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1.
PLoS Pathog ; 17(4): e1009560, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33930088

RESUMO

Herpes-Simplex Virus 1 (HSV-1) infects most humans when they are young, sometimes with fatal consequences. Gene expression occurs in a temporal order upon lytic HSV-1 infection: immediate early (IE) genes are expressed, then early (E) genes, followed by late (L) genes. During this infection cycle, the HSV-1 genome has the potential for exposure to APOBEC3 (A3) proteins, a family of cytidine deaminases that cause C>U mutations on single-stranded DNA (ssDNA), often resulting in a C>T transition. We developed a computational model for the mutational pressure of A3 on the lytic cycle of HSV-1 to determine which viral kinetic gene class is most vulnerable to A3 mutations. Using in silico stochastic methods, we simulated the infectious cycle under varying intensities of A3 mutational pressure. We found that the IE and E genes are more vulnerable to A3 than L genes. We validated this model by analyzing the A3 evolutionary footprints in 25 HSV-1 isolates. We find that IE and E genes have evolved to underrepresent A3 hotspot motifs more so than L genes, consistent with greater selection pressure on IE and E genes. We extend this model to two-step infections, such as those of polyomavirus, and find that the same pattern holds for over 25 human Polyomavirus (HPyVs) genomes. Genes expressed earlier during infection are more vulnerable to mutations than those expressed later.


Assuntos
Desaminases APOBEC/fisiologia , Herpesvirus Humano 1/fisiologia , Proteínas Imediatamente Precoces/genética , Mutagênese/genética , Polyomavirus/fisiologia , Algoritmos , Regulação Viral da Expressão Gênica , Genes Precoces/genética , Herpes Simples/genética , Herpes Simples/virologia , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/patogenicidade , Interações Hospedeiro-Patógeno/genética , Humanos , Modelos Teóricos , Mutação , Polyomavirus/genética , Polyomavirus/patogenicidade , Infecções por Polyomavirus/genética , Infecções por Polyomavirus/virologia , Replicação Viral/genética
2.
Virol J ; 18(1): 111, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-34082771

RESUMO

It has been reported that polyomaviruses are the microbes which can be a cause of several human pathological conditions including cancers, nephropathy, progressive multifocal leukoencephalopathy and gynaecological disease. Although investigators proposed some mechanisms used by the viruses to induce the disorders, the roles played by chemokines in the pathogenesis of polyomaviruses infections are yet to be clarified. This review article investigated recent studies regarding the roles played by chemokines in the pathogenesis of the polyomaviruses infections. The research in the literature revealed that CXC chemokines, including CXCL1, CXCL5, CXCL8, CXCL9, CXCL10, CXCL11, CXCL12 and CXCL16, significantly participate in the pathogenesis of polyomaviruses. CC chemokines, such as CCL2, CCL5 and CCL20 also participate in the induction of the pathological conditions. Therefore, it appears that CXC chemokines may be considered as the strategic factors involved in the pathogenesis of polyomaviruses.


Assuntos
Quimiocinas CC/imunologia , Quimiocinas CXC/imunologia , Infecções por Polyomavirus/imunologia , Polyomavirus , Humanos , Polyomavirus/patogenicidade
3.
Virus Genes ; 57(3): 284-288, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33970402

RESUMO

Lyon IARC polyomavirus (LIPyV), a newly discovered polyomavirus (PyV), was first identified in 2017 in human skin samples in the USA. Later, it was detected in several other countries in samples of human and feline origin. Our aim was to find out if the virus occurs in China. To this end, 100 fecal samples were collected from cats with diarrhea in Guangxi Province during 2016 and 2018 and tested with polymerase chain reaction (PCR). Only 2 samples that originated from two related individuals were found to be positive. Based on the sequence identity of the 240-bp PCR products, the two positive samples supposedly contained identical viruses. Therefore, only one of them, which was designated as LIPyV-GXNN01, was selected for full genome amplification, cloning, sequencing and analysis. LIPyV-GXNN01, which comprises 5,263 nucleotides, has an early region that consists of small T antigen (ST-Ag) and large T antigen (LT-Ag) and a late region coding for the VP1, VP2, and VP3 structural proteins. Moreover, the LIPyV-GXNN01 strain structural proteins share 95.9-99.4%, 97.6-99.2%, and 97.1-99.2% nucleic acid identity with the VP1, VP2, and VP3of other LIPyV reference strains, respectively. A phylogenetic analysis revealed that GXNN01 clustered together with previously reported LIPyV strain. This present study is the first report of LIPyV in China.


