Simian virus 40 (SV40) is a monkey virus with tumorigenic potential in rodents and is associated with several types of human cancers, including lymphomas. A related Merkel cell polyomavirus causes carcinoma in humans by expressing truncated large tumor antigen (LT), with truncations caused by APOBEC family of cytidine deaminase-induced mutations. AID (activation-induced cytidine deaminase), a member of the APOBEC family, is the initiator of the antibody diversification process known as somatic hypermutation and its aberrant expression and targeting is a frequent source of lymphomagenesis. In this study, we investigated whether AID could cause mutations in SV40 LT. We demonstrate that the SV40 enhancer has strong somatic hypermutation targeting activity in several cell types and that AID-induced mutations accumulate in SV40 LT in B cells and kidney cells and cause truncated LT expression in B cells. Our results argue that the ability of the SV40 enhancer to target somatic hypermutation to LT is a potential source of LT truncation events that could contribute to tumorigenesis in various cell types, thereby linking SV40 infection with malignant development through a novel mutagenic pathway.

• MeSH
• AICDA (aktivací indukovaná cytidindeamináza) MeSH
• antigeny transformující polyomavirové genetika   metabolismus   MeSH
• antigeny virové nádorové genetika   metabolismus   MeSH
• B-lymfocyty virologie   metabolismus   imunologie   MeSH
• buněčné linie MeSH
• cytidindeaminasa * genetika   metabolismus   MeSH
• infekce onkogenními viry genetika   virologie   MeSH
• karcinogeneze genetika   MeSH
• lidé MeSH
• mutace MeSH
• opičí virus SV40 * genetika   MeSH
• polyomavirové infekce genetika   virologie   MeSH
• somatická hypermutace imunoglobulinových genů genetika   MeSH
• zesilovače transkripce * genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

BK polyomavirus (BKPyV) infection in humans is usually asymptomatic but ultimately results in viral persistence. In immunocompromised hosts, virus reactivation can lead to nephropathy or hemorrhagic cystitis. The urinary tract serves as a silent reservoir for the virus. Recently, it has been demonstrated that human bladder microvascular endothelial cells (HBMVECs) serve as viral reservoirs, given their unique response to infection, which involves interferon (IFN) production. The aim of the present study was to better understand the life cycle of BKPyV in HBMVECs, uncover the molecular pathway leading to IFN production, and to identify the connection between the viral life cycle and the activation of the IFN response. Here, in the early stage of infection, BKPyV virions were found in internalized monopinocytic vesicles, while later they were detected in late endosomes, lysosomes, tubuloreticular structures, and vacuole-like vesicles. The production of viral progeny in these cells started at 36 h postinfection. Increased cell membrane permeability and peaks of virion release coincided with the leakage of viral and cellular DNA into the cytosol at approximately 60 h postinfection. Leaked DNA colocalized with and activated cGAS, leading to the activation of STING and the consequent transcription of IFNB and IFN-related genes; in contrast, the IFN response was attenuated by exposure to the cGAS inhibitor, G140. These findings highlight the importance of the cGAS-STING pathway in the innate immune response of HBMVECs to BKPyV.

• MeSH
• endoteliální buňky * virologie   MeSH
• interferony metabolismus   MeSH
• kultivované buňky MeSH
• lidé MeSH
• membránové proteiny metabolismus   genetika   MeSH
• močový měchýř * virologie   MeSH
• nukleotidyltransferasy metabolismus   genetika   MeSH
• polyomavirové infekce virologie   imunologie   MeSH
• replikace viru MeSH
• signální transdukce * MeSH
• virion MeSH
• virus BK * fyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

