A Chicken Model to Study Hepatitis E Virus Pathogenesis

研究戊型肝炎病毒发病机制的鸡模型

• 批准号: 6895775
• 负责人: XIANG-JIN MENG
• 金额: $ 21.7万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-15 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6895775
• 关键词: Macaca mulatta; biological models; chickens; clinical research; complementary DNA; cross immunity; disease /disorder etiology; disease reservoirs; enzyme linked immunosorbent assay; functional /structural genomics; gene deletion mutation; gene expression; human tissue; immunologic substance development /preparation; in situ hybridization; infectious hepatitis; model design /development; molecular cloning; polymerase chain reaction; reagent /indicator; swine; tissue mosaicism; virus RNA; virus cytopathogenic effect; virus replication; zoonosis

DESCRIPTION (provided by applicant): Hepatitis E virus (HEV), the causative agent of hepatitis E, is an important public health problem in developing countries. HEV is also endemic in the U.S. The mortality rate is reportedly up to 20% in infected pregnant women. Due to the lack of a practical animal model and an in vitro cell culture system, the replication and pathogenesis of HEV is poorly understood and a vaccine for HEV is still not available. This proposal is based on our recent discoveries of a novel avian HEV from chickens in 2000 and a novel swine HEV from pigs in 1997. Both avian HEV and swine HEV are antigenically and genetically related to human HEV. We have shown that swine HEV infects non-human primates and a U.S. human strain of HEV infects pigs, and that pig handlers are at risk of zoonotic HEV infection. Avian HEV causes a hepatitis disease in chickens that is similar to human hepatitis E. The central hypotheses of this proposal are that hepatitis E is a zoonosis and that, like pigs, chickens are also animal reservoirs for HEV, and that chickens are a useful animal model system for HEV. The long-term objectives of the project are to define and understand the mechanism of HEV replication and pathogenesis by using HEV infection in chickens as an animal model system and by using avian-swine, avian-human and swine-human HEV chimeras to identify genes that are functionally important for these processes. In this proposal, we aim to: 1) systematically characterize the course of HEV replication and pathogenesis in a homologous model (avian HEV infection in chickens), 2) to identify the initial and extrahepatic sites of HEV replication in infected chickens, 3) to construct an infectious cDNA clone of avian HEV for future study of the structural and functional relationship of HEV genes by using HEV chimeras, and 4) to evaluate the potential risk of zoonotic infection by avian HEV. This will be accomplished by using standard techniques including in situ hybridization, PCR, cloning and sequencing, gene expression, and serological and pathological methods. The proposed studies will significantly advance our understanding of the mechanisms of HEV replication, pathogenesis and natural history. The information gained will be very useful for developing small animal models for HEV research and for devising strategies to prevent and control this important disease.

描述（由申请人提供）：丙型肝炎E乙型肝炎病毒（HEV）是发展中国家的重要公共卫生问题。据报道，在美国，HEV在美国也是流行的，感染孕妇的死亡率高达20％。由于缺乏实用的动物模型和体外细胞培养系统，因此对HEV的复制和发病机理知之甚少，而HEV的疫苗仍然无法使用。该提议是基于我们最近发现的2000年鸡的新型禽链球菌的发现，以及1997年的猪猪HEV的新型猪HEV。禽链球菌和猪HEV都与人类HEV抗原和遗传有关。我们已经表明，猪HEV感染非人类灵长类动物和美国HEV的人类菌株会感染猪，并且猪处理人员有人畜共患病的风险。禽流链球菌在鸡中引起与人类乙型肝炎相似的肝炎。该提案的中心假设是丙型肝炎是人畜共患病，像猪一样，鸡也是鸡的动物储层，而鸡是HEV的有用动物模型。该项目的长期目标是通过在鸡中使用HEV感染作为动物模型系统，并使用鸟雄，禽类和猪-Human HEV嵌合体来识别对这些过程在功能上重要的基因，从而定义和了解HEV复制和发病机理的机制。 In this proposal, we aim to: 1) systematically characterize the course of HEV replication and pathogenesis in a homologous model (avian HEV infection in chickens), 2) to identify the initial and extrahepatic sites of HEV replication in infected chickens, 3) to construct an infectious cDNA clone of avian HEV for future study of the structural and functional relationship of HEV genes by using HEV chimeras, and 4) to评估鸟类HEV的人畜共患感染的潜在风险。这将通过使用标准技术来实现，包括原位杂交，PCR，克隆和测序，基因表达以及血清学和病理学方法。拟议的研究将大大提高我们对HEV复制，发病机理和自然历史机制的理解。获得的信息对于开发用于HEV研究的小动物模型以及制定预防和控制这种重要疾病的策略将非常有用。