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1.
Proc Natl Acad Sci U S A ; 119(4)2022 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-35046024

RESUMO

Transmissible vaccines have the potential to revolutionize how zoonotic pathogens are controlled within wildlife reservoirs. A key challenge that must be overcome is identifying viral vectors that can rapidly spread immunity through a reservoir population. Because they are broadly distributed taxonomically, species specific, and stable to genetic manipulation, betaherpesviruses are leading candidates for use as transmissible vaccine vectors. Here we evaluate the likely effectiveness of betaherpesvirus-vectored transmissible vaccines by developing and parameterizing a mathematical model using data from captive and free-living mouse populations infected with murine cytomegalovirus (MCMV). Simulations of our parameterized model demonstrate rapid and effective control for a range of pathogens, with pathogen elimination frequently occurring within a year of vaccine introduction. Our results also suggest, however, that the effectiveness of transmissible vaccines may vary across reservoir populations and with respect to the specific vector strain used to construct the vaccine.


Assuntos
Betaherpesvirinae/genética , Vetores Genéticos/genética , Imunogenicidade da Vacina , Modelos Teóricos , Vacinas/imunologia , Algoritmos , Doenças dos Animais/prevenção & controle , Doenças dos Animais/transmissão , Doenças dos Animais/virologia , Animais , Teorema de Bayes , Reservatórios de Doenças , Vetores de Doenças , Vetores Genéticos/imunologia , Infecções por Herpesviridae/veterinária , Camundongos , Muromegalovirus , Prevalência , Vacinas/genética
2.
Viruses ; 13(10)2021 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-34696402

RESUMO

Cell-cell fusion is a fundamental and complex process that occurs during reproduction, organ and tissue growth, cancer metastasis, immune response, and infection. All enveloped viruses express one or more proteins that drive the fusion of the viral envelope with cellular membranes. The same proteins can mediate the fusion of the plasma membranes of adjacent cells, leading to the formation of multinucleated syncytia. While cell-cell fusion triggered by alpha- and gammaherpesviruses is well-studied, much less is known about the fusogenic potential of betaherpesviruses such as human cytomegalovirus (HCMV) and human herpesviruses 6 and 7 (HHV-6 and HHV-7). These are slow-growing viruses that are highly prevalent in the human population and associated with several diseases, particularly in individuals with an immature or impaired immune system such as fetuses and transplant recipients. While HHV-6 and HHV-7 are strictly lymphotropic, HCMV infects a very broad range of cell types including epithelial, endothelial, mesenchymal, and myeloid cells. Syncytia have been observed occasionally for all three betaherpesviruses, both during in vitro and in vivo infection. Since cell-cell fusion may allow efficient spread to neighboring cells without exposure to neutralizing antibodies and other host immune factors, viral-induced syncytia may be important for viral dissemination, long-term persistence, and pathogenicity. In this review, we provide an overview of the viral and cellular factors and mechanisms identified so far in the process of cell-cell fusion induced by betaherpesviruses and discuss the possible consequences for cellular dysfunction and pathogenesis.


Assuntos
Células Gigantes/fisiologia , Infecções por Herpesviridae/metabolismo , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Betaherpesvirinae/metabolismo , Betaherpesvirinae/patogenicidade , Fusão Celular , Citomegalovirus/fisiologia , Células Gigantes/virologia , Herpesviridae/fisiologia , Infecções por Herpesviridae/virologia , Herpesvirus Humano 6/imunologia , Herpesvirus Humano 7/imunologia , Humanos , Proteínas do Envelope Viral/metabolismo , Internalização do Vírus
3.
Viruses ; 13(9)2021 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-34578438

RESUMO

An evolutionary arms race occurs between viruses and hosts. Hosts have developed an array of antiviral mechanisms aimed at inhibiting replication and spread of viruses, reducing their fitness, and ultimately minimising pathogenic effects. In turn, viruses have evolved sophisticated counter-measures that mediate evasion of host defence mechanisms. A key aspect of host defences is the ability to differentiate between self and non-self. Previous studies have demonstrated significant suppression of CpG and UpA dinucleotide frequencies in the coding regions of RNA and small DNA viruses. Artificially increasing these dinucleotide frequencies results in a substantial attenuation of virus replication, suggesting dinucleotide bias could facilitate recognition of non-self RNA. The interferon-inducible gene, zinc finger antiviral protein (ZAP) is the host factor responsible for sensing CpG dinucleotides in viral RNA and restricting RNA viruses through direct binding and degradation of the target RNA. Herpesviruses are large DNA viruses that comprise three subfamilies, alpha, beta and gamma, which display divergent CpG dinucleotide patterns within their genomes. ZAP has recently been shown to act as a host restriction factor against human cytomegalovirus (HCMV), a beta-herpesvirus, which in turn evades ZAP detection by suppressing CpG levels in the major immediate-early transcript IE1, one of the first genes expressed by the virus. While suppression of CpG dinucleotides allows evasion of ZAP targeting, synonymous changes in nucleotide composition that cause genome biases, such as low GC content, can cause inefficient gene expression, especially in unspliced transcripts. To maintain compact genomes, the majority of herpesvirus transcripts are unspliced. Here we discuss how the conflicting pressures of ZAP evasion, the need to maintain compact genomes through the use of unspliced transcripts and maintaining efficient gene expression may have shaped the evolution of herpesvirus genomes, leading to characteristic CpG dinucleotide patterns.


