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1.
Biochem Biophys Res Commun ; 585: 162-168, 2021 12 31.
Artigo em Inglês | MEDLINE | ID: mdl-34808499

RESUMO

tRNase ZS (ELAC1) and TRNT1 function in tRNA recycling. Recently, we have shown that these genes are upregulated in the cells infected with Theiler's mouse encephalitis virus (TMEV), implying that tRNA recycling functions in response to viral infection. To address the molecular mechanism underlying the ELAC1 upregulation in the cells infected with TMEV, we performed luciferase assays using various plasmid constructs harboring the ELAC1 promoter region. The luciferase expression from a construct containing the full-length ELAC1 promoter was augmented by TMEV, poly IC, IFN-ß, or IFN-γ. We identified four IFN-stimulated responsible elements (ISREs) in the proximal promoter region. The luciferase expression from the constructs that lack all the ISREs was strongly reduced compared with that from the constructs with the four ISREs in the presence of IFN-ß or IFN-γ. The observation that the ISREs from the ELAC1 promoter are essential for the gene upregulation by IFN-ß or IFN-γ suggests that the ELAC1 gene is upregulated by IFNs.


Assuntos
Interferons/farmacologia , Regiões Promotoras Genéticas/genética , RNA de Transferência/genética , Transcrição Gênica , Proteínas Supressoras de Tumor/genética , Regulação para Cima/efeitos dos fármacos , Antivirais/farmacologia , Sequência de Bases , Células HeLa , Humanos , Interferon beta/farmacologia , Interferon gama/farmacologia , RNA de Transferência/metabolismo , Elementos de Resposta/genética , Theilovirus/efeitos dos fármacos , Theilovirus/fisiologia , Regulação para Cima/genética
2.
Arch Virol ; 163(5): 1279-1284, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29362931

RESUMO

While most disease-modifying drugs (DMDs) regulate multiple sclerosis (MS) by suppressing inflammation, they can potentially suppress antiviral immunity, causing progressive multifocal leukoencephalopathy (PML). The DMD glatiramer acetate (GA) has been used for MS patients who are at high risk of PML. We investigated whether GA is safe for use in viral infections by using a model of MS induced by infection with Theiler's murine encephalomyelitis virus (TMEV). Treatment of TMEV-infected mice with GA neither enhanced viral loads nor suppressed antiviral immune responses, while it resulted in an increase in the Foxp3/Il17a ratio and IL-4/IL-10 production. This is the first study to suggest that GA could be safe for MS patients with a proven viral infection.


Assuntos
Infecções por Cardiovirus/imunologia , Acetato de Glatiramer/uso terapêutico , Fatores Imunológicos/uso terapêutico , Leucoencefalopatia Multifocal Progressiva/imunologia , Theilovirus/imunologia , Animais , Infecções por Cardiovirus/virologia , Modelos Animais de Doenças , Acetato de Glatiramer/administração & dosagem , Acetato de Glatiramer/efeitos adversos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/efeitos adversos , Interleucina-10/biossíntese , Interleucina-10/imunologia , Interleucina-4/biossíntese , Interleucina-4/imunologia , Camundongos , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/imunologia , Theilovirus/efeitos dos fármacos , Carga Viral/efeitos dos fármacos
3.
J Neurovirol ; 23(6): 825-838, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28913765

RESUMO

Teriflunomide is an oral therapy approved for the treatment of relapsing remitting multiple sclerosis (MS), showing both anti-inflammatory and antiviral properties. Currently, it is uncertain whether one or both of these properties may explain teriflunomide's beneficial effect in MS. Thus, to learn more about its mechanisms of action, we evaluated the effect of teriflunomide in the Theiler's encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) model, which is both a viral infection and an excellent model of the progressive disability of MS. We assessed the effects of the treatment on central nervous system (CNS) viral load, intrathecal immune response, and progressive neurological disability in mice intracranially infected with TMEV. In the TMEV-IDD model, we showed that teriflunomide has both anti-inflammatory and antiviral properties, but there seemed to be no impact on disability progression and intrathecal antibody production. Notably, benefits in TMEV-IDD were mostly mediated by effects on various cytokines produced in the CNS. Perhaps the most interesting result of the study has been teriflunomide's antiviral activity in the CNS, indicating it may have a role as an antiviral prophylactic and therapeutic compound for CNS viral infections.


