Pathogenesis Of Enteric Viral Hepatitis

肠道病毒性肝炎的发病机制

• 批准号: 7964477
• 负责人: Robert H. Purcell
• 金额: $ 104.08万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7964477
• 关键词: Acute Hepatitis; Adult; Animal Model; Animals; Antibodies; Asia; Attenuated; Base Pairing; Birds; Cell Culture Techniques; Chickens; Comparative Study; Complementary DNA; Detection; Developed Countries; Developing Countries; Development; Diagnostic tests; Double-Stranded RNA; Engineering; Enteral; Family suidae; Genes; Hepatitis A; Hepatitis A Vaccines; Hepatitis A Virus; Hepatitis C; Hepatitis C virus; Hepatitis E; Hepatitis E virus; Hepatitis Viruses; Immune response; In Vitro; Infection; Interferons; International; Laboratory Animals; Life; Light; Marketing; Microarray Analysis; Middle East; Modeling; Molecular; Molecular Analysis; Molecular Probes; Movement; Mutation; Northern Africa; Pan Genus; Pathogenesis; RNA Viruses; Replicon; Serological; System; United States; Up-Regulation; Vaccines; Variant; Viral; Viral hepatitis; Virulence; Virulent; Virus; Virus Diseases; attenuation; base; in vivo; interest; nonhuman primate; pathogen; response; tool

We have studied the pathogenesis of viral hepatitis and the molecular basis for virulence and attenuation of these important pathogens. We have shown previously that virulence and attenuation of hepatitis A virus (HAV) 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 as robust an up-regulation of certain interferon stimulated genes as 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. Specifically, in FY 2009, we compared the innate and adaptive immune responses to HAV infection in several experimentally infected chimpanzees, including animals that received virulent inocula and those that were infected with attenuated strains of HAV. Animals infected with virulent strains had a robust innate immune response (although not as robust as that seen in HCV-infected chimpanzees), whereas the response was less marked in the attenuated infections. Interestingly, innate immune responses were abbreviated in the latter chimpanzees, but detection of the innate immune response was almost as sensitive a diagnostic test of infection as was detection of specific serologic or molecular probes of HAV infection. The adaptive immune responses were also present, but not as robust as the adaptive immune responses in HCV infections of chimpanzees. It will be important to search for viral mechanisms of control that may block some of these systems. 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. Specifically, in FY 2009, we compared the innate and adaptive immune responses of several chimpanzees to experimental HEV infections with those observed in chimpanzees that had been experimentally infected with HCV or HAV. In comparison with those infections, HEV infections were characterized by an abbreviated and somewhat shortened adaptive immune response. This is particularly interesting in light of other observations that antibody titers tend to diminish more rapidly in HEV infections than in infections with the other hepatitis viruses.

我们研究了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。我们以前已经表明，甲型肝炎病毒（HAV）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，甲肝病毒不会像丙肝病毒和丙肝病毒感染那样引发某些干扰素刺激基因的强烈上调。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。具体来说，在2009财政年度，我们比较了几只实验感染的黑猩猩对甲肝病毒感染的先天免疫和适应性免疫反应，包括那些接受了强毒性疫苗接种的动物和那些感染了甲肝病毒减毒株的动物。感染了毒性毒株的动物有很强的先天免疫反应（尽管不像感染丙型肝炎病毒的黑猩猩那样强），而在减毒感染中，这种反应不那么明显。有趣的是，先天免疫反应在后一种黑猩猩中被缩短了，但是对先天免疫反应的检测几乎和对甲型肝炎感染的特定血清学或分子探针的检测一样敏感。适应性免疫反应也存在，但不像黑猩猩感染HCV时的适应性免疫反应那么强。寻找可能阻断其中一些系统的病毒控制机制将是重要的。