RESUMEN
Dengue virus (DENV) and Japanese encephalitis virus (JEV) are important arthropod-borne viruses from the Flaviviridae family. DENV is a global public health problem with significant social and economic impacts, especially in tropical and subtropical areas. JEV is a neurotropic arbovirus endemic to east and southeast Asia. There are no U.S. FDA-approved antiviral drugs available to treat or to prevent DENV and JEV infections, leaving nearly one-third of the world's population at risk for infection. Therefore, it is crucial to discover potent antiviral agents against these viruses. Nucleoside analogs, as a class, are widely used for the treatment of viral infections. In this study, we discovered nucleoside analogs that possess potent and selective anti-JEV and anti-DENV activities across all serotypes in cell-based assay systems. Both viruses were susceptible to sugar-substituted 2'-C-methyl analogs with either cytosine or 7-deaza-7-fluoro-adenine nucleobases. Mouse studies confirmed the anti-DENV activity of these nucleoside analogs. Molecular models were assembled for DENV serotype 2 (DENV-2) and JEV RNA-dependent RNA polymerase replication complexes bound to nucleotide inhibitors. These models show similarities between JEV and DENV-2, which recognize the same nucleotide inhibitors. Collectively, our findings provide promising compounds and a structural rationale for the development of direct-acting antiviral agents with dual activity against JEV and DENV infections.
Asunto(s)
Antivirales/farmacología , Virus del Dengue/efectos de los fármacos , Dengue/tratamiento farmacológico , Virus de la Encefalitis Japonesa (Subgrupo)/efectos de los fármacos , Nucleósidos/análogos & derivados , Animales , Antivirales/química , Chlorocebus aethiops , Dengue/sangre , Dengue/patología , Virus del Dengue/genética , Virus del Dengue/fisiología , Evaluación Preclínica de Medicamentos/métodos , Virus de la Encefalitis Japonesa (Subgrupo)/genética , Virus de la Encefalitis Japonesa (Subgrupo)/fisiología , Encefalitis por Arbovirus/tratamiento farmacológico , Ratones , Modelos Moleculares , Nucleósidos/química , Nucleósidos/farmacología , ARN Polimerasa Dependiente del ARN/química , ARN Polimerasa Dependiente del ARN/metabolismo , Células Vero , Proteínas Virales/química , Proteínas Virales/metabolismo , Replicación Viral/efectos de los fármacosRESUMEN
We report herein that neuroinvasion by vesicular stomatitis virus (VSV) activates microglia and induces a peripheral dendritic cell (DC)-dependent inflammatory response in the central nervous system (CNS). VSV neuroinvasion rapidly induces multiple brain chemokine and proinflammatory cytokine mRNAs that display bimodal kinetics. Peripheral DC ablation or T cell depletion suppresses the second wave of this response demonstrating that infiltrating T cells are primarily responsible for the bimodal characteristics of this response. The robust infiltrate associated with VSV encephalitis likely depends on sustained production of brain CCL19 and CCR7 expression on infiltrating inflammatory cells.