Assuntos
Anti-Inflamatórios/farmacologia , Antivirais/farmacologia , Infecções por Cardiovirus/tratamento farmacológico , Crotonatos/farmacologia , Esclerose Múltipla/tratamento farmacológico , Toluidinas/farmacologia , Animais , Anticorpos Antivirais/biossíntese , Infecções por Cardiovirus/imunologia , Infecções por Cardiovirus/virologia , Citocinas/antagonistas & inibidores , Citocinas/biossíntese , Modelos Animais de Doenças , Progressão da Doença , Feminino , Hidroxibutiratos , Injeções Intraperitoneais , Camundongos , Esclerose Múltipla/imunologia , Esclerose Múltipla/virologia , Nitrilas , Theilovirus/efeitos dos fármacos , Theilovirus/crescimento & desenvolvimento , Theilovirus/imunologia , Carga Viral/efeitos dos fármacos
4.
J Neurovirol ; 22(3): 316-26, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26567013

RESUMO

In this study, we demonstrate the upregulation in the expression of caspases 1 and 11 by SJL/J mouse brain astrocytes infected with the BeAn strain of Theiler's murine encephalomyelitis virus (TMEV). The upregulation of both proteases hints at protection of astrocytic cells from apoptotic death. We therefore looked for the reason of the demonstrated absence of programmed cell death in BeAn-infected SJL/J astrocytes. Complementary RNA (cRNA) from mock- and TMEV-infected cells was hybridized to the whole murine genome U74v2 DNA microarray from Affymetrix. Those experiments demonstrated the upregulation of gene expression for caspases 1 and 11 in infected cells. We further confirmed and validated their messenger RNA (mRNA) increase by reverse transcriptase quantitative real-time PCR (qPCR). The presence of both enzymatically active caspases 1 and 11 was demonstrated in cell lysates using a colorimetric and fluorymetric assay, respectively. We also show that overexpressed caspase 11 activated caspase 1 after preincubation of cytosol in vitro following a time-dependent process. This induction was neutralized by an anti-caspase 11 polyclonal antibody. These results demonstrate the activation of the caspase 1 precursor by caspase 11 and suggest a new mechanism of protection of BeAn-infected astrocytes from apoptosis. The direct experimental evidence that the protection effect demonstrated in this article was mediated by caspase 1, is provided by the fact that its specific inhibitor Z-WEHD-FMK induced de novo apoptotic death.


Assuntos
Astrócitos/virologia , Infecções por Cardiovirus/virologia , Caspase 1/genética , Caspases/genética , Interações Hospedeiro-Patógeno , Theilovirus/genética , Clorometilcetonas de Aminoácidos/farmacologia , Animais , Animais Recém-Nascidos , Anticorpos/farmacologia , Apoptose/efeitos dos fármacos , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Infecções por Cardiovirus/patologia , Caspase 1/metabolismo , Inibidores de Caspase/farmacologia , Caspases/metabolismo , Caspases Iniciadoras , Regulação da Expressão Gênica , Camundongos , Cultura Primária de Células , RNA Complementar/genética , RNA Complementar/metabolismo , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Theilovirus/efeitos dos fármacos , Theilovirus/metabolismo
5.
Mol Neurobiol ; 53(8): 5217-28, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-26409478

RESUMO

Demyelination underlies early neurological symptoms in multiple sclerosis (MS); however, axonal damage is considered critical for permanent chronic deficits. The precise mechanisms by which axonal injury occurs in MS are unclear; one hypothesis is the absence or failure of remyelination, suggesting that promoting remyelination may protect axons from death. This report provides direct evidence that promoting oligodendrocyte remyelination protects axons and maintains transport function. Persistent Theiler's virus infection of Swiss Jim Lambert (SJL)/J mice was used as a model of MS to assess the effects of remyelination on axonal injury following demyelination in the spinal cord. Remyelination was induced using an oligodendrocyte/myelin-specific recombinant human monoclonal IgM, rHIgM22. The antibody is endowed with strong anti-apoptotic and pro-proliferative effects on oligodendrocyte progenitor cells. We used (1)H-magnetic resonance spectroscopy (MRS) at the brainstem to measure N-acetyl-aspartate (NAA) as a surrogate of neuronal health and spinal cord integrity. We found increased brainstem NAA concentrations at 5 weeks post-treatment with rHIgM22, which remained stable out to 10 weeks. Detailed spinal cord morphology studies revealed enhanced remyelination in the rHIgM22-treated group but not in the isotype control antibody- or saline-treated groups. Importantly, we found rHIgM22-mediated remyelination protected small- and medium-caliber mid-thoracic spinal cord axons from damage despite similar demyelination and inflammation across all experimental groups. The most direct confirmation of remyelination-mediated protection of descending neurons was an improvement in retrograde transport. Treatment with rHIgM22 significantly increased the number of retrograde-labeled neurons in the brainstem, indicating that preserved axons are functionally competent. This is direct validation that remyelination preserves spinal cord axons and protects functional axon integrity.


