in plasma are indicative of determining different disease types of EBV-related febrile diseases, while EBV-miR-BART22 and EBV-miR-BART2-3p may be potential therapeutic targets.

The expression levels of Hsa-miR-320d, EBV-miR-BART22, and EBV-miR-BART2-3p suggest that they may be used as transcriptional features for early differential diagnosis of EBV-related febrile diseases, and EBV-miR-BART22 and EBV-miR-BART2-3p may be potential therapeutic targets.

SLE affects females rather than males with a ratio of about 9:1. Owing to the high morbidity with multiple organ involvement, SLE flare-up remains a challenge for women's health. In an accumulation of the past 70 years of studies globally, EBV has been found to be strongly associated with SLE. In the past two decades, EBV reactivation has been proven as prevalent in SLE patients as well as being strongly associated with higher SLE activity and higher prevalence of SLE flare. Hence, strategies to control EBV reactivation in SLE including pharmacological (such as Tenofovir prodrugs TDF and TAF) and non-pharmacological approaches are being developed. The heterogeneity of SLE constitutes clinical challenges, suggesting a stratification of SLE into subgroups based on EBV reactivation or non-reactivation is reasonable. Future-wise, adding anti-EBV reactivation medication to current immunosuppressants for the subgroup of SLE patients with EBV reactivation could be beneficial to achieve long-term remission of SLE.

Epstein-Barr virus (EBV) contributes to ~1% of all human cancers including several B-cell neoplasms. A characteristic feature of EBV life cycle is its ability to transform metabolically quiescent B-lymphocytes into hyperproliferating B-cell blasts with the establishment of viral latency, while intermittent lytic cycle induction is necessary for the production of progeny virus. Our RNA-Seq analyses of both latently infected naïve B-lymphocytes and transformed B-lymphocytes upon lytic cycle replication indicate a contrasting expression pattern of a membrane-associated carbonic anhydrase isoform CA9, an essential component for maintaining cell acid-base homeostasis. We show that while CA9 expression is transcriptionally activated during latent infection model, lytic cycle replication restrains its expression. Pharmacological inhibition of CA-activity using specific inhibitors retards EBV induced B-cell transformation, inhibits B-cells outgrowth and colony formation ability of transformed B-lymphocytes through lowering the intracellular pH, induction of cell apoptosis and facilitating degradation of CA9 transcripts. Reanalyses of ChIP-Seq data along with utilization of EBNA2 knockout virus, ectopic expression of EBNA2 and sh-RNA mediated knockdown of CA9 expression we further demonstrate that EBNA2 mediated CA9 transcriptional activation is essential for EBV latently infected B-cell survival. In contrast, during lytic cycle reactivation CA9 expression is transcriptionally suppressed by the key EBV lytic cycle transactivator, BZLF1 through its transactivation domain. Overall, our study highlights the dynamic alterations of CA9 expression and its activity in regulating pH homeostasis act as one of the major drivers for EBV induced B-cell transformation and subsequent B-cell lymphomagenesis.

Epstein-Barr virus (EBV) is a highly dangerous virus that is globally prevalent and closely linked to the development of nasopharyngeal cancer (NPC). Plasma EBV DNA analysis is an effective strategy for early detection, prognostication and monitoring of treatment response of NPC.

Here, we present a novel molecular diagnostic technique termed EBV-MCDA-LFB, which integrates multiple cross displacement amplification (MCDA) with nanoparticle-based lateral flow (LFB) to enable simple, rapid and specific detection of EBV. In the EBV-MCDA-LFB system, a set of 10 primers was designed for rapidly amplifying the highly conserved tandem repeat BamHI-W region of the EBV genome. Subsequently, the LFB facilitate direct assay reading, eliminating the use of extra instruments and reagents.

