Pathogenesis Of Enteric Viral Hepatitis

我们正在研究病毒性肝炎的发病机制以及这些重要病原体的毒力和减毒的分子基础。甲型肝炎我们以前已经表明，毒力和减毒主要由两个基因控制：VP 1/2A和2C。然而，减毒突变在体内被强烈选择，导致毒性变体的出现。这对甲型肝炎减毒活疫苗的开发具有重要意义。甲型肝炎的发病机制也正在通过微阵列分析在黑猩猩模型中研究。先天反应和适应性反应都有记录。有趣的是，HAV不会触发某些干扰素刺激基因的上调，这些基因在HCV和HDV感染中高度上调。这是令人惊讶的，因为HAV和HCV都是具有双链复制形式的单链RNA病毒，而HDV是具有广泛碱基配对的单链病毒，其被认为是双链RNA。 因此，PKR和RIG-I/MDA-5途径，感测双链RNA细胞内将预期触发先天免疫反应类似的三种病毒。寻找可能阻断这些系统的病毒控制机制将是重要的。 戊型肝炎虽然在美国很少见，但戊型肝炎是整个亚洲，中东和北非成人急性肝炎的唯一最重要原因。像大多数肝炎病毒一样，它在细胞培养中复制很差或根本不复制，并且不能传播给小型实验室动物。我们已经开发了复制子的研究戊型肝炎病毒在体外，这些工具是允许一个详细的病毒复制的分子分析，可以在体内证实与分子工程感染性的cDNA克隆的病毒。此外，我们正在与同事一起开发小动物模型（猪中的猪HEV，鸡中的禽HEV），这些模型与HEV的非人灵长类动物模型一起，为研究戊型肝炎病毒的比较发病机制提供了前所未有的机会。最后，戊型肝炎也通过微阵列进行了研究，并且已经看到了活跃的先天性但弱的适应性免疫应答。

We are studying the pathogenesis of viral hepatitis and the molecular basis for virulence and attenuation of these important pathogens. Hepatitis A. We have shown previously that virulence and attenuation are controlled principally by two genes: VP1/2A and 2C. However, attenuating mutations are strongly selected against in vivo, resulting in the emergence of virulent variants. This has important implications for the development of live attenuated hepatitis A vaccines. The pathogenesis of hepatitis A is also being studied in the chimpanzee model by microarray analysis. Both innate and adaptive responses have been recorded. Interestingly, HAV does not trigger the up-regulation of certain interferon stimulated genes that are highly upregulated in HCV and HDV infections. This is surprising because HAV and HCV are both single-stranded RNA viruses with a double-stranded replicative form and HDV is a single-stranded virus with extensive base pairing that is perceived as double-stranded RNA. Thus, the PKR and RIG-I/MDA-5 pathways that sense double-stranded RNA intracellularly would be expected to trigger an innate immune response similarly in the three viruses. It will be important to search for viral mechanisms of control that may block these systems. Hepatitis E. Although rare in the United States, hepatitis E is the single most important cause of acute hepatitis among adults throughout Asia, the Middle East and North Africa. Like most of the hepatitis viruses, it replicates poorly or not at all in cell culture and cannot be transmitted to small laboratory animals. We have developed replicons for the study of HEV in vitro; these tools are permitting a detailed molecular analysis of viral replication that can be confirmed in vivo with molecularly engineered infectious cDNA clones of the virus. In addition, with colleagues, we are developing small animal models (swine HEV in swine, avian HEV in chickens) that, with nonhuman primate models of HEV, provide an unprecedented opportunity for studying the comparative pathogenesis of hepatitis E viruses. Finally, hepatitis E has also been studied by microarray and a brisk innate but weak adaptive immune response has been seen.