Asunto(s)
Encéfalo/metabolismo , Citocinas/metabolismo , Encefalitis por Arbovirus/patología , Microglía/fisiología , Vesiculovirus/patogenicidad , Animales , Encéfalo/inmunología , Encéfalo/virología , Citocinas/genética , Toxina Diftérica/farmacología , Toxina Diftérica/uso terapéutico , Modelos Animales de Enfermedad , Encefalitis por Arbovirus/tratamiento farmacológico , Encefalitis por Arbovirus/metabolismo , Citometría de Flujo , Factor de Crecimiento Similar a EGF de Unión a Heparina , Péptidos y Proteínas de Señalización Intercelular/genética , Infiltración Leucémica/tratamiento farmacológico , Leucocitos/efectos de los fármacos , Leucocitos/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Microglía/inmunología , ARN Mensajero/metabolismo , Vesiculovirus/inmunologíaRESUMEN
Natural products provide a vast array of chemical structures to explore in the discovery of new medicines. Although secondary metabolites produced by microbes have been developed to treat a variety of diseases, including bacterial and fungal infections, to date there has been limited investigation of natural products with antiviral activity. In this report, we used a phenotypic cell-based replicon assay coupled with an iterative biochemical fractionation process to identify, purify, and characterize antiviral compounds produced by marine microbes. We isolated a compound from Streptomyces kaviengensis, a novel actinomycetes isolated from marine sediments obtained off the coast of New Ireland, Papua New Guinea, which we identified as antimycin A1a. This compound displays potent activity against western equine encephalitis virus in cultured cells with half-maximal inhibitory concentrations of less than 4 nM and a selectivity index of greater than 550. Our efforts also revealed that several antimycin A analogues display antiviral activity, and mechanism of action studies confirmed that these Streptomyces-derived secondary metabolites function by inhibiting the cellular mitochondrial electron transport chain, thereby suppressing de novo pyrimidine synthesis. Furthermore, we found that antimycin A functions as a broad spectrum agent with activity against a wide range of RNA viruses in cultured cells, including members of the Togaviridae, Flaviviridae, Bunyaviridae, Picornaviridae, and Paramyxoviridae families. Finally, we demonstrate that antimycin A reduces central nervous system viral titers, improves clinical disease severity, and enhances survival in mice given a lethal challenge with western equine encephalitis virus. Our results provide conclusive validation for using natural product resources derived from marine microbes as source material for antiviral drug discovery, and they indicate that host mitochondrial electron transport is a viable target for the continued development of broadly active antiviral compounds.
Asunto(s)
Actinobacteria/química , Antivirales/farmacología , Sedimentos Geológicos/microbiología , Animales , Antimicina A/química , Antimicina A/farmacología , Antimicina A/uso terapéutico , Antivirales/química , Antivirales/aislamiento & purificación , Productos Biológicos/química , Productos Biológicos/aislamiento & purificación , Productos Biológicos/farmacología , Línea Celular , Sistema Nervioso Central/efectos de los fármacos , Sistema Nervioso Central/patología , Sistema Nervioso Central/virología , Fraccionamiento Químico , Transporte de Electrón/efectos de los fármacos , Virus de la Encefalitis/efectos de los fármacos , Encefalitis por Arbovirus/tratamiento farmacológico , Encefalitis por Arbovirus/patología , Encefalitis por Arbovirus/virología , Ensayos Analíticos de Alto Rendimiento , Humanos , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , ARN Viral/metabolismo , Estándares de Referencia , Reproducibilidad de los Resultados , Streptomyces/química , Análisis de Supervivencia , Transcripción Genética/efectos de los fármacosRESUMEN
Worldwide, arboviral illnesses constitute the most important international infectious threat to human neurological health and welfare. Before the availability of effective immunizations, approximately 50,000 cases of Japanese encephalitis occurred in the world each year, one-fifth of which cases proved lethal and a much larger number were left with severe neurological handicaps. With global climate change and perhaps other factors, the prevalences of some arboviral illnesses appear to be increasing. Arboviral illnesses, including Japanese encephalitis, tick-borne encephalitis, Yellow fever, and others, are emerging as possible global health care threats because of biological warfare. This chapter will review ecology, pathophysiology, diagnosis, management, and outcome of the forms of arboviral encephalitis that are of greatest importance in North America, together with some of the most important arboviral encephalitides prevalent in other parts of the world.
Asunto(s)
Infecciones por Bunyaviridae/epidemiología , Encefalitis por Arbovirus , Infecciones por Flaviviridae/epidemiología , Infecciones por Reoviridae/epidemiología , Infecciones por Togaviridae/epidemiología , Antivirales/uso terapéutico , Diagnóstico Diferencial , Encefalitis por Arbovirus/diagnóstico , Encefalitis por Arbovirus/tratamiento farmacológico , Encefalitis por Arbovirus/epidemiología , Encefalitis por Arbovirus/prevención & control , Humanos , América del Norte/epidemiologíaRESUMEN
Murray Valley encephalitis virus (MVEV) is a mosquito-borne virus that is found across Australia, Papua New Guinea and Irian Jaya. MVEV is endemic to northern Australia and causes occasional outbreaks across south-eastern Australia. 2011 saw a dramatic increase in MVEV activity in endemic regions and the re-emergence of MVEV in south-eastern Australia. This followed significant regional flooding and increased numbers of the main mosquito vector, Culex annulirostris, and was evident from the widespread seroconversion of sentinel chickens, fatalities among horses and several cases in humans, resulting in at least three deaths. The last major outbreak in Australia was in 1974, during which 58 cases were identified and the mortality rate was about 20%. With the potential for a further outbreak of MVEV in the 2011-2012 summer and following autumn, we highlight the importance of this disease, its clinical characteristics and radiological and laboratory features. We present a suspected but unproven case of MVEV infection to illustrate some of the challenges in clinical management. It remains difficult to establish an early diagnosis of MVEV infection, and there is a lack of proven therapeutic options.