BK virus (BKPyV) is a causative agent of BKPyV-associated nephropathy and graft rejections in kidney transplant patients. It establishes persistent infection in the kidneys, which can lead to reactivation in an immunosuppressed state or transmission to kidney recipients. Complications in the case of donor-derived infections can be caused by differences between the four known BKPyV subtypes, as prior infection with one subtype does not guarantee protection against de novo infection with other subtypes. The recipient and donor pretransplant serotyping is not routinely performed since simple ELISA tests employing antigens derived from the major viral capsid protein 1 (VP1) are hindered by the high cross-reactivity of anti-VP1 antibodies against all subtypes. Identifying subtype-specific epitopes in VP1 could lead to the design of specific antigens and the improvement of serodiagnostics for kidney transplantation. We aimed to study the surface residues responsible for the interactions with the subtype-specific antibodies by focusing on the DE and EF loops of VP1, which have only a small number of distinct amino acid differences between the most common subtypes, BKPyV-I and BKPyV-IV. We designed two mutant virus-like particles (VLPs): we introduced BKPyV-I characteristic amino acid residues (either H139N in the DE loop or D175E and I178V changes in the EF loop) into the base sequence of a BKPyV-IV VP1. This way, we created BKPyV-IV mutant VLPs with the sequence of either the BKPyV-I DE loop or the BKPyV-I EF loop. These mutants were then used as competing antigens in an antigen competition assay with a panel of patient sera, and changes in antibody reactivity were assessed by ELISA. We found that the changes introduced into the BKPyV-IV VP1 EF loop restrict antibody recognition in most samples and that converting the BKPyV-IV DE loop into its BKPyV-I equivalent attracts anti-VP1 BKPyV-I antibodies. Although our results did not lead to the discovery of a subtype-specific epitope on the VP1, they suggested that the arrangement of the EF loop in VP1 might dictate the mode of interaction between virus and anti-VP1 antibodies in general and that the interactions between the antibodies and the viral capsid might be very complex. Consequently, an antigen competition assay as an assay to distinguish between BKPyV serotypes might prove difficult to interpret.

• MeSH
• ELISA MeSH
• ledviny MeSH
• lidé MeSH
• nemoci ledvin * MeSH
• sérotypizace MeSH
• transplantace ledvin * MeSH
• virus BK * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Progresivní multifokální leukoencefalopatie je vzácným demyelinizačním onemocněním CNS, vyskytujícím se téměř výhradně u imunokompromitovaných osob - nejčastěji jako pozdní komplikace infekce virem HIV. V této práci prezentujeme pacienta s PML, u něhož byla tato diagnóza prvotní diagnózou, která vedla ke zjištění HIV infekce, a zároveň se jedná o prvního pacienta s touto diagnózou na Neurologické klinice FN Olomouc.

Progressive multifocal leukoencephalopathy is a rare demyelinating disorder of the central nervous system, which is found almost entirely in immunocompromised persons - mostly as late complication of HIV infection. We present a case report of rare situation, in which the diagnosis of PML preceded the diagnosis of long-lasting HIV infection. This patient was also the first patient with this diagnosis in Neurology department of The University Hospital Olomouc.

• MeSH
• antiretrovirové látky terapeutické užití   MeSH
• diferenciální diagnóza MeSH
• HIV séropozitivita MeSH
• lidé středního věku MeSH
• lidé MeSH
• magnetická rezonanční tomografie MeSH
• oportunní infekce doprovázející AIDS * diagnóza   farmakoterapie   komplikace   MeSH
• počítačová rentgenová tomografie MeSH
• progrese nemoci MeSH
• progresivní multifokální leukoencefalopatie * diagnóza   imunologie   patofyziologie   MeSH
• virus JC izolace a purifikace   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

• MeSH
• humanizované monoklonální protilátky aplikace a dávkování   farmakologie   klasifikace   terapeutické užití   MeSH
• injekce subkutánní metody   MeSH
• integrin alfa4 antagonisté a inhibitory   MeSH
• lidé středního věku MeSH
• lidé MeSH
• natalizumab * aplikace a dávkování   farmakologie   terapeutické užití   MeSH
• nukleární magnetická rezonance biomolekulární klasifikace   metody   MeSH
• roztroušená skleróza diagnóza   farmakoterapie   MeSH
• virus JC imunologie   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

