Search Results (79)

Schizophrenia is a challenging multifactorial neuropsychiatric disease that involves interactions between genetic susceptibility and environmental insults. Increasing evidence implicates viral infections as significant environmental contributors, particularly during sensitive neurodevelopmental periods. This review synthesises current findings on the viral hypothesis of schizophrenia, encompassing a wide array of neurotropic viruses, including influenza viruses, herpesviruses (HSV-1 and 2, CMV, VZV, EBV, HHV-6 and 8), hepatitis B and C viruses, HIV, HERVs, HTLV, Zika virus, BoDV, coronaviruses (including SARS-CoV-2), and others. These pathogens can contribute to schizophrenia through mechanisms such as direct microinvasion, persistent central nervous system infection, immune-mediated neuroinflammation, molecular mimicry, and the disturbance of the blood–brain barrier. Prenatal exposure to viral infections can trigger maternal immune activation, resulting in cytokine-mediated alterations in the neurological development of the foetus that persist into adulthood. Genetic studies highlight the role of immune-related loci, including major histocompatibility complex polymorphisms, in modulating susceptibility to infection and neurodevelopmental outcomes. Clinical data also support the “mild encephalitis” hypothesis, suggesting that a subset of schizophrenia cases involve low-grade chronic neuroinflammation. Although antipsychotics have some immunomodulatory effects, adjunctive anti-inflammatory therapies show promise, particularly in treatment-resistant cases. Despite compelling associations, pathogen-specific links remain inconsistent, emphasising the need for longitudinal studies and integrative approaches such as viromics to unravel causal relationships. This review supports a “multi-hit” model in which viral infections interfere with hereditary and immunological susceptibilities, enhancing schizophrenia risk. Elucidating these virus–immune–brain interactions may facilitate the discovery of biomarkers, targeted prevention, and novel therapeutic strategies for schizophrenia. Full article

AIDS-related malignant lymphomas (ARLs) are the lymphomas that develop in association with HIV infection. According to the introduction of combination antiretroviral therapy (cART), the life expectancy of People Living with HIV (PLWH) has markedly improved; however, approximately one-third of PLWH have passed away from the complications of malignancies, even in well-controlled PLWH. HIV itself is not tumorigenic, and most of these tumors are due to co-infection with oncogenic viruses. γ-herpes viruses (Epstein–Barr virus: EBV and Kaposi sarcoma-associated herpesvirus: KSHV) are the most significant risk factors for ARLs. Immunodeficiency, chronic inflammation, accelerated aging, and genetic instability caused by HIV infection, as well as HIV accessory molecules, are thought to promote lymphomagenesis. The prognosis of ARLs is comparable to that of non-HIV cases in the cART era. Intensive chemotherapy with autologous stem cell transplantation is also available for relapsed/refractory ARLs. Since the early stage of HIV infection has no symptoms, significant numbers of HIV-infected individuals have not noticed HIV infection until the onset of AIDS (so-called Ikinari AIDS). Since the ratio of these patients is more than 30% in Japan, hematologists should carefully consider the possibility of HIV infection in cases of lymphoma. Even in an era of cART, ARL remains a critical complication in PLWH, warranting continuous surveillance. 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

Nasal-type extranodal natural killer/T-cell lymphoma (ENKTL) is a rare, aggressive non-Hodgkin lymphoma associated with the Epstein–Barr virus (EBV). It predominantly affects middle-aged men and is most common in East Asia and Latin America. Due to its nonspecific symptoms, including nasal obstruction and discharge, ENKTL is frequently misdiagnosed as chronic rhinosinusitis or fungal infection, leading to delays in diagnosis and treatment. This case report presents a 46-year-old Algerian male with persistent nasal obstruction, foul-smelling nasal discharge, and progressive midfacial destruction. Multiple biopsies initially suggested chronic rhinosinusitis with fungal infection, delaying the definitive diagnosis. Subsequent deep biopsies confirmed ENKTL through histopathological and immunohistochemical analysis. ENKTL is characterized by its locally invasive nature, leading to necrotizing lesions and midfacial destruction. Histopathological confirmation through multiple well-targeted biopsies is crucial to prevent misdiagnosis. However, the prognosis remains poor, with a 5-year survival rate ranging from 20% to 65%. Full article

Background and Clinical Significance: Methotrexate is widely used as a disease-modifying antirheumatic drug for rheumatoid arthritis (RA), yet prolonged immunosuppression may lead to rare complications, including Epstein–Barr virus (EBV)-positive lymphoproliferative disorders (LPDs). Case Presentation: We present the case of a 70-year-old woman with RA on chronic immunosuppressive therapy who developed symptoms resembling recurrent tonsillitis. CT imaging revealed bilateral necrotic palatine tonsils and extensive necrotic lymphadenopathy involving the cervical, mediastinal, and axillary regions. Bilateral tonsillectomy was performed due to concerns about malignancy or infection, and histopathology confirmed a polymorphic EBV-positive LPD with Hodgkin-like features, consistent with iatrogenic immunodeficiency-associated LPD. Methotrexate was subsequently discontinued, and the patient was managed conservatively without systemic chemotherapy. Clinical recovery was observed during follow-up. Conclusions: This case highlights the importance of considering methotrexate-associated LPDs in the differential diagnosis of atypical tonsillar infections in immunosuppressed patients, particularly when necrotic features or systemic lymphadenopathy are present. The pathogenesis may involve EBV reactivation under impaired immune surveillance due to methotrexate, leading to abnormal B-cell proliferation and clonal expansion. This case is contextualized through a comparative analysis of published reports, highlighting clinical features and treatment responses of methotrexate-associated EBV-positive LPDs in the form of a focused literature review. 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

