Search Results (54)

JC Polyomavirus (JCPyV) is a non-enveloped virus with circular double stranded DNA responsible for the rare but fatal demyelinating disease known as progressive multifocal leukoencephalopathy (PML). In its host, this virus exists in two different forms: one found in the periphery, named archetype, and another found in the central nervous system, named prototype. This form usually harbors recombinations in the non-coding control region (NCCR), a key region that contains sequences regulating viral replication and containing binding sites for cellular transcription factors. This form also contains mutations in the capsid protein, especially VP1. Due to the diversity of the JCPyV, a natural polymorphism also exists between the different genotypes. In this review, we aimed to summarize the main features of the archetype and prototype strains in order to facilitate the interpretation of sequence data that are increasingly generated by new sequencing technologies. This will also help to distinguish mutations associated with the natural polymorphism from those specific to the prototype form. Full article

Colorectal cancer (CRC) remains a significant global health burden, with growing evidence highlighting microbial contributions to its pathogenesis. Certain genotoxigenic bacteria, such as Escherichia coli, Campylobacter jejuni, and Helicobacter pylori, produce virulence factors that induce DNA damage, genomic instability, and chronic inflammation—key features of carcinogenesis. At the same time, viruses such as JC polyomavirus (JCPyV), considered potentially oncogenic, and established oncogenic viruses like Epstein–Barr virus (EBV) and human papillomavirus (HPV) have been detected in colorectal tissues and are linked to cell cycle regulation, apoptosis, and DNA repair through their viral proteins. Intriguingly, recent findings suggest that bacterial genotoxins may promote the reactivation or transcriptional activity of persistent viruses such as JCPyV and EBV, possibly through DNA damage-induced stress and activation of NF-κB- or ATM-dependent signaling pathways. Despite these advances, interactions between oncogenic viruses and bacteria within the colon microbiome remain underexplored. This review integrates current evidence and provides future perspectives for addressing potential genotoxic collaboration between bacteria and viruses that could contribute to colorectal tumorigenesis. Elucidating these interactions could reveal novel biomarkers and therapeutic targets for the prevention and treatment of CRC. Full article

Background/Objectives: The genitourinary microbiome and metabolome may contribute to prostate cancer (PC) biology, but evidence remains limited. This pilot study characterizes the urinary microbiota and volatilome in men with PC and investigates microbial and viral DNA in prostate tissue, comparing findings with benign prostatic hyperplasia (BPH). Methods: We prospectively enrolled 21 non-metastatic PC patients undergoing radical prostatectomy and 17 BPH controls. Lesional and non-lesional prostate tissues and urine were collected from PC patients, as well as urine samples from BPH participants. DNA samples were tested for sexually transmitted pathogens by multiplex real-time PCR. Urine and prostate tissue were analyzed for human polyomaviruses (JCPyV, BKPyV, MCPyV) by qPCR, bacterial profiles via 16S rRNA gene sequencing, and urinary volatile organic metabolites (VOMs) using HS-SPME/GC-MS. Microbial and metabolic profiles were compared, and taxa–metabolites were assessed. Results: JCPyV and BKPyV were detected in urine and tissue from PC patients; MCPyV was detected only in tissue, at low frequency. In BPH, viral prevalence was lower and MCPyV was absent. JCPyV/BKPyV co-infection was common in cancer. No sexually transmitted pathogen emerged. PC patients showed greater urinary microbial diversity and five enriched genera, along with specific metabolic pathways. 36 urinary VOMs were identified, with 14 differing significantly, with positive correlations between PC-associated genera and metabolites. In contrast, prostate tissue was low-biomass, dominated by Pseudomonas, and showed no significant differences between lesional and non-lesional areas. Conclusions: This preliminary, hypothesis-generating study indicates that urinary, rather than tissue, microbial and volatilome signatures show clearer differences between PC and BPH. These findings suggest possible microbiota–metabolite interactions in PC but require validation in larger cohorts. Full article

