Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.038
Filtrar
1.
Med Hypotheses ; 146: 110447, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33383524

RESUMO

The pathogen burden, defined by the frequency of antibodies to several viruses and a parasite, is greater in Hispanic whites and black populations than it is in non-Hispanic whites, in the USA. The poor and those without higher education also have higher pathogen burdens. The most frequent pathogen that was measured, was the Herpes simplex virus type 1 (HSV-1). This virus can inactivate most of the elements in the immune system, that are designed to protect against the incursions of viruses, bacteria and other pathogens. HSV-1 can also damage the blood brain barrier (BBB), which prevents the entry of pathogens into the central nervous system. Without the help of HSV-1, the COVID-19 virus may not be able to cause serious illness or death in humans. A prophylactic treatment to contain HSV-1, could be vital in the fight against COVID-19.


Assuntos
/epidemiologia , Grupos Étnicos , Herpes Simples/epidemiologia , Herpesvirus Humano 1/patogenicidade , Modelos Biológicos , Afro-Americanos , Barreira Hematoencefálica , /virologia , Grupo com Ancestrais do Continente Europeu , Herpes Simples/prevenção & controle , Herpes Simples/virologia , Hispano-Americanos , Interações entre Hospedeiro e Microrganismos , Humanos , Pandemias , Estados Unidos/epidemiologia
2.
Rev. Hosp. Ital. B. Aires (2004) ; 40(4): 219-222, dic. 2020. ilus
Artigo em Espanhol | LILACS | ID: biblio-1145550

RESUMO

La erupción variceliforme de Kaposi es una infección cutánea diseminada, causada en la mayor parte de los casos por el virus Herpes simple tipo 1. Se suele presentar en pacientes con alteraciones preexistentes de la barrera cutánea, especialmente en niños con dermatitis atópica. Se comunica el caso de un paciente de 84 años, quien negaba enfermedades cutáneas previas, que consultó por lesiones dolorosas y pruriginosas, en la piel del tórax y el abdomen, de 3 semanas de evolución. Con sospecha de una enfermedad infecciosa viral, bacteriana, ampollar o neutrofílica, se realizó inmunofluorescencia directa para herpes, cultivo y biopsia de piel para estudio histológico. La inmunofluorescencia fue positiva para Herpes simple tipo 1 y el estudio histopatológico mostró cambios compatibles con infección herpética y enfermedad de Darier. La enfermedad de Darier es una genodermatosis infrecuente que se suele manifestar en la adolescencia. Si bien su diagnóstico en la ancianidad es excepcional, este caso ilustra que se debe considerar en todos los pacientes que presenten erupción variceliforme. (AU)


Kaposi's varicelliform rash is a disseminated cutaneous infection, caused by Herpes virus 1. It usually presents in patients with pre-existing skin barrier disorders, especially in children with atopic dermatitis. We report the case of an 84-year-old patient, who reported having no previous skin diseases, who consulted for painful, itchy, 3-week-old skin lesions. As we suspected viral, bacterial, bullous or neutrophilic disease, direct immunofluorescence, culture, and skin biopsy for histological study were performed. Immunofluorescence was positive for Herpes simplex type 1 and the histopathological study showed changes compatible with herpetic infection and Darier's disease. Darier's disease is a rare genodermatosis that usually manifests in adolescence. Although its diagnosis in old age is anecdotal, it should be considered in patients with a varicelliform rash. (AU)


Assuntos
Humanos , Masculino , Idoso de 80 Anos ou mais , Erupção Variceliforme de Kaposi/diagnóstico , Doença de Darier/diagnóstico , Aciclovir/administração & dosagem , Foscarnet/uso terapêutico , Herpesvirus Humano 1/patogenicidade , Técnica Direta de Fluorescência para Anticorpo , Herpes Simples/complicações , Erupção Variceliforme de Kaposi/etiologia , Erupção Variceliforme de Kaposi/patologia , Erupção Variceliforme de Kaposi/tratamento farmacológico , Doença de Darier/etiologia
3.
PLoS Pathog ; 16(12): e1009166, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33370402

RESUMO

Herpes simplex virus 1 (HSV-1) infects skin and mucosal epithelial cells and then travels along axons to establish latency in the neurones of sensory ganglia. Although viral gene expression is restricted during latency, the latency-associated transcript (LAT) locus encodes many RNAs, including a 2 kb intron known as the hallmark of HSV-1 latency. Here, we studied HSV-1 infection and the role of the LAT locus in human skin xenografts in vivo and in cultured explants. We sequenced the genomes of our stock of HSV-1 strain 17syn+ and seven derived viruses and found nonsynonymous mutations in many viral proteins that had no impact on skin infection. In contrast, deletions in the LAT locus severely impaired HSV-1 replication and lesion formation in skin. However, skin replication was not affected by impaired intron splicing. Moreover, although the LAT locus has been implicated in regulating gene expression in neurones, we observed only small changes in transcript levels that were unrelated to the growth defect in skin, suggesting that its functions in skin may be different from those in neurones. Thus, although the LAT locus was previously thought to be dispensable for lytic infection, we show that it is a determinant of HSV-1 virulence during lytic infection of human skin.