Assuntos
Anticorpos/farmacologia , Axônios/metabolismo , Doenças Desmielinizantes/patologia , Oligodendroglia/metabolismo , Remielinização/efeitos dos fármacos , Animais , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Axônios/efeitos dos fármacos , Axônios/patologia , Tronco Encefálico/metabolismo , Tronco Encefálico/patologia , Infecções por Cardiovirus/patologia , Infecções por Cardiovirus/virologia , Camundongos , Oligodendroglia/efeitos dos fármacos , Medula Espinal/patologia , Theilovirus/efeitos dos fármacos , Theilovirus/fisiologia
6.
J Pharmacol Exp Ther ; 353(2): 318-29, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25755209

RESUMO

Central nervous system infections can underlie the development of epilepsy, and Theiler's murine encephalomyelitis virus (TMEV) infection in C57BL/6J mice provides a novel model of infection-induced epilepsy. Approximately 50-65% of infected mice develop acute, handling-induced seizures during the infection. Brains display acute neuropathology, and a high number of mice develop spontaneous, recurrent seizures and behavioral comorbidities weeks later. This study characterized the utility of this model for drug testing by assessing whether antiseizure drug treatment during the acute infection period attenuates handling-induced seizures, and whether such treatment modifies associated comorbidities. Male C57BL/6J mice infected with TMEV received twice-daily valproic acid (VPA; 200 mg/kg), carbamazepine (CBZ; 20 mg/kg), or vehicle during the infection (days 0-7). Mice were assessed twice daily during the infection period for handling-induced seizures. Relative to vehicle-treated mice, more CBZ-treated mice presented with acute seizures; VPA conferred no change. In mice displaying seizures, VPA, but not CBZ, reduced seizure burden. Animals were then randomly assigned to acute and long-term follow-up. VPA was associated with significant elevations in acute (day 8) glial fibrillary acidic protein (astrocytes) immunoreactivity, but did not affect NeuN (neurons) immunoreactivity. Additionally, VPA-treated mice showed improved motor performance 15 days postinfection (DPI). At 36 DPI, CBZ-treated mice traveled significantly less distance through the center of an open field, indicative of anxiety-like behavior. CBZ-treated mice also presented with significant astrogliosis 36 DPI. Neither CBZ nor VPA prevented long-term reductions in NeuN immunoreactivity. The TMEV model thus provides an etiologically relevant platform to evaluate potential treatments for acute seizures and disease modification.


Assuntos
Anticonvulsivantes/farmacologia , Comportamento Animal/efeitos dos fármacos , Carbamazepina/farmacologia , Epilepsia do Lobo Temporal/tratamento farmacológico , Epilepsia do Lobo Temporal/etiologia , Theilovirus/fisiologia , Ácido Valproico/farmacologia , Animais , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/uso terapêutico , Ansiedade/induzido quimicamente , Carbamazepina/efeitos adversos , Carbamazepina/uso terapêutico , Infecções por Cardiovirus/complicações , Comorbidade , Proteínas de Ligação a DNA , Modelos Animais de Doenças , Epilepsia do Lobo Temporal/complicações , Epilepsia do Lobo Temporal/virologia , Proteína Glial Fibrilar Ácida , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/metabolismo , Teste de Desempenho do Rota-Rod , Theilovirus/efeitos dos fármacos , Fatores de Tempo , Ácido Valproico/efeitos adversos , Ácido Valproico/uso terapêutico
7.
Int Immunol ; 27(7): 333-44, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25721871

RESUMO

Dimethyl fumarate (DMF) is a modifier of the nuclear factor (erythroid-derived 2)-2 (Nrf2)-kelch-like ECH-associated protein 1 (Keap1) pathway. DMF treatment in the effector phase significantly suppressed the development of Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) both clinically and histologically. DMF treatment leads to an enhanced Nrf2 antioxidant response in TMEV-IDD mice. DMF treatment in the effector phase significantly suppressed the level of IL-17A mRNA. DMF is known to inhibit differentiation of T helper 17 (Th17) cells via suppressing NF-κB. Taken together, our data suggest that DMF treatment in the effector phase may suppress TMEV-IDD not only via enhancing the antioxidant response but also via suppressing IL-17A.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas do Citoesqueleto/metabolismo , Doenças Desmielinizantes/tratamento farmacológico , Fumarato de Dimetilo/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Theilovirus/efeitos dos fármacos , Animais , Doenças Desmielinizantes/metabolismo , Doenças Desmielinizantes/virologia , Feminino , Proteína 1 Associada a ECH Semelhante a Kelch , Camundongos , Camundongos Endogâmicos
8.
PLoS One ; 9(4): e94486, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24718491

RESUMO

In patients with multiple sclerosis (MS) and in mice with experimental autoimmune encephalomyelitis (EAE), proliferating autoreactive T cells play an important role in the pathogenesis of the disease. Due to the importance of these myelin-specific T cells, these cells have been therapeutic targets in a variety of treatments. Previously we found that Lenaldekar (LDK), a novel small molecule, could inhibit exacerbations in a preclinical model of MS when given at the start of an EAE exacerbation. In those studies, we found that LDK could inhibit human T cell recall responses and murine myelin responses in vitro. In these new studies, we found that LDK could inhibit myelin specific T cell responses through the insulin-like growth factor-1 receptor (IGF-1R) pathway. Alteration of this pathway led to marked reduction in T cell proliferation and expansion. Blocking this pathway could account for the observed decreases in clinical signs and inflammatory demyelinating disease, which was accompanied by axonal preservation. Our data indicate that IGF-1R could be a potential target for new therapies for the treatment of autoimmune diseases where autoreactive T cell expansion is a requisite for disease.