Polyomaviruses (BKPyV and JCPyV) and herpesviruses (EBV, CMV) usually infect people during childhood, and may be associated, in some clinical states, with immunocompromised individuals. The aim of this study was to investigate the occurrence and coexistence of polyomavirus (BKPyV and JCPyV) and herpesvirus (CMV and EBV) DNAemia in pediatric hematology/oncology patients, including HCT recipients, and to assess the clinical relevance of polyomaviruses DNAemia. Whole blood samples of 99 children (including 71 patients undergoing HCT) were analyzed for the DNA of the herpes- and polyomaviruses. Co-existence of herpesvirus DNAemia was checked for the patients and clinically analyzed in detail, especially for those positive for BKPyV DNA. BKPyV DNAemia was detected in 15 (15.2%) patients, with viral loads ranging from 1.2 × 10³–1.7 × 10⁷ DNA IU/mL. No JCPyV DNA was detected in any of the samples. Coinfections with EBV or CMV DNAemia were observed in a subset of BKPyV-positive patients. BKPyV DNAemia was more frequent among children with leukemia and in those undergoing HCT. Our findings highlight the clinical associations between BKPyV and herpesvirus DNAemia in immunocompromised pediatric patients. Routine BKPyV DNA monitoring, alongside standard herpesvirus screening, may provide clinically valuable insights in high-risk pediatric cohorts, particularly those with hematologic malignancies and post-HCT status. Full article

Background/Objectives: Recently, many researchers have evaluated various viruses, including polyomaviruses (JCV, BKV) and EBV, as potential factors playing a role in the development and/or progression of prostate cancer (PCa), one of the most common cancers in men. Therefore, we aimed to assess the frequency of the JCPyV DNA in tissue collected from PCa patients. Methods: We detected the presence of viral DNA (PCR) in 49.6% of clinical samples, including 71.9% with single EBV infection and 28.1% with EBV/JCV co-infection. We did not detect BKV or a single JCV infection. Therefore, we compared patients with EBV mono-infection with EBV/JCV co-infected patients in the context of risk group, Gleason score, and TNM classification. Results: Our results showed differences in clinicopathological features between single EBV infection and EBV/JCV co-infection. In the group of patients with single EBV infection, most patients were classified as medium/high risk, while in the group with EBV/JCV co-infection, most patients were classified as low risk. Conclusions: Among patients with single EBV infection, a more advanced stage of cancer was observed than in EBV/JCV co-infection. Moreover, the level of anti-EBVCA and anti-EBNA antibodies as well as EBV load was higher in the case of single infection compared to EBV/JCV co-infection. Higher antibody levels were detected in more advanced tumor stages in single EBV infection. Does JCV only “reside” in prostate cells or is it a co-factor in EBV infection? In light of these studies, there is a need to clarify the role of JCV virus in the development and/or progression of prostate cancer. Full article

Polyomaviruses (PyVs) are non-enveloped double-stranded DNA viruses that can cause significant morbidity in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients, particularly BK polyomavirus (BKPyV) and JC polyomavirus (JCPyV). BKPyV is primarily associated with hemorrhagic cystitis (HC), while JCPyV causes progressive multifocal leukoencephalopathy (PML). The pathogenesis of these diseases involves viral reactivation under immunosuppressive conditions, leading to replication in tissues such as the kidney, bladder, and central nervous system. BKPyV-HC presents as hematuria and urinary symptoms, graded by severity. PML, though rare after allo-HSCT, manifests as neurological deficits due to JCPyV replication in glial cells. Diagnosis relies on nucleic acid amplification testing for DNAuria or DNAemia as well as clinical criteria. Management primarily involves supportive care, as no antiviral treatments have proven consistently effective for either virus and need further research. This review highlights the virology, clinical presentations, and management challenges of PyV-associated diseases post-allo-HSCT, emphasizing the need for improved diagnostic tools and therapeutic approaches to mitigate morbidity and mortality in this vulnerable population. Full article