Assuntos
Herpes Simples/virologia , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/patogenicidade , MicroRNAs/genética , Pele/virologia , Virulência/genética , Animais , Xenoenxertos , Humanos , Camundongos , Fatores de Virulência/genética
4.
Nat Commun ; 11(1): 4894, 2020 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-32994400

RESUMO

Identification of the complete set of translated genes of viruses is important to understand viral replication and pathogenesis as well as for therapeutic approaches to control viral infection. Here, we use chemical proteomics, integrating bio-orthogonal non-canonical amino acid tagging and high-resolution mass spectrometry, to characterize the newly synthesized herpes simplex virus 1 (HSV-1) proteome in infected cells. In these infected cells, host cellular protein synthesis is shut-off, increasing the chance to preferentially detect viral proteomes. We identify nine previously cryptic orphan protein coding sequences whose translated products are expressed in HSV-1-infected cells. Functional characterization of one identified protein, designated piUL49, shows that it is critical for HSV-1 neurovirulence in vivo by regulating the activity of virally encoded dUTPase, a key enzyme that maintains accurate DNA replication. Our results demonstrate that cryptic orphan protein coding genes of HSV-1, and probably other large DNA viruses, remain to be identified.


Assuntos
Encefalite por Herpes Simples/virologia , Herpesvirus Humano 1/patogenicidade , Pirofosfatases/metabolismo , Proteínas Virais/metabolismo , Fatores de Virulência/metabolismo , Animais , Encéfalo/patologia , Encéfalo/virologia , Chlorocebus aethiops , Replicação do DNA , Modelos Animais de Doenças , Encefalite por Herpes Simples/patologia , Feminino , Genes Virais/genética , Células HEK293 , Células HeLa , Herpesvirus Humano 1/genética , Humanos , Camundongos , Biossíntese de Proteínas , Proteômica/métodos , Células Vero , Proteínas Virais/genética , Fatores de Virulência/genética , Replicação Viral
5.
Nat Commun ; 11(1): 4148, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32811834

RESUMO

We evaluate gene editing of HSV in a well-established mouse model, using adeno-associated virus (AAV)-delivered meganucleases, as a potentially curative approach to treat latent HSV infection. Here we show that AAV-delivered meganucleases, but not CRISPR/Cas9, mediate highly efficient gene editing of HSV, eliminating over 90% of latent virus from superior cervical ganglia. Single-cell RNA sequencing demonstrates that both HSV and individual AAV serotypes are non-randomly distributed among neuronal subsets in ganglia, implying that improved delivery to all neuronal subsets may lead to even more complete elimination of HSV. As predicted, delivery of meganucleases using a triple AAV serotype combination results in the greatest decrease in ganglionic HSV loads. The levels of HSV elimination observed in these studies, if translated to humans, would likely significantly reduce HSV reactivation, shedding, and lesions. Further optimization of meganuclease delivery and activity is likely possible, and may offer a pathway to a cure for HSV infection.


Assuntos
Desoxirribonucleases/genética , Dependovirus/genética , Infecções Oculares/terapia , Edição de Genes/métodos , Herpes Simples/terapia , Herpesvirus Humano 1/genética , Latência Viral/genética , Animais , Sistemas CRISPR-Cas/genética , Células Cultivadas , Chlorocebus aethiops , Infecções Oculares/genética , Infecções Oculares/virologia , Feminino , Células HEK293 , Herpes Simples/genética , Herpesvirus Humano 1/patogenicidade , Humanos , Camundongos , Neurônios/metabolismo , Neurônios/virologia , RNA-Seq , Análise de Célula Única , Gânglio Cervical Superior/metabolismo , Gânglio Cervical Superior/virologia , Células Vero
6.
J Virol ; 94(18)2020 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-32611749