Asunto(s)
Virus de la Encefalitis del Valle Murray/aislamiento & purificación , Encefalitis por Arbovirus , Corticoesteroides/uso terapéutico , Anciano , Antivirales/uso terapéutico , Encefalitis por Arbovirus/diagnóstico , Encefalitis por Arbovirus/tratamiento farmacológico , Encefalitis por Arbovirus/prevención & control , Resultado Fatal , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Factores Inmunológicos/uso terapéutico , Imagen por Resonancia Magnética , MasculinoRESUMEN
Many viruses, including flaviviruses, display affinity for cell surface heparan sulfate (HS) proteoglycans with biological relevance in virus attachment/entry. This raises the possibility of the application of HS mimetics in antiviral therapy. We have evaluated the antiviral effect of the sulfated polysaccharides, suramin, pentosan polysulfate (PPS) and PI-88, which are currently approved or in trial for clinical use, against dengue virus (DEN) and the encephalitic flaviviruses, Japanese encephalitis virus, West Nile virus, and Murray Valley encephalitis virus. A flow cytometry-based method for the measurement of inhibition of virus infectivity was developed, which showed the in vitro antiviral activity of the three compounds, albeit with differences in efficiency which were virus-dependent. The 50% effective concentration (EC(50)) values for DEN inhibition were in the order: PPSAsunto(s)
Antivirales/farmacología
, Virus del Dengue/efectos de los fármacos
, Dengue/tratamiento farmacológico
, Virus de la Encefalitis Japonesa (Subgrupo)/efectos de los fármacos
, Heparitina Sulfato/farmacología
, Oligosacáridos/farmacología
, Animales
, Antivirales/química
, Antivirales/uso terapéutico
, Línea Celular
, Modelos Animales de Enfermedad
, Evaluación Preclínica de Medicamentos
, Encefalitis por Arbovirus/tratamiento farmacológico
, Femenino
, Infecciones por Flavivirus/tratamiento farmacológico
, Heparitina Sulfato/uso terapéutico
, Inyecciones Intraperitoneales
, Masculino
, Ratones
, Ratones Endogámicos C57BL
, Ratones Noqueados
, Oligosacáridos/química
, Oligosacáridos/uso terapéutico
, Poliéster Pentosan Sulfúrico/química
, Poliéster Pentosan Sulfúrico/farmacología
, Poliéster Pentosan Sulfúrico/uso terapéutico
, Suramina/química
, Suramina/farmacología
, Suramina/uso terapéutico
, Resultado del Tratamiento
RESUMEN
Murray Valley encephalitis (MVE) is an important mosquitoborne flavivirus infection endemic to Australia and Papua New Guinea. We report the first imported case of MVE in Europe. A 23-year-old tourist developed severe encephalitis after having returned to Germany from a long-term trip across the Australian continent. The diagnosis was suspected on the basis of clinical findings and the patient's travel history and was confirmed by serological findings. The patient made a prolonged but complete recovery. Our case coincides with a recently reported spread of MVE virus in Australia. This emphasizes the need for continuous surveillance in areas of endemicity and appropriate protection when traveling through regions in which the MVE virus is endemic.
Asunto(s)
Virus de la Encefalitis del Valle Murray , Encefalitis por Arbovirus/transmisión , Adulto , Antivirales/uso terapéutico , Australia/epidemiología , Encefalitis por Arbovirus/tratamiento farmacológico , Encefalitis por Arbovirus/epidemiología , Encefalitis por Arbovirus/inmunología , Alemania/epidemiología , Humanos , Masculino , Papúa Nueva Guinea/epidemiología , ViajeRESUMEN
We report the case of a 34-year old patient who first complained of fever, confusion and transient ophthalmoplegia and then developed akinetic mutism, frontal lobe, pyramidal tract and extrapyramidal signs. Clinical and electrophysiological data support a diagnosis of encephalitis lethargica. Magnetic resonance imaging showed hyperintensive lesions in various brain regions. The patient responded to corticosteroid treatment. Two years after the onset of the first clinical signs he had recovered completely and today, after 5 years, he shows no sign of disease.