The outcomes showed that the 65°C within 40 minutes was the optimal reaction setting for the EBV-MCDA system. The sensitivity of EBV-MCDA-LFB assay reached 7 copies per reaction when using EBV recombinant plasmid, and it showed 100% specificity without any cross-reactivity with other pathogens. The feasibility of the EBV-MCDA-LFB method for EBV detection was successfully validated by 49 clinical plasma samples. The complete detection process, consisting of rapid template extraction (15 minutes), MCDA reaction (65°C for 40 minutes), and LFB result reading (2 minutes), can be finalized within a 60-minutes duration.

EBV-MCDA-LFB assay designed here is a fast, extremely sensitive and specific technique for detecting EBV in field and at the point-of-care (PoC), which is especially beneficial for countries and regions with a high prevalence of the disease and limited economic resources.

Host-virus Protein-Protein Interactions (PPIs) play pivotal roles in biological processes crucial for viral pathogenesis and by extension, inform antiviral drug discovery and therapeutics innovations. Despite efforts to develop the Epstein-Barr virus (EBV)-host PPI network, there remain significant knowledge gaps and a limited number of interacting human proteins deciphered. Furthermore, understanding the dynamics of the EBV-host PPI network in the distinct lytic and latent viral stages remains elusive. In this study, we report a comprehensive map of the EBV-human protein interactions, encompassing 1752 human and 61 EBV proteins by integrating data from the public repository HPIDB (v3.0) as well as curated high-throughput proteomic data from the literature. To address the stage-specific nature of EBV infection, we generated two detailed subset networks representing the latent and lytic stages, comprising 747 and 481 human proteins, respectively. Functional and pathway enrichment analysis of these subsets uncovered the profound impact of EBV proteins on cancer. The identification of highly connected proteins and the characterization of intrinsically disordered and cancer-related proteins provide valuable insights into potential therapeutic targets. Moreover, the exploration of drug-protein interactions revealed notable associations between hub proteins and anticancer drugs, offering novel perspectives for controlling EBV pathogenesis. This study represents, to the best of our knowledge, the first comprehensive investigation of the two distinct stages of EBV infection using high-throughput datasets. This makes a contribution to our understanding of EBV-host interactions and provides a foundation for future drug discovery and therapeutic interventions.

At present, timely and accurate diagnosis and effective treatment of Epstein- Barr Virus (EBV) infection-associated fever remain a difficult challenge. EBV encodes 44 mature microRNAs (miRNAs) that inhibit viral lysis, adjust inflammatory response, regulate cellular apoptosis, promote tumor genesis and metastasis, and regulate tumor cell metabolism. Herein, we have collected the specific expression data of EBV-miRNAs in EBV-related fevers, including infectious mononucleosis (IM), EBVassociated hemophagocytic lymphohistiocytosis (EBV-HLH), chronic active EBV infection (CAEBV), and EBV-related tumors, and proposed the potential value of EBVmiRNAs as biomarkers to assist in the identification, diagnosis, and prognosis of EBVrelated fever, as well as therapeutic targets for drug development.

Epstein-Barr virus (EBV) is a prevalent oncogenic virus estimated to infect greater than 90% of the world's population. Following initial infection, it establishes latency in host B cells. EBV has developed a multitude of techniques to avoid detection by the host immune system and establish lifelong infection. T cells, as important contributors to cell-mediated immunity, make an attractive target for these immunoevasive strategies. Indeed, EBV has evolved numerous mechanisms to modulate T cell responses. For example, it can augment expression of programmed cell death ligand-1 (PD-L1), which inhibits T cell function, and downregulates the interferon response, which has a strong impact on T cell regulation. It also modulates interleukin secretion and can influence major histocompatibility complex (MHC) expression and presentation. In addition to facilitating persistent EBV infection, these immunoregulatory mechanisms have significant implications for evasion of the immune response by tumor cells. This review dissects the mechanisms through which EBV avoids detection by host T cells and discusses how these mechanisms play into tumor survival. It concludes with an overview of cancer treatments targeting T cells in the setting of EBV-associated malignancy.