RESUMO

Us3 proteins of herpes simplex virus 1 (HSV-1) and HSV-2 are multifunctional serine-threonine protein kinases. Here, we identified an HSV-2 tegument protein, UL7, as a novel physiological substrate of HSV-2 Us3. Mutations in HSV-2 UL7, which precluded Us3 phosphorylation of the viral protein, significantly reduced mortality, viral replication in the vagina, and development of vaginal disease in mice following vaginal infection. These results indicated that Us3 phosphorylation of UL7 in HSV-2 was required for efficient viral replication and pathogenicity in vivo Of note, this phosphorylation was conserved in UL7 of chimpanzee herpesvirus (ChHV), which phylogenetically forms a monophyletic group with HSV-2 and the resurrected last common ancestral UL7 for HSV-2 and ChHV. In contrast, the phosphorylation was not conserved in UL7s of HSV-1, which belongs to a sister clade of the monophyletic group, the resurrected last common ancestor for HSV-1, HSV-2, and ChHV, and other members of the genus Simplexvirus that are phylogenetically close to these viruses. Thus, evolution of Us3 phosphorylation of UL7 coincided with the phylogeny of simplex viruses. Furthermore, artificially induced Us3 phosphorylation of UL7 in HSV-1, in contrast to phosphorylation in HSV-2, had no effect on viral replication and pathogenicity in mice. Our results suggest that HSV-2 and ChHV have acquired and maintained Us3 phosphoregulation of UL7 during their evolution because the phosphoregulation had an impact on viral fitness in vivo, whereas most other simplex viruses have not because the phosphorylation was not necessary for efficient fitness of the viruses in vivo IMPORTANCE It has been hypothesized that the evolution of protein phosphoregulation drives phenotypic diversity across species of organisms, which impacts fitness during their evolution. However, there is a lack of information regarding linkage between the evolution of viral phosphoregulation and the phylogeny of virus species. In this study, we clarified the novel HSV-2 Us3 phosphoregulation of UL7 in infected cells, which is important for viral replication and pathogenicity in vivo We also showed that the evolution of Us3 phosphoregulation of UL7 was linked to the phylogeny of viruses that are phylogenetically close to HSV-2 and to the phosphorylation requirements for the efficient in vivo viral fitness of HSV-2 and HSV-1, which are representative of viruses that have and have not evolved phosphoregulation, respectively. This study reports the first evidence showing that evolution of viral phosphoregulation coincides with phylogeny of virus species and supports the hypothesis regarding the evolution of viral phosphoregulation during viral evolution.


Assuntos
Regulação Viral da Expressão Gênica , Herpes Genital/virologia , Herpesvirus Humano 2/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas da Matriz Viral/genética , Proteínas Virais/genética , Proteínas Estruturais Virais/genética , Sequência de Aminoácidos , Animais , Chlorocebus aethiops , Modelos Animais de Doenças , Evolução Molecular , Feminino , Aptidão Genética , Células HEK293 , Herpes Genital/mortalidade , Herpesvirus Humano 1/classificação , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/metabolismo , Herpesvirus Humano 1/patogenicidade , Herpesvirus Humano 2/classificação , Herpesvirus Humano 2/metabolismo , Herpesvirus Humano 2/patogenicidade , Humanos , Camundongos , Fosforilação , Filogenia , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Vagina/virologia , Células Vero , Proteínas da Matriz Viral/metabolismo , Proteínas Virais/metabolismo , Proteínas Estruturais Virais/metabolismo , Virulência , Replicação Viral
7.
J Virol ; 94(18)2020 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-32669329

RESUMO

Herpesviruses exist in nature within each host animal. Ten herpesviruses have been isolated from bats and their biological properties reported. A novel bat alphaherpesvirus, which we propose to name "Pteropus lylei-associated alphaherpesvirus (PLAHV)," was isolated from urine of the fruit bat Pteropus lylei in Vietnam and characterized. The entire genome sequence was determined to be 144,008 bp in length and predicted to include 72 genes. PLAHV was assigned to genus Simplexvirus with other bat alphaherpesviruses isolated from pteropodid bats in Southeast Asia and Africa. The replication capacity of PLAHV in several cells was evaluated in comparison with that of herpes simplex virus 1 (HSV-1). PLAHV replicated better in the bat-originated cell line and less in human embryonic lung fibroblasts than HSV-1 did. PLAHV was serologically related to another bat alphaherpesvirus, Pteropodid alphaherpesvirus 1 (PtAHV1), isolated from a Pteropus hypomelanus-related bat captured in Indonesia, but not with HSV-1. PLAHV caused lethal infection in mice. PLAHV was as susceptible to acyclovir as HSV-1 was. Characterization of this new member of bat alphaherpesviruses, PLAHV, expands the knowledge on bat-associated alphaherpesvirology.IMPORTANCE A novel bat alphaherpesvirus, Pteropus lylei-associated alphaherpesvirus (PLAHV), was isolated from urine of the fruit bat Pteropus lylei in Vietnam. The whole-genome sequence was determined and was predicted to include 72 open reading frames in the 144,008-bp genome. PLAHV is circulating in a species of fruit bats, Pteropus lylei, in Asia. This study expands the knowledge on bat-associated alphaherpesvirology.