We aim to investigate the role of the Herpesviridae family (HHV) in the onset and progression of prostate cancer (PCa) and to profile the local PCa immunological status. A total of 116 “tru-cut” biopsies (58 PCa and 58 benign prostatic hyperplasia [BPH]) and 49 formalin-fixed paraffin-embedded (FFPE) instances of PCa were analysed using real-time qPCR and histological examination. Infection with CMV, EBV, HHV6, and HHV7 was detected in 11.5% of the “tru-cut” biopsies (25.9% in BPH and 6.9% in the PCa group). In the formalin-fixed paraffin-embedded (FFPE) samples, infection was detected in 69.4% of the patients, with individual rates of EBV (47%), HHV6 (38%), HHV7 (41%), CMV (2.9%), HSV2 (2.9%), and VZV (5.8%). In the HHV-infected PCa cases, the histopathological landscape included intratumor lymphocyte infiltration with fibrosis and necrosis, periductal chronic inflammatory reaction and granulomatous lesions with foci of abscesses and necrosis, as well as inflammatory infiltration, chronic lymphadenitis, prostatic intraepithelial atrophy (PIA), and high-grade prostatic intraepithelial neoplasia (HGPIN). The majority of HHV-infected PCa patients were predominantly classified as grade G3/G4/G5 tumours, exhibiting perineural, perivascular, and lymphovascular invasion, seminal vesicle invasion, senile vesicle amyloidosis, and lymph node metastasis. Statistical analysis demonstrated a significant association between HHV infection and PCa (χ² ≈ 20.3, df = 1, p < 0.0001; Fisher’s exact test, p < 0.0001) with an odds ratio of 6.50 (95% CI: 2.80–15.12). These findings suggest that long-term HHV infection could contribute to a complicated and potentially altered immune PCa tumour environment due to inflammation. This may serve as a predictor of aggressive disease progression. Full article

Epstein–Barr virus (EBV) constitutes a very common pathogen and a well-characterized carcinogen. EBV has the ability to establish a chronic latent infection, during which only a subset of the viral genes is expressed. EBV is implicated in multiple malignancies, including Hodgkin’s lymphoma (HL). HL mainly affects adolescents and young adults and has an overall favorable prognosis. However, relapsed or refractory disease still poses a therapeutic challenge. EBV does not only induce malignant transformation but also hinders the detection and clearance of the neoplastic cells by the immune system. The proteins and non-coding RNAs expressed in latency IIa, which is associated with HL, employ a variety of mechanisms to target different steps of innate and adaptive immunity, to take advantage of the immunosuppressant effect of immune checkpoints, and to shape the microenvironment to support the survival and proliferation of malignant cells. They suppress the expression or promote the degradation of pattern-recognition receptors, interfere with type I interferon and proinflammatory cytokine mediated signaling, and hinder the effector function of natural killer cells. The processing and presentation of peptides to CD4 and CD8 T cells are also hampered. EBV induces the expression of immune checkpoints, the secretion of immunosuppressive cytokines, and the efflux of regulatory T cells in the tumor microenvironment. The current review provides a comprehensive overview of the molecular mechanisms underlying this complex interplay between EBV and the immune system in HL with focus on clinical data from the pediatric population, which is the key for developing novel, effective therapeutic interventions. Full article

Gastric cancer (GC) is one of the most common cancers in the world. It is a multi-factorial disease influenced by both genetic and environmental factors such as diet, obesity, radiation exposure, and infectious agents. Viral infections usually lead to chronic inflammation, which can initiate the development of cancers. To date, only a few studies have been published about Epstein–Barr virus (EBV) and human papillomavirus (HPV) infections in the context of the development of GC. In particular, research on the development of cancer among people under 45 years of age, including the impacts of EBV and HPV, is rare, and clear results have not been obtained. The aim of this study was to analyze the frequency of occurrence of EBV and HPV in GC, particularly in early-onset gastric cancer (EOGC). Tissue material from 135 patients with GC, including 84 men and 51 women, was examined. RT-PCR was performed to detect EBV, and PCR was performed to detect HPV. There were no significant impacts of EBV and HPV infections on any subtype of GC. There was also no statistically significant dependence of gender and location of the tumor on any subtype of GC. Further research on the impacts of infectious agents such as EBV and HPV on GC should be conducted using larger populations. 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