JC polyomavirus (JCPyV) establishes a persistent, asymptomatic kidney infection in most of the population. However, JCPyV can reactivate in immunocompromised individuals and cause progressive multifocal leukoencephalopathy (PML), a fatal demyelinating disease with no approved treatment. Mutations in the hypervariable non-coding control region (NCCR) of the JCPyV genome have been linked to disease outcomes and neuropathogenesis, yet few metanalyses document these associations. Many online sequence entries, including those on NCBI databases, lack sufficient sample information, limiting large-scale analyses of NCCR sequences. Machine learning techniques, however, can augment available data for analysis. This study employs a previously compiled dataset of 989 JCPyV NCCR sequences from GenBank with associated patient PML status and viral tissue source to train multilayer perceptrons for predicting missing information within the dataset. The PML status and tissue source models were 100% and 87.8% accurate, respectively. Within the dataset, 348 samples had an unconfirmed PML status, where 259 were predicted as No PML and 89 as PML sequences. Of the 63 sequences with unconfirmed tissue sources, eight samples were predicted as urine, 13 as blood, and 42 as cerebrospinal fluid. These models can improve viral sequence identification and provide insights into viral mutations and pathogenesis. Full article

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease caused by the JC polyomavirus (JCPyV). Based on the clinical criteria, PML is diagnosed via polymerase chain reaction (PCR) detection of JCPyV DNA in cerebrospinal fluid (CSF) in combination with neurological and imaging findings. Although the utility of CSF JCPyV testing using ultrasensitive PCR assays has been suggested, its potential requires further evaluation. This study retrospectively analyzed the detection performance of ultrasensitive PCR for CSF JCPyV in patients who underwent brain tissue examination based on the pathological diagnostic criteria for PML. Of the 110 patients with pathologically confirmed definite PML or not PML, standard and ultrasensitive CSF testing was performed for 36 and 74 patients, respectively. The sensitivity of ultrasensitive CSF JCPyV testing of the initial specimens was 85%. With the addition of the follow-up testing, this figure increased to 95%. The specificity and false-positive rate of ultrasensitive CSF JCPyV testing, including follow-up, were 100% and 0%, respectively. No statistically significant correlation was observed between CSF and brain JCPyV levels. The results of this study demonstrate the high sensitivity and accuracy of ultrasensitive CSF JCPyV testing and provide essential information for the clinical diagnosis of PML. Full article

JC polyomavirus (JCPyV) infects the majority of the population and initially establishes a persistent but asymptomatic infection of the kidneys. In healthy individuals, the infection remains controlled by the host immune system, but for individuals experiencing prolonged immunosuppression, the infection can reactivate and spread to the brain, where it causes progressive multifocal leukoencephalopathy (PML), which is a fatal neurodegenerative disease. Currently, there are no approved therapies to treat PML, and affected individuals suffer rapid motor weakness and cognitive deterioration. To identify novel therapeutic treatments for JCPyV infection, receptor agonists/antagonists identified in a previously published drug screen were evaluated for their antiviral properties. Seven drugs were selected and validated using infectivity assays, and the mechanism of inhibition was further explored for G protein coupled receptor (GPCR)-associated inhibitors due to the role of the GPCR 5-hydroxytryptamine 2 receptors (5-HT₂Rs) in JCPyV entry. The inhibitors cetirizine and paroxetine both reduced infection early in the JCPyV infectious cycle. Paroxetine specifically reduced viral internalization through altering the receptor density of 5-HT_2CR, inhibiting β-arrestin recruitment to the receptor, and reducing MAPK signaling through ERK. These findings highlight the potential of receptor signaling and viral entry mechanisms as possible targets for antiviral drug development. Further, this research suggests that FDA-approved receptor agonists/antagonists currently used to treat other medical conditions could be repurposed into antivirals for the possible treatment of JCPyV infection and the fatal disease PML. Full article