Epstein-Barr virus-associated gastric cancer (EBVaGC) is regarded as a distinct molecular subtype of GC, accounting for approximately 9% of all GC cases. Clinically, EBVaGC patients are found to have a significantly lower frequency of lymph node metastasis and better prognosis than uninfected individuals. RNA N6-methyladenosine (m6A) modification has an indispensable role in modulating tumour progression in various cancer types. However, its impact on EBVaGC remains unclear.

Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and m6A dot blot were conducted to compare the m6A modification levels between EBVaGC and EBV-negative GC (EBVnGC) cells. Western blot, real-time quantitative PCR (RT-qPCR) and immunohistochemistry were applied to explore the underlying mechanism of the reduced m6A modification in EBVaGC. The biological function of fat mass and obesity-associated protein (FTO) was determined in vivo and in vitro. The target genes of FTO were screened by MeRIP-seq, RT-qPCR and Western blot. The m6A binding proteins of target genes were verified by RNA pulldown and RNA immunoprecipitation assays. Chromatin immunoprecipitation and Luciferase report assays were performed to investigate the mechanism how EBV up-regulated FTO expression.

M6A demethylase FTO was notably increased in EBVaGC, leading to a reduction in m6A modification, and higher FTO expression was associated with better clinical outcomes. Furthermore, FTO depressed EBVaGC cell metastasis and aggressiveness by reducing the expression of target gene AP-1 transcription factor subunit (FOS). Methylated FOS mRNA was specifically recognized by the m6A 'reader' insulin-like growth factor 2 mRNA binding protein 1/2 (IGF2BP1/2), which enhanced its transcripts stability. Moreover, MYC activated by EBV in EBVaGC elevated FTO expression by binding to a specific region of the FTO promoter.

Mechanistically, our work uncovered a crucial suppressive role of FTO in EBVaGC metastasis and invasiveness via an m6A-FOS-IGF2BP1/2-dependent manner, suggesting a promising biomarker panel for GC metastatic prediction and therapy.

Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (EBV-HLH) is a common subtype of HLH with heterogeneous clinical presentations from self-limited to death, of which adults are worse than children.

To establish predictors of mortality risk in adult EBV-HLH patients for timely and appropriate treatment.

Patients with confirmed EBV-HLH admitted to Beijing Friendship Hospital from January 2015 to December 2019 were enrolled and statistical analysis of their laboratory test results was performed.

Among 246 adult patients with EBV-HLH, the deceased were older (p < 0.05), with fewer blood cells (p < 0.05), poorer renal function (p < 0.01), higher levels of procalcitonin (PCT) (p < 0.01), as well as soluble interleukin-2 receptor (sCD25) (p < 0.01). The overall median survival time of patients was 135 days, 87 days for patients without transplantation and 294 days with transplantation (p < 0.001). A combined index of sCD25, PCT, and estimated glomerular filtration rate (eGFR) was obtained to predict prognosis, named the Improved HLH index (IH index), and patients were divided into three groups meeting IH- (i.e. sCD25 ≤ 18,000 pg/mL, PCT ≤ 1.8 ng/mL, eGFR ≥ 90 mL/min/1.73m²), IH1+ (i.e. only sCD25 > 18,000 pg/mL or only eGFR < 90 mL/min/1.73m²), and IH2+ (i.e. the rest), respectively. In patients with the HScore ≥ 169 or meeting HLH-04, those meeting IH2+ had significantly worse prognoses than those who met IH1+ or IH- (p < 0.001). In the group meeting IH + or IH2+, patients who received allo-HSCT had better prognoses than those who did not (p < 0.05), but there was still a significant difference in prognosis among the three groups in transplanted patients (p < 0.001).

The IH index can early identify adult patients with a poor prognosis of EBV-HLH, initiating timely and appropriate treatment.KEY MESSAGESA combined index of sCD25, PCT, and eGFR was obtained to predict prognosis, named the Improved Hemophagocytic Lymphohistiocytosis index (IH index).IH index can early identify adult patients with a poor prognosis of EBV-HLH, initiating timely and appropriate treatment.