RESUMEN
Hepatitis E virus (HEV) is an etiological agent of acute hepatitis E, a self-limiting disease prevalent in developing countries. HEV can cause fulminant hepatic failure with high mortality rates in pregnant women, and genotype 3 is reported to trigger chronic hepatitis in immunocompromised individuals worldwide. Screening of plant extracts for compounds with potential anti-HEV effects led to the identification of a 70% ethanol extract of Lysimachia mauritiana (LME) that interferes with replication of the swine HEV genotype 3 replicon. Furthermore, LME significantly inhibited replication of HEV genotype 3 and expression of HEV ORF2 in infected cells without exerting cytotoxic effects. Collectively, our findings demonstrate the potential utility of LME in the development of novel antiviral drugs against HEV infection.
Asunto(s)
Antivirales/farmacología , Virus de la Hepatitis E/efectos de los fármacos , Hepatitis E/veterinaria , Hepatitis E/virología , Extractos Vegetales/farmacología , Primulaceae/química , Enfermedades de los Porcinos/virología , Replicación Viral/efectos de los fármacos , Animales , Antivirales/química , Antivirales/aislamiento & purificación , Etanol , Genotipo , Hepatitis E/tratamiento farmacológico , Virus de la Hepatitis E/genética , Virus de la Hepatitis E/fisiología , Humanos , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Porcinos , Enfermedades de los Porcinos/tratamiento farmacológico , Proteínas Virales/genética , Proteínas Virales/metabolismoRESUMEN
Hepatitis E virus (HEV) causes an acute, self-limiting hepatitis in healthy individuals and leads to chronic disease in immunocompromised individuals. HEV infection in pregnant women results in a more severe outcome, with the mortality rate going up to 30%. Though the virus usually causes sporadic infection, epidemics have been reported in developing and resource-starved countries. No specific antiviral exists against HEV. A combination of interferon and ribavirin therapy has been used to control the disease with some success. Zinc is an essential micronutrient that plays crucial roles in multiple cellular processes. Zinc salts are known to be effective in reducing infections caused by few viruses. Here, we investigated the effect of zinc salts on HEV replication. In a human hepatoma cell (Huh7) culture model, zinc salts inhibited the replication of genotype 1 (g-1) and g-3 HEV replicons and g-1 HEV infectious genomic RNA in a dose-dependent manner. Analysis of a replication-defective mutant of g-1 HEV genomic RNA under similar conditions ruled out the possibility of zinc salts acting on replication-independent processes. An ORF4-Huh7 cell line-based infection model of g-1 HEV further confirmed the above observations. Zinc salts did not show any effect on the entry of g-1 HEV into the host cell. Furthermore, our data reveal that zinc salts directly inhibit the activity of viral RNA-dependent RNA polymerase (RdRp), leading to inhibition of viral replication. Taken together, these studies unravel the ability of zinc salts in inhibiting HEV replication, suggesting their possible therapeutic value in controlling HEV infection.IMPORTANCE Hepatitis E virus (HEV) is a public health concern in resource-starved countries due to frequent outbreaks. It is also emerging as a health concern in developed countries owing to its ability to cause acute and chronic infection in organ transplant and immunocompromised individuals. Although antivirals such as ribavirin have been used to treat HEV cases, there are known side effects and limitations of such therapy. Our discovery of the ability of zinc salts to block HEV replication by virtue of their ability to inhibit the activity of viral RdRp is important because these findings pave the way to test the efficacy of zinc supplementation therapy in HEV-infected patients. Since zinc supplementation therapy is known to be safe in healthy individuals and since high-dose zinc is used in the treatment of Wilson's disease, it may be possible to control HEV-associated health problems following a similar treatment regimen.