Worldwide, the incidence of renal cell carcinoma (RCC) is rising, accounting for approximately 2% of all cancer diagnoses and deaths. The etiology of RCC is still obscure. Here, we assessed the presence of HPyVs in paraffin-embedded tissue (FFPE) resected tissue from patients with RCC by using different molecular techniques. Fifty-five FFPE tissues from 11 RCC patients were included in this study. Consensus and HPyV-specific primers were used to screen for HPyVs. Both PCR approaches revealed that HPyV is frequently detected in the tissues of RCC kidney resections. A total of 78% (43/55) of the tissues tested were positive for at least one HPyV (i.e., MCPyV, HPyV6, HPyV7, BKPyV, JCPyV, or WUyV). Additionally, 25 tissues (45%) were positive for only one HPyV, 14 (25%) for two HPyVs, 3 (5%) for three HPyVs, and 1 one (1%) tissue specimen was positive for four HPyVs. Eleven (20%) RCC specimens were completely devoid of HPyV sequences. MCPyV was found in 24/55 RCC tissues, HPyV7 in 19, and HPyV6 in 8. The presence of MCPyV and HPyV6 was confirmed by specific FISH or RNA-ISH. In addition, we aimed to confirm HPyV gene expression by IHC. Our results strongly indicate that these HPyVs infect RCC and nontumor tissues, possibly indicating that kidney tissues serve as a reservoir for HPyV latency. Whether HPyVs possibly contribute to the etiopathogenesis of RCC remains to be elucidated. Full article

Cigarette smoking is a primary contributor to mortality risks and is associated with various diseases. Among these, COPD represents a significant contributor to global mortality and disability. The objective of this study is to investigate the effect of smoking on a selected battery of variables, with an emphasis on DNA damage. A total of 87 elderly patients diagnosed with COPD, divided into three groups based on their smoking history (current, former, never-smokers), were evaluated using a cross-sectional approach. Clinical features including mortality and inflammatory/oxidative parameters (Lymphocytes/Monocytes, Neutrophils/Lymphocytes, Platelets/Lymphocytes ratio), SII, MDA, 8-Oxo-dG, and IL6 (ELISA assay), as well as DNA damage (comet assay), were investigated. Virus infection, i.e., influenza A virus subtype H1N1, JC polyomavirus (JCPyV), BK polyomavirus (BKPyV), and Torquetenovirus (TTV), was also tested. Current smokers exhibit higher levels of comorbidity (CIRS; p < 0.001), Platelets/Lymphocytes ratio (p < 0.001), systemic immune inflammation (p < 0.05), and DNA damage (p < 0.001). Former smokers also showed higher values for parameters associated with oxidative damage and showed a much lower probability of surviving over 5 years compared to never- and current smokers (p < 0.0017). This study showed a clear interaction between events which are relevant to the oxidative pathway and cigarette smoking. A category of particular interest is represented by former smokers, especially for lower survival, possibly due to the presence of more health problems. Our findings raise also the attention to other parameters which are significantly affected by smoking and are useful to monitor COPD patients starting a program of pulmonary rehabilitation (DNA damage, inflammation parameters, and selected viral infections). Full article

Progressive Multifocal Leukoencephalopathy (PML) is a possibly fatal demyelinating disease and John Cunningham Polyomavirus (JCPyV) is believed to cause this condition. The so-called JCPyV was initially reported in lymphoma and Human Immunodeficiency Virus (HIV) cases, whereas nowadays, its incidence is increasing in Multiple Sclerosis (MS) cases treated with natalizumab (Tysabri). However, there are conflicting literature data on its pathology and diagnosis, whereas some misdiagnosed reports exist, giving rise to further questions towards the topic. In reality, the so-called PML and the supposed JCPyV are not what they seem to be. In addition, novel and more frequent PML-like conditions may be reported, especially after the Coronavirus Disease 2019 (COVID-19) pandemic. Full article

Pituitary neuroendocrine tumors (PitNETs) are generally benign but comprise an aggressive, invasive, therapy-resistant, metastatic subset, underpinning a need for novel therapeutic targets. PitNETs exhibit low mutation rates but are associated with conditions linked to alternative splicing, an alternative oncogene pathway activation mechanism. PitNETs express the neurotrophin receptor TrkA, which exhibits oncogenic alternative TrkAIII splicing in other neuroendocrine tumors. We, therefore, assessed whether TrkAIII splicing represents a potential oncogenic participant in PitNETs. TrkAIII splicing was RT-PCR assessed in 53 PitNETs and TrkA isoform(s) expression and activation were assessed by confocal immunofluorescence. TrkAIII splicing was also compared to HIF1α, HIF2α, SF3B1, SRSF2, U2AF1, and JCPyV large T antigen mRNA expression, Xbp1 splicing, and SF3B1 mutation. TrkAIII splicing was detected in all invasive and most non-invasive PitNETs and was significantly elevated in invasive cases. In PitNET lineages, TrkAIII splicing was significantly elevated in invasive PIT1 PitNETs and high in invasive and non-invasive SF1 and TPIT lineages. Immunoreactivity consistent with TrkAIII activation characterized PitNET expressing TrkAIII mRNA, and invasive Pit1 PitNETs exhibited elevated HIF2α expression. TrkAIII splicing did not associate with SF3B1 mutations, altered SF3B1, SRSF2, and U2AF1 or JCPyV large T antigen expression, or Xbp1 splicing. Therefore, TrkAIII splicing is common in PitNETs, is elevated in invasive, especially PIT1 tumors, can result in intracellular TrkAIII activation, and may involve hypoxia. The data support a role for TrkAIII splicing in PitNET pathogenesis and progression and identify TrkAIII as a novel potential target in refractory PitNETs. Full article

