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American Journal of Transplantation :... May 2024BK polyomavirus (BKPyV) infection causes various diseases in immunocompromised patients. Cells from human lung and kidney were infected with BKPyV and treated with...
BK polyomavirus (BKPyV) infection causes various diseases in immunocompromised patients. Cells from human lung and kidney were infected with BKPyV and treated with commercially available intravenous immunoglobulin G (IVIG). Its effects on BKPyV replication and spread of infection were investigated, focusing on administration timing. IVIG treatment 3 hours after infection suppressed BKPyV replication assessed by real-time PCR and expression of the viral capsid protein 1 and large T-antigen. IVIG effectively reduced the number of BKPyV-infected cells 2 weeks after infection in an antibody titer-dependent manner. Virus release in the culture supernatants was not influenced by IVIG treatment 6-80 hours and 3-9 days after infection. Collectively, IVIG did not affect viral release from infected cells but inhibited the spread of infection by neutralizing the released virus and blocking the new infected cell formation, indicating greater efficacy in early localized infection. BKPyV replication resumed in IVIG-treated cultures at 7 days after IVIG removal. Early prophylactic administration of IVIG is expected to reduce the growth and spread of BKPyV infection, resulting in the reduction of infected cell lesions and prevention of BKPyV-associated diseases.
Topics: Humans; BK Virus; Virus Replication; Polyomavirus Infections; Immunoglobulins, Intravenous; Tumor Virus Infections; Cells, Cultured; Immunoglobulin G
PubMed: 37977231
DOI: 10.1016/j.ajt.2023.11.007 -
Medicina (Kaunas, Lithuania) Jul 2023C3 glomerulonephritis (C3GN) is a rare cause of end-stage kidney disease and frequently recurrent in allografts following kidney transplantation (KT). Herein, we...
C3 glomerulonephritis (C3GN) is a rare cause of end-stage kidney disease and frequently recurrent in allografts following kidney transplantation (KT). Herein, we describe the case of a kidney transplant recipient who developed recurrent C3GN along with BK-virus-associated nephropathy (BKVAN) following KT. A 33-year-old man diagnosed with membranoproliferative glomerulonephritis 17 years ago underwent preemptive KT with a donor kidney from his aunt. Proteinuria gradually increased after 3 months following KT, and graft biopsy was performed 30 months after KT. Histopathological examination revealed recurrent C3GN. The dosages of triple immunosuppressive maintenance therapy agents were increased. Subsequently, serum C3 levels recovered to normal levels. However, at 33 months following KT, the BK viral load increased and graft function gradually deteriorated; a second graft biopsy was performed at 46 months following KT, which revealed BKVAN and decreased C3GN activity. The dosages of immunosuppressive agents were decreased; subsequently, BKVAN improved and graft function was maintained with normal serum C3 levels at 49 months following KT. This case indicates that C3GN is highly prone to recurrence following KT and that immunosuppressive therapy for C3GN increases the risk of BKVAN.
Topics: Male; Humans; Adult; Kidney Transplantation; Glomerulonephritis; Immunosuppressive Agents; Glomerulonephritis, Membranoproliferative; Nephritis, Interstitial
PubMed: 37512118
DOI: 10.3390/medicina59071308 -
BMC Research Notes Dec 2023Prior studies have shown controversial results on the vertical transmission of BK virus (BKV). The present study aimed to assess the possibility of BKV vertical...
OBJECTIVE
Prior studies have shown controversial results on the vertical transmission of BK virus (BKV). The present study aimed to assess the possibility of BKV vertical transmission from mother to fetus in the product of conception (embryo, fetuses, and/or placentas) over the three stages of pregnancy.
RESULTS
Of the 26 placental studied tissues, 6 were in the first trimester, and none of which were positive. Only one out of the 13 (7.7%) placental materials in the second trimester was positive. Only one out of 7 (14%) placental materials of the third trimester was positive. There were cases that no virus was detected in their placental but BKV was detected in their other tissues. Among 26 conceptuses, 17 (65%) were negative for BKV and 9 (34.6%) were positive, 7/13 (54%) were positive in the second, and 2/7 (29%) were positive in the third trimester fetuses. BKV was most frequently detected in the liver (eight cases), heart (three cases), and placenta (2 cases). There were cases that no virus was detected in their placental but BKV was detected in their other tissues.
Topics: Pregnancy; Female; Humans; Placenta; Pregnancy Trimester, Third; BK Virus; Pregnancy Complications, Infectious; Fetus; Polyomavirus Infections
PubMed: 38082354
DOI: 10.1186/s13104-023-06643-1 -
Microbiology Spectrum Mar 2024Porcine reproductive and respiratory syndrome virus (PRRSV) is an RNA virus with constantly emerging recombinant and mutant strains. Because of the high genetic...
