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Establishment of laboratory transgenic mouse strains for hepatitis C virus infection

丙型肝炎病毒感染实验室转基因小鼠品系的建立

基本信息

批准号：
09358018
负责人：
YONEKAWA Hiromichi
金额：
$ 16.51万
依托单位：
Tokyo Metropolitan Organization for Medical Research
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1999
项目状态：
已结题

项目摘要

The hepatitis C virus (HCV) is the major causative agent of non-A/non-B hepatitis. A major characteristic of HCV infection is the extremely high (up to 80%) risk of chronicity; in addition, chronic infection of HCV can frequently leads to liver cirrhosis and hepatocellular carcinoma. An important issue regarding the pathogenesis of HCV-associated liver lesions is to determine whether HCV proteins might have a direct effect on cellular phenotype. however, little was known about this respect. To address this question, we tried to establish animal model for HCV. Introducing an efficient Cre/loxP conditional transgenesis, we created several lines of transgenic mice with HCVcDNA (nucleotides 294-3435). After administration of adenovirus that expresses Cre recombinase, the HCV genome introduced as a transgene can express several HCV-specific core proteins in most hepatocytes of the transgenic mice. Moreover, pathological changes and elevated level of serum alanine animotransferase suggested that liver injury occurred in the transgenic mice that express the HCV transgene. A CD4 and CD8 positive cells depletion assay normalized both the serum alanine aminotransferase increases and the pathological changes in the liver. These results suggested that HCV proteins are not directly cytopathic and that the host immune response plays a pivotal role in HCV infection. Thus, this HCV cDNA transgenic mouse provides a powerful tool with which to investigate the immune responses and pathogenesis of HCV infection.

丙型肝炎病毒是非甲非乙型肝炎的主要病原体。丙型肝炎病毒感染的一个主要特征是极高的慢性化风险(高达80%)；此外，丙型肝炎病毒的慢性感染经常会导致肝硬化和肝细胞癌。关于丙型肝炎病毒相关性肝损害发病机制的一个重要问题是确定丙型肝炎病毒蛋白是否对细胞表型有直接影响。然而，人们对此知之甚少。为了解决这个问题，我们尝试建立了丙型肝炎病毒的动物模型。引入一种有效的Cre/loxP条件转基因方法，我们建立了几个带有HCVcDNA(核苷酸294-3435)的转基因小鼠系。以转基因形式导入的丙型肝炎病毒基因组在注射表达Cre重组酶的腺病毒后，可在转基因小鼠的大多数肝细胞中表达多种丙型肝炎病毒特异的核心蛋白。此外，病理改变和血清丙氨酸氨基转移酶水平的升高表明，表达丙型肝炎病毒转基因的转基因小鼠发生了肝损伤。CD4和CD8阳性细胞耗竭试验使血清丙氨酸氨基转移酶升高和肝脏病理改变恢复正常。这些结果表明，丙型肝炎病毒蛋白不是直接的细胞病变，宿主免疫反应在丙型肝炎病毒感染中起着关键作用。因此，该转基因小鼠为研究丙型肝炎病毒感染的免疫应答和致病机制提供了有力的工具。