Asunto(s)
Antivirales/farmacología , Virus de la Hepatitis E/efectos de los fármacos , Hepatitis E/tratamiento farmacológico , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , Replicación Viral/efectos de los fármacos , Compuestos de Zinc/farmacología , Carcinoma Hepatocelular/enzimología , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/virología , Hepatitis E/virología , Virus de la Hepatitis E/enzimología , Virus de la Hepatitis E/genética , Humanos , Neoplasias Hepáticas/enzimología , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/virología , ARN Viral/genética , Células Tumorales CultivadasRESUMEN
Hepatitis E virus (HEV) infections are the most common cause of acute hepatitis, but they can also take a chronic course. There is no specific therapy for acute hepatitis, and current treatment is supportive. Choosing ribavirin as the first-line therapy for chronic HEV is advisable, especially in solid organ transplant patients. Pegylated interferon-α has been used successfully for treatment of hepatitis E but is associated with major side effects. Cholestasis is one of the most common, but devastating, manifestations in hepatitis E. Current therapy for HEV aims to treat symptoms. Therapy generally involves several measures, such as vitamins for adequate nutrition, albumin and plasma for supporting treatment, symptomatic treatment for cutaneous pruritus, and ursodeoxycholic acid and S-adenosylmethionine, and Traditional Chinese medicine for removing jaundice. Patients with underlying liver disease may develop liver failure. For these patients, supportive treatment is the foundation. Ribavirin has successfully been used to prevent liver transplantation. Prevention and treatment of complications are important for treatment of liver failure. Liver support devices are intended to support liver function until such time as native liver function recovers or until liver transplantation. Liver transplantation is widely considered as irreplaceable and definitive treatment for acute-on-chronic liver failure, particularly for patients who do not improve with supportive measures to sustain life.
Asunto(s)
Antivirales/uso terapéutico , Virus de la Hepatitis E/efectos de los fármacos , Hepatitis E/tratamiento farmacológico , Animales , Hepatitis E/virología , Virus de la Hepatitis E/genética , Virus de la Hepatitis E/aislamiento & purificación , Virus de la Hepatitis E/fisiología , HumanosRESUMEN
BACKGROUND & AIMS: Hepatitis E virus (HEV) is a major cause of acute hepatitis as well as chronic infection in immunocompromised individuals; however, in vivo infection models are limited. The aim of this study was to establish a small animal model to improve our understanding of HEV replication mechanisms and permit the development of effective therapeutics. METHODS: UPA/SCID/beige mice repopulated with primary human hepatocytes were used for infection experiments with HEV genotype (GT) 1 and 3. Virological parameters were determined at the serological and intrahepatic level by real time PCR, immunohistochemistry and RNA in situ hybridization. RESULTS: Establishment of HEV infection was achieved after intravenous injection of stool-derived virions and following co-housing with HEV-infected animals but not via inoculation of serum-derived HEV. GT 1 infection resulted in a rapid rise of viremia and high stable titres in serum, liver, bile and faeces of infected mice for more than 25 weeks. In contrast, viremia in GT 3 infected mice developed more slowly and displayed lower titres in all analysed tissues as compared to GT 1. HEV-infected human hepatocytes could be visualized using HEV ORF2 and ORF3 specific antibodies and HEV RNA in situ hybridization probes. Finally, six-week administration of ribavirin led to a strong reduction of viral replication in the serum and liver of GT 1 infected mice. CONCLUSION: We established an efficient model of HEV infection to test the efficacy of antiviral agents and to exploit mechanisms of HEV replication and interaction with human hepatocytes in vivo.
Asunto(s)
Antivirales/uso terapéutico , Virus de la Hepatitis E/genética , Hepatitis E/tratamiento farmacológico , Hígado/virología , ARN Viral/análisis , Replicación Viral/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Hepatitis E/virología , Humanos , Hibridación in Situ , Hígado/patología , Ratones , Ratones SCID , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
We report about a 44-year old patient with severe acute hepatitis E after herbage walking-to ur. Transmission occurred with ingestion of contaminated herbs. Symptoms were jaundice, dark urine, rheumatic pains and distinctive fatigue. We could document a benign self-limiting course under regular clinical controls. Hepatitis Eisa worldwide common cause for acute hepatitis with jaundice. In Switzerland contamination of this autochthonic infection is aquired by consumption of pork and venison (seroprevalence up to 22%). Infection can be without symptoms but also can result in acute liver failure. Extrahepatic symptoms are not uncommon.