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system (CNS) caused by reactivation of dormant JC polyomavirus (JCPyV). PML was mainly observed in immunocompromised individuals, such as HIV-positive patients, autoimmune disease patients, and cancer patients. Given that the presence of anti-JCPyV antibodies in serum is a risk indicator for PML development, it is essential to monitor anti-JCPyV antibody levels. In the present study, we established reporter-based single-infection neutralization assays for JCPyV and the genetically similar BK polyoma virus (BKPyV). We then confirmed the lack of cross-reactivity between the two viruses using test sera obtained from mice immunized with plasmids encoding the JCPyV or BKPyV capsid. Next, we compared neutralization antibody titers in sera from healthy donors, patients with multiple sclerosis (MS), and HIV-positive patients using an in-house enzyme-linked immunosorbent assay (ELISA) with JCPyV-like particles (virus-like particles; VLPs). A positive correlation was demonstrated between the neutralization titer (75% infectious concentration; IC75) against JCPyV and the antibody titer obtained by VLP-based JCPyV ELISA. This assay system may be applied to detect antibodies against other PyVs by generation of pseudoviruses using the respective capsid expression plasmids, and is expected to contribute to the surveillance of PyV as well as basic research on these viruses. Full article

Background and Objectives: John Cunningham polyomavirus (JCPyV) is a highly prevalent virus in the human population. The prevalence of JCPyV in patients with central nervous system disorders has not been examined extensively. The aim of this study was to analyze the prevalence of JCPyV DNA/antibodies in patients with neuroinvasive diseases (NID) of unknown etiology. Materials and Methods: The study included 132 patients with NID (febrile headache, meningitis, encephalitis) tested from January 2021 to December 2022. The control group consisted of 47 asymptomatic individuals. In patients with NID, serum and cerebrospinal fluid (CSF) samples were collected in the acute phase of the disease. CSF samples were tested for JCPyV DNA (PCR), while serum samples were tested for JCPyV IgG antibodies (ELISA). In controls, serum samples were tested for JCPyV IgG antibodies (ELISA). Results: JCPyV DNA was not detected in any of the CSF samples from patients with NID. JCPyV IgG antibodies were detected in 88.6% of patients and 74.5% of controls (p < 0.001). In the patients’ group, a significant difference in the IgG prevalence was observed between males (94.6%) and females (81.0%). In addition, significant differences in the seropositivity between age groups were found. The lowest seroprevalence (28.6%) was in patients less than 20 years, followed by a sharp increase in the 20–29-year group (69.2%), after which the seroprevalence remained stable (90.0–94.1%) in patients up to 69 years. All patients older than 70 years were JCPyV IgG-seropositive. No significant difference in the seroprevalence was found in patients presenting with febrile headache (81.6%), meningitis (93.3%), or meningoencephalitis (91.3%). No difference in the seropositivity between genders was found in controls. Although the seropositivity steadily increased in older participants, these differences were not significant. Analyzing the JCPyV antibody levels in patients with NID, the median antibody titers differed significantly between groups, ranging from 248 AU/mL (younger age groups) to 400 AU/mL (older age groups). Conclusions: Higher seroprevalence in the patients’ group highlights the need to further investigate the possible association of JCPyV and NID. Full article