Assuntos
Alphaherpesvirinae/genética , Fosfatos de Dinucleosídeos/metabolismo , Genoma Viral , Herpesviridae/genética , Proteínas de Ligação a RNA/metabolismo , Alphaherpesvirinae/metabolismo , Alphaherpesvirinae/fisiologia , Animais , Betaherpesvirinae/genética , Betaherpesvirinae/metabolismo , Betaherpesvirinae/fisiologia , Evolução Molecular , Gammaherpesvirinae/genética , Gammaherpesvirinae/metabolismo , Gammaherpesvirinae/fisiologia , Expressão Gênica , Herpesviridae/metabolismo , Herpesviridae/fisiologia , Interações Hospedeiro-Patógeno , Humanos , Interferons/metabolismo , Splicing de RNA , RNA Viral/genética , RNA Viral/metabolismo , Proteínas de Ligação a RNA/química , Transdução de Sinais , Proteínas Virais/metabolismo
4.
Int J Mol Sci ; 22(14)2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34299120

RESUMO

The human immune system boasts a diverse array of strategies for recognizing and eradicating invading pathogens. Human betaherpesviruses, a highly prevalent subfamily of viruses, include human cytomegalovirus (HCMV), human herpesvirus (HHV) 6A, HHV-6B, and HHV-7. These viruses have evolved numerous mechanisms for evading the host response. In this review, we will highlight the complex interplay between betaherpesviruses and the human immune response, focusing on protein function. We will explore methods by which the immune system first responds to betaherpesvirus infection as well as mechanisms by which viruses subvert normal cellular functions to evade the immune system and facilitate viral latency, persistence, and reactivation. Lastly, we will briefly discuss recent advances in vaccine technology targeting betaherpesviruses. This review aims to further elucidate the dynamic interactions between betaherpesviruses and the human immune system.


Assuntos
Betaherpesvirinae/imunologia , Betaherpesvirinae/patogenicidade , Infecções por Herpesviridae/virologia , Evasão da Resposta Imune , Imunidade , Infecções por Herpesviridae/imunologia , Humanos
5.
Mol Cell ; 81(13): 2823-2837.e9, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34015248

RESUMO

DNA-induced liquid-liquid phase separation of cyclic GMP-AMP synthase (cGAS) triggers a potent response to detect pathogen infection and promote innate immune signaling. Whether and how pathogens manipulate cGAS-DNA condensation to mediate immune evasion is unknown. We report the identification of a structurally related viral tegument protein family, represented by ORF52 and VP22 from gamma- and alpha-herpesvirinae, respectively, that employs a conserved mechanism to restrict cGAS-DNA phase separation. ORF52/VP22 proteins accumulate into, and effectively disrupt, the pre-formed cGAS-DNA condensation both in vitro and in cells. The inhibition process is dependent on DNA-induced liquid-liquid phase separation of the viral protein rather than a direct interaction with cGAS. Moreover, highly abundant ORF52 proteins carried within viral particles are able to target cGAS-DNA phase separation in early infection stage. Our results define ORF52/VP22-type tegument proteins as a family of inhibitors targeting cGAS-DNA phase separation and demonstrate a mechanism for how viruses overcome innate immunity.


Assuntos
Alphaherpesvirinae , Betaherpesvirinae , DNA , Infecções por Herpesviridae , Evasão da Resposta Imune , Nucleotidiltransferases , Proteínas Estruturais Virais , Alphaherpesvirinae/química , Alphaherpesvirinae/genética , Alphaherpesvirinae/imunologia , Betaherpesvirinae/química , Betaherpesvirinae/genética , Betaherpesvirinae/imunologia , DNA/química , DNA/genética , DNA/imunologia , Células HEK293 , Células HeLa , Infecções por Herpesviridae/genética , Infecções por Herpesviridae/imunologia , Humanos , Imunidade Inata , Nucleotidiltransferases/química , Nucleotidiltransferases/genética , Nucleotidiltransferases/imunologia , Proteínas Estruturais Virais/química , Proteínas Estruturais Virais/genética , Proteínas Estruturais Virais/imunologia
6.
Rio de Janeiro; s.n; 2021. xvi,84 p. ilus.
Tese em Português | LILACS | ID: biblio-1337974

RESUMO

Guimarães Os vírus têm sido considerados como importantes patógenos no desenvolvimento de neoplasias em glândulas salivares, dentre estes, destacam-se os Betaherpesvirus humano como o Citomegalovirus humano (HCMV), Herpesvirus humano 6 (HHV-6) e Herpesvirus humano 7 (HHV-7). Os betaherpesvírus são característicos por apresentarem alta prevalência na população mundial, sem apresentar sazonalidade, capazes de causar infecção latente e reativação viral em seus hospedeiros. Devido a detecção destes vírus em amostras de saliva, tem sido proposto em alguns estudos a ação de betaherpesvírus em algumas patogenias de glândulas salivares, como a formação de patogenias nestes órgãos. Neoplasias em glândulas salivares representam cerca de 3-6% de todas as neoplasias de cabeça e pescoço, com incidência mundial anual de aproximadamente 0,4-13,5% por 100.000 indivíduos. Apesar de haver dados de detecção de betaherpesvírus em neoplasias salivares e em amostras de saliva, ainda existem estudos insuficientes que explorem o papel destes vírus nestas patogenias salivares. O objetivo deste estudo foi investigar a presença dos Betaherpesvirus humano (HCMV, HHV-6 e HHV-7) em neoplasias de glândula salivar parafinadas. Um ensaio de qPCR foi realizado para amplificação das regiões U54, U56 e U37 do HCMV, HHV-6 e HHV-7, respectivamente para quantificar a carga viral em 68 amostras parafinadas de lesões salivares. Dentre as 68 amostras processadas, 51,4% eram de mucocele (35/68), 39,7% de adenoma pleomórfico (27/68) e 8,8% de carcinoma mucoepidermoóide (6/68). A detecção de betaherpesvírus nestas lesões foi alta, apresentando maior detecção para HCMV com 52,9%, 47,05% para HHV-6 e 39,7% para HHV-7, possuindo predominância de detecção de betaherpesvírus na lesão do tipo adenoma pleomórfico. Foi observado que 50,0% das amostras apresentaram tripla-infecção por HCMV/HHV-6/HHV-7, sendo detectado 20,0% de coinfecções por HCMV/HHV-6, 20,0% de HCMV/HHV-7 e 10,0% de HHV-6/HHV-7, com coinfecções ocorrendo na lesão do tipo adenoma pleomórfico em maior taxa. A alta detecção de HCMV, HHV-6 e HHV-7 em glândulas salivares, indica que este órgão pode ser possível de sítio de replicação destes vírus


The viruses have been considered as important pathogens in the development of neoplasms in salivary glands, between these, Human betaherpesvirus such as Human cytomegalovirus (HCMV), Human herpesvirus 6 (HHV-6) and Human herpesvirus 7 (HHV-7) stand out. Betaherpesvirus is characteristic because they have a high prevalence in the world population, without presenting seasonality, capable of causing latent infection and viral reactivation in their hosts. Due to the detection of these viruses in saliva samples, the action of betaherpesvirus in some pathogenesis of salivary glands, such as the formation of pathogenesis in these organs, has been proposed in some studies. Salivary gland neoplasms account for about 3-6% of all head and neck neoplasms, with an annual worldwide incidence of approximately 0,4-13,5% per 100,000 individuals. Although there are data for the detection of betaherpesvirus in salivary neoplasms and saliva samples, thereare still insufficient studies exploring the role of these viruses in these salivary pathogeneses. The aim of this study was to investigate the presence of human Betaherpesvirus (HCMV, HHV-6 and HHV-7) in paraffin salivary gland neoplasms. A qPCR assay was performed to amplify the U54, U56 and U37 regions of HCMV, HHV-6 and HHV-7, respectively to quantify the viral load in 68 paraffin samples of salivary lesions. Among the 68 samples processed,51,4%were mucocele (35/68), 39.7% pleomorphic adenoma (27/68) and 8,8% mucoepidermoid carcinoma (6/68). The detection of betaherpesvirus in these lesions was high, presenting higher detection for HCMV with 52,9%, 47,05% for HHV6 and 39,7% for HHV-7, with predominance of detection of betaherpesvirus in the lesion of the pleomorphic adenoma type. It was observed that 50.0% of the samples presented triple-infection by HCMV/HHV-6/HHV-7, and 20.0% of co-infections by HCMV/HHV-6, 20.0% of HCMV/HHV-7 and 10.0% of HHV-6/HHV-7 were detected, with co-infections occurring with higher predominance of pleomorphic adenoma lesion. The high detection of HCMV, HHV-6 and HHV-7 in salivary glands indicates that this organ may be possible from replication site.


Assuntos
Neoplasias das Glândulas Salivares , Betaherpesvirinae , Herpesvirus Humano 6 , Herpesvirus Humano 7
7.
Nat Commun ; 11(1): 5951, 2020 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-33230120

RESUMO

Rabies is a viral zoonosis transmitted by vampire bats across Latin America. Substantial public health and agricultural burdens remain, despite decades of bats culls and livestock vaccinations. Virally vectored vaccines that spread autonomously through bat populations are a theoretically appealing solution to managing rabies in its reservoir host. We investigate the biological and epidemiological suitability of a vampire bat betaherpesvirus (DrBHV) to act as a vaccine vector. In 25 sites across Peru with serological and/or molecular evidence of rabies circulation, DrBHV infects 80-100% of bats, suggesting potential for high population-level vaccine coverage. Phylogenetic analysis reveals host specificity within neotropical bats, limiting risks to non-target species. Finally, deep sequencing illustrates DrBHV super-infections in individual bats, implying that DrBHV-vectored vaccines might invade despite the highly prevalent wild-type virus. These results indicate DrBHV as a promising candidate vector for a transmissible rabies vaccine, and provide a framework to discover and evaluate candidate viral vectors for vaccines against bat-borne zoonoses.


Assuntos
Betaherpesvirinae/fisiologia , Quirópteros/virologia , Raiva/epidemiologia , Raiva/veterinária , Animais , Betaherpesvirinae/classificação , Betaherpesvirinae/genética , Coevolução Biológica , Bovinos , Quirópteros/classificação , Genoma Viral/genética , Infecções por Herpesviridae/epidemiologia , Infecções por Herpesviridae/veterinária , Infecções por Herpesviridae/virologia , Especificidade de Hospedeiro , Mamíferos/classificação , Mamíferos/virologia , Peru/epidemiologia , Filogenia , Raiva/prevenção & controle , Raiva/transmissão , Vírus da Raiva/imunologia , Vírus da Raiva/fisiologia , Estudos Soroepidemiológicos , Superinfecção/veterinária , Superinfecção/virologia
8.
Virology ; 548: 236-249, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32791352

RESUMO

Species-specific guinea pig cytomegalovirus (GPCMV) causes congenital CMV and the virus encodes homolog glycoprotein complexes to human CMV, including gH-based trimer (gH/gL/gO) and pentamer-complex (PC). Platelet-derived growth factor receptor alpha (gpPDGFRA), only present on fibroblast cells, was identified via CRISPR as the putative receptor for PC-independent GPCMV infection. Immunoprecipitation assays demonstrated direct interaction of gH/gL/gO with gpPDGFRA but not in absence of gO. Expression of viral gB also resulted in precipitation of gB/gH/gL/gO/gpPDGFRA complex. Cell-cell fusion assays determined that expression of gpPDGFRA and gH/gL/gO in adjacent cells enabled cell fusion, which was not enhanced by gB. N-linked gpPDGFRA glycosylation inhibition had limited effect and blocking tyrosine kinase (TK) transduction had no impact on infection. Ectopically expressed gpPDGFRA or TK-domain mutant in trophoblast or epithelial cells previously non-susceptible to GPCMV(PC-) enabled viral infection. In contrast, transient human PDGFRA expression did not complement GPCMV(PC-) infection, a potential basis for viral species specificity.


Assuntos
Betaherpesvirinae/fisiologia , Infecções por Herpesviridae/veterinária , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Doenças dos Roedores/metabolismo , Proteínas Virais/metabolismo , Animais , Betaherpesvirinae/genética , Fusão Celular , Cobaias , Infecções por Herpesviridae/genética , Infecções por Herpesviridae/metabolismo , Ligação Proteica , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Doenças dos Roedores/genética , Doenças dos Roedores/virologia , Proteínas Virais/química , Proteínas Virais/genética , Internalização do Vírus
9.
J Zoo Wildl Med ; 51(2): 303-307, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32549559

RESUMO

Elephant endotheliotropic herpesvirus (EEHV) causes a disease that primarily affects juvenile Asian (Elephas maximus) elephants, causing acute hemorrhage and death. Due to the severity of the disease, many zoos have developed EEHV active surveillance programs. Currently, trunk washes are the standard for testing elephants for shedding of EEHV, but it has also been detected from other mucosal surfaces. This study compared the efficacy of oral swabs and trunk washes for the detection of EEHV shedding using previously validated quantitative polymerase chain reaction (qPCR) methods. Oral swab and trunk wash samples from three juvenile elephants at the Dublin Zoo in Ireland were collected in tandem and tested from April to September 2017. Of the 51 paired samples, 21 trunk wash samples were positive for EEHV1, while only 2 of the oral swab samples were positive for EEHV1, suggesting that trunk wash samples are more effective for detecting shedding of EEHV in Asian elephants compared with oral swabs.


Assuntos
Betaherpesvirinae/isolamento & purificação , Elefantes , Infecções por Herpesviridae/veterinária , Manejo de Espécimes/veterinária , Viremia/veterinária , Animais , Animais de Zoológico , Coleta de Amostras Sanguíneas/veterinária , Feminino , Infecções por Herpesviridae/diagnóstico , Infecções por Herpesviridae/virologia , Irlanda , Masculino , Viremia/diagnóstico , Viremia/virologia
10.
J Zoo Wildl Med ; 51(2): 433-437, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32549575

RESUMO

Elephant endotheliotropic herpesvirus (EEHV) hemorrhagic disease (EEHV-HD) threatens Asian elephant (Elephas maximus) population sustainability in North America. Clusters of cases have also been reported in African elephants (Loxodonta africana). Risk to range country elephant populations is unknown. Currently, EEHV detection depends upon sampling elephants trained for invasive blood and trunk wash collection. To evaluate noninvasive sample collection options, paired invasively collected (blood, trunk wash and oral swabs), and noninvasively collected (chewed plant and fecal) samples were compared over 6 wk from 9 Asian elephants and 12 African elephants. EEHV shedding was detected simultaneously in a paired trunk wash and fecal sample from one African elephant. Elephant γ herpesvirus-1 shedding was identified in six chewed plant samples collected from four Asian elephants. Noninvasively collected samples can be used to detect elephant herpesvirus shedding. Longer sampling periods are needed to evaluate the clinical usefulness of noninvasive sampling for EEHV detection.


Assuntos
Betaherpesvirinae/isolamento & purificação , Elefantes , Infecções por Herpesviridae/veterinária , Manejo de Espécimes/veterinária , Ração Animal/virologia , Animais , Animais de Zoológico , Coleta de Amostras Sanguíneas/veterinária , Fezes/virologia , Feminino , Microbiologia de Alimentos , Infecções por Herpesviridae/diagnóstico , Infecções por Herpesviridae/virologia , Irlanda , Masculino , Manejo de Espécimes/classificação , Manejo de Espécimes/instrumentação
11.
J Biol Chem ; 295(10): 3189-3201, 2020 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-31980459

RESUMO

Herpesviruses uniquely express two essential nuclear egress-regulating proteins forming a heterodimeric basic structure of the nuclear egress complex (core NEC). These core NECs serve as a hexameric lattice-structured platform for capsid docking and recruit viral and cellular NEC-associated factors that jointly exert nuclear lamina- and membrane-rearranging functions (multicomponent NEC). Here, we report the X-ray structures of ß- and γ-herpesvirus core NECs obtained through an innovative recombinant expression strategy based on NEC-hook::NEC-groove protein fusion constructs. This approach yielded the first structure of γ-herpesviral core NEC, namely the 1.56 Å structure of Epstein-Barr virus (EBV) BFRF1-BFLF2, as well as an increased resolution 1.48 Å structure of human cytomegalovirus (HCMV) pUL50-pUL53. Detailed analysis of these structures revealed that the prominent hook segment is absolutely required for core NEC formation and contributes approximately 80% of the interaction surface of the globular domains of NEC proteins. Moreover, using HCMV::EBV hook domain swap constructs, computational prediction of the roles of individual hook residues for binding, and quantitative binding assays with synthetic peptides presenting the HCMV- and EBV-specific NEC hook sequences, we characterized the unique hook-into-groove NEC interaction at various levels. Although the overall physicochemical characteristics of the protein interfaces differ considerably in these ß- and γ-herpesvirus NECs, the binding free energy contributions of residues displayed from identical positions are similar. In summary, the results of our study reveal critical details of the molecular mechanism of herpesviral NEC interactions and highlight their potential as an antiviral drug target.


Assuntos
Betaherpesvirinae/metabolismo , Gammaherpesvirinae/metabolismo , Proteínas Virais/química , Sequência de Aminoácidos , Cristalografia por Raios X , Citomegalovirus/metabolismo , Células HeLa , Herpesvirus Humano 4/metabolismo , Humanos , Peptídeos/química , Peptídeos/metabolismo , Estrutura Terciária de Proteína , Proteínas Recombinantes de Fusão/biossíntese , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/isolamento & purificação , Ressonância de Plasmônio de Superfície , Proteínas Virais/genética , Proteínas Virais/metabolismo
12.
J Gen Virol ; 101(3): 284-289, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31958050

RESUMO

Infections with human herpesviruses share several molecular characteristics, but the diversified medical outcomes are distinct to viral subfamilies and species. Notably, both clinical and molecular correlates of infection are a challenging field and distinct patterns of virus-host interaction have rarely been defined; this study therefore focuses on the search for virus-specific molecular indicators. As previous studies have demonstrated the impact of herpesvirus infections on changes in host signalling pathways, we illustrate virus-modulated expression levels of individual cellular protein kinases. Current data reveal (i) α-, ß- and γ-herpesvirus-specific patterns of kinase modulation as well as (ii) differential levels of up-/downregulated kinase expression and phosphorylation, which collectively suggest (iii) defined signalling patterns specific for the various viruses (VSS) that may prove useful for defining molecular indicators. Combined, the study confirms the correlation between herpesviral replication and modulation of signalling kinases, possibly exploitable for the in vitro characterization of viral infections.


Assuntos
Alphaherpesvirinae/metabolismo , Betaherpesvirinae/metabolismo , Fibroblastos/metabolismo , Gammaherpesvirinae/metabolismo , Infecções por Herpesviridae/metabolismo , Linfócitos/metabolismo , Proteínas Quinases/metabolismo , Replicação Viral/fisiologia , Células Cultivadas , Infecções por Herpesviridae/virologia , Interações Hospedeiro-Patógeno , Humanos , Fosforilação , Transdução de Sinais/fisiologia , Regulação para Cima
13.
Emerg Infect Dis ; 26(1): 63-69, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31855135

RESUMO

In recent years, an alarming number of cases of lethal acute hemorrhagic disease have occurred in Asian elephant calves raised in logging camps in Myanmar. To determine whether these deaths were associated with infection by elephant endotheliotropic herpesvirus (EEHV), we conducted diagnostic PCR subtype DNA sequencing analysis on necropsy tissue samples collected from 3 locations. We found that EEHV DNA from 7 PCR loci was present at high levels in all 3 calves and was the same EEHV1A virus type that has been described in North America, Europe, and other parts of Asia. However, when analyzed over 5,610 bp, the strains showed major differences from each other and from all previously characterized EEHV1A strains. We conclude that these 3 elephant calves in Myanmar died from the same herpesvirus disease that has afflicted young Asian elephants in other countries over the past 20 years.


Assuntos
Betaherpesvirinae , Elefantes/virologia , Infecções por Herpesviridae/veterinária , Animais , Animais Recém-Nascidos/virologia , Betaherpesvirinae/genética , Feminino , Infecções por Herpesviridae/epidemiologia , Infecções por Herpesviridae/patologia , Infecções por Herpesviridae/virologia , Masculino , Mianmar/epidemiologia , Filogenia , Reação em Cadeia da Polimerase/veterinária , Análise de Sequência de DNA
14.
Nat Rev Immunol ; 20(2): 113-127, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31666730

RESUMO

The coordinated activities of innate and adaptive immunity are critical for effective protection against viruses. To counter this, some viruses have evolved sophisticated strategies to circumvent immune cell recognition. In particular, cytomegaloviruses encode large arsenals of molecules that seek to subvert T cell and natural killer cell function via a remarkable array of mechanisms. Consequently, these 'immunoevasins' play a fundamental role in shaping the nature of the immune system by driving the evolution of new immune receptors and recognition mechanisms. Here, we review the diverse strategies adopted by cytomegaloviruses to target immune pathways and outline the host's response.


Assuntos
Imunidade Adaptativa/imunologia , Infecções por Citomegalovirus/imunologia , Citomegalovirus/patogenicidade , Evasão da Resposta Imune/imunologia , Imunidade Inata/imunologia , Complexo Principal de Histocompatibilidade/imunologia , Proteínas Virais/imunologia , Animais , Betaherpesvirinae/patogenicidade , Proteínas do Capsídeo/imunologia , Infecções por Herpesviridae/imunologia , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Camundongos , Muromegalovirus/patogenicidade , Proteínas de Ligação a RNA/imunologia , Proteínas do Envelope Viral/imunologia
15.
BMC Infect Dis ; 19(1): 773, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31484497

RESUMO

BACKGROUND: The etiology of acute liver failure (ALF) is often unknown and reported to be associated with herpesviruses in a number of cases. In this study, we examined for betaherpesviruses infections in patients with ALF of unknown etiology using a multiplex qPCR to Betaherpesviruses subfamily. METHODS: Liver explant and serum samples from 27 patients with ALF of unknown etiology were analyzed with the aid of multiplex qPCR to identify betaherpesviruses. All positive samples were sequenced to confirm herpes infection and liver enzyme levels evaluated. RESULTS: Betaherpesviruses infection was effectively detected using multiplex qPCR. Six (22%) HHV-6, one (3%) HCMV and two (7%) dual infections (one with HHV-7/HHV-6, and the other with HHV-7/ HCMV). Interestingly, HHV-7 was only detected in the presence of other betaherpesviruses. Sequencing information confirmed betaherpesviruses infection. High hepatic enzyme levels and INR values> 1.5 were determined in all betaherpesvirus-positive patients. CONCLUSIONS: Multiplex qPCR facilitated efficient quantification, indicating that differentiation between betaherpesviruses is possible with the sole use of real-time PCR. Liver explant and serum samples were positive for some betaherpesviruses, and coinfection of HHV-7 with HHV-6 and HCMV was additionally detected. Based on these results, we propose that ALF patients should be screened for the presence of betaherpesviruses.


Assuntos
Betaherpesvirinae/genética , Betaherpesvirinae/isolamento & purificação , Infecções por Herpesviridae/diagnóstico , Falência Hepática Aguda/diagnóstico , Reação em Cadeia da Polimerase em Tempo Real , Adolescente , Adulto , Brasil/epidemiologia , Criança , DNA Viral/sangue , DNA Viral/isolamento & purificação , Diagnóstico Diferencial , Feminino , Infecções por Herpesviridae/epidemiologia , Infecções por Herpesviridae/virologia , Humanos , Incidência , Falência Hepática Aguda/epidemiologia , Falência Hepática Aguda/virologia , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real/métodos , Adulto Jovem
16.
PLoS One ; 14(7): e0219288, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31276571

RESUMO

The elephant endotheliotropic herpesvirus (EEHV) has been a known cause of death of young elephants in Thailand for over a decade. In this study, we report on the demography, disease characteristics and mortality of 58 elephants with confirmed EEHV hemorrhagic disease between January 2006 and August 2018 using retrospective data subjected to survival analysis. Median age of EEHV presentation was 29 months, and the mortality rate was 68.97% with a median survival time of 36 h. Most EEHV cases occurred in the north of Thailand, the region where most of the country's captive elephants reside. The hazard ratio analysis identified application of medical procedures and antiviral medications as being significant factors correlated to the risk of death. Our results indicate a need to focus EEHV monitoring efforts on young elephants and to follow current protocols that advise starting treatments before clinical signs appear.


Assuntos
Betaherpesvirinae/patogenicidade , Elefantes/virologia , Infecções por Herpesviridae/mortalidade , Animais , Herpesviridae/patogenicidade , Infecções por Herpesviridae/epidemiologia , Estudos Retrospectivos , Análise de Sobrevida , Tailândia
17.
J Wildl Dis ; 55(3): 663-667, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30694725

RESUMO

Neotropical wild rodents from Costa Rica were analyzed for the presence of herpesviruses (order Herpesvirales, family Herpesviridae). Using a broadly generic PCR, herpesvirus sequences were detected in 5% (8/160) of liver and heart samples: seven putative gammaherpesviruses in samples from Talamancan oryzomys (Nephelomys devius), sprightly colilargo (Oligoryzomys vegetus), Mexican deer mouse (Peromyscus nudipes), and Chiriqui harvest mouse (Reithrodontomys creper) and one putative betaherpesvirus in long-tailed singing mouse (Scotinomys xerampelinus). Results from this study could guide ecological investigations targeting the prevalence and host associations of herpesviruses in wild rodents from Costa Rica.


Assuntos
Betaherpesvirinae/isolamento & purificação , Gammaherpesvirinae/isolamento & purificação , Infecções por Herpesviridae/veterinária , Doenças dos Roedores/virologia , Roedores/virologia , Animais , Costa Rica/epidemiologia , Infecções por Herpesviridae/epidemiologia , Infecções por Herpesviridae/virologia , Doenças dos Roedores/epidemiologia
18.
Adv Exp Med Biol ; 1045: 167-207, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29896668

RESUMO

Virions are the vehicle for cell-to-cell and host-to-host transmission of viruses. Virions need to be assembled reliably and efficiently, be released from infected cells, survive in the extracellular environment during transmission, recognize and then trigger entry of appropriate target cells, and disassemble in an orderly manner during initiation of a new infection. The betaherpesvirus subfamily includes four human herpesviruses (human cytomegalovirus and human herpesviruses 6A, 6B, and 7), as well as viruses that are the basis of important animal models of infection and immunity. Similar to other herpesviruses, betaherpesvirus virions consist of four main parts (in order from the inside): the genome, capsid, tegument, and envelope. Betaherpesvirus genomes are dsDNA and range in length from ~145 to 240 kb. Virion capsids (or nucleocapsids) are geometrically well-defined vessels that contain one copy of the dsDNA viral genome. The tegument is a collection of several thousand protein and RNA molecules packed into the space between the envelope and the capsid for delivery and immediate activity upon cellular entry at the initiation of an infection. Betaherpesvirus envelopes consist of lipid bilayers studded with virus-encoded glycoproteins; they protect the virion during transmission and mediate virion entry during initiation of new infections. Here, we summarize the mechanisms of betaherpesvirus virion assembly, including how infection modifies, reprograms, hijacks, and otherwise manipulates cellular processes and pathways to produce virion components, assemble the parts into infectious virions, and then transport the nascent virions to the extracellular environment for transmission.


Assuntos
Betaherpesvirinae/fisiologia , Infecções por Herpesviridae/virologia , Vírion/fisiologia , Montagem de Vírus , Liberação de Vírus , Animais , Betaherpesvirinae/genética , Humanos , Vírion/genética
19.
Adv Exp Med Biol ; 1045: 227-249, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29896670

RESUMO

Betaherpesvirus possesses a large genome DNA with a lot of open reading frames, indicating abundance in the variety of viral protein factors. Because the complicated pathogenicity of herpesvirus reflects the combined functions of these factors, analyses of individual proteins are the fundamental steps to comprehensively understand about the viral life cycle and the pathogenicity. In this chapter, structural aspects of the betaherpesvirus-encoded proteins are introduced. Betaherpesvirus-encoded proteins of which structural information is available were summarized and subcategorized into capsid proteins, tegument proteins, nuclear egress complex proteins, envelope glycoproteins, enzymes, and immune-modulating factors. Structure of capsid proteins are analyzed in capsid by electron cryomicroscopy at quasi-atomic resolution. Structural information of teguments is limited, but a recent crystallographic analysis of an essential tegument protein of human herpesvirus 6B is introduced. As for the envelope glycoproteins, crystallographic analysis of glycoprotein gB has been done, revealing the fine-tuned structure and the distribution of its antigenic domains. gH/gL structure of betaherpesvirus is not available yet, but the overall shape and the spatial arrangement of the accessory proteins are analyzed by electron microscopy. Nuclear egress complex was analyzed from the structural perspective in 2015, with the structural analysis of cytomegalovirus UL50/UL53. The category "enzymes" includes the viral protease, DNA polymerase and terminase for which crystallographic analyses have been done. The immune-modulating factors are viral ligands or receptors for immune regulating factors of host immune cells, and their communications with host immune molecules are demonstrated in the aspect of molecular structure.


Assuntos
Betaherpesvirinae/metabolismo , Infecções por Herpesviridae/virologia , Proteínas Estruturais Virais/química , Proteínas Estruturais Virais/metabolismo , Animais , Betaherpesvirinae/química , Betaherpesvirinae/genética , Núcleo Celular/virologia , Humanos , Proteínas Estruturais Virais/genética , Liberação de Vírus
20.
Adv Exp Med Biol ; 1045: 251-270, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29896671

RESUMO

Two of the four betaherpesviruses, Cytomegalovirus (CMV) and human herpesvirus 6B (HHV-6B), play an important role in opportunistic infections in hematopoietic stem cell transplant (HSCT) recipients. These viruses are ubiquitous in humans and can latently infect mononuclear lymphocytes, complicating the diagnosis of the diseases they cause. Although the detection of viral DNA in a patient's peripheral blood by real-time PCR is widely used for monitoring viral infection, it is insufficient for the diagnosis of virus-associated disease. Theoretically, end-organ disease should be confirmed by detecting either viral antigen or significant amounts of viral DNA in a tissue sample obtained from the involved organ; however, this is often difficult to perform in clinical practice. The frequency of CMV-associated diseases has decreased gradually as a result of the introduction of preemptive or prophylactic treatments; however, CMV and HHV-6B infections remain a major problem in HSCT recipients. Measurement of viral DNA load in peripheral blood or plasma using real-time PCR is commonly used for monitoring these infections. Additionally, recent data suggest that an assessment of host immune response, particularly cytotoxic T-cell response, may be a reliable tool for predicting these viral infections. The antiviral drugs ganciclovir and foscarnet are used as first-line treatments; however, it is well known that these drugs have side effects, such as bone marrow suppression and nephrotoxicity. Further research is required to develop less-toxic antiviral drugs.


Assuntos
Betaherpesvirinae/metabolismo , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Infecções por Herpesviridae/virologia , Complicações Intraoperatórias/virologia , Animais , Antivirais/administração & dosagem , Betaherpesvirinae/efeitos dos fármacos , Betaherpesvirinae/genética , Infecções por Herpesviridae/tratamento farmacológico , Humanos , Complicações Intraoperatórias/tratamento farmacológico
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