Assuntos
Antígenos Virais de Tumores/genética , Diarreia/genética , Genoma Viral/genética , Polyomavirus/genética , Animais , Gatos , Diarreia/virologia , Humanos , Anotação de Sequência Molecular , Polyomavirus/isolamento & purificação , Polyomavirus/patogenicidade , Infecções por Polyomavirus/genética , Infecções por Polyomavirus/virologia , Proteínas Estruturais Virais/genética , Sequenciamento Completo do Genoma
4.
Virus Genes ; 56(4): 430-438, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32447589

RESUMO

The question of whether some cases of interstitial cystitis may have an infectious etiology has been debated for some time. Previous studies have looked for the presence of certain specific viruses, but generally did not use the types of sensitive and unbiased approaches that are currently available. As part of the MAPP (Multidisciplinary Approach to the Study of Chronic Pelvic Pain) Research Network, we examined urine specimens from interstitial cystitis patients who provided specimens over time and also reported various symptoms at the time of urine collection. We first performed next-generation sequencing to look for the presence of viruses in urines, and detected two human polyomaviruses that are known to be excreted into urine, BKPyV and JCPyV. We were especially interested in BKPyV because it is a known cause of another bladder disease, hemorrhagic cystitis, in bone marrow transplant recipients. Further analysis of individual samples indicates a trend toward higher excretion of polyomaviruses in patients experiencing increased symptoms.


Assuntos
Cistite Intersticial/virologia , Infecções por Polyomavirus/virologia , Polyomavirus/isolamento & purificação , Infecções Tumorais por Vírus/virologia , Cistite Intersticial/urina , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Polyomavirus/genética , Polyomavirus/patogenicidade , Infecções por Polyomavirus/urina , Infecções Tumorais por Vírus/urina
5.
J Cell Physiol ; 234(6): 8295-8315, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30390301

RESUMO

Polyomavirus family consists of a highly diverse group of small DNA viruses. The founding family member (MPyV) was first discovered in the newborn mouse in the late 1950s, which induces solid tumors in a wide variety of tissue types that are the epithelial and mesenchymal origin. Later, other family members were also isolated from a number of mammalian, avian and fish species. Some of these viruses significantly contributed to our current understanding of the fundamentals of modern biology such as transcription, replication, splicing, RNA editing, and cell transformation. After the discovery of first two human polyomaviruses (JC virus [JCV] and BK virus [BKV]) in the early 1970s, there has been a rapid expansion in the number of human polyomaviruses in recent years due to the availability of the new technologies and brought the present number to 14. Some of the human polyomaviruses cause considerably serious human diseases, including progressive multifocal leukoencephalopathy, polyomavirus-associated nephropathy, Merkel cell carcinoma, and trichodysplasia spinulosa. Emerging evidence suggests that the expression of the polyomavirus genome is more complex than previously thought. In addition to encoding universally expressed regulatory and structural proteins (LT-Ag, Sm t-Ag, VP1, VP2, and VP3), some polyomaviruses express additional virus-specific regulatory proteins and microRNAs. This review summarizes the recent advances in polyomavirus genome expression with respect to the new viral proteins and microRNAs other than the universally expressed ones. In addition, a special emphasis is devoted to the recent structural and functional discoveries in the field of polyomavirus agnoprotein which is expressed only by JCV, BKV, and simian virus 40 genomes.


Assuntos
Genoma Viral/genética , MicroRNAs/genética , Polyomavirus/genética , Proteínas Virais Reguladoras e Acessórias/genética , Carcinoma de Célula de Merkel/genética , Carcinoma de Célula de Merkel/virologia , DNA Viral/genética , Regulação Viral da Expressão Gênica/genética , Humanos , Leucoencefalopatia Multifocal Progressiva/genética , Leucoencefalopatia Multifocal Progressiva/virologia , Polyomavirus/patogenicidade , Replicação Viral/genética
6.
J Virol ; 92(16)2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-29875236

RESUMO

Polyomaviruses (PyVs) can cause serious disease in immunosuppressed hosts. Several pathogenic PyVs encode microRNAs (miRNAs), small RNAs that regulate gene expression via RNA silencing. Despite recent advances in understanding the activities of PyV miRNAs, the biological functions of PyV miRNAs during in vivo infections are mostly unknown. The studies presented here used murine polyomavirus (MuPyV) as a model to assess the roles of the PyV miRNAs in a natural host. This analysis revealed that a MuPyV mutant that is unable to express miRNAs has enhanced viral DNA loads in select tissues at late times after infection. This is consistent with the PyV miRNAs functioning to reduce viral replication during the persistent phase of infection in a natural host. Additionally, the MuPyV miRNA locus promotes viruria during the acute phase of infection as evidenced by a defect in shedding during infection with the miRNA mutant virus. The viruria defect of the miRNA mutant virus could be rescued by infecting Rag2-/- mice. These findings implicate the miRNA locus as functioning in both the persistent and acute phases of infection and suggest a role for MuPyV miRNA in evading the adaptive immune response.IMPORTANCE MicroRNAs are expressed by diverse viruses, but for only a few is there any understanding of their in vivo function. PyVs can cause serious disease in immunocompromised hosts. Therefore, increased knowledge of how these viruses interact with the immune response is of clinical relevance. Here we show a novel activity for a viral miRNA locus in promoting virus shedding. This work indicates that in addition to any role for the PyV miRNA locus in long-term persistence, it also has biological activity during the acute phase. As this mutant phenotype is alleviated by infection of mice lacking an adaptive immune response, our work also connects the in vivo activity of the PyV miRNA locus to the immune response. Given that PyV-associated disease is associated with alterations in the immune response, our findings help to better understand how the balance between PyVs and the immune response becomes altered in pathogenic states.