Assuntos
Encefalomielite Autoimune Experimental/tratamento farmacológico , Hidrazonas/uso terapêutico , Inflamação/patologia , Fator de Crescimento Insulin-Like I/antagonistas & inibidores , Terapia de Alvo Molecular , Quinolinas/uso terapêutico , Animais , Axônios/efeitos dos fármacos , Axônios/patologia , Encefalomielite Autoimune Experimental/imunologia , Feminino , Humanos , Hidrazonas/farmacologia , Fator de Crescimento Insulin-Like I/metabolismo , Interleucina-2/metabolismo , Camundongos Endogâmicos C57BL , Proteína Proteolipídica de Mielina/imunologia , Fragmentos de Peptídeos/imunologia , Quinolinas/farmacologia , Receptor IGF Tipo 1/metabolismo , Recidiva , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Theilovirus/efeitos dos fármacos , Theilovirus/fisiologia
9.
J Neuroimmunol ; 244(1-2): 84-93, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22329906

RESUMO

Multiple sclerosis is one of the most common demyelinating central nervous system diseases in young adults. Theiler's murine encephalomyelitis (TME) is a widely used virus-induced murine model for human myelin disorders. Immunosuppressive approaches generally reduce antiviral immunity and therefore increase virus dissemination with clinical worsening. In the present study, the progressive course of TME was significantly delayed due to a five-week cuprizone feeding period. Cuprizone was able to minimize demyelinating leukomyelitis without virus exacerbation. This phenomenon is supposed to be a consequence of selective inhibition of detrimental inflammatory responses with maintained protective immunity against the virus.


Assuntos
Quelantes/uso terapêutico , Cuprizona/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Theilovirus/efeitos dos fármacos , Animais , Citocinas/sangue , Citocinas/imunologia , Modelos Animais de Doenças , Feminino , Camundongos , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Esclerose Múltipla/virologia , Theilovirus/imunologia
10.
PLoS One ; 6(10): e26001, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22022490

RESUMO

Our laboratory demonstrated that a natural human serum antibody, sHIgM12, binds to neurons in vitro and promotes neurite outgrowth. We generated a recombinant form, rHIgM12, with identical properties. Intracerebral infection with Theiler's Murine Encephalomyelitis Virus (TMEV) of susceptible mouse strains results in chronic demyelinating disease with progressive axonal loss and neurologic dysfunction similar to progressive forms of multiple sclerosis. To study the effects of rHIgM12 on the motor function of TMEV-infected mice, we monitored spontaneous nocturnal activity over many weeks. Nocturnal behavior is a sensitive measure of rodent neurologic function because maximal activity changes are expected to occur during the normally active night time monitoring period. Mice were placed in activity boxes eight days prior to treatment to collect baseline spontaneous activity. After treatment, activity in each group was continuously recorded over 8 weeks. We chose a long 8-week monitoring period for two reasons: (1) we previously demonstrated that IgM induced remyelination is present by 5 weeks post treatment, and (2) TMEV-induced demyelinating disease in this strain progresses very slowly. Due to the long observation periods and large data sets, differences among treatment groups may be difficult to appreciate studying the original unfiltered recordings. To clearly delineate changes in the highly fluctuating original data we applied three different methods: (1) binning, (2) application of Gaussian low-pass filters (GF) and (3) polynomial fitting. Using each of the three methods we showed that compared to control IgM and saline, early treatment with rHIgM12 induced improvement in both horizontal and vertical motor function, whereas later treatment improved only horizontal activity. rHIgM12 did not alter activity of normal, uninfected mice. This study supports the hypothesis that treatment with a neuron-binding IgM not only protects neurons in vitro, but also influences functional motor improvement.


Assuntos
Anticorpos Monoclonais/farmacologia , Doenças Desmielinizantes/fisiopatologia , Atividade Motora/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Animais , Anticorpos Monoclonais/administração & dosagem , Infecções por Cardiovirus/fisiopatologia , Infecções por Cardiovirus/virologia , Escuridão , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Humanos , Injeções Intraperitoneais , Camundongos , Ligação Proteica/efeitos dos fármacos , Theilovirus/efeitos dos fármacos
11.
J Neurol Sci ; 308(1-2): 41-8, 2011 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-21726878

RESUMO

FTY720 (fingolimod) has demonstrated efficacy in multiple sclerosis (MS). We evaluated the effects of FTY720 on progressive disability, viral load, and antibody responses in mice infected with Theiler's murine encephalomyocarditis virus (TMEV). FTY720 and phosphorylated FTY720 (FTY720-P) were detected in the brain after intraperitoneal injection of the drug. Bioactivity of FTY720 was confirmed by reduced numbers of mononuclear cells in the spleen and blood after treatment. No significant differences were found in disability progression, viral load, and serum antibody responses between the FTY720-treated versus the PBS-treated mice. There was less production of IgG within the CNS in the FTY-treated group on some measures.