Assuntos
Alphaherpesvirinae/genética , Quirópteros/virologia , Genoma Viral , Infecções por Herpesviridae/veterinária , Proteínas Virais/genética , Aciclovir/farmacologia , Alphaherpesvirinae/classificação , Alphaherpesvirinae/efeitos dos fármacos , Alphaherpesvirinae/patogenicidade , Animais , Antivirais/farmacologia , Células COS , Linhagem Celular , Chlorocebus aethiops , Fibroblastos/virologia , Expressão Gênica , Tamanho do Genoma , Células HeLa , Infecções por Herpesviridae/tratamento farmacológico , Infecções por Herpesviridae/epidemiologia , Infecções por Herpesviridae/mortalidade , Herpesvirus Humano 1/classificação , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/crescimento & desenvolvimento , Herpesvirus Humano 1/patogenicidade , Humanos , Camundongos , Filogenia , Análise de Sobrevida , Células Vero , Vietnã/epidemiologia , Proteínas Virais/metabolismo , Replicação Viral
8.
PLoS One ; 15(7): e0236183, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32697805

RESUMO

BACKGROUND: Herpetic keratitis (HK) models using whole human corneas are essential for studying virus-host relationships, because of high species specificity and the role of interactions between corneal cell populations that cell culture cannot reproduce. Nevertheless, the two current corneal storage methods (hypothermia and organ culture (OC)) do not preserve corneas in good physiological condition, as they are characterized by epithelial abrasion, stromal oedema, and excessive endothelial mortality. METHODS: To rehabilitate human corneas intended for scientific use, we used an active storage machine (ASM) that restores two physiological parameters that are essential for corneal homeostasis: intraocular pressure and storage medium renewal (21mmHg and 2.6 µL/min, respectively). ASM storage regenerates a normal multilayer epithelium in 2 weeks. We infected six pairs of corneas unsuitable for graft by inoculating the epithelium with herpes simplex virus type 1 (HSV-1), and compared each ASM-stored cornea with the other cornea stored in the same medium using the conventional OC method. RESULTS: Only corneas in the ASM developed a dendritic (n = 3) or geographic (n = 2) epithelial ulcer reproducing typical HSV-1-induced clinical lesions. Corneas in OC showed only extensive desquamations. None of the uninfected controls showed epithelial damage. Histology, immunohistochemistry, transmission electron microscopy and polymerase chain reaction on corneal tissue confirmed infection in all cases (excluding negative controls). CONCLUSIONS: The ASM provides an innovative ex vivo model of HK in whole human cornea that reproduces typical epithelial lesions.


Assuntos
Córnea/patologia , Herpesvirus Humano 1/patogenicidade , Ceratite Herpética/patologia , Técnicas de Cultura de Órgãos/instrumentação , Preservação de Órgãos/instrumentação , Idoso , Idoso de 80 Anos ou mais , Córnea/diagnóstico por imagem , Córnea/ultraestrutura , Córnea/virologia , Interações entre Hospedeiro e Microrganismos , Humanos , Ceratite Herpética/diagnóstico , Ceratite Herpética/tratamento farmacológico , Ceratite Herpética/virologia , Microscopia Eletrônica de Transmissão , Pessoa de Meia-Idade , Técnicas de Cultura de Órgãos/métodos , Preservação de Órgãos/métodos , Microscopia com Lâmpada de Fenda
9.
Sci Adv ; 6(5): eaax9318, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-32064341

RESUMO

Viral infections kill millions of people and new antivirals are needed. Nontoxic drugs that irreversibly inhibit viruses (virucidal) are postulated to be ideal. Unfortunately, all virucidal molecules described to date are cytotoxic. We recently developed nontoxic, broad-spectrum virucidal gold nanoparticles. Here, we develop further the concept and describe cyclodextrins, modified with mercaptoundecane sulfonic acids, to mimic heparan sulfates and to provide the key nontoxic virucidal action. We show that the resulting macromolecules are broad-spectrum, biocompatible, and virucidal at micromolar concentrations in vitro against many viruses [including herpes simplex virus (HSV), respiratory syncytial virus (RSV), dengue virus, and Zika virus]. They are effective ex vivo against both laboratory and clinical strains of RSV and HSV-2 in respiratory and vaginal tissue culture models, respectively. Additionally, they are effective when administrated in mice before intravaginal HSV-2 inoculation. Lastly, they pass a mutation resistance test that the currently available anti-HSV drug (acyclovir) fails.


Assuntos
Ciclodextrinas/farmacologia , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 2/efeitos dos fármacos , Viroses/tratamento farmacológico , Aciclovir/química , Aciclovir/farmacologia , Animais , Antivirais/síntese química , Antivirais/química , Antivirais/farmacologia , Ciclodextrinas/síntese química , Ciclodextrinas/química , Feminino , Ouro/química , Heparitina Sulfato/química , Heparitina Sulfato/farmacologia , Herpesvirus Humano 1/patogenicidade , Herpesvirus Humano 2/patogenicidade , Humanos , Nanopartículas Metálicas/química , Camundongos , Simplexvirus/efeitos dos fármacos , Simplexvirus/patogenicidade , Viroses/virologia , Zika virus/efeitos dos fármacos , Zika virus/patogenicidade
10.
J Immunol ; 204(7): 1904-1918, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32075857

RESUMO

IFN regulatory factor 3 (IRF3) is critical for the transcription of type I IFNs in defensing virus and promoting inflammatory responses. Although several kinds of posttranslational modifications have been identified to modulate the activity of IRF3, whether atypical ubiquitination participates in the function regulation, especially the DNA binding capacity of IRF3, is unknown. In this study, we found that the ovarian tumor domain containing deubiquitinase OTUD1 deubiquitinated IRF3 and attenuated its function. An atypical ubiquitination, K6-linked ubiquitination, was essential for the DNA binding capacity of IRF3 and subsequent induction of target genes. Mechanistically, OTUD1 cleaves the viral infection-induced K6-linked ubiquitination of IRF3, resulting in the disassociation of IRF3 from the promoter region of target genes, without affecting the protein stability, dimerization, and nuclear translocation of IRF3 after a viral infection. Otud1 -/- cells as well as Otud1 -/- mice produced more type I IFNs and proinflammatory cytokines after viral infection. Otud1 -/- mice were more resistant to lethal HSV-1 and VSV infection. Consistent with the former investigations that IRF3 promoted inflammatory responses in LPS-induced sepsis, Otud1 -/- mice were more susceptible to LPS stimulation. Taken together, our findings revealed that the DNA binding capacity of IRF3 in the innate immune signaling pathway was modulated by atypical K6-linked ubiquitination and deubiquitination process, which was regulated by the deubiquitinase OTUD1.


Assuntos
Fator Regulador 3 de Interferon/metabolismo , Interferon Tipo I/metabolismo , Proteases Específicas de Ubiquitina/metabolismo , Ubiquitinação/fisiologia , Animais , Linhagem Celular , Células HEK293 , Herpes Simples/metabolismo , Herpesvirus Humano 1/patogenicidade , Humanos , Imunidade Inata/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Regiões Promotoras Genéticas/fisiologia , Estabilidade Proteica , Transdução de Sinais/fisiologia
11.
J Virol ; 94(9)2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32075924

RESUMO

Alzheimer's Disease (AD) is the sixth leading cause of death in the United States. Recent studies have established a potential link between herpes simplex virus 1 (HSV-1) infection and the development of AD. HSV-1 DNA has been detected in AD amyloid plaques in human brains, and treatment with the antiviral acyclovir (ACV) was reported to block the accumulation of the AD-associated proteins beta-amyloid (Aß) and hyper-phosphorylated tau (p-tau) in Vero and glioblastoma cells. Our goal was to determine whether the accumulation of AD-related proteins is attributable to acute and/or latent HSV-1 infection in mature hippocampal neurons, a region of the brain severely impacted by AD. Primary adult murine hippocampal neuronal cultures infected with HSV-1, with or without antivirals, were assessed for Aß and p-tau expression over 7 days postinfection. P-tau expression was transiently elevated in HSV-1-infected neurons, as well as in the presence of antivirals alone. Infected neurons, as well as uninfected neurons treated with antivirals, had a greater accumulation of Aß42 than uninfected untreated neurons. Furthermore, Aß42 colocalized with HSV-1 latency-associated transcript (LAT) expression. These studies suggest that p-tau potentially acts as an acute response to any perceived danger-associated molecular pattern (DAMP) in primary adult hippocampal neurons, while Aß aggregation is a long-term response to persistent threats, including HSV-1 infection.IMPORTANCE Growing evidence supports a link between HSV-1 infection and Alzheimer's disease (AD). Although AD is clearly a complex multifactorial disorder, an infectious disease etiology provides alternative therapy opportunities for this devastating disease. Understanding the impact that HSV-1 has on mature neurons and the proteins most strongly associated with AD pathology may identify specific mechanisms that could be manipulated to prevent progression of neurodegeneration and dementia.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Herpesvirus Humano 1/fisiologia , Neurônios/metabolismo , Aciclovir/farmacologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/virologia , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Antivirais/farmacologia , Encéfalo/metabolismo , Chlorocebus aethiops , Feminino , Herpes Simples/metabolismo , Herpesvirus Humano 1/metabolismo , Herpesvirus Humano 1/patogenicidade , Hipocampo/metabolismo , Camundongos , Neurônios/virologia , Fragmentos de Peptídeos/metabolismo , Fosforilação , Placa Amiloide/metabolismo , Cultura Primária de Células , Células Vero , Replicação Viral/efeitos dos fármacos , Proteínas tau/metabolismo , Proteínas tau/farmacologia
12.
BMC Infect Dis ; 20(1): 150, 2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32070282

RESUMO

BACKGROUND: Human encephalitis can originate from a variety of different aetiologies, of which infection is the most common one. The diagnostic work-up is specifically challenging in patients with travel history since a broader spectrum of unfamiliar additional infectious agents, e. g. tropical disease pathogens, needs to be considered. Here we present a case of encephalitis of unclear aetiology in a female traveller returning from Africa, who in addition developed an atypical herpes simplex virus (HSV) encephalitis in close temporal relation with high-dose steroid treatment. CASE PRESENTATION: A previously healthy 48-year-old female presented with confusion syndrome and impaired vigilance which had developed during a six-day trip to The Gambia. The condition rapidly worsened to a comatose state. Extensive search for infectious agents including a variety of tropical disease pathogens was unsuccessful. As encephalitic signs persisted despite of calculated antimicrobial and antiviral therapy, high-dose corticosteroids were applied intravenously based on the working diagnosis of an autoimmune encephalitis. The treatment did, however, not improve the patient's condition. Four days later, bihemispheric signal amplification in the insular and frontobasal cortex was observed on magnetic resonance imaging (MRI). The intracranial pressure rapidly increased and could not be controlled by conservative treatment. The patient died due to tonsillar herniation 21 days after onset of symptoms. Histological examination of postmortem brain tissue demonstrated a generalized lymphocytic meningoencephalitis. Immunohistochemical reactions against HSV-1/2 indicated an atypical manifestation of herpesviral encephalitis in brain tissue. Moreover, HSV-1 DNA was detected by a next-generation sequencing (NGS) metagenomics approach. Retrospective analysis of cerebrospinal fluid (CSF) and serum samples revealed HSV-1 DNA only in specimens one day ante mortem. CONCLUSIONS: This case shows that standard high-dose steroid therapy can contribute to or possibly even trigger fulminant cerebral HSV reactivation in a critically ill patient. Thus, even if extensive laboratory diagnostics including wide-ranging search for infectious pathogens has been performed before and remained without results, continuous re-evaluation of potential differential diagnoses especially regarding opportunistic infections or reactivation of latent infections is of utmost importance, particularly if new symptoms occur.


Assuntos
Encefalite por Herpes Simples/diagnóstico , Encefalite por Herpes Simples/tratamento farmacológico , Encefalite por Herpes Simples/etiologia , Herpes Simples/diagnóstico , Herpesvirus Humano 1/isolamento & purificação , Esteroides/efeitos adversos , Autopsia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , DNA Viral/sangue , DNA Viral/líquido cefalorraquidiano , Encefalite/diagnóstico , Feminino , Gâmbia , Doença de Hashimoto/diagnóstico , Herpes Simples/diagnóstico por imagem , Herpes Simples/virologia , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/patogenicidade , Herpesvirus Humano 2/patogenicidade , Humanos , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Estudos Retrospectivos , Esteroides/uso terapêutico , Viagem
13.
PLoS One ; 15(2): e0228252, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32027675

RESUMO

Herpes simplex virus type-1 (HSV-1) can cause severe ocular infection and blindness. We have previously shown that the HSV-1 VC2 vaccine strain is protective in mice and guinea pigs against genital herpes infection following vaginal challenge with HSV-1 or HSV-2. In this study, we evaluated the efficacy of VC2 intramuscular vaccination in mice against herpetic keratitis following ocular challenge with lethal human clinical strain HSV-1(McKrae). VC2 vaccination in mice produced superior protection and morbidity control in comparison to its parental strain HSV-1(F). Specifically, after HSV-1(McKrae) ocular challenge, all VC2 vaccinated- mice survived, while 30% of the HSV-1(F)- vaccinated and 100% of the mock-vaccinated mice died post challenge. VC2-vaccinated mice did not exhibit any symptoms of ocular infection and completely recovered from initial conjunctivitis. In contrast, HSV-1(F)-vaccinated mice developed time-dependent progressive keratitis characterized by corneal opacification, while mock-vaccinated animals exhibited more severe stromal keratitis characterized by immune cell infiltration and neovascularization in corneal stroma with corneal opacification. Cornea in VC2-immunized mice exhibited significantly increased infiltration of CD3+ T lymphocytes and decreased infiltration of Iba1+ macrophages in comparison to mock- or HSV-1(F)-vaccinated groups. VC2 immunization produced higher virus neutralization titers than HSV-1(F) post challenge. Furthermore, VC-vaccination significantly increased the CD4 T central memory (TCM) subsets and CD8 T effector memory (TEM) subsets in the draining lymph nodes following ocular HSV-1 (McKrae) challenge, then mock- or HSV-1(F)-vaccination. These results indicate that VC2 vaccination produces a protective immune response at the site of challenge to protect against HSV-1-induced ocular pathogenesis.


Assuntos
Vacinas contra o Vírus do Herpes Simples/imunologia , Herpes Simples/prevenção & controle , Herpesvirus Humano 1/patogenicidade , Animais , Antígenos Virais/imunologia , Córnea/patologia , Córnea/virologia , Feminino , Herpes Simples/patologia , Herpes Simples/veterinária , Herpesvirus Humano 1/metabolismo , Humanos , Injeções Intramusculares , Camundongos , Camundongos SCID , Vacinação
14.
Hum Genet ; 139(6-7): 911-918, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32040615

RESUMO

Herpes simplex virus 1 (HSV-1) encephalitis (HSE) is the most common sporadic viral encephalitis in Western countries. Over the last 15 years, human genetic and immunological studies have provided proof-of-principle that childhood HSE can result from inborn errors of central nervous system (CNS)-specific, cell-intrinsic immunity to HSV-1. HSE-causing mutations of eight genes disrupt known (TLR3-dependent IFN-α/ß immunity) and novel (dependent on DBR1 or snoRNA31) antiviral mechanisms. Monogenic inborn errors confer susceptibility to forebrain (TLR3-IFN or snoRNA31) or brainstem (DBR1) HSE. Most of these disorders display incomplete clinical penetrance, with the possible exception of DBR1 deficiency. They account for a small, but non-negligible proportion of cases (about 7%). These findings pave the way for the gradual definition of the genetic and immunological architecture of childhood HSE, with both biological and clinical implications.


Assuntos
Doenças do Sistema Nervoso Central/genética , Encefalite por Herpes Simples/genética , Predisposição Genética para Doença , Herpes Simples/imunologia , Herpesvirus Humano 1/imunologia , Interações Hospedeiro-Patógeno/genética , Imunidade Celular/imunologia , Doenças do Sistema Nervoso Central/epidemiologia , Doenças do Sistema Nervoso Central/imunologia , Doenças do Sistema Nervoso Central/virologia , Criança , Encefalite por Herpes Simples/epidemiologia , Encefalite por Herpes Simples/imunologia , Encefalite por Herpes Simples/virologia , Herpes Simples/complicações , Herpes Simples/virologia , Herpesvirus Humano 1/patogenicidade , Interações Hospedeiro-Patógeno/imunologia , Humanos , Mutação
16.
Nat Commun ; 11(1): 293, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31941886

RESUMO

Infection by viruses, including herpes simplex virus-1 (HSV-1), and cellular stresses cause widespread disruption of transcription termination (DoTT) of RNA polymerase II (RNAPII) in host genes. However, the underlying mechanisms remain unclear. Here, we demonstrate that the HSV-1 immediate early protein ICP27 induces DoTT by directly binding to the essential mRNA 3' processing factor CPSF. It thereby induces the assembly of a dead-end 3' processing complex, blocking mRNA 3' cleavage. Remarkably, ICP27 also acts as a sequence-dependent activator of mRNA 3' processing for viral and a subset of host transcripts. Our results unravel a bimodal activity of ICP27 that plays a key role in HSV-1-induced host shutoff and identify CPSF as an important factor that mediates regulation of transcription termination. These findings have broad implications for understanding the regulation of transcription termination by other viruses, cellular stress and cancer.


Assuntos
Herpesvirus Humano 1/patogenicidade , Interações Hospedeiro-Patógeno/fisiologia , Proteínas Imediatamente Precoces/metabolismo , Terminação da Transcrição Genética , Animais , Linhagem Celular , Fator de Especificidade de Clivagem e Poliadenilação/metabolismo , Células HeLa , Herpes Simples/genética , Herpes Simples/virologia , Herpesvirus Humano 1/genética , Interações Hospedeiro-Patógeno/genética , Humanos , Proteínas Imediatamente Precoces/genética , Proteínas Imediatamente Precoces/fisiologia , Processamento Pós-Transcricional do RNA , RNA Mensageiro/genética
18.
J Leukoc Biol ; 107(1): 105-112, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31729784

RESUMO

Bortezomib suppressing NF-κB activity is an effective therapy for patients with myeloma or lymphoma. However, this drug can cause adverse effects, neutropenia, and recurrent infections of herpes viruses. Among herpes viruses, HSV-1 can reactivate to induce mortality. The important issues regarding how bortezomib diminishes neutrophils, whether bortezomib can induce HSV-1 reactivation, and how bortezomib exacerbates HSV-1 infection, need investigation. Using the murine model, we found that bortezomib induced HSV-1 reactivation. Bortezomib diminished neutrophil numbers in organs of uninfected and HSV-1-infected mice and turned a nonlethal infection to lethal with elevated tissue viral loads. In vitro results showed that bortezomib and HSV-1 collaborated to enhance the death and apoptosis of mouse neutrophils. The leukocyte deficiency induced by chemotherapies is generally believed to be the cause for aggravating virus infections. Here we show the potential of pathogen to exacerbate chemotherapy-induced leukocyte deficiency.


Assuntos
Antineoplásicos/toxicidade , Bortezomib/toxicidade , Herpes Simples/etiologia , Herpesvirus Humano 1/patogenicidade , Neutrófilos/patologia , Carga Viral , Ativação Viral , Animais , Modelos Animais de Doenças , Feminino , Herpes Simples/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/virologia
19.
J Virol ; 94(4)2020 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-31748392

RESUMO

Myelin and lymphocyte protein (MAL) is a tetraspan integral membrane protein that resides in detergent-insoluble membrane fractions enriched in condensed membranes. MAL is expressed in oligodendrocytes, in Schwann cells, where it is essential for the stability of myelin, and at the apical membrane of epithelial cells, where it has a critical role in transport. In T lymphocytes, MAL is found at the immunological synapse and plays a crucial role in exosome secretion. However, no involvement of MAL in viral infections has been reported so far. Here, we show that herpes simplex virus 1 (HSV-1) virions travel in association with MAL-positive structures to reach the end of cellular processes, which contact uninfected oligodendrocytes. Importantly, the depletion of MAL led to a significant decrease in infection, with a drastic reduction in the number of lytic plaques in MAL-silenced cells. These results suggest a significant role for MAL in viral spread at cell contacts. The participation of MAL in the cell-to-cell spread of HSV-1 may shed light on the involvement of proteolipids in this process.IMPORTANCE Herpes simplex virus 1 (HSV-1) is a neurotropic pathogen that can infect many types of cells and establish latent infections in neurons. HSV-1 may spread from infected to uninfected cells by two main routes: by cell-free virus or by cell-to-cell spread. In the first case, virions exit into the extracellular space and then infect another cell from the outside. In the second case, viral transmission occurs through cell-to-cell contacts via a mechanism that is still poorly understood. A third mode of spread, using extracellular vesicles, also exists. In this study, we demonstrate the important role for a myelin protein, myelin and lymphocyte protein (MAL), in the process of cell-to-cell viral spread in oligodendrocytes. We show that MAL is involved in trafficking of virions along cell processes and that MAL depletion produces a significant alteration in the viral cycle, which reduces cell-to cell spread of HSV-1.


Assuntos
Herpes Simples/metabolismo , Herpesvirus Humano 1/metabolismo , Proteínas Proteolipídicas Associadas a Linfócitos e Mielina/metabolismo , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Células Epiteliais/metabolismo , Herpes Simples/virologia , Herpesvirus Humano 1/patogenicidade , Humanos , Linfócitos/metabolismo , Proteínas de Membrana/metabolismo , Proteínas da Mielina/metabolismo , Proteínas Proteolipídicas Associadas a Linfócitos e Mielina/química , Proteínas Proteolipídicas Associadas a Linfócitos e Mielina/fisiologia , Neurônios/metabolismo , Neurônios/virologia , Oligodendroglia/metabolismo , Oligodendroglia/virologia , Proteolipídeos/química , Proteolipídeos/metabolismo , Linfócitos T/metabolismo
20.
J Virol ; 94(4)2020 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-31748398

RESUMO

Molecular chaperones and cochaperones are the most abundant cellular effectors of protein homeostasis, assisting protein folding and preventing aggregation of misfolded proteins. We have previously shown that herpes simplex virus 1 (HSV-1) infection results in the drastic spatial reorganization of the cellular chaperone Hsc70 into nuclear domains called VICE (Virus Induced Chaperone Enriched) domains and that this recruitment is dependent on the viral immediate early protein ICP22. Here, we present several lines of evidence supporting the notion that ICP22 functions as a virally encoded cochaperone (J-protein/Hsp40) functioning together with its Hsc70 partner to recognize and manage aggregated and misfolded proteins. We show that ICP22 results in (i) nuclear sequestration of nonnative proteins, (ii) reduction of cytoplasmic aggresomes in cells expressing aggregation-prone proteins, and (iii) thermoprotection against heat inactivation of firefly luciferase, and (iv) sequence homology analysis indicated that ICP22 contains an N-terminal J domain and a C-terminal substrate binding domain, similar to type II cellular J proteins. ICP22 may thus be functionally similar to J-protein/Hsp40 cochaperones that function together with their HSP70 partners to prevent aggregation of nonnative proteins. This is not the first example of a virus hijacking a function of a cellular chaperone, since simian immunodeficiency virus T antigen was previously shown to contain a J domain; however, this the first known example of the acquisition of a functional J-like protein by a virus and suggests that HSV has taken advantage of the adaptable nature of J proteins to evolve a multifunctional cochaperone that functions with Hsc70 to promote lytic infection.IMPORTANCE Viruses have evolved a variety of strategies to succeed in a hostile environment. The herpes simplex virus 1 (HSV-1) immediate early protein ICP22 plays several roles in the virus life cycle, including downregulation of cellular gene expression, upregulation of late viral gene expression, inhibition of apoptosis, prevention of aggregation of nonnative proteins, and the recruitment of a cellular heat shock protein, Hsc70, to nuclear domains. We present evidence that ICP22 functionally resembles a cellular J-protein/HSP40 family cochaperone, interacting specifically with Hsc70. We suggest that HSV has taken advantage of the adaptable nature of J proteins to evolve a multifunctional cochaperone that functions with Hsc70 to promote lytic infection.


Assuntos
Proteínas de Choque Térmico HSP40/metabolismo , Herpesvirus Humano 1/metabolismo , Proteínas Imediatamente Precoces/metabolismo , Animais , Núcleo Celular/metabolismo , Chlorocebus aethiops , Células HEK293 , Herpes Simples/virologia , Herpesvirus Humano 1/patogenicidade , Herpesvirus Humano 1/fisiologia , Humanos , Proteínas Imediatamente Precoces/genética , Chaperonas Moleculares/metabolismo , Fosforilação , Dobramento de Proteína , RNA Polimerase II/metabolismo , Células Vero , Proteínas Virais/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...