Assuntos
MicroRNAs/metabolismo , Infecções por Polyomavirus/patologia , Infecções por Polyomavirus/virologia , Polyomavirus/patogenicidade , RNA Viral/metabolismo , Urina/virologia , Animais , Camundongos , MicroRNAs/genética , Polyomavirus/genética , RNA Viral/genética , Eliminação de Partículas Virais
7.
Transfusion ; 59(12): 3689-3697, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31633816

RESUMO

BACKGROUND: Human polyomaviruses (HPyVs), like herpesviruses, cause persistent infection in a large part of the population. In immunocompromised and elderly patients, PyVs cause severe diseases such as nephropathy (BK polyomavirus [BKPyV]), progressive multifocal leukoencephalopathy (JC polyomavirus [JCPyV]), and skin cancer (Merkel cell polyomavirus [MCPyV]). Like cytomegalovirus, donor-derived PyV can cause disease in kidney transplant recipients. Possibly blood components transmit PyVs as well. To study this possibility, as a first step we determined the presence of PyV DNA in Dutch blood donations. STUDY DESIGN AND METHODS: Blood donor serum samples (n = 1016) were analyzed for the presence of DNA of 14 HPyVs using HPyV species-specific quantitative polymerase chain reaction (PCR) procedures. PCR-positive samples were subjected to confirmation by sequencing. Individual PCR findings were compared with the previously reported PyV serostatus. RESULTS: MC polyomavirus DNA was detected in 39 donors (3.8%), JCPyV and TS polyomavirus (TSPyV) DNA in five donors (both 0.5%), and HPyV9 DNA in four donors (0.4%). BKPyV, WU polyomavirus (WUPyV), HPyV6, MW polyomavirus (MWPyV), and LI polyomavirus (LIPyV) DNA was detected in one or two donors. Amplicon sequencing confirmed the expected product for BKPyV, JCPyV, WUPyV, MCPyV, HPyV6, TSPyV, MWPyV, HPyV9, and LIPyV. For JCPyV a significant association was observed between detection of viral DNA and the level of specific IgG antibodies. CONCLUSION: In 5.4% of Dutch blood donors PyV DNA was detected, including DNA from pathogenic PyVs such as JCPyV. As a next step, the infectivity of PyV in donor blood and transmission via blood components to immunocompromised recipients should be investigated.


Assuntos
Doadores de Sangue/estatística & dados numéricos , DNA Viral/análise , Polyomavirus/genética , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Polyomavirus/isolamento & purificação , Polyomavirus/patogenicidade , Prevalência , Adulto Jovem
8.
J Cell Physiol ; 233(5): 4137-4155, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29044559

RESUMO

Although the human neurotropic polyomavirus, JC virus (JCV), was isolated almost a half century ago, understanding the molecular mechanisms governing its biology remains highly elusive. JCV infects oligodendrocytes and astrocytes in the central nervous system (CNS) and causes a rare fatal brain disease known as progressive multifocal leukoencephalopathy (PML) in immunocompromised individuals including AIDS. It has a small circular DNA genome (∼5 kb) and generates two primary transcripts from its early and late coding regions, producing several predicted alternatively spliced products mainly by cis-splicing. Here, we report the discovery and characterization of two novel open reading frames (ORF1 and ORF2) associated with JCV late transcripts, generated by an unusual splicing process called trans-splicing. These ORFs result from (i) the trans-splicing of two different lengths of the 5'-short coding region of VP1 between the coding regions of agnoprotein and VP2 after replacing the intron located between these two coding regions and (ii) frame-shifts occurring within the VP2 coding sequences terminated by a stop codon. ORF1 and ORF2 are capable of encoding 58 and 72 aa long proteins respectively and are expressed in infected cells and PML patients. Each ORF protein shares a common coding region with VP1 and has a unique coding sequence of their own. When the expression of the unique coding regions of ORFs is blocked by a stop codon insertion in the viral background, the mutant virus replicates less efficiently when compared to wild-type, suggesting that the newly discovered ORFs play critical roles in the JCV life cycle.