UNLABELLED
Porcine reproductive and respiratory syndrome virus (PRRSV) is an RNA virus with constantly emerging recombinant and mutant strains. Because of the high genetic diversity of PRRSV, current vaccines only provide partial protection against the infection of heterologous strains, which makes it a challenge for PRRSV prevention and control. Tubercidin is a naturally extracted compound with potential antiviral properties. However, whether tubercidin has anti-PRRSV ability is unknown. Our study found that tubercidin showed effective antiviral effects on PRRSV replication. In terms of mechanism, tubercidin suppressed PRRSV at the entry, replication, and release steps of the viral life cycle. Additionally, we demonstrated that tubercidin treatment promoted the activation of retinoic acid-inducible gene I and nuclear factor kappa-light-chain-enhancer of activated B cell signaling pathway, thus increasing the type I interferon and inflammatory cytokine expression. Furthermore, tubercidin restrained the viral non-structural protein 2 expression and viral dsRNA synthesis and ultimately inhibited PRRSV replication. Hence, our data showed that tubercidin is promising and has potential antiviral ability against PRRSV replication .
IMPORTANCE
Porcine reproductive and respiratory syndrome (PRRS) is one of the most important swine diseases, which causes huge economic loss worldwide. However, there is no effective therapeutic method for PRRS prevention and control. Here, we found that tubercidin, a naturally extracted adenosine analog, exhibited strong anti-porcine reproductive and respiratory syndrome virus (PRRSV) activity. Mechanically, tubercidin inhibited viral binding, replication, and release. Tubercidin suppressed PRRSV non-structural protein 2 expression, which is important for the formation of replication and transcription complex, leading to the block of viral RNA synthesis and PRRSV replication. Moreover, tubercidin could activate retinoic acid-inducible gene I/nuclear factor kappa-light-chain-enhancer of activated B cell innate immune signaling pathway and increased the expression of interferons and proinflammatory cytokines, which was the other way to inhibit PRRSV replication. Our work evaluated the potential value of tubercidin as an antiviral agent on PRRSV replication and provided a new way to prevent PRRSV replication .
Topics: Swine; Animals; Porcine respiratory and reproductive syndrome virus; NF-kappa B; Porcine Reproductive and Respiratory Syndrome; Tubercidin; Cytokines; DEAD Box Protein 58; Antiviral Agents; Tretinoin
PubMed: 38299833
DOI: 10.1128/spectrum.03479-23 -
Journal of Clinical Medicine Apr 2024The John Cunningham virus (JCV) is a polyomavirus that usually infects people at a young age and does not cause any symptoms in immunocompetent individuals. However, in... (Review)
Review
The John Cunningham virus (JCV) is a polyomavirus that usually infects people at a young age and does not cause any symptoms in immunocompetent individuals. However, in immunocompromised individuals, such as kidney transplant recipients, JCV can cause severe and potentially fatal disease. Unfortunately, JCV has not been researched as extensively as the BK virus and is not mentioned in relevant kidney transplant guidelines. This lack of attention to JCV can lead to less consideration in kidney transplant patients' care. Surveillance using locally available diagnostic methods is of the utmost importance. The presence of JCV can be diagnosed with urine decoy cells, viruria, or viremia verified by the PCR method. A low threshold for considering JCV as a possible cause of any neurological or renal dysfunction in kidney transplant recipients must be maintained. In such cases, kidney and brain biopsy are indicated. Maintaining the appropriate immunosuppression while avoiding over-immunosuppression to prevent JCV disease is crucial, and the approach should be individual, according to overall immunological risk. We hypothesize that the presence of the JCV can indicate overt immunosuppression and identify kidney transplant recipients more prone to opportunistic infections and diseases, including some malignancies. To explore that, future observational studies are needed.
PubMed: 38673491
DOI: 10.3390/jcm13082217 -
Infection Aug 2023BK Polyomavirus (BKPyV) infection manifests as renal inflammation and can cause kidney damage. Tumor necrosis factor-α (TNF-α) is increased in renal inflammation and...
PURPOSE
BK Polyomavirus (BKPyV) infection manifests as renal inflammation and can cause kidney damage. Tumor necrosis factor-α (TNF-α) is increased in renal inflammation and injury. The aim of this study was to investigate the effect of TNF-α blockade on BKPyV infection.
METHODS
Urine specimens from 22 patients with BKPyV-associated nephropathy (BKPyVN) and 35 non-BKPyVN kidney transplant recipients were analyzed.
RESULTS
We demonstrated increased urinary levels of TNF-α and its receptors, TNFR1 and TNFR2, in BKPyVN patients. Treating BKPyV-infected human proximal tubular cells (HRPTECs) with TNF-α stimulated the expression of large T antigen and viral capsid protein-1 mRNA and proteins and BKPyV promoter activity. Knockdown of TNFR1 or TNFR2 expression caused a reduction in TNF-α-stimulated viral replication. NF-κB activation induced by overexpression of constitutively active IKK2 significantly increased viral replication and the activity of the BKPyV promoter containing an NF-κB binding site. The addition of a NF-κB inhibitor on BKPyV-infected cells suppressed viral replication. Blockade of TNF-α functionality by etanercept reduced BKPyV-stimulated expression of TNF-α, interleukin-1β (IL-1β), IL-6 and IL-8 and suppressed TNF-α-stimulated viral replication. In cultured HRPTECs and THP-1 cells, BKPyV infection led to increased expression of TNF-α, interleukin-1 β (IL-1β), IL-6 and TNFR1 and TNFR2 but the stimulated magnitude was far less than that induced by poly(I:C). This may suggest that BKPyV-mediated autocrine effect is not a major source of TNFα.
CONCLUSION
TNF-α stimulates BKPyV replication and inhibition of its signal cascade or functionality attenuates its stimulatory effect. Our study provides a therapeutic anti-BKPyV target.
Topics: Humans; BK Virus; Tumor Necrosis Factor-alpha; Receptors, Tumor Necrosis Factor, Type I; Receptors, Tumor Necrosis Factor, Type II; NF-kappa B; Interleukin-6; Polyomavirus Infections; Inflammation
PubMed: 36512270
DOI: 10.1007/s15010-022-01962-0 -
PLoS Biology Mar 2024Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has affected approximately 800 million people since the start of the Coronavirus Disease 2019 (COVID-19)...
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has affected approximately 800 million people since the start of the Coronavirus Disease 2019 (COVID-19) pandemic. Because of the high rate of mutagenesis in SARS-CoV-2, it is difficult to develop a sustainable approach for prevention and treatment. The Envelope (E) protein is highly conserved among human coronaviruses. Previous studies reported that SARS-CoV-1 E deficiency reduced viral propagation, suggesting that E inhibition might be an effective therapeutic strategy for SARS-CoV-2. Here, we report inhibitory peptides against SARS-CoV-2 E protein named iPep-SARS2-E. Leveraging E-induced alterations in proton homeostasis and NFAT/AP-1 pathway in mammalian cells, we developed screening platforms to design and optimize the peptides that bind and inhibit E protein. Using Vero-E6 cells, human-induced pluripotent stem cell-derived branching lung organoid and mouse models with SARS-CoV-2, we found that iPep-SARS2-E significantly inhibits virus egress and reduces viral cytotoxicity and propagation in vitro and in vivo. Furthermore, the peptide can be customizable for E protein of other human coronaviruses such as Middle East Respiratory Syndrome Coronavirus (MERS-CoV). The results indicate that E protein can be a potential therapeutic target for human coronaviruses.
Topics: Mice; Animals; Chlorocebus aethiops; Humans; SARS-CoV-2; COVID-19; Cell Line; Vero Cells; Peptides; Mammals
PubMed: 38483887
DOI: 10.1371/journal.pbio.3002522 -
Cancer Prevention Research... Oct 2023FGFR3 and PIK3CA are among the most frequently mutated genes in bladder tumors. We hypothesized that recurrent mutations in these genes might be caused by common...
UNLABELLED
FGFR3 and PIK3CA are among the most frequently mutated genes in bladder tumors. We hypothesized that recurrent mutations in these genes might be caused by common carcinogenic exposures such as smoking and other factors. We analyzed 2,816 bladder tumors with available data on FGFR3 and/or PIK3CA mutations, focusing on the most recurrent mutations detected in ≥10% of tumors. Compared to tumors with other FGFR3/PIK3CA mutations, FGFR3-Y375C was more common in tumors from smokers than never-smokers (P = 0.009), while several APOBEC-type driver mutations were enriched in never-smokers: FGFR3-S249C (P = 0.013) and PIK3CA-E542K/PIK3CA-E545K (P = 0.009). To explore possible causes of these APOBEC-type mutations, we analyzed RNA sequencing (RNA-seq) data from 798 bladder tumors and detected several viruses, with BK polyomavirus (BKPyV) being the most common. We then performed IHC staining for polyomavirus (PyV) Large T-antigen (LTAg) in an independent set of 211 bladder tumors. Overall, by RNA-seq or IHC-LTAg, we detected PyV in 26 out of 1,010 bladder tumors with significantly higher detection (P = 4.4 × 10-5), 25 of 554 (4.5%) in non-muscle-invasive bladder cancers (NMIBC) versus 1 of 456 (0.2%) of muscle-invasive bladder cancers (MIBC). In the NMIBC subset, the FGFR3/PIK3CA APOBEC-type driver mutations were detected in 94.7% (18/19) of PyV-positive versus 68.3% (259/379) of PyV-negative tumors (P = 0.011). BKPyV tumor positivity in the NMIBC subset with FGFR3- or PIK3CA-mutated tumors was also associated with a higher risk of progression to MIBC (P = 0.019). In conclusion, our results support smoking and BKPyV infection as risk factors contributing to bladder tumorigenesis in the general patient population through distinct molecular mechanisms.
PREVENTION RELEVANCE
Tobacco smoking likely causes one of the most common mutations in bladder tumors (FGFR3-Y375C), while viral infections might contribute to three others (FGFR3-S249C, PIK3CA-E542K, and PIK3CA-E545K). Understanding the causes of these mutations may lead to new prevention and treatment strategies, such as viral screening and vaccination.
Topics: Humans; Urinary Bladder Neoplasms; Mutation; Urinary Bladder; Class I Phosphatidylinositol 3-Kinases; Virus Diseases
PubMed: 37477495
DOI: 10.1158/1940-6207.CAPR-23-0112 -
Molecular Therapy : the Journal of the... Oct 2023Spinal muscular atrophy is an autosomal recessive disease resulting in motor neuron degeneration and progressive life-limiting motor deficits when untreated....
Spinal muscular atrophy is an autosomal recessive disease resulting in motor neuron degeneration and progressive life-limiting motor deficits when untreated. Onasemnogene abeparvovec is an adeno-associated virus serotype 9-based gene therapy that improves survival, motor function, and motor milestone achievement in symptomatic and presymptomatic patients. Although the adeno-associated virus genome is maintained as an episome, theoretical risk of tumorigenicity persists should genomic insertion occur. We present the case of a 16-month-old male with spinal muscular atrophy who was diagnosed with an epithelioid neoplasm of the spinal cord approximately 14 months after receiving onasemnogene abeparvovec. In situ hybridization analysis detected an onasemnogene abeparvovec nucleic acid signal broadly distributed in many but not all tumor cells. Integration site analysis on patient formalin-fixed, paraffin-embedded tumor samples failed to detect high-confidence integration sites of onasemnogene abeparvovec. The finding was considered inconclusive because of limited remaining tissue/DNA input. The improved life expectancy resulting from innovative spinal muscular atrophy therapies, including onasemnogene abeparvovec, has created an opportunity to analyze the long-term adverse events and durability of these therapies as well as identify potential disease associations that were previously unrecognized because of the premature death of these patients.
PubMed: 37598295
DOI: 10.1016/j.ymthe.2023.08.013 -
Effect of Leflunomide on Treatment of Pediatric Renal Transplant Recipients With BK Virus Infection.Experimental and Clinical... Oct 2023Infection with the BK virus is a significant complication after renal transplant and can progress to BK virus nephropathy and graft dysfunction. There is no consensus on...
OBJECTIVES
Infection with the BK virus is a significant complication after renal transplant and can progress to BK virus nephropathy and graft dysfunction. There is no consensus on the management of BK virus infection in pediatric renal transplant recipients. The most common therapeutic option is immunosuppression reduction, which can increase rejection risk. We aimed to examine the effect of leflunomide, an agent with antiviral and immunosuppressive actions, in a case series of pediatric renal transplant recipients with BK virus infection.
MATERIALS AND METHODS
Routine screening with blood BK virus DNA polymerase chain reaction was performed regularly in all of our renal transplant patients. When BK virus was detected, we reduced tacrolimus levels, discontinued mycophenolate mofetil, and started active treatment with leflunomide. Treatment with leflunomide was continued until BK virus was undetectable by polymerase chain reaction in at least 2 blood samples 2 weeks apart.
RESULTS
All pediatric patients developed BK virus infection in a mean period of 3.9 months after transplant. Graft dysfunction was evident in all patients with 20% to 100% elevation of creatinine from baseline. Afterleflunomide initiation, all patients had undetectable levels of BK virus by plasma polymerase chain reaction in at least 2 different samples within a mean period of 3.4 months, and renal function had normalized back to the baseline. None of our patients had evidence of hepatotoxicity or anemia on regular monitoring, with no other adverse events. Renal function remained stable in the follow-up period with no reoccurrence of BK viremia up to the date of this writing.
CONCLUSIONS
Treatment with leflunomide resulted in rapid BK virus clearance and preservation of renal function with no adverse effects.
Topics: Humans; Child; Leflunomide; Kidney Transplantation; Kidney; Immunosuppressive Agents; Transplant Recipients; Polyomavirus Infections; BK Virus; Tumor Virus Infections
PubMed: 37965958
DOI: 10.6002/ect.2023.0258