Asunto(s)
Hepatitis E/diagnóstico , Hepatitis E/transmisión , Medicina de Hierbas , Pasatiempos , Ictericia/etiología , Pruebas de Función Hepática , Plantas Medicinales/virología , Adulto , Diagnóstico Diferencial , Genotipo , Hepatitis E/virología , Virus de la Hepatitis E/genética , Humanos , Ictericia/virología , Masculino , Factores de RiesgoRESUMEN
Hepatitis E virus (HEV) is one of the most important causes of acute hepatitis worldwide. Although most infections are self-limiting, mortality is particularly high in pregnant women. Chronic infections can occur in transplant and other immune-compromised patients. Successful treatment of chronic hepatitis E has been reported with ribavirin and pegylated interferon-alpha, however severe side effects were observed. We employed the cutthroat trout virus (CTV), a non-pathogenic fish virus with remarkable similarities to HEV, as a potential surrogate for HEV and established an antiviral assay against this virus using the Chinook salmon embryo (CHSE-214) cell line. Ribavirin and the respective trout interferon were found to efficiently inhibit CTV replication. Other known broad-spectrum inhibitors of RNA virus replication such as the nucleoside analog 2'-C-methylcytidine resulted only in a moderate antiviral activity. In its natural fish host, CTV levels largely fluctuate during the reproductive cycle with the virus detected mainly during spawning. We wondered whether this aspect of CTV infection may serve as a surrogate model for the peculiar pathogenesis of HEV in pregnant women. To that end the effect of three sex steroids on in vitro CTV replication was evaluated. Whereas progesterone resulted in marked inhibition of virus replication, testosterone and 17ß-estradiol stimulated viral growth. Our data thus indicate that CTV may serve as a surrogate model for HEV, both for antiviral experiments and studies on the replication biology of the Hepeviridae.
Asunto(s)
Antivirales/farmacología , Modelos Animales de Enfermedad , Virus de la Hepatitis E/fisiología , Hepatitis E/virología , Complicaciones Infecciosas del Embarazo/virología , Virus ARN/fisiología , Replicación Viral/efectos de los fármacos , Animales , Evaluación Preclínica de Medicamentos , Femenino , Virus de la Hepatitis E/efectos de los fármacos , Virus de la Hepatitis E/genética , Humanos , Embarazo , Virus ARN/efectos de los fármacos , Virus ARN/genética , SalmónRESUMEN
To analyze the changes that occur in pigs during hepatitis E virus (HEV) infection, 256 serial serum samples were obtained from 32 pigs from one pig farm at ages 0 (cord blood), 15, 30, 60, 75, 90, 120, and 150 days. All HEV markers were assayed in these samples and showed that total anti-HEV antibodies and IgG formed two peaks. The first peak occurred at 0-60 days and the second after 75 days. No markers of infection, such as HEV RNA, antigen and anti-HEV IgM, were detectable during the first peak. Most newborn piglets (< 24 h of age) were negative for total anti-HEV and IgG. However, colostrum from all of the sows had evidence of these antibodies. Thus, the anti-HEV in the first peak was assumed to be acquired from maternal milk. Some infectious markers were positive at the beginning of second peak. PCR products were cloned and sequenced and the results indicated those sequences belonged to HEV genotype 4. The antibody present during the second peak may be induced by natural infection with HEV. In conclusion, pigs are susceptible to HEV infection and may remain infectious after the first peak of anti-HEV antibody.
Asunto(s)
Hepatitis E/veterinaria , Enfermedades de los Porcinos/virología , Animales , Animales Recién Nacidos , China , Calostro/inmunología , Femenino , Anticuerpos Antihepatitis/sangre , Antígenos de la Hepatitis/sangre , Hepatitis E/inmunología , Hepatitis E/virología , Virus de la Hepatitis E/clasificación , Virus de la Hepatitis E/genética , Virus de la Hepatitis E/inmunología , Interacciones Huésped-Patógeno/inmunología , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Filogenia , Embarazo , ARN Viral/sangre , ARN Viral/genética , Sus scrofa , Porcinos , Enfermedades de los Porcinos/inmunologíaRESUMEN
Hepatitis E is endemic in developing countries and may occur as imported hepatitis in industrialized countries. A 46-year-old Japanese man developed immunoserologically diagnosed acute hepatitis E in Japan 4 months after he had made a trip to China. He had bought a Chinese herbal medicine there, taking it occasionally until approximately 6 weeks prior to the onset of acute hepatitis. Nucleotide sequencing of the 3' terminal region of the viral cDNA amplified from the patient's serum by polymerase chain reaction revealed a high degree of homology (99.8% of 752 nucleotides) with the Chinese strain. Thus, the results of sequencing suggest that his hepatitis E was caused by infection with the Chinese strain, via the Chinese herbal medicine.