Karcinom z Merkelových buněk (Merkel cell carcinoma, MCC) je relativně vzácný primární kožní neuroendokrinní karcinom s incidencí zhruba 3 případy na 1 000 000 obyvatel za rok, který se typicky vyskytuje v partiích chronicky exponovaných slunečnímu záření (obličej, kůže hlavy, krk). Mezi etiopatogenetické faktory patří zejména působení Merkelova polyomaviru (zhruba 80 % všech MCC), chronická expozice ultrafialovému záření a oslabení imunitního systému. Nádory asociované s virovou infekcí a nádory bez ní jsou biologicky odlišné, nádory bez prokázaného viru mají výrazně vyšší mutační nálož včetně mutací p53 a Rb. Z terapeutického hlediska však není odlišení obou subtypů MCC zatím zásadní, neboť oba mají obdobně nepříznivou prognózu a stejný terapeutický management. Histologicky má MCC charakter high-grade neuroendokrinního karcinomu, diferenciálně diagnosticky je nutno odlišit například malobuněčnou variantu melanomu, lymfohistiocytární neoplazie, Ewingův sarkom a kožní metastázy neuroendokrinních karcinomů jiného primárního origa. V případě diagnostické nejistoty lze využít druhého čtení na jiném pracovišti patologie.

Merkel cell carcinoma (MCC) is a relatively rare primary cutaneous neuroendocrine carcinoma with an incidence of approximately 3/1000000 per year, typically occurring in areas chronically exposed to sunlight (face, scalp, neck). The etiopathogenetic factors include mainly the action of Merkel polyomavirus (approximately 80% of all MCC), chronic ultraviolet exposure and a suppressed immune system. Tumors associated with viral infection and those without are biologically distinct; tumors without proven virus have a significantly higher mutational load, including p53 and Rb mutations. From a therapeutic point of view, however, the distinction between the two subtypes of MCC is not yet crucial, as both have a similarly unfavorable prognosis and the same therapeutic management. Histologically, MCC is a high-grade neuroendocrine carcinoma, in differential diagnosis it is necessary to distinguish, for example, small cell variant of melanoma, lymphohistiocytic neoplasms, Ewing's sarcoma and cutaneous metastases of neuroendocrine carcinomas of other primary origin. In case of diagnostic uncertainty, a second opinion at another pathology department can be used.

• MeSH
• imunohistochemie metody   MeSH
• lidé MeSH
• Merkelův nádor * diagnóza   etiologie   patologie   MeSH
• Polyomavirus patogenita   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

BK polyomavirus (BKPyV) often reactivates after kidney transplantation, causing BKPyV-associated nephropathy (BKPyVAN) in 1%-10% of cases with a potential detrimental effect on allograft survival. Kidney transplant recipients are regularly screened for BKPyV DNA in plasma. As this strategy may not always reduce the risk of BKPyVAN, other predictive markers are needed. To evaluate the role of pretransplant BKPyV-specific antibody, 210 kidney transplant recipients and 130 donors were screened for BKPyV DNA and BKPyV-specific antibodies. We found that the donor BKPyV immunoglobulin G (IgG) seroprevalence and antibody level were strongly associated with BKPyV-DNAemia and BKPyVAN, although multivariant analysis found the presence of anti-BKPyV-specific antibodies as a predictive factor only for BKPyV-DNAemia. The pretransplant recipient status had no effect on posttransplant BKPyV-DNAemia and BKVAN. BKPyV IgG levels remained stable in BKPyV-negative recipients during 1-year follow-up, while a considerable increase was observed in BKPyV-positive patients. The presence of anti-BKPyV-specific antibodies in kidney allograft donors is a good and reliable predictive marker for posttransplant BKPyV replication with relevance to risk stratification in transplant recipients.

• MeSH
• imunoglobulin G MeSH
• intersticiální nefritida * komplikace   MeSH
• lidé MeSH
• polyomavirové infekce * MeSH
• séroepidemiologické studie MeSH
• transplantace ledvin * škodlivé účinky   MeSH
• virus BK * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: The proportion of Merkel cell carcinomas (MCCs) in solid-organ transplant recipients (SOTR) harbouring Merkel cell polyomavirus (MCPyV) is unknown, as are factors affecting their outcomes. OBJECTIVE: To describe clinicopathological features of MCC in SOTR, investigate the tumoral MCPyV-status and identify factors associated with tumour outcomes. METHODS: Retrospective, international, cohort-study. MCPyV-status was investigated by immunohistochemistry and polymerase chain reaction. RESULTS: A total of 30 SOTR and 44 consecutive immunocompetent patients with MCC were enrolled. SOTR were younger at diagnosis (69 vs. 78 years, P < 0.001). Thirty-three percent of SOTR MCCs were MCPyV-positive vs. 91% of immunocompetent MCCs (P = 0.001). Solid-organ transplantation was associated with an increased cumulative incidence of progression (SHR: 3.35 [1.57-7.14], P = 0.002), MCC-specific mortality (SHR: 2.55 [1.07-6.06], P = 0.034) and overall mortality (HR: 3.26 [1.54-6.9], P = 0.002). MCPyV-positivity and switching to an mTOR inhibitor (mTORi) after MCC diagnosis were associated with an increased incidence of progression (SHR: 4.3 [1.5-13], P = 0.008 and SHR: 3.6 [1.1-12], P = 0.032 respectively) in SOTR. LIMITATIONS: Retrospective design and heterogeneity of SOTR cohort. CONCLUSIONS: MCPyV appears to play a less prominent role in the aetiopathogenesis of MCC in SOTR. SOTR have a worse prognosis than their immunocompetent counterparts and switching to an mTORi after the diagnosis of MCC does not improve progression.

