Pathogenesis of Parenteral Viral Hepatitis

肠外病毒性肝炎的发病机制

• 批准号: 7732665
• 负责人: Robert H. Purcell
• 金额: $ 68.5万
• 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/7732665
• 关键词: Acute; Acute Hepatitis; Affect; Animals; Antigens; Antiviral Agents; Antiviral resistance; CD8B1 gene; Cells; Chronic Hepatitis; Chronic Hepatitis B; Chronic Phase; Cirrhosis; Clinical; DNA; Disease; Down-Regulation; Event; Excision; Experimental Models; Genes; Genetic Heterogeneity; Goals; Hepatitis; Hepatitis B; Hepatitis B Virus; Hepatitis C; Hepatitis C virus; Hepatitis Viruses; Hepatocyte; Host Defense; Human; Immune response; Infection; Institutes; Interferon Type II; Interferon-alpha; Interferons; Liver; Longitudinal Studies; Malignant neoplasm of liver; Mediating; Messenger RNA; Microarray Analysis; Molecular; Outcome; Pan Genus; Pan troglodytes; Pathogenesis; Pathogenicity; Patients; Pattern; Phase; Play; Prevention strategy; Prophylactic treatment; Proteins; Residual state; Role; Simian B disease; Study models; System; T-Lymphocyte; Time; Transfusion; Viral; Viral Drug Resistance; Viral hepatitis; Virulence; Virus; Virus Diseases; Virus Replication; Week; attenuation; base; comparative; interferon therapy; intrahepatic; man; pathogen; response; therapy outcome; virus host interaction

We are studying the pathogenesis of viral hepatitis and the molecular basis for virulence and attenuation of these important pathogens. In collaborative studies with Dr. Frank Chisari (Scripps Institute) we have studied in chimpanzees the mechanism by which the host clears a hepatitis B virus infection and the relationship of these mechanisms to clinical disease. We demonstrated that the clearance of the template for HBV synthesis, covalently closed circular HBV DNA, is eliminated from hepatocytes by non-cytolytic mechanisms mediated principally by interferon gamma in the liver. Elimination of residual hepatocytes containing HBV antigens is a later event that is mediated by cytolytic CD8 positive T cells and is temporally related to the hepatitis phase of the infection. The spectrum of virus-induced and immune response-related genes involved in acute hepatitis B were further studied by microarray analysis of intrahepatic messenger RNAs up-regulated and down-regulated during the course of hepatitis B infections in chimpanzees. Surprisingly, we could not detect evidence of an innate immune response to infection, suggesting that HBV can subvert the host immune response, but we did detect a strong adaptive immune response during the clearance phase of infection; this correlated with the inhibition of viral replication and removal of infected cells described above. Interestingly, in additional studies of chronic HBV infection in chimpanzees, we found an innate immune response that was missing in acute, self-limiting infections of HBV. This occurred at a time of liver damage, suggesting that viral and cellular products released from dead and dying hepatocytes could trigger other innate host defenses, such as TLR-3. However, the up-regulated innate immune responses were weak and insufficient to affect virus replication. The genetic heterogeneity of hepatitis C virus is believed to play an important role in its pathogenicity. We have previously examined this relationship by determining the genetic heterogeneity of HCV isolates that were recovered from patients who were infected following transfusion in order to study the early phase of infection and from patients undergoing interferon therapy in order to study changes during the later phase of chronic infection. Distinctive patterns of dynamic change in the sequence of viral clones during the first several weeks of infection were observed and these correlated with the outcome of infection. Similarly, the pattern of dynamic changes in sequence during interferon therapy was predictive of the outcome. These findings may be useful in predicting the outcome of therapy with interferon early in the course of treatment. Although considerable information has been gained from these longitudinal studies of patients, it is difficult to study the mechanisms of pathogenesis in such systems. Chimpanzees, which are the only animals other than man that are susceptible to infection with HCV, provide an experimental model for studying the interactions of the host and the virus in the pathogenesis of hepatitis C. Collaborative studies with Frank Chisari have demonstrated that, as in hepatitis B virus infections, in hepatitis C virus infections the cellular immune response plays an important role in noncytolytic down-regulation of viral replication and cytolytic removal of residual infected cells. These two mechanisms are sequential and overlapping and the former appears to be mediated by interferon gamma and the latter by CD8 positive cells and, perhaps by interferon gamma through its proinflammatory activity. These studies have also revealed that type 1 interferon (interferon alpha/beta)-activated antiviral proteins are expressed in response to the viral infections, but that HCV is resistant to the antiviral activity of this innate immune response. Microarray studies of the host immune responses to viral hepatitis and how the hepatitis viruses attempt to circumvent the responses, are yielding important information on pathogenesis of these diseases, and the studies are being extended to the other hepatitis viruses in order to delineate the comparative pathogenesis of these agents in a single host, the chimpanzee, which is the only non-human host that is susceptible to all human hepatitis viruses. Currently, we are also studying the pathogenesis of HDV infections by microarray analysis and have identified both innate and adaptive immune responses to such infections. Immune responses to HDV infection were similar to those we observed during HCV infection: both a strong innate and a strong adaptive immune response. The innate immune response was sufficient to down-regulate HBV replication in HBV chronically infected chimpanzees that were superinfected with HDV. Thus, HBV, although unable to trigger an innate immune response, is highly sensitive to such a response when provided by another virus.