Persistence is a strategy used by many viruses to evade eradication by the immune system, ensuring their permanence and transmission within the host and optimizing viral fitness. During persistence, viruses can trigger various phenomena, including target organ damage, mainly due to an inflammatory state induced by infection, as well as cell proliferation and/or immortalization. In addition to immune evasion and chronic inflammation, factors contributing to viral persistence include low-level viral replication, the accumulation of viral mutants, and, most importantly, maintenance of the viral genome and reliance on viral oncoprotein production. This review focuses on the process of genome integration, which may occur at different stages of infection (e.g., HBV), during the chronic phase of infection (e.g., HPV, EBV), or as an essential part of the viral life cycle, as seen in retroviruses (HIV, HTLV-1). It also explores the close relationship between integration, persistence, and oncogenesis. Several models have been proposed to describe the genome integration process, including non-homologous recombination, looping, and microhomology models. Integration can occur either randomly or at specific genomic sites, often leading to genome destabilization. In some cases, integration results in the loss of genomic regions or impairs the regulation of oncogene and/or oncosuppressor expression, contributing to tumor development. Full article

Chronic kidney disease is a really important heath issue, and transplantation is an intervention that can greatly increase patient quality of life and survival. The aim of this study was to perform a comprehensive evaluation of the BK virus, CMV, and EBV in kidney transplant recipients (KTRs); to assess the prevalence of infections; and to test if our detection method would be feasible for use in follow-ups with KTRs. A total of 157 KTRs registered at the Clinical Hospital “Dr. C. I. Parhon”, Iași, Romania, were selected using specific inclusion/exclusion criteria. We tested the blood samples from each patient for BK, EBV, and CMV using a multiplex real-time PCR (qPCR) assay and the TaqMan PCR principle. The highest prevalence was detected for BKV (11/157, 7%), followed by CMV (9/157, 5.7%) and EBV (5/157, 3.2%). By simultaneously detecting three possible nephropathic viruses and oncogenes in KTRs using multiplex real-time PCR, we aimed to optimize their monitoring and follow-up. The prevalence of the tested nephropathogenic viruses—BKV, CMV, and EBV—was comparable to that analyzed in other studies. We demonstrate that the use of qPCR for viral detection in KTRs is a robust, cost-effective method for case monitoring. Full article

Antiretroviral therapy (ART) has significantly extended the lifespan of people living with Human Immunodeficiency Virus (HIV) or Acquired Immunodeficiency Syndrome (AIDS), thereby transforming the disease into a manageable chronic condition. However, this increased longevity has led to a higher incidence of non-AIDS-defining cancers (NADCs) among this population. In this holistic review, we explore the complex interactions between HIV, ART, and cancer development, focusing on how ART influences tumor initiation and progression in people living with HIV/AIDS (PLWHA). Our findings from this reveal several critical aspects of cancer risk in PLWHA. Firstly, while ART restores immune function, it does not fully normalize it. Chronic immune activation and persistent inflammation continue to be prevalent, creating a conducive environment for oncogenesis. Additionally, PLWHA are more susceptible to persistent infections with oncogenic viruses such as human papillomavirus (HPV) and Epstein–Barr virus (EBV), further increasing cancer risk. Some ART drugs have been implicated in genotoxicity and mitochondrial dysfunction, potentially promoting tumorigenesis. ART-induced metabolic changes, including insulin resistance and dyslipidemia, are also associated with heightened cancer risk. Common NADCs in PLWHA include lung cancer, liver cancer, anal cancer, and Hodgkin lymphoma, each with distinct etiologies linked to both HIV-related and ART-related factors. The interplay between HIV infection, chronic inflammation, immune restoration via ART, and the direct effects of ART drugs creates a unique cancer risk profile in PLWHA. Although ART reduces the incidence of AIDS-defining cancers, it does not confer the same protective effect against NADCs. Persistent HIV-related inflammation and immune activation, despite viral suppression, are key factors in cancer development. Additionally, long-term exposure to ART may introduce new oncogenic risks. These insights highlight the need for integrated cancer screening and prevention strategies tailored to PLWHA. Future research is needed to focus on identifying biomarkers for early cancer detection and developing ART regimens with lower oncogenic potential. Healthcare providers should be vigilant in monitoring PLWHA for cancer and adopt comprehensive screening protocols to mitigate the increased cancer risk associated with ART. Full article

EBV infects more than 90% of people globally, causing lifelong infection. The phases of the EBV life cycle encompass primary infection, latency, and subsequent reactivation or lytic phase. The primary infection usually happens without noticeable symptoms, commonly in early life stages. If it manifests after childhood, it could culminate in infectious mononucleosis. Regarding potential late consequences, EBV is associated with multiple sclerosis, rheumatoid arthritis, chronic active EBV infection, lymphomas, and carcinomas. Previous reports that the lytic phase plays a negligible or merely secondary role in the oncogenesis of EBV-related tumors are steadily losing credibility. The right mechanisms through which the lytic cycle contributes to carcinogenesis are still unclear, but it is now recognized that lytic genes are expressed to some degree in different cancer-type cells, implicating their role here. The lytic infection is a persistent aspect of virus activity, continuously stimulating the immune system. EBV shows different strategies to modulate and avoid the immune system, which is thought to be a key factor in its ability to cause cancer. So, the principal goal of our review is to explore the EBV’s lytic phase contribution to oncogenesis. Full article