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衰减的分子基础。甲型肝炎的毒力和衰减主要由两个基因控制：VP1/2A和2C。然而，减毒突变在体内被强烈选择，导致毒性变异的出现。这对研制甲型肝炎减毒活疫苗具有重要意义。甲型肝炎的发病机制也正在黑猩猩模型中通过微阵列分析进行研究。先天反应和适应性反应都有记录。有趣的是，甲肝病毒不会引发某些干扰素刺激基因的上调，而这些基因在丙肝病毒和丙肝病毒感染中是高度上调的。这是令人惊讶的，因为甲肝病毒和丙肝病毒都是具有双链复制形式的单链RNA病毒，而丙肝病毒是具有广泛碱基配对的单链病毒，被认为是双链RNA。因此，在细胞内感知双链RNA的PKR和RIG-I/MDA-5通路可能会在三种病毒中引发类似的先天免疫反应。寻找可能阻断这些系统的病毒控制机制将是很重要的。

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.