我们正在研究病毒肝炎的发病机理以及这些重要病原体的毒力和衰减的分子基础。 在与弗兰克·奇萨里（Frank Chisari）博士（Scripps Institute）的合作研究中，我们在黑猩猩中研究了宿主清除乙型肝炎病毒感染以及这些机制与临床疾病的关系的机制。我们证明了HBV合成模板的清除率，即共价闭合的圆形HBV DNA，通过肝脏中主要是由肝脏中的干扰素伽马介导的非胞溶液机制从肝细胞中消除的。消除含有HBV抗原的残留肝细胞是由细胞溶解CD8阳性T细胞介导的，与感染的肝炎相有关。通过对黑猩猩的肝炎感染过程中肝内信使RNA上调和下调的微阵列分析，通过微阵列分析进行了微阵列分析，进一步研究了病毒诱导的和免疫反应相关的基因的光谱。令人惊讶的是，我们无法检测到对感染的先天免疫反应的证据，这表明HBV可以颠覆宿主的免疫反应，但我们确实在清除感染阶段发现了强烈的适应性免疫反应。这与抑制病毒复制和上述感染细胞的去除有关。有趣的是，在黑猩猩的慢性HBV感染的其他研究中，我们发现HBV急性，自限性感染缺失了先天免疫反应。 这发生在肝脏损伤时，表明从死亡和垂死的肝细胞释放的病毒和细胞产物可能会触发其他先天的宿主防御，例如TLR-3。但是，上调的先天免疫反应较弱，不足以影响病毒复制。 据信丙型肝炎病毒的遗传异质性在其致病性中起着重要作用。我们先前已经通过确定从输血后感染的患者中回收的HCV分离株的遗传异质性来研究这种关系，以研究感染的早期阶段以及正在接受干扰素治疗的患者，以便研究慢性感染后期的变化。在感染的前几周观察到了病毒克隆序列的动态变化的独特模式，这些模式与感染的结果相关。同样，干扰素治疗期间序列动态变化的模式可以预测结果。这些发现在治疗过程中早期预测干扰素治疗的结果可能很有用。 尽管从患者的这些纵向研究中获得了大量信息，但很难研究这种系统中的发病机理。黑猩猩是易于受到HCV感染的人以外的唯一动物，为研究宿主和病毒的相互作用提供了一个实验模型。与弗兰克·奇萨里（Frank Chisari残留感染细胞的病毒复制和细胞溶解切除。这两种机制是顺序的和重叠的，前者似乎是由干扰素伽玛和后者介导的，而后者是由CD8阳性细胞以及干扰素伽马通过其促炎活性介导的。这些研究还表明，1型干扰素（干扰素α/β）激活的抗病毒蛋白是对病毒感染的响应表达的，但HCV对这种先天免疫反应的抗病毒活性具有抵抗力。微阵列对宿主对病毒肝炎的免疫反应以及肝炎病毒的免疫反应以及如何试图规避反应，产生有关这些疾病发病机理的重要信息，并将研究延伸到其他肝炎病毒，以扩展到其他宿主的疾病中，这些人与偶像的疾病相比，仅是偶像的人，是奇迹，是奇迹，是奇迹，是奇迹，是奇迹，是奇迹，这是奇迹，是奇迹，是这种疾病，是奇迹，这是奇迹，这是奇迹，病毒。 目前，我们还通过微阵列分析研究了HDV感染的发病机理，并确定了对此类感染的先天和适应性免疫反应。对HDV感染的免疫反应与我们在HCV感染期间观察到的免疫反应相似：既有先天性和强大的适应性免疫反应。 先天性免疫反应足以下调HBV慢性感染的黑猩猩的HBV复制，这些黑猩猩被HDV叠加了。因此，HBV尽管无法触发先天免疫反应，但在另一种病毒提供时对这种反应高度敏感。