Assuntos
Vírus JC/genética , Leucoencefalopatia Multifocal Progressiva/genética , Polyomavirus/genética , Trans-Splicing/genética , Encéfalo/virologia , Códon de Terminação/genética , DNA Viral/classificação , DNA Viral/genética , Éxons/genética , Regulação Viral da Expressão Gênica , Genoma Viral/genética , Humanos , Vírus JC/patogenicidade , Leucoencefalopatia Multifocal Progressiva/virologia , Fases de Leitura Aberta , Polyomavirus/patogenicidade , Replicação Viral/genética
9.
PLoS Biol ; 13(12): e1002330, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26717410

RESUMO

During pregnancy, the ETS transcription factor ELF5 establishes the milk-secreting alveolar cell lineage by driving a cell fate decision of the mammary luminal progenitor cell. In breast cancer, ELF5 is a key transcriptional determinant of tumor subtype and has been implicated in the development of insensitivity to anti-estrogen therapy. In the mouse mammary tumor virus-Polyoma Middle T (MMTV-PyMT) model of luminal breast cancer, induction of ELF5 levels increased leukocyte infiltration, angiogenesis, and blood vessel permeability in primary tumors and greatly increased the size and number of lung metastasis. Myeloid-derived suppressor cells, a group of immature neutrophils recently identified as mediators of vasculogenesis and metastasis, were recruited to the tumor in response to ELF5. Depletion of these cells using specific Ly6G antibodies prevented ELF5 from driving vasculogenesis and metastasis. Expression signatures in luminal A breast cancers indicated that increased myeloid cell invasion and inflammation were correlated with ELF5 expression, and increased ELF5 immunohistochemical staining predicted much shorter metastasis-free and overall survival of luminal A patients, defining a group who experienced unexpectedly early disease progression. Thus, in the MMTV-PyMT mouse mammary model, increased ELF5 levels drive metastasis by co-opting the innate immune system. As ELF5 has been previously implicated in the development of antiestrogen resistance, this finding implicates ELF5 as a defining factor in the acquisition of the key aspects of the lethal phenotype in luminal A breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias Pulmonares/secundário , Pulmão/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas Proto-Oncogênicas c-ets/metabolismo , Animais , Neoplasias da Mama/imunologia , Neoplasias da Mama/fisiopatologia , Neoplasias da Mama/virologia , Permeabilidade Capilar , Proliferação de Células , Proteínas de Ligação a DNA , Feminino , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Hemorragia/etiologia , Hemorragia/prevenção & controle , Humanos , Leucócitos/imunologia , Leucócitos/patologia , Pulmão/irrigação sanguínea , Pulmão/imunologia , Pulmão/patologia , Neoplasias Pulmonares/irrigação sanguínea , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/prevenção & controle , Depleção Linfocítica , Camundongos Transgênicos , Células Mieloides/imunologia , Células Mieloides/patologia , Proteínas de Neoplasias/genética , Neovascularização Patológica/etiologia , Neovascularização Patológica/prevenção & controle , Infiltração de Neutrófilos , Polyomavirus/patogenicidade , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Recombinantes de Fusão/metabolismo , Análise de Sobrevida , Fatores de Transcrição , Carga Tumoral
10.
Nature ; 487(7408): 491-5, 2012 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-22810586

RESUMO

Genotypic differences greatly influence susceptibility and resistance to disease. Understanding genotype-phenotype relationships requires that phenotypes be viewed as manifestations of network properties, rather than simply as the result of individual genomic variations. Genome sequencing efforts have identified numerous germline mutations, and large numbers of somatic genomic alterations, associated with a predisposition to cancer. However, it remains difficult to distinguish background, or 'passenger', cancer mutations from causal, or 'driver', mutations in these data sets. Human viruses intrinsically depend on their host cell during the course of infection and can elicit pathological phenotypes similar to those arising from mutations. Here we test the hypothesis that genomic variations and tumour viruses may cause cancer through related mechanisms, by systematically examining host interactome and transcriptome network perturbations caused by DNA tumour virus proteins. The resulting integrated viral perturbation data reflects rewiring of the host cell networks, and highlights pathways, such as Notch signalling and apoptosis, that go awry in cancer. We show that systematic analyses of host targets of viral proteins can identify cancer genes with a success rate on a par with their identification through functional genomics and large-scale cataloguing of tumour mutations. Together, these complementary approaches increase the specificity of cancer gene identification. Combining systems-level studies of pathogen-encoded gene products with genomic approaches will facilitate the prioritization of cancer-causing driver genes to advance the understanding of the genetic basis of human cancer.


Assuntos
Genes Neoplásicos/genética , Genoma Humano/genética , Interações Hospedeiro-Patógeno , Neoplasias/genética , Neoplasias/metabolismo , Vírus Oncogênicos/patogenicidade , Proteínas Virais/metabolismo , Adenoviridae/genética , Adenoviridae/metabolismo , Adenoviridae/patogenicidade , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/metabolismo , Herpesvirus Humano 4/patogenicidade , Interações Hospedeiro-Patógeno/genética , Humanos , Neoplasias/patologia , Vírus Oncogênicos/genética , Vírus Oncogênicos/metabolismo , Fases de Leitura Aberta/genética , Papillomaviridae/genética , Papillomaviridae/metabolismo , Papillomaviridae/patogenicidade , Polyomavirus/genética , Polyomavirus/metabolismo , Polyomavirus/patogenicidade , Receptores Notch/metabolismo , Transdução de Sinais , Técnicas do Sistema de Duplo-Híbrido , Proteínas Virais/genética
11.
J Virol ; 90(14): 6379-6386, 2016 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-27147740

RESUMO

UNLABELLED: The APOBEC3 family of DNA cytosine deaminases has important roles in innate immunity and cancer. It is unclear how DNA tumor viruses regulate these enzymes and how these interactions, in turn, impact the integrity of both the viral and cellular genomes. Polyomavirus (PyVs) are small DNA pathogens that contain oncogenic potentials. In this study, we examined the effects of PyV infection on APOBEC3 expression and activity. We demonstrate that APOBEC3B is specifically upregulated by BK polyomavirus (BKPyV) infection in primary kidney cells and that the upregulated enzyme is active. We further show that the BKPyV large T antigen, as well as large T antigens from related polyomaviruses, is alone capable of upregulating APOBEC3B expression and activity. Furthermore, we assessed the impact of A3B on productive BKPyV infection and viral genome evolution. Although the specific knockdown of APOBEC3B has little short-term effect on productive BKPyV infection, our informatics analyses indicate that the preferred target sequences of APOBEC3B are depleted in BKPyV genomes and that this motif underrepresentation is enriched on the nontranscribed stand of the viral genome, which is also the lagging strand during viral DNA replication. Our results suggest that PyV infection upregulates APOBEC3B activity to influence virus sequence composition over longer evolutionary periods. These findings also imply that the increased activity of APOBEC3B may contribute to PyV-mediated tumorigenesis. IMPORTANCE: Polyomaviruses (PyVs) are a group of emerging pathogens that can cause severe diseases, including cancers in immunosuppressed individuals. Here we describe the finding that PyV infection specifically induces the innate immune DNA cytosine deaminase APOBEC3B. The induced APOBEC3B enzyme is fully functional and therefore may exert mutational effects on both viral and host cell DNA. We provide bioinformatic evidence that, consistent with this idea, BK polyomavirus genomes are depleted of APOBEC3B-preferred target motifs and enriched for the corresponding predicted reaction products. These data imply that the interplay between PyV infection and APOBEC proteins may have significant impact on both viral evolution and virus-induced tumorigenesis.


Assuntos
Citidina Desaminase/metabolismo , Regulação da Expressão Gênica , Genoma Viral , Túbulos Renais/enzimologia , Antígenos de Histocompatibilidade Menor/metabolismo , Infecções por Polyomavirus/virologia , Polyomavirus/patogenicidade , Replicação Viral , Células Cultivadas , Citidina Desaminase/antagonistas & inibidores , Citidina Desaminase/genética , Humanos , Túbulos Renais/virologia , Antígenos de Histocompatibilidade Menor/genética , Polyomavirus/genética , Infecções por Polyomavirus/patologia , RNA Interferente Pequeno/genética , Ativação Transcricional , Regulação para Cima
12.
PLoS Pathog ; 11(10): e1005104, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26474293

RESUMO

Murine polyomavirus (MuPyV) causes tumors of various origins in newborn mice and hamsters. Infection is initiated by attachment of the virus to ganglioside receptors at the cell surface. Single amino acid exchanges in the receptor-binding pocket of the major capsid protein VP1 are known to drastically alter tumorigenicity and spread in closely related MuPyV strains. The virus represents a rare example of differential receptor recognition directly influencing viral pathogenicity, although the factors underlying these differences remain unclear. We performed structural and functional analyses of three MuPyV strains with strikingly different pathogenicities: the low-tumorigenicity strain RA, the high-pathogenicity strain PTA, and the rapidly growing, lethal laboratory isolate strain LID. Using ganglioside deficient mouse embryo fibroblasts, we show that addition of specific gangliosides restores infectability for all strains, and we uncover a complex relationship between virus attachment and infection. We identify a new infectious ganglioside receptor that carries an additional linear [α-2,8]-linked sialic acid. Crystal structures of all three strains complexed with representative oligosaccharides from the three main pathways of ganglioside biosynthesis provide the molecular basis of receptor recognition. All strains bind to a range of sialylated glycans featuring the central [α-2,3]-linked sialic acid present in the established receptors GD1a and GT1b, but the presence of additional sialic acids modulates binding. An extra [α-2,8]-linked sialic acid engages a protein pocket that is conserved among the three strains, while another, [α-2,6]-linked branching sialic acid lies near the strain-defining amino acids but can be accommodated by all strains. By comparing electron density of the oligosaccharides within the binding pockets at various concentrations, we show that the [α-2,8]-linked sialic acid increases the strength of binding. Moreover, the amino acid exchanges have subtle effects on their affinity for the validated receptor GD1a. Our results indicate that both receptor specificity and affinity influence MuPyV pathogenesis.