Assuntos
Modelos Animais de Doenças , Imunossupressores/uso terapêutico , Esclerose Múltipla/patologia , Esclerose Múltipla/virologia , Propilenoglicóis/uso terapêutico , Esfingosina/análogos & derivados , Theilovirus/efeitos dos fármacos , Animais , Infecções por Cardiovirus/tratamento farmacológico , Infecções por Cardiovirus/imunologia , Infecções por Cardiovirus/patologia , Feminino , Cloridrato de Fingolimode , Imunossupressores/farmacologia , Injeções Intraperitoneais , Camundongos , Esclerose Múltipla/tratamento farmacológico , Propilenoglicóis/farmacologia , Esfingosina/farmacologia , Esfingosina/uso terapêutico , Theilovirus/imunologia , Carga Viral/efeitos dos fármacos , Carga Viral/imunologia
12.
Cell Stress Chaperones ; 16(5): 505-15, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21445704

RESUMO

Theiler's murine encephalomyelitis virus (TMEV) is a positive-sense RNA virus belonging to the Cardiovirus genus in the family Picornaviridae. In addition to other host cellular factors and pathways, picornaviruses utilise heat shock proteins (Hsps) to facilitate their propagation in cells. This study investigated the localisation of Hsps 70 and 90 in TMEV-infected BHK-21 cells by indirect immunofluorescence and confocal microscopy. The effect of Hsp90 inhibitors novobiocin (Nov) and geldanamycin (GA) on the development of cytopathic effect (CPE) induced by infection was also examined. Hsp90 staining was uniformly distributed in the cytoplasm of uninfected cells but was found concentrated in the perinuclear region during late infection where it overlapped with the signal for non-structural protein 2C within the viral replication complex. Hsp70 redistributed into the vicinity of the viral replication complex during late infection, but its distribution did not overlap with that of 2C. Inhibition of Hsp90 by GA and Nov had a negative effect on virus growth over a 48-h period as indicated by no observable CPE in treated compared to untreated cells. 2C was detected by Western analysis of GA-treated infected cell lysates at doses between 0.01 and 0.125 µM, suggesting that processing of viral precursors was not affected in the presence of this drug. In contrast, 2C was absent in cell lysates of Nov-treated cells at doses above 10 µM, although CPE was evident 48 hpi. This is the first study describing the dynamic behaviour of Hsps 70 and 90 in TMEV-infected cells and to identify Hsp90 as an important host factor in the life cycle of this virus.


Assuntos
Benzoquinonas/metabolismo , Infecções por Cardiovirus/metabolismo , Inibidores Enzimáticos/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Lactamas Macrocíclicas/metabolismo , Novobiocina/metabolismo , Theilovirus/fisiologia , Animais , Benzoquinonas/farmacologia , Linhagem Celular/efeitos dos fármacos , Linhagem Celular/virologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Humanos , Lactamas Macrocíclicas/farmacologia , Novobiocina/farmacologia , Theilovirus/efeitos dos fármacos , Theilovirus/patogenicidade , Replicação Viral/efeitos dos fármacos
13.
J Autoimmun ; 36(2): 142-54, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21273044

RESUMO

Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease (TMEV-IDD) serves as virus-induced model of chronic progressive multiple sclerosis. Infection of susceptible SJL/J mice leads to life-long CNS virus persistence and a progressive autoimmune demyelinating disease mediated by myelin-specific T cells activated via epitope spreading. In contrast, virus is rapidly cleared by a robust CTL response in TMEV-IDD-resistant C57BL/6 mice. We investigated whether differential induction of regulatory T cells (Tregs) controls susceptibility to TMEV-IDD. Infection of disease-susceptible SJL/J, but not B6 mice, leads to rapid activation and expansion of Tregs resulting in an unfavorable CNS ratio of Treg:Teffector cells. In addition, anti-CD25-induced inactivation of Tregs in susceptible SJL/J, but not resistant B6, mice results in significantly decreased clinical disease concomitant with enhanced anti-viral CD4(+), CD8(+) and antibody responses resulting in decreased CNS viral titers. This is the first demonstration that virus-induced Treg activation regulates susceptibility to autoimmune disease differentially in susceptible and resistant strains of mice and provides a new mechanistic explanation for the etiology of infection-induced autoimmunity.