• MeSH
• infekce onkogenními viry * komplikace   MeSH
• lidé MeSH
• Merkelův nádor * patologie   MeSH
• Merkelův polyomavirus * MeSH
• nádory kůže * patologie   MeSH
• polyomavirové infekce * MeSH
• retrospektivní studie MeSH
• TOR serin-threoninkinasy MeSH
• transplantace orgánů * škodlivé účinky   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH

All renal transplant recipients should undergo a regular screening for BK viral (BKV) viremia. Gradual reduction of immunosuppression is recommended in patients with persistent plasma BKV viremia for 3 weeks after the first detection, reflecting the presence of probable or suspected BKV-associated nephropathy. Reduction of immunosuppression is also a primary intervention in biopsy proven nephropathy associated with BKV (BKVN). Thus, allograft biopsy is not required to treat patients with BKV viremia with stabilized graft function. There is a lack of proper randomised clinical trials recommending treatment in the form of switching from tacrolimus to cyclosporin-A, from mycophenolate to mTOR inhibitors or leflunomide, or the additive use of intravenous immunoglobulins, leflunomide or cidofovir. Fluoroquinolones are not recommended for prophylaxis or therapy. There are on-going studies to evaluate the possibility of using a multi-epitope anti-BKV vaccine, administration of BKV-specific T cell immunotherapy, BKV-specific human monoclonal antibody and RNA antisense oligonucleotides. Retransplantation after allograft loss due to BKVN can be successful if BKV viremia is definitively removed, regardless of allograft nephrectomy.

• MeSH
• imunosupresiva terapeutické užití   MeSH
• leflunomid terapeutické užití   MeSH
• lidé MeSH
• nemoci ledvin * farmakoterapie   MeSH
• polyomavirové infekce * diagnóza   farmakoterapie   MeSH
• transplantace ledvin * MeSH
• viremie diagnóza   farmakoterapie   MeSH
• virus BK * genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

DNA virus infections are often lifelong and can cause serious diseases in their hosts. Their recognition by the sensors of the innate immune system represents the front line of host defence. Understanding the molecular mechanisms of innate immunity responses is an important prerequisite for the design of effective antivirotics. This review focuses on the present state of knowledge surrounding the mechanisms of viral DNA genome sensing and the main induced pathways of innate immunity responses. The studies that have been performed to date indicate that herpesviruses, adenoviruses, and polyomaviruses are sensed by various DNA sensors. In non-immune cells, STING pathways have been shown to be activated by cGAS, IFI16, DDX41, or DNA-PK. The activation of TLR9 has mainly been described in pDCs and in other immune cells. Importantly, studies on herpesviruses have unveiled novel participants (BRCA1, H2B, or DNA-PK) in the IFI16 sensing pathway. Polyomavirus studies have revealed that, in addition to viral DNA, micronuclei are released into the cytosol due to genotoxic stress. Papillomaviruses, HBV, and HIV have been shown to evade DNA sensing by sophisticated intracellular trafficking, unique cell tropism, and viral or cellular protein actions that prevent or block DNA sensing. Further research is required to fully understand the interplay between viruses and DNA sensors.

• MeSH
• DNA virů metabolismus   MeSH
• Herpesviridae * genetika   metabolismus   MeSH
• infekce DNA virem * MeSH
• lidé MeSH
• Polyomavirus * genetika   MeSH
• přirozená imunita MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH