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1.
Emerg Infect Dis ; 30(6): 1240-1244, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38782018

RESUMO

A 2022 canine gastroenteritis outbreak in the United Kingdom was associated with circulation of a new canine enteric coronavirus closely related to a 2020 variant with an additional spike gene recombination. The variants are unrelated to canine enteric coronavirus-like viruses associated with human disease but represent a model for coronavirus population adaptation.


Assuntos
Infecções por Coronavirus , Surtos de Doenças , Doenças do Cão , Gastroenterite , Filogenia , Animais , Cães , Surtos de Doenças/veterinária , Doenças do Cão/virologia , Doenças do Cão/epidemiologia , Reino Unido/epidemiologia , Gastroenterite/virologia , Gastroenterite/epidemiologia , Gastroenterite/veterinária , Infecções por Coronavirus/veterinária , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/virologia , Coronavirus Canino/genética , Coronavirus Canino/classificação , Humanos , Glicoproteína da Espícula de Coronavírus/genética
2.
PLoS Pathog ; 15(3): e1007667, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30901352

RESUMO

Host innate immune defences play a critical role in restricting the intracellular propagation and pathogenesis of invading viral pathogens. Here we show that the histone H3.3 chaperone HIRA (histone cell cycle regulator) associates with promyelocytic leukaemia nuclear bodies (PML-NBs) to stimulate the induction of innate immune defences against herpes simplex virus 1 (HSV-1) infection. Following the activation of innate immune signalling, HIRA localized at PML-NBs in a Janus-Associated Kinase (JAK), Cyclin Dependent Kinase (CDK), and Sp100-dependent manner. RNA-seq analysis revealed that HIRA promoted the transcriptional upregulation of a broad repertoire of host genes that regulate innate immunity to HSV-1 infection, including those involved in MHC-I antigen presentation, cytokine signalling, and interferon stimulated gene (ISG) expression. ChIP-seq analysis revealed that PML, the principle scaffolding protein of PML-NBs, was required for the enrichment of HIRA onto ISGs, identifying a role for PML in the HIRA-dependent regulation of innate immunity to virus infection. Our data identifies independent roles for HIRA in the intrinsic silencing of viral gene expression and the induction of innate immune defences to restrict the initiation and propagation of HSV-1 infection, respectively. These intracellular host defences are antagonized by the HSV-1 ubiquitin ligase ICP0, which disrupts the stable recruitment of HIRA to infecting viral genomes and PML-NBs at spatiotemporally distinct phases of infection. Our study highlights the importance of histone chaperones to regulate multiple phases of intracellular immunity to virus infection, findings that are likely to be highly pertinent in the cellular restriction of many clinically important viral pathogens.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Fibroblastos/imunologia , Infecções por Herpesviridae/imunologia , Herpesvirus Humano 1/patogenicidade , Chaperonas de Histonas/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Imunidade Inata/imunologia , Fatores de Transcrição/metabolismo , Proteínas de Ciclo Celular/genética , Células Cultivadas , Fibroblastos/citologia , Fibroblastos/virologia , Regulação Viral da Expressão Gênica , Infecções por Herpesviridae/metabolismo , Infecções por Herpesviridae/virologia , Chaperonas de Histonas/genética , Humanos , Fatores de Transcrição/genética , Replicação Viral
4.
PLoS Pathog ; 14(1): e1006769, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29309427

RESUMO

Detection of viral nucleic acids plays a critical role in the induction of intracellular host immune defences. However, the temporal recruitment of immune regulators to infecting viral genomes remains poorly defined due to the technical difficulties associated with low genome copy-number detection. Here we utilize 5-Ethynyl-2'-deoxyuridine (EdU) labelling of herpes simplex virus 1 (HSV-1) DNA in combination with click chemistry to examine the sequential recruitment of host immune regulators to infecting viral genomes under low multiplicity of infection conditions. Following viral genome entry into the nucleus, PML-nuclear bodies (PML-NBs) rapidly entrapped viral DNA (vDNA) leading to a block in viral replication in the absence of the viral PML-NB antagonist ICP0. This pre-existing intrinsic host defence to infection occurred independently of the vDNA pathogen sensor IFI16 (Interferon Gamma Inducible Protein 16) and the induction of interferon stimulated gene (ISG) expression, demonstrating that vDNA entry into the nucleus alone is not sufficient to induce a robust innate immune response. Saturation of this pre-existing intrinsic host defence during HSV-1 ICP0-null mutant infection led to the stable recruitment of PML and IFI16 into vDNA complexes associated with ICP4, and led to the induction of ISG expression. This induced innate immune response occurred in a PML-, IFI16-, and Janus-Associated Kinase (JAK)-dependent manner and was restricted by phosphonoacetic acid, demonstrating that vDNA polymerase activity is required for the robust induction of ISG expression during HSV-1 infection. Our data identifies dual roles for PML in the sequential regulation of intrinsic and innate immunity to HSV-1 infection that are dependent on viral genome delivery to the nucleus and the onset of vDNA replication, respectively. These intracellular host defences are counteracted by ICP0, which targets PML for degradation from the outset of nuclear infection to promote vDNA release from PML-NBs and the onset of HSV-1 lytic replication.


Assuntos
Regulação Viral da Expressão Gênica/efeitos dos fármacos , Herpes Simples/metabolismo , Herpesvirus Humano 1/fisiologia , Interações Hospedeiro-Patógeno , Corpos de Inclusão Viral/metabolismo , Proteína da Leucemia Promielocítica/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Proteínas Virais/metabolismo , Linhagem Celular , Linhagem Celular Transformada , Células Cultivadas , Química Click , Deleção de Genes , Herpes Simples/tratamento farmacológico , Herpes Simples/patologia , Herpes Simples/virologia , Herpesvirus Humano 1/crescimento & desenvolvimento , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Imunidade Inata/efeitos dos fármacos , Corpos de Inclusão Viral/efeitos dos fármacos , Corpos de Inclusão Viral/patologia , Corpos de Inclusão Viral/virologia , Cinética , Lisogenia/efeitos dos fármacos , Mutação , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fosfoproteínas/antagonistas & inibidores , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Proteína da Leucemia Promielocítica/antagonistas & inibidores , Proteína da Leucemia Promielocítica/genética , Interferência de RNA , Inibidores da Transcriptase Reversa/farmacologia , Ubiquitina-Proteína Ligases/genética , Proteínas Virais/genética , Internalização do Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
5.
J Virol ; 89(3): 1502-11, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25410861

RESUMO

UNLABELLED: Herpesviruses have a characteristic particle structure comprising an icosahedral capsid, which contains the DNA genome and is, in turn, surrounded by a proteinaceous tegument layer and a lipid envelope. In herpes simplex virus, the interaction between the capsid and tegument is limited to the capsid vertices and involves two minor capsid proteins, pUL17 and pUL25, and the large inner tegument protein pUL36. pUL17 and pUL25 form a heterodimeric structure, the capsid vertex-specific component (CVSC), that lies on top of the peripentonal triplexes, while pUL36 has been reported to connect the CVSC to the penton. In this study, we used virus mutants with deletions in the genes for pUL36 and another inner tegument protein, pUL37, to analyze the contributions of these proteins to CVSC structure. Using electron cryomicroscopy and icosahedral reconstruction of mutants that express pUL17 and pUL25 but not pUL36, we showed that in contrast to accepted models, the CVSC is not formed from pUL17 and pUL25 on their own but requires a contribution from pUL36. In addition, the presence of full-length pUL36 results in weak density that extends the CVSC toward the penton, suggesting either that this extra density is formed directly by pUL36 or that pUL36 stabilizes other components of the vertex-tegument interface. IMPORTANCE: Herpesviruses have complex particles that are formed as a result of a carefully controlled sequence of assembly steps. The nature of the interaction between two of the major particle compartments, the icosahedral capsid and the amorphous tegument, has been extensively studied, but the identity of the interacting proteins and their roles in forming the connections are still unclear. In this study, we used electron microscopy and three-dimensional reconstruction to analyze virus particles formed by mutants that do not express particular interacting proteins. We show that the largest viral protein, pUL36, which occupies the layer of tegument closest to the capsid, is essential for formation of structurally normal connections to the capsid. This demonstrates the importance of pUL36 in the initial stages of tegument addition and provides new insights into the process of virus particle assembly.


Assuntos
Proteínas do Capsídeo/metabolismo , Herpesvirus Humano 1/fisiologia , Proteínas Virais/fisiologia , Montagem de Vírus , Animais , Capsídeo/metabolismo , Linhagem Celular , Microscopia Crioeletrônica , Deleção de Genes , Processamento de Imagem Assistida por Computador , Proteínas Virais/genética
6.
Nucleic Acids Res ; 42(2): 1257-69, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24141094

RESUMO

The P body protein LSm1 stimulates translation and replication of hepatitis C virus (HCV). As the liver-specific microRNA-122 (miR-122) is required for HCV replication and is associated with P bodies, we investigated whether regulation of HCV by LSm1 involves miR-122. Here, we demonstrate that LSm1 contributes to activation of HCV internal ribosome entry site (IRES)-driven translation by miR-122. This role for LSm1 is specialized for miR-122 translation activation, as LSm1 depletion does not affect the repressive function of miR-122 at 3' untranslated region (UTR) sites, or miR-122-mediated cleavage at a perfectly complementary site. We find that LSm1 does not influence recruitment of the microRNA (miRNA)-induced silencing complex to the HCV 5'UTR, implying that it regulates miR-122 function subsequent to target binding. In contrast to the interplay between miR-122 and LSm1 in translation, we find that LSm1 is not required for miR-122 to stimulate HCV replication, suggesting that miR-122 regulation of HCV translation and replication have different requirements. For the first time, we have identified a protein factor that specifically contributes to activation of HCV IRES-driven translation by miR-122, but not to other activities of the miRNA. Our results enhance understanding of the mechanisms by which miR-122 and LSm1 regulate HCV.


Assuntos
Hepacivirus/genética , MicroRNAs/metabolismo , Biossíntese de Proteínas , Proteínas Proto-Oncogênicas/fisiologia , Proteínas de Ligação a RNA/fisiologia , Regiões 3' não Traduzidas , Regiões 5' não Traduzidas , Linhagem Celular , Hepacivirus/fisiologia , Humanos , Complexo de Inativação Induzido por RNA/metabolismo , Replicação Viral
7.
Prog Mol Biol Transl Sci ; 102: 101-39, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21846570

RESUMO

MicroRNAs (miRNAs) are small non-coding RNA molecules that have emerged in recent years as central regulators of eukaryotic gene expression. In mammalian systems, miRNAs are associated with numerous pathological and physiological pathways. miRNAs are important in many viral infections, with different viral families expressing their own miRNAs, manipulating host miRNA expression, or showing direct or indirect regulation by host or viral miRNAs. In this chapter we will examine the current evidence for interplay between the miRNA pathway and viral infections in mammals.


Assuntos
MicroRNAs/genética , MicroRNAs/metabolismo , Viroses/genética , Animais , Sequência de Bases , Células/metabolismo , Regulação da Expressão Gênica/genética , Humanos , Dados de Sequência Molecular , RNA Viral/genética , RNA Viral/metabolismo
8.
Nucleic Acids Res ; 39(17): 7716-29, 2011 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-21653556

RESUMO

In animals, microRNAs (miRNAs) generally repress gene expression by binding to sites in the 3'-untranslated region (UTR) of target mRNAs. miRNAs have also been reported to repress or activate gene expression by binding to 5'-UTR sites, but the extent of such regulation and the factors that govern these different responses are unknown. Liver-specific miR-122 binds to sites in the 5'-UTR of hepatitis C virus (HCV) RNA and positively regulates the viral life cycle, in part by stimulating HCV translation. Here, we characterize the features that allow miR-122 to activate translation via the HCV 5'-UTR. We find that this regulation is a highly specialized process that requires uncapped RNA, the HCV internal ribosome entry site (IRES) and the 3' region of miR-122. Translation activation does not involve a previously proposed structural transition in the HCV IRES and is mediated by Argonaute proteins. This study provides an important insight into the requirements for the miR-122-HCV interaction, and the broader consequences of miRNAs binding to 5'-UTR sites.


Assuntos
Regiões 5' não Traduzidas , Hepacivirus/genética , MicroRNAs/metabolismo , Iniciação Traducional da Cadeia Peptídica , RNA Viral/química , Proteínas Argonautas/fisiologia , Sítios de Ligação , Linhagem Celular , Humanos , MicroRNAs/antagonistas & inibidores , MicroRNAs/química , Fases de Leitura Aberta , Análogos de Capuz de RNA/metabolismo , RNA Viral/metabolismo
9.
J Gen Virol ; 91(Pt 9): 2145-51, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20505007

RESUMO

Secondary envelopment of herpes simplex virus type 1 has been demonstrated as taking place at the trans-Golgi network (TGN). The inner tegument proteins pUL36 and pUL37 and the envelope glycoproteins gD and gE are known to be important for secondary envelopment. We compared the cellular localizations of capsids from a virus mutant lacking the UL37 gene with those of a virus mutant lacking the genes encoding gD and gE. Although wild-type capsids accumulated at the TGN, capsids of the pUL37(-) mutant were distributed throughout the cytoplasm and showed no association with TGN-derived vesicles. This was in contrast to capsids from a gD(-)gE(-) mutant, which accumulated in the vicinity of TGN vesicles, but did not colocalize with them, suggesting that they were transported to the TGN but were unable to undergo envelopment. We conclude that the inner tegument protein pUL37 is required for directing capsids to the TGN, where secondary envelopment occurs.


Assuntos
Herpesvirus Humano 1/fisiologia , Proteínas Estruturais Virais/fisiologia , Transporte Biológico Ativo , Capsídeo/fisiologia , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/fisiologia , Linhagem Celular , Genes Virais , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Células HeLa , Herpesvirus Humano 1/genética , Humanos , Mutação , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Estruturais Virais/genética , Montagem de Vírus/genética , Montagem de Vírus/fisiologia , Rede trans-Golgi/virologia
10.
Genome Biol ; 11(1): 201, 2010 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-20122293

RESUMO

An inhibitor of microRNA-122 reduces viral load in chimpanzees that are chronically infected with hepatitis C virus, suggesting that such an approach might have therapeutic potential in humans.


Assuntos
Hepacivirus/genética , Hepatite C Crônica/virologia , MicroRNAs/genética , Animais , Biópsia , Ensaios Clínicos como Assunto , Humanos , Fígado/patologia , Oligonucleotídeos/genética , Pan troglodytes
11.
J Virol ; 83(1): 105-16, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18971278

RESUMO

Studies with herpes simplex virus type 1 (HSV-1) have shown that secondary envelopment and virus release are blocked in mutants deleted for the tegument protein gene UL36 or UL37, leading to the accumulation of DNA-containing capsids in the cytoplasm of infected cells. The failure to assemble infectious virions has meant that the roles of these genes in the initial stages of infection could not be investigated. To circumvent this, cells infected at a low multiplicity were fused to form syncytia, thereby allowing capsids released from infected nuclei access to uninfected nuclei without having to cross a plasma membrane. Visualization of virus DNA replication showed that a UL37-minus mutant was capable of transmitting infection to all the nuclei within a syncytium as efficiently as the wild-type HSV-1 strain 17(+) did, whereas infection by UL36-minus mutants failed to spread. Thus, these inner tegument proteins have differing functions, with pUL36 being essential during both the assembly and uptake stages of infection, while pUL37 is needed for the formation of virions but is not required during the initial stages of infection. Analysis of noninfectious enveloped particles (L-particles) further showed that pUL36 and pUL37 are dependent on each other for incorporation into tegument.


Assuntos
Herpesvirus Humano 1/fisiologia , Proteínas Virais/metabolismo , Proteínas Estruturais Virais/metabolismo , Internalização do Vírus , Células Cultivadas , Deleção de Genes , Herpesvirus Humano 1/genética , Humanos , Ligação Proteica , Proteínas Virais/genética , Proteínas Estruturais Virais/genética , Montagem de Vírus
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