Assuntos
Doenças Desmielinizantes/imunologia , Modelos Animais de Doenças , Esclerose Múltipla/imunologia , Linfócitos T Reguladores/imunologia , Theilovirus/imunologia , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Infecções por Cardiovirus/imunologia , Infecções por Cardiovirus/metabolismo , Infecções por Cardiovirus/patologia , Infecções por Cardiovirus/prevenção & controle , Proliferação de Células , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/patologia , Sistema Nervoso Central/virologia , Doenças Desmielinizantes/metabolismo , Doenças Desmielinizantes/patologia , Doenças Desmielinizantes/prevenção & controle , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/imunologia , Fatores de Transcrição Forkhead/metabolismo , Proteína Relacionada a TNFR Induzida por Glucocorticoide , Humanos , Subunidade alfa de Receptor de Interleucina-2/imunologia , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Camundongos Transgênicos , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Receptores de Fator de Crescimento Neural/imunologia , Receptores do Fator de Necrose Tumoral/imunologia , Índice de Gravidade de Doença , Linfócitos T Reguladores/metabolismo , Theilovirus/efeitos dos fármacos
14.
Virol J ; 5: 89, 2008 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-18680564

RESUMO

BACKGROUND: Demyelinating strains of Theiler's murine encephalomyelitis virus (TMEV) such as the DA strain are the causative agents of a persistent infection that induce a multiple sclerosis-like disease in the central nervous system of susceptible mice. Viral persistence, mainly associated with macrophages, is considered to be an important disease determinant that leads to chronic inflammation, demyelination and autoimmunity. In a previous study, we described the establishment of a persistent DA infection in RAW macrophages, which were therefore named DRAW. RESULTS: In the present study we explored the potential of diverse compounds to modulate viral persistence in these DRAW cells. Hemin was found to increase viral yields and to induce cell lysis. Enviroxime and neutralizing anti-TMEV monoclonal antibody were shown to decrease viral yields, whereas interferon-alpha and interferon-gamma completely cleared the persistent infection. We also compared the cytokine pattern secreted by uninfected RAW, DRAW and interferon-cured DRAW macrophages using a cytokine protein array. The chemokine RANTES was markedly upregulated in DRAW cells and restored to a normal expression level after abrogation of the persistent infection with interferon-alpha or interferon-gamma. On the other hand, the chemokine MCP-1 was upregulated in the interferon-cured DRAW cells. CONCLUSION: We have identified several compounds that modulate viral replication in an in vitro model system for TMEV persistence. These compounds now await further testing in an in vivo setting to address fundamental questions regarding persistent viral infection and immunopathogenesis.


Assuntos
Antivirais/farmacologia , Infecções por Cardiovirus/tratamento farmacológico , Macrófagos/virologia , Theilovirus/efeitos dos fármacos , Theilovirus/fisiologia , Replicação Viral/efeitos dos fármacos , Animais , Infecções por Cardiovirus/genética , Infecções por Cardiovirus/imunologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Quimiocina CCL5/genética , Quimiocina CCL5/metabolismo , Citocinas/imunologia , Expressão Gênica/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Theilovirus/imunologia
15.
Artigo em Russo | MEDLINE | ID: mdl-17672126

RESUMO

Influence of moraprenylphosphates (phosphorylated polyprenol of plant origin) upon the accumulation of Taylor murine encephalomyelitis virus VP3 protein in the susceptible cell cultures was studied. It has been shown that moraprenylphosphates inhibited the accumulation of VP3 at early stages of infectious process. Moraprenylphosphates were found to decrease infectivity of the virus as well as virus-induced cellular apoptosis. Mechanisms of immunomodulating and antiviral activity of moraprenylphosphates and prospects of their use as antiviral drugs have been discussed.


Assuntos
Antivirais/farmacologia , Fosfatos de Poli-Isoprenil/farmacologia , Theilovirus/efeitos dos fármacos , Animais , Proteínas do Capsídeo/biossíntese , Proteínas do Capsídeo/efeitos dos fármacos , Infecções por Cardiovirus/virologia , Linhagem Celular/efeitos dos fármacos , Linhagem Celular/virologia , Cricetinae , Camundongos , Theilovirus/patogenicidade , Theilovirus/fisiologia , Virulência/efeitos dos fármacos
16.
J Neuroimmunol ; 172(1-2): 85-93, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16375978

RESUMO

From mice infected with the DA strain of Theiler's murine encephalomyelitis virus (TMEV), CD8+ cytotoxic T lymphocytes (CTLs) could be detected after stimulation with TMEV infected antigen presenting cells (APCs). These CTLs killed not only TMEV infected but also uninfected syngeneic cells. Killing was associated with interferon (IFN)-gamma production in ELISPOT assays. The CTLs were efficiently induced by vaccinia virus encoding DA virus capsid proteins, but not by APCs infected with the GDVII strain of TMEV. The CTLs produced IFN-gamma in response to TMEV infected, but not uninfected, astrocytes. The CTLs could be maintained in the presence of interleukin (IL)-2. We hypothesized that, in DA virus infection, CD8+ CTLs specific for viral capsid protein could recognize self protein on oligodendrocytes by molecular mimicry, leading to demyelination.