Assuntos
Proteínas do Capsídeo/metabolismo , Infecções por Polyomavirus/metabolismo , Polyomavirus/patogenicidade , Infecções Tumorais por Vírus/metabolismo , Internalização do Vírus , Animais , Proteínas do Capsídeo/química , Cristalização , Imunofluorescência , Camundongos , Ligação Proteica/fisiologia , Conformação Proteica
13.
PLoS Pathog ; 11(8): e1005112, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26302170

RESUMO

Trichodysplasia spinulosa-associated Polyomavirus (TSPyV) was isolated from a patient suffering from trichodysplasia spinulosa, a skin disease that can appear in severely immunocompromised patients. While TSPyV is one of the five members of the polyomavirus family that are directly linked to a human disease, details about molecular recognition events, the viral entry pathway, and intracellular trafficking events during TSPyV infection remain unknown. Here we have used a structure-function approach to shed light on the first steps of TSPyV infection. We established by cell binding and pseudovirus infection studies that TSPyV interacts with sialic acids during attachment and/or entry. Subsequently, we solved high-resolution X-ray structures of the major capsid protein VP1 of TSPyV in complex with three different glycans, the branched GM1 glycan, and the linear trisaccharides α2,3- and α2,6-sialyllactose. The terminal sialic acid of all three glycans is engaged in a unique binding site on TSPyV VP1, which is positioned about 18 Å from established sialic acid binding sites of other polyomaviruses. Structure-based mutagenesis of sialic acid-binding residues leads to reduction in cell attachment and pseudovirus infection, demonstrating the physiological relevance of the TSPyV VP1-glycan interaction. Furthermore, treatments of cells with inhibitors of N-, O-linked glycosylation, and glycosphingolipid synthesis suggest that glycolipids play an important role during TSPyV infection. Our findings elucidate the first molecular recognition events of cellular infection with TSPyV and demonstrate that receptor recognition by polyomaviruses is highly variable not only in interactions with sialic acid itself, but also in the location of the binding site.


Assuntos
Proteínas do Capsídeo/metabolismo , Infecções por Polyomavirus/metabolismo , Polyomavirus/patogenicidade , Internalização do Vírus , Animais , Sítios de Ligação , Proteínas do Capsídeo/química , Linhagem Celular , Citometria de Fluxo , Glicolipídeos/química , Glicolipídeos/metabolismo , Humanos , Espectroscopia de Ressonância Magnética , Mutagênese Sítio-Dirigida , Polyomavirus/química , Polyomavirus/metabolismo , Conformação Proteica , Ácidos Siálicos/química , Ácidos Siálicos/metabolismo , Difração de Raios X
14.
J Med Virol ; 89(4): 742-747, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27632801

RESUMO

BRAF inhibitors are highly effective therapies in treating a subset of melanomas but are associated with induction of secondary cutaneous squamous cell carcinoma (cSCC). Recently, Human Polyomavirus 6 (HPyV6) was found to actively express viral proteins in BRAF inhibitor-induced cSCCs; however, the specific cellular mechanisms by which HPyV6 may facilitate neoplastic cell growth require further investigation. The current study describes a novel pathogenic mechanism of action for HPyV6 small tumor (sT) antigen which involves binding to protein phosphatase 2A (PP2A) via its WFG motif and zinc binding sites. Our findings demonstrate an important role of HPyV6 sT for activation of PP2A's downstream oncogenic pathways (MEK/ERK/c-Jun), which may underlie the pathogenesis of BRAF inhibitor-induced neoplasms. J. Med. Virol. 89:742-747, 2017. © 2016 Wiley Periodicals, Inc.