Asunto(s)
Encefalitis por Arbovirus/diagnóstico , Adulto , Corteza Cerebral/patología , Corteza Cerebral/fisiopatología , Electroencefalografía/efectos de los fármacos , Encefalitis por Arbovirus/tratamiento farmacológico , Encefalitis por Arbovirus/fisiopatología , Estudios de Seguimiento , Humanos , Imagen por Resonancia Magnética , Masculino , Metilprednisolona/uso terapéutico , Examen Neurológico/efectos de los fármacos , Enfermedad de Parkinson Posencefalítica/patología , Enfermedad de Parkinson Posencefalítica/fisiopatologíaRESUMEN
Cerebrospinal fluid samples from 257 patients with suspected herpes simplex virus encephalitis were prospectively analyzed by herpes simplex virus polymerase chain reaction. The polymerase chain reaction indicated herpes simplex virus encephalitis in 9 serologically proven cases and in 14 additional patients. Increased polymerase chain reaction signals were observed together with more severe neurological symptoms (P < 0.01) and within the first days of acyclovir treatment (P < 0.05).
Asunto(s)
Encefalitis por Arbovirus/diagnóstico , Herpes Simple/diagnóstico , Reacción en Cadena de la Polimerasa/métodos , Simplexvirus/aislamiento & purificación , Aciclovir/uso terapéutico , Adolescente , Adulto , Factores de Edad , Anciano , Secuencia de Bases , Preescolar , ADN Viral/líquido cefalorraquídeo , Encefalitis por Arbovirus/tratamiento farmacológico , Encefalitis por Arbovirus/microbiología , Estudios de Evaluación como Asunto , Reacciones Falso Negativas , Reacciones Falso Positivas , Herpes Simple/tratamiento farmacológico , Humanos , Lactante , Persona de Mediana Edad , Datos de Secuencia Molecular , Sensibilidad y EspecificidadAsunto(s)
Antivirales , Lincomicina/uso terapéutico , Animales , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Virus de la Encefalitis/efectos de los fármacos , Virus de la Encefalitis/fisiología , Encefalitis por Arbovirus/tratamiento farmacológico , Encefalitis por Arbovirus/mortalidad , Encefalomielitis/tratamiento farmacológico , Encefalomielitis/mortalidad , Ratones , Células Vero , Replicación Viral/efectos de los fármacosRESUMEN
The effects of cytarabine on neurological forms of Argentina Hemorrhagic Fever were evaluated in 125 patients. The mortality was 12.88 per cent compared to 61.40 per cent in untreated patients. (p less than 0.0001). The efficiency of this treatment depends on its early application. No side effect was observed.
Asunto(s)
Citarabina/uso terapéutico , Encefalitis por Arbovirus/tratamiento farmacológico , Fiebre Hemorrágica Americana/complicaciones , Adulto , Anciano , Encefalitis por Arbovirus/sangre , Encefalitis por Arbovirus/etiología , Humanos , Persona de Mediana Edad , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Enfermedades del Sistema Nervioso/etiología , Factores de TiempoRESUMEN
Since effective antiviral treatment is available for herpes simplex encephalitis (HSE), early diagnosis or exclusion of herpes simplex etiology is essential for prognosis. In a retrospective study of 25 cases of acute viral encephalitis not caused by herpes simplex virus (non-HSE), we investigated whether HSE can be excluded in the early phase before serological evidence is present. Using clinical means, history, investigations of CSF (protein, cells), EEG, and CCT, HSE could not be excluded with reliability. This is because clinical signs and laboratory results are not pathognomonic for any form of viral encephalitis, even if periodic activity in EEG and temporal attenuation in CCT are more frequent in HSE than in other forms of encephalitis. Therefore, in all cases of severe encephalitis, acyclovir therapy should be initiated early.