Assuntos
Antígenos CD8/fisiologia , Proteínas do Capsídeo/fisiologia , Interferon gama/metabolismo , Linfócitos T Citotóxicos/imunologia , Theilovirus/fisiologia , Animais , Antígenos CD8/análise , Linhagem Celular , Cricetinae , Citocinas/metabolismo , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Células Matadoras Naturais/imunologia , Camundongos , Modelos Imunológicos , Baço/metabolismo , Baço/patologia , Theilovirus/efeitos dos fármacos
17.
J Interferon Cytokine Res ; 21(10): 785-92, 2001 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11710989

RESUMO

Interferon-beta (IFN-beta) has been used successfully to treat patients with relapsing-remitting multiple sclerosis (MS). IFN-tau is a new class of type I IFN that is secreted by the trophoblast and is the signal for maternal recognition of pregnancy in sheep. IFN-tau has potent immunosuppressive and antiviral activities similar to other type I IFN but is less cytotoxic than IFN-alpha/beta. The current investigation concerns the effect of recombinant ovine IFN-tau (rOvIFN-tau) on the modulation of MHC class I and II expression on cloned mouse cerebrovascular endothelial (CVE) cells. IFN-tau induced tyrosine phosphorylation of Stat1 and upregulated the expression of MHC class I on CVE. One proposed action by which type I IFN reduce the relapse rate in MS is via interference with IFN-gamma-induced MHC class II expression. IFN-tau was shown to downregulate IFN-gamma-induced MHC class II expression on CVE and, hence, may be of potential therapeutic value in downregulating inflammation in the central nervous system (CNS). IFN-tau did not upregulate the expression of MHC class II on CVE. IFN-tau also inhibited the replication of Theiler's virus in CVE. These in vitro results suggest that IFN-tau may be of therapeutic value in the treatment of virus-induced demyelinating disease.


Assuntos
Antivirais/farmacologia , Endotélio Vascular/metabolismo , Antígenos de Histocompatibilidade/metabolismo , Interferon Tipo I/farmacologia , Miocárdio/citologia , Proteínas da Gravidez/farmacologia , Theilovirus/efeitos dos fármacos , Animais , Infecções por Cardiovirus/terapia , Células Clonais , Proteínas de Ligação a DNA/metabolismo , Regulação para Baixo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/virologia , Citometria de Fluxo , Camundongos , Camundongos Endogâmicos BALB C , Esclerose Múltipla/terapia , Fosforilação , Fator de Transcrição STAT1 , Ovinos , Theilovirus/crescimento & desenvolvimento , Transativadores/metabolismo , Regulação para Cima , Replicação Viral/efeitos dos fármacos
18.
J Neuroimmunol ; 108(1-2): 22-8, 2000 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-10900333

RESUMO

We studied the effect of high-dose mouse IgG on TMEV-induced demyelinating disease (TMEV-IDD). We injected TMEV intracerebrally into susceptible SJL/J mice and induced TMEV-IDD. Mouse IgG were injected intraperitonealy, and clinical course and various immunological indicators were studied. The results show that TMEV-IDD was significantly suppressed both clinically and histologically (P<0.01) when IgG were administered in the effector phase. The delayed type hypersensitivity and T cell proliferative response specific for TMEV were decreased by this treatment. In an ELISPOT assay, the number of TNF-alpha producing lymphocytes in the spinal cords was low in high-dose IgG treated mice compared with PBS treated control mice. These data suggest that administration of IgG suppresses TMEV-IDD and may be promising treatment to prevent exacerbation of human multiple sclerosis.


Assuntos
Doenças Desmielinizantes/imunologia , Doenças Desmielinizantes/terapia , Imunoglobulina G/administração & dosagem , Imunoglobulina G/farmacologia , Theilovirus/efeitos dos fármacos , Theilovirus/fisiologia , Animais , Anticorpos Antivirais/análise , Anticorpos Antivirais/imunologia , Especificidade de Anticorpos , Infecções por Cardiovirus/imunologia , Infecções por Cardiovirus/fisiopatologia , Infecções por Cardiovirus/terapia , Infecções por Cardiovirus/virologia , Doenças Desmielinizantes/virologia , Modelos Animais de Doenças , Feminino , Hipersensibilidade Tardia/imunologia , Imunoglobulina G/imunologia , Interferon gama/metabolismo , Interleucinas/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos , Esclerose Múltipla/imunologia , Esclerose Múltipla/terapia , Medula Espinal/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
19.
Eur J Pharmacol ; 372(1): 75-83, 1999 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-10374717

RESUMO

Intracerebral (i.c.) inoculation of susceptible strains of mice with Theiler's murine encephalomyelitis virus (TMEV) results in immune-mediated demyelinating disease. Interleukin-1 receptors are expressed in the brain of mice, in particular in the hippocampus, and have been implicated in neuroimmunoendocrine interactions. In the present study we investigated the regulation of interleukin-1 receptors in the hippocampus of a susceptible (SJL/J) and a resistant (BALB/c) strain of mice infected with TMEV, at different time intervals of the disease. Our results show that interleukin-1 receptors in the hippocampus were decreased in TMEV-infected mice at early times post-infection (10 and 14 days p.i.). The reduction in interleukin-1 receptors only occurred in the susceptible strain of mice (SJL/J), whereas interleukin-1 binding in the hippocampus of TMEV-infected resistant mice (BALB/c) showed values similar to those in control animals. The TMEV-induced down-regulation of interleukin-1 receptors was secondary to a marked decrease in the affinity of the receptor (control: Kd = 10.5 pM; TMEV: Kd = 1.30 pM) accompanied by a decrease in receptor number (control: Bmax = 2.189 fmol/mg protein; TMEV: B max = 0.84 fmol/mg protein). We also investigated the effects of glucocorticoid treatment on the regulation of hippocampal interleukin-1 receptors of TMEV-infected mice. Dexamethasone treatment in the early phase (500 microg/kg or 1 mg/kg during days 5-10 p.i.) of the disease significantly reversed the deficits in hippocampal interleukin-1 receptors observed at 10 days p.i. in SJL/J mice, and suppressed neurological signs of demyelination. These results suggest that: (i) the reduction of interleukin-1 receptors may be a consequence, at least in part, of local production of interleukin-1 at early times during TMEV infection; (ii) interleukin-1 seems to be a critical factor for the susceptibility to TMEV-induced demyelination and (iii) the protective effect of dexamethasone appears to be related to its ability to reverse the reduction in interleukin-1 receptors during the early disease. These results suggest that interleukin-1 is a pivotal mediator in TMEV-induced demyelination.


Assuntos
Anti-Inflamatórios/farmacologia , Dexametasona/farmacologia , Hipocampo/efeitos dos fármacos , Poliomielite/fisiopatologia , Receptores de Interleucina-1/efeitos dos fármacos , Theilovirus/efeitos dos fármacos , Animais , Doenças Desmielinizantes/patologia , Doenças Desmielinizantes/prevenção & controle , Doenças Desmielinizantes/virologia , Feminino , Hipocampo/metabolismo , Hipocampo/virologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos , Poliomielite/virologia , Receptores de Interleucina-1/metabolismo , Especificidade da Espécie , Theilovirus/crescimento & desenvolvimento , Fatores de Tempo
20.
Structure ; 5(7): 961-78, 1997 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-9261087

RESUMO

BACKGROUND: Polioviruses are human pathogens and the causative agents of poliomyelitis. Polioviruses are icosahedral single-stranded RNA viruses, which belong to the picornavirus family, and occur as three distinct serotypes. All three serotypes of poliovirus can infect primates, but only type 2 can infect mice. The crystal structures of a type 1 and a type 3 poliovirus are already known. Structural studies of poliovirus type 2 Lansing (PV2L) were initiated to try to enhance our understanding of the differences in host range specificity, antigenicity and receptor binding among the three serotypes of poliovirus. RESULTS: The crystal structure of the mouse neurovirulent PV2L complexed with a potent antiviral agent, SCH48973, was determined at 2.9 A resolution. Structural differences among the three poliovirus serotypes occur primarily in the loop regions of the viral coat proteins (VPs), most notably in the loops of VP1 that cluster near the fivefold axes of the capsid, where the BC loop of PV2L is disordered. Unlike other known structures of enteroviruses, the entire polypeptide chain of PV2L VP4 is visible in the electron density and RNA bases are observed stacking with conserved aromatic residues (Tyr4020 and Phe4046) of VP4. The broad-spectrum antiviral agent SCH48973 is observed binding in a pocket within the beta-barrel of VP1, in approximately the same location that natural 'pocket factors' bind to polioviruses. SCH48973 forms predominantly hydrophobic interactions with the pocket residues. CONCLUSIONS: Some of the conformational changes required for infectivity and involved in the control of capsid stability and neurovirulence in mice may occur in the vicinity of the fivefold axis of the poliovirus, where there are significant structural differences among the three poliovirus serotypes in the surface exposed loops of VP1 (BC, DE, and HI). A surface depression is located at the fivefold axis of PV2L that is not present in the other two poliovirus serotypes. The observed interaction of RNA with VP4 supports the observation that loss of VP4 ultimately leads to the loss of viral RNA. A model is proposed that suggests dual involvement of the virion fivefold and pseudo-threefold axes in receptor-mediated initiation of infection by picornaviruses.


Assuntos
Antivirais/química , Éteres Fenílicos/química , Theilovirus/química , Adaptação Fisiológica , Animais , Antivirais/farmacologia , Cálcio/química , Cálcio/metabolismo , Cristalização , Cristalografia por Raios X , Éteres Difenil Halogenados , Humanos , Camundongos , Modelos Biológicos , Ácidos Mirísticos/química , Ácidos Mirísticos/metabolismo , Éteres Fenílicos/farmacologia , Picornaviridae/química , Picornaviridae/metabolismo , Hidrocarbonetos Policíclicos Aromáticos/química , Hidrocarbonetos Policíclicos Aromáticos/metabolismo , Conformação Proteica , Estrutura Terciária de Proteína , RNA Viral/química , RNA Viral/metabolismo , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Sorotipagem , Relação Estrutura-Atividade , Temperatura , Theilovirus/classificação , Theilovirus/efeitos dos fármacos , Replicação Viral
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