Assuntos
Antígenos Virais de Tumores/metabolismo , Interações Hospedeiro-Patógeno , Sistema de Sinalização das MAP Quinases , Polyomavirus/patogenicidade , Proteína Fosfatase 2/metabolismo , Humanos , Ligação Proteica , Mapeamento de Interação de Proteínas
15.
Annu Rev Microbiol ; 66: 213-36, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22994493

RESUMO

The large tumor antigen (T antigen) encoded by simian virus 40 is an amazing molecular machine because it orchestrates viral infection by modulating multiple fundamental viral and cellular processes. T antigen is required for viral DNA replication, transcription, and virion assembly. In addition, T antigen targets multiple cellular pathways, including those that regulate cell proliferation, cell death, and the inflammatory response. Ectopic T antigen expression results in the immortalization and transformation of many cell types in culture and T antigen induces neoplasia when expressed in rodents. The analysis of the mechanisms by which T antigen carries out its many functions has proved to be a powerful way of gaining insights into cell biology. The accelerating pace at which new polyomaviruses are being discovered provides a collection of novel T antigens that, like simian virus 40, can be used to discover and study key cellular regulatory systems.


Assuntos
Antígenos Virais de Tumores/metabolismo , Polyomavirus/patogenicidade , Fatores de Virulência/metabolismo , Animais , Transformação Celular Viral , Interações Hospedeiro-Patógeno , Humanos , Polyomavirus/genética , Polyomavirus/fisiologia , Montagem de Vírus , Replicação Viral
16.
Cytotherapy ; 19(11): 1302-1316, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28927823

RESUMO

Rapid restoration of virus-specific T immunity via adoptive transfer of ex vivo generated T cells has been proven as a powerful therapy for patients with advanced cancers and refractory viral infections such as cytomegalovirus (CMV) and Epstein-Barr virus (EBV). BK virus (BKV), John Cunningham virus (JCV), and Merkel cell carcinoma virus (MCV) are the members of the rapidly growing human polyomavirus (hPyV) family that commonly infects most healthy humans. These viruses have a clearly established potential for causing severe end-organ damage or malignant transformation, especially in individuals with weakened immunity who are unable to mount or regain endogenous T-cell responses as a result of underlying leukemia or iatrogenic immunosuppression in autoimmunity, bone marrow and solid organ transplant settings. Here we will discuss recent advances in using T-cell-based immunotherapies to save patients suffering from PyV-associated diseases including hemorrhagic cystitis, BKV virus-associated nephropathy, and JC-associated progressive multifocal leukoencephalopathy (PML). We will also review progress in the understanding of Merkel cell carcinoma (MCC) as a virally driven tumor that is amenable to immune intervention and can be targeted with adoptively transferred T cells specific for viral oncoproteins.


Assuntos
Transplante de Células/métodos , Imunoterapia Adotiva/métodos , Infecções por Polyomavirus/terapia , Herpesvirus Humano 4/patogenicidade , Humanos , Hospedeiro Imunocomprometido , Nefropatias/virologia , Polyomavirus/patogenicidade , Infecções por Polyomavirus/imunologia , Linfócitos T/transplante
17.
Toxicol Pathol ; 45(5): 593-603, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28782456

RESUMO

We report the identification, pathogenesis, and transmission of a novel polyomavirus in severe combined immunodeficient F344 rats with null Prkdc and interleukin 2 receptor gamma genes. Infected rats experienced weight loss, decreased fecundity, and mortality. Large basophilic intranuclear inclusions were observed in epithelium of the respiratory tract, salivary and lacrimal glands, uterus, and prostate gland. Unbiased viral metagenomic sequencing of lesioned tissues identified a novel polyomavirus, provisionally named Rattus norvegicus polyomavirus 2 (RatPyV2), which clustered with Washington University (WU) polyomavirus in the Wuki clade of the Betapolyomavirus genus. In situ hybridization analyses and quantitative polymerase chain reaction (PCR) results demonstrated viral nucleic acids in epithelium of respiratory, glandular, and reproductive tissues. Polyomaviral disease was reproduced in Foxn1rnu nude rats cohoused with infected rats or experimentally inoculated with virus. After development of RatPyV2-specific diagnostic assays, a survey of immune-competent rats from North American research institutions revealed detection of RatPyV2 in 7 of 1,000 fecal samples by PCR and anti-RatPyV2 antibodies in 480 of 1,500 serum samples. These findings suggest widespread infection in laboratory rat populations, which may have profound implications for established models of respiratory injury. Additionally, RatPyV2 infection studies may provide an important system to investigate the pathogenesis of WU polyomavirus diseases of man.


Assuntos
Infecções por Polyomavirus , Polyomavirus , Infecções Tumorais por Vírus , Animais , Feminino , Pulmão/virologia , Masculino , Metagenômica , Polyomavirus/genética , Polyomavirus/isolamento & purificação , Polyomavirus/patogenicidade , Infecções por Polyomavirus/complicações , Infecções por Polyomavirus/genética , Infecções por Polyomavirus/transmissão , Infecções por Polyomavirus/virologia , Ratos , Análise de Sequência de DNA , Imunodeficiência Combinada Severa/complicações , Distribuição Tecidual , Infecções Tumorais por Vírus/complicações , Infecções Tumorais por Vírus/genética , Infecções Tumorais por Vírus/transmissão , Infecções Tumorais por Vírus/virologia , Carga Viral/genética
18.
Arkh Patol ; 79(2): 22-28, 2017.
Artigo em Russo | MEDLINE | ID: mdl-28418354

RESUMO

AIM: Тo compare morphological changes and results of immunohistochemical (IHC) identification of viruses (polyomaviruses, adenoviruses, and herpesviruses) in the biopsy specimens with their clinical manifestations in recipients of renal transplants. MATERIAL AND METHODS: Morphological and IHC studies were conducted using 71 needle renal transplant biopsy specimens from patients in the study group and 10 renal biopsy specimens from those in the control group. A number of clinical indicators were estimated. RESULTS: IHC examination revealed the expression of adenoviral antigens more commonly in patients with posttransplant nephritis than in recipients without nephritis or in control individuals (p<0.05). The association of patient age and time after kidney transplantation with the severity of viral damage was confirmed: graft loss in children occurred within the first months of surgery (p<0.05). Polyomavirus was detected by PCR in patients with the morphological patterns of polyomavirus nephropathy. Determination of HSV-1 and HSV-2 in the biopsy specimens showed no significant associations with morphological changes. CONCLUSION: By taking into account a variety of factors that influence the development of viral nephritis, morphological and IHC examinations should be combined with evaluation of clinical findings.


Assuntos
Rim/virologia , Nefrite/virologia , Transplantes/virologia , Adenoviridae/isolamento & purificação , Adenoviridae/patogenicidade , Adolescente , Adulto , Biópsia , Criança , Pré-Escolar , DNA Viral/isolamento & purificação , Feminino , Herpesviridae/isolamento & purificação , Herpesviridae/patogenicidade , Humanos , Rim/patologia , Transplante de Rim/efeitos adversos , Masculino , Pessoa de Meia-Idade , Imagem Molecular/métodos , Nefrite/patologia , Polyomavirus/isolamento & purificação , Polyomavirus/patogenicidade , Transplantes/transplante , Adulto Jovem
19.
Acta Derm Venereol ; 96(4): 442-7, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26554531

RESUMO

Malignant tumours are the foremost complications of immunosuppressive treatment. They are a major challenge for organ transplant recipients and their treating physicians. This paper reviews the aetiology and current treatment of an unusual neuroendocrine skin cancer, Merkel cell carcinoma (MCC), caused by a Merkel cell polyomavirus infection. MCC occurs more frequently than expected in immunosuppressed subjects, especially in organ transplant recipients. The current literature comprises reports of 79 organ transplant recipients with MCC. The risk of MCC in organ transplant recipients is increased up to 66-182-fold compared with the general population. In addition to the increased risk of developing MCC, immunosuppressed individuals have poorer MCC-specific survival. The aim of this review article is to familiarize organ transplant doctors with this unique and clinically challenging skin cancer, and to provide recent data on the diagnosis and current treatment recommendations for an immunosuppressed population.


Assuntos
Carcinoma de Célula de Merkel/imunologia , Carcinoma de Célula de Merkel/virologia , Hospedeiro Imunocomprometido , Imunossupressores/efeitos adversos , Transplante de Órgãos/efeitos adversos , Neoplasias Cutâneas/imunologia , Carcinoma de Célula de Merkel/epidemiologia , Carcinoma de Célula de Merkel/terapia , Interações Hospedeiro-Parasita , Humanos , Polyomavirus/imunologia , Polyomavirus/patogenicidade , Medição de Risco , Fatores de Risco , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/terapia , Neoplasias Cutâneas/virologia , Resultado do Tratamento
20.
Duodecim ; 132(5): 439-45, 2016.
Artigo em Fi | MEDLINE | ID: mdl-27089617

RESUMO

The number of polyomaviruses causing infections in humans is as high as thirteen. The BK and JC polyomaviruses and the diseases caused by them are best known. For the present, the Merkel cell polyomavirus is the only human polyomavirus considered to be a causative agent of cancer. Other disease associations of polyomaviruses are also subject to active research. All polyomavirus infections are usually harmless respiratory or intestinal infections of childhood. Polyomaviruses, remain in the body for the rest of life, i.e. they persist as part of the body microbiome. Upon weakening of cell-mediated immunity they can also become reactivated and cause clinical problems.


Assuntos
Enteropatias/virologia , Neoplasias/virologia , Infecções por Polyomavirus/virologia , Polyomavirus/patogenicidade , Infecções Respiratórias/virologia , Humanos , Enteropatias/imunologia , Microbiota , Infecções por Polyomavirus/imunologia , Infecções Respiratórias/imunologia
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