Asunto(s)
Encefalitis por Arbovirus/diagnóstico , Adolescente , Adulto , Anciano , Diagnóstico Diferencial , Electroencefalografía , Encefalitis por Arbovirus/tratamiento farmacológico , Encefalitis por Arbovirus/etiología , Femenino , Herpesvirus Humano 3/aislamiento & purificación , Herpesvirus Humano 4/aislamiento & purificación , Humanos , Pruebas Inmunológicas , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tomografía Computarizada por Rayos XAsunto(s)
Encefalitis por Arbovirus/tratamiento farmacológico , Fiebres Hemorrágicas Virales/tratamiento farmacológico , Animales , Arenaviridae/efectos de los fármacos , Cricetinae , Encefalitis por Arbovirus/mortalidad , Fiebres Hemorrágicas Virales/mortalidad , Humanos , Ratones , Rhabdoviridae/efectos de los fármacos , Ribavirina/uso terapéutico , Togaviridae/efectos de los fármacosRESUMEN
The injection of herpes simplex virus type 1 (HSV-1) into the vitreous body of the eye in the 18 day old albino rabbits consistently induced herpes encephalitis with 90% survival. In the untreated rabbits the lesions follow a defined anatomical pathway producing a progressive disease not dissimilar to the natural human disease in that HSV travels slowly by cell-to-cell infection of neuroglia. The effects of adenine arabinoside (ara-A) and cytarabine (ara-C) on HSV encephalitis in rabbit model were studied by starting the treatment on 4th day post-inoculation of HSV. Deaths due to toxic side effects were caused by ara-A and ara-C in 30% and 50% of animals respectively, compared with 10% in untreated animals. Neurological signs, such as head jerking, ataxia and frequent epileptiform fits, occurred in ara-A, and ara-C and untreated rabbits. Comparative histological studies of optic nerves and brains showed that ara-A and ara-C had no beneficial effect, but surprisingly enhanced the disease.
Asunto(s)
Citarabina/uso terapéutico , Encefalitis por Arbovirus/tratamiento farmacológico , Herpes Simple/tratamiento farmacológico , Vidarabina/uso terapéutico , Animales , Encéfalo/patología , Modelos Animales de Enfermedad , Encefalitis por Arbovirus/patología , Nervio Óptico/patología , Conejos , Simplexvirus/efectos de los fármacosRESUMEN
A combination therapy of human interferon, vidarabine, and dexamethasone was administered to six patients with proven (Patients I-III) or presumed (Patients IV-VI) herpes simplex virus encephalitis (HSVE). Interferon combined with dexamethasone was given to one patient with presumed HSVE (Patient VII). Leucopenia and elevated serum transaminase levels appeared in all patients and a diffuse bleeding in one of them. Patients II, III and IV died, 26, 43, and 209 days after the onset of encephalitis, respectively. Patients I, V, VI, and VII were left with moderate brain damage although their physical condition was good. HSV encephalitis presents diagnostic difficulties, complementary diagnostic methods are needed, and current therapeutic trials must be considered as preliminary.
Asunto(s)
Dexametasona/uso terapéutico , Encefalitis por Arbovirus/tratamiento farmacológico , Herpes Simple/tratamiento farmacológico , Interferones/uso terapéutico , Vidarabina/uso terapéutico , Adulto , Encéfalo/patología , Ensayos Clínicos como Asunto , Quimioterapia Combinada , Electroencefalografía , Encefalitis por Arbovirus/diagnóstico , Femenino , Herpes Simple/diagnóstico , Humanos , Masculino , Técnicas Microbiológicas , Persona de Mediana Edad , Tomografía Computarizada por Rayos XRESUMEN
From 218 patients aged 15 to 72 years suffering from inflammatory infectious diseases of the central nervous system, 162 patients were treated with high doses of immunoglobulins (Ig). The therapeutic results were compared with those of the 56 patients without an additive therapy, separately for bacterial and viral infections. If we compare recoveries and deaths or survivals but defective recoveries, the chi-square test reveals that treatment with Ig at the 0.1 percent level is superior to treatment without Ig in a highly significant manner in favor of the use of Ig. Using other criteria, such as the duration of fever and the length of hospital confinement, calculations using Student's t-test also show significant results in favor of Ig. Early beginning of therapy with high doses of Ig given intravenously, or if necessary intrathecally, proved to be of great therapeutic value in lowering the number of